Computed tomography arthrography versus magnetic resonance imaging for diagnosis of osteochondral lesions of the talus.

INTRODUCTION: Osteochondral lesions of the talus (OLT) usually have non-specific clinical symptoms, and radiographs have a low sensitivity for detecting OLT. The purpose of this study is to compare the diagnostic value of CT arthrography (CTa) with that of MRI using arthroscopy as the reference standard for grading OLT. MATERIALS AND METHODS: We retrospectively reviewed patients who had OLT between 2015 and 2020. Patients with symptomatic OLT as a surgical indication, who were treated arthroscopically, and underwent both CTa and MRI before surgery were included. OLT was evaluated by both CTa and MRI using arthroscopy as the standard. We graded CTa, MRI, arthroscopic findings using Mintz classification. RESULTS: Thirty-five patients were included. Accuracy rates of MRI and CTa for grading OLT, compared to those of arthroscopy, were 57.1% and 88.6%, respectively. Among 15 mismatched cases in MRI, 12 lesions (80%) were matched in CTa and arthroscopy. CTa had significantly higher diagnostic performance than MRI for the detection of grade III lesions (p = 0.041). Using the receiver operating characteristics curves, the area under the curve values for lesion grading were 0.893 for CTa and 0.762 for MRI. CONCLUSION: CTa was statistically significantly better in detecting chondral flapping or subchondral exposure lesions for OLT than MRI on using arthroscopy as the reference standard. Because the stability of the OLT is essential in determining the treatment method, if an OLT is observed on MRI and is suspected to cause ankle pain, we recommend additional CTa examination to determine the more correct treatment strategies for OLT. LEVEL OF EVIDENCE: Diagnostic Level III.

Efficacy of Far Cortical Locking Screws in Treating Distal Tibia Fractures in Comparison With That of Standard Locking Screws.

There are no clinical studies about treatment of distal tibia fractures using far cortical locking (FCL) screws, even though it has been shown to be superior to standard locking screws in biomechanical studies. We compared the efficacy of FCL screws to that of traditional locking screws. Twenty-five distal tibia fractures were treated with minimally invasive plate osteosynthesis using traditional locking screws, whereas 20 were treated using FCL screws. We retrospectively compared time taken for callus formation and radiographic bone union between 2 groups. The effect of age, sex, diabetes, and smoking history on bone healing was analyzed. Complications were also noted. As a result, there was no significant difference in age (p = .292), sex (p = 1.0), diabetes (p = 1.0), or smoking history (p = .704) between 2 groups. Time to callus formation was 77.5 days in the FCL group, and 96 days in the traditional group (p = .023). Average time to bone union was 134.8 days, and 163.1 days in the FCL group and the traditional group, respectively (p = .017). There was one case of screw loosening in the FCL group, and one case of screw breakage in the traditional group. This study suggests that FCL screws promote quicker healing of distal tibia fractures than traditional locking screws.

Utility of a Molecular Signature for Predicting Recurrence and Progression in Non-Muscle-Invasive Bladder Cancer Patients: Comparison with the EORTC, CUETO and 2021 EAU Risk Groups.

To evaluate the utility of different risk assessments in non-muscle-invasive bladder cancer (NMIBC) patients, a total of 178 NMIBC patients from Chungbuk National University Hospital (CBNUH) were enrolled, and the predictive value of the molecular signature-based subtype predictor (MSP888) and risk calculators based on clinicopathological factors (EORTC, CUETO and 2021 EAU risk scores) was compared. Of the 178 patients, 49 were newly analyzed by the RNA-sequencing, and their MSP888 subtype was evaluated. The ability of the EORTC, MSP888 and two molecular subtyping systems of bladder cancer (Lund and UROMOL subtypes) to predict progression of 460 NMIBC patients from the UROMOL project was assessed. Cox regression analyses showed that the MSP888 was an independent predictor of NMIBC progression in the CBNUH cohort (p = 0.043). Particularly in patients without an intravesical BCG immunotherapy, MSP888 significantly linked with risk of disease recurrence and progression (both p < 0.05). However, the EORTC, CUETO and 2021 EAU risk scores showed disappointing results with respect to estimating the NMIBC prognosis. In the UROMOL cohort, the MSP888, Lund and UROMOL subtypes demonstrated a similar capacity to predict NMIBC progression (all p < 0.05). Conclusively, the MSP888 is favorable for stratifying patients to facilitate optimal treatment.

Anti-Metastatic Effect of Pyruvate Dehydrogenase Kinase 4 Inhibition in Bladder Cancer via the ERK, SRC, and JNK Pathways.

Bladder cancer is a common global cancer with a high percentage of metastases and high mortality rate. Thus, it is necessary to identify new biomarkers that can be helpful in diagnosis. Pyruvate dehydrogenase kinase 4 (PDK4) belongs to the PDK family and plays an important role in glucose utilization in living organisms. In the present study, we evaluated the role of PDK4 in bladder cancer and its related protein changes. First, we observed elevated PDK4 expression in high-grade bladder cancers. To screen for changes in PDK4-related proteins in bladder cancer, we performed a comparative proteomic analysis using PDK4 knockdown cells. In bladder cancer cell lines, PDK4 silencing resulted in a lower rate of cell migration and invasion. In addition, a PDK4 knockdown xenograft model showed reduced bladder cancer growth in nude mice. Based on our results, PDK4 plays a critical role in the metastasis and growth of bladder cancer cells through changes in ERK, SRC, and JNK.

Calcifying characteristics of peripheral vascular smooth muscle cells of chronic kidney disease patients with critical limb ischemia.

The role of vascular smooth muscle cells (VSMCs) in vascular calcification, which is related to chronic kidney disease (CKD), has been studied in greater detail in the major arteries relative to the peripheral arteries. We compared the calcifying characteristics of peripheral VSMCs relative to non-pathologic major VSMCs in patients with severe peripheral artery disease (PAD). We isolated peripheral VSMCs from the posterior tibial artery of 10 patients with CKD who underwent below-knee amputation for critical limb ischemia (CLI). Using normal human aortic VSMCs as a control group, we cultured the cells in normal and high phosphate media for 10 days, and subsequently tested by immunofluorescence staining. We compared the calcification levels between the two groups using various assays, tests for cell viability, and scanning electron microscopy. As a result, calcification of pathologic peripheral VSMCs increased significantly with time (p = 0.028) and was significantly higher than that in human aortic VSMCs in calcium assays (p = 0.043). Dead cells in the pathologic VSMC group were more distinct in high phosphate media than in human aortic VSMCs. In conclusion, VSMCs from the peripheral artery of patients with severe CKD and CLI who underwent amputation surgery showed marked calcifying characteristics compared to normal human aortic VSMCs.

Effect of pre-operative internal obturator muscle mass index in MRI on biochemical recurrence of prostate cancer patients after radical prostatectomy: a multi-center study.

BACKGROUND: Recent reports show that the pre-operative or post-operative skeletal mass index (sarcopenia) affects survival rates for various cancers; however, the link between prostate cancer survival and sarcopenia is unclear. Therefore, this study examined the effect of the pre-operative internal obturator muscle (IOM) mass index on biochemical recurrence (BCR) of prostate cancer (PCa) patients who underwent radical prostatectomy. METHODS: In total, 222 patients, who underwent open, laparoscopic, or robot-assisted radical prostatectomy at seven centers in 2011 and were followed up for 5 years, were enrolled. BCR was examined in the context of pre-operative IOM mass index and BMI. RESULTS: The mean age of the patients was 67.82 ± 6.23 years, and the mean pre-operative prostate-specific antigen (PSA) level was 11.61 ± 13.22 ng/ml. There was no significant difference in baseline characteristics between the low and high IOM mass index groups (p > 0.05). Age, pre-op PSA level, ECE, and T-stage were associated with BCR (p = 0.049, p < 0.001, p = 0.001, p = 0.004, respectively). BMI, prostate volume, Gleason score, resection margin, N-stage, M-stage and IOM mass index was not associated with BCR (p > 0.05). CONCLUSIONS: Pre-operative IOM mass index was not associated with BCR; however, long-term follow-up is necessary to evaluate cancer-specific and overall survival of PCa patients.

Prognostic Value of BUB1 for Predicting Non-Muscle-Invasive Bladder Cancer Progression.

Non-muscle-invasive bladder cancer (NMIBC) is a common disease with a high recurrence rate requiring lifetime surveillance. Although NMIBC is not life-threatening, it can progress to muscle-invasive bladder cancer (MIBC), a lethal form of the disease. The management of the two diseases differs, and patients with MIBC require aggressive treatments such as chemotherapy and radical cystectomy. NMIBC patients at a high risk of progression benefit from early immediate cystectomy. Thus, identifying concordant markers for accurate risk stratification is critical to predict the prognosis of NMIBC. Candidate genetic biomarkers associated with NMIBC prognosis were screened by RNA-sequencing of 24 tissue samples, including 16 NMIBC and eight normal controls, and by microarray analysis (GSE13507). Lastly, we selected and investigated a mitotic checkpoint serine/threonine kinase, BUB1, that regulates chromosome segregation during the cell cycle. BUB1 gene expression was tested in 86 NMIBC samples and 15 controls by real-time qPCR. The performance of BUB1 as a prognostic biomarker for NMIBC was validated in the internal Chungbuk cohort (GSE13507) and the external UROMOL cohort (E-MTAB-4321). BUB1 expression was higher in NMIBC patients than in normal controls (p < 0.05), and the overexpression of BUB1 was correlated with NMIBC progression (log-rank test, p = 0.007). In in vitro analyses, BUB1 promoted the proliferation of bladder cancer cells by accelerating the G2/M transition of the cell cycle. Conclusively, BUB1 modulates the G2/M transition to promote the proliferation of bladder cancer cells, suggesting that it could serve as a prognostic marker in NMIBC.

A Molecular Signature Determines the Prognostic and Therapeutic Subtype of Non-Muscle-Invasive Bladder Cancer Responsive to Intravesical Bacillus Calmette-Guérin Therapy.

Non-muscle-invasive bladder cancer (NMIBC) is clinically heterogeneous; thus, many patients fail to respond to treatment and relapse. Here, we identified a molecular signature that is both prognostic and predictive for NMIBC heterogeneity and responses to Bacillus Calmette-Guérin (BCG) therapy. Transcriptomic profiling of 948 NMIBC patients identified a signature-based subtype predictor, MSP888, along with three distinct molecular subtypes: DP.BCG+ (related to progression and response to BCG treatment), REC.BCG+ (related to recurrence and response to BCG treatment), and EP (equivocal prognosis). Patients with the DP.BCG+ subtype showed worse progression-free survival but responded to BCG treatment, whereas those with the REC.BCG+ subtype showed worse recurrence-free survival but responded to BCG treatment. Multivariate analyses revealed that MSP888 showed independent clinical utility for predicting NMIBC prognosis (each p = 0.001 for progression and recurrence, respectively). Comparative analysis of this classifier and previously established molecular subtypes (i.e., Lund taxonomy and UROMOL class) revealed that a great proportion of patients were similar between subtypes; however, the MSP888 predictor better differentiated biological activity or responsiveness to BCG treatment. Our data increase our understanding of the mechanisms underlying the poor prognosis of NMIBC and the effectiveness of BCG therapy, which should improve clinical practice and complement other diagnostic tools.

Relationship between calf muscle cross-sectional area and ankle fracture.

BACKGROUND: Whether calf muscles and peroneal muscles have a role in the occurrence of an ankle fractures remains unclear. This study aimed to quantify the calf muscle mass and peroneal muscle mass in patients with an ankle fracture and in controls, then to analyze them together with demographic factors to identify the effects of the regional muscles on the risk of developing ankle fracture. METHODS: A total of 101 ankles with computed tomography (CT) images were retrospectively reviewed. Of them, 51 ankles showed fractures (all unilateral) and 50 ankles, in controls who underwent CT for screening the other diseases, were clinically diagnosed with simple contusion. The cross-sectional areas (CSA) of the calf muscles and the peroneal muscles were measured at approximately 6 cm above the Achilles myotendinous junction in the axial plane of ankle CT. These parameters were compared between the two groups and analyzed with respect to age, sex, body mass index (BMI), laterality, and bone attenuations of the ankle. RESULTS: The demographic factors, including bone attenuation of the ankle showed no significant association with ankle fracture. The ratio of the CSA of the peroneal muscle group to the CSA of the entire calf muscle group was smaller in patients with an fracture (0.12 ± 0.03) than in controls (0.14 ± 0.02) (p = 0.027). The odds ratio for the effect of the calf muscle CSA on the risk of developing ankle fractures was 1.38 (95% confidence interval 1.12-1.69, p = 0.003), whereas that for the effect of peroneal muscle CSA on the risk of developing ankle fractures was 0.18 (95% confidence interval 0.05 to 0.66, p = 0.010). CONCLUSION: The ratio of the peroneal muscle CSA to the entire calf muscle CSA was negatively related to the occurrence of ankle fractures in this study. Further prospective studies on whether peroneal muscle-strengthening exercise are effective in preventing ankle fractures may be needed. LEVEL OF EVIDENCE: III, case-control study.

A Low Geriatric Nutritional Risk Index is Associated with Aggressive Pathologic Characteristics and Poor Survival after Nephrectomy in Clear Renal Cell Carcinoma: A Multicenter Retrospective Study.

Purpose: To investigated the prognostic significance of the geriatric nutritional risk index (GNRI) in patients with surgically treated clear cell renal cell carcinoma (ccRCC).Patients and methods: We retrospectively selected 4,591 consecutive patients with surgically treated ccRCC from a multi-institutional Korean collaboration between 1988 and 2015. The clinical significance of the GNRI as a continuous and categorical variable was determined.Results: Preoperative low GNRI was significantly associated with older age, low body mass index, presence of diabetes, poor performance status, and presence of symptoms at diagnosis, as well as pathologic features such as aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, sarcomatous differentiation, and tumor necrosis. A low GNRI was significantly associated with a short recurrence-free survival (RFS) in localized (pT1-2N0M0) ccRCC and cancer-specific survival (CSS) in the entire cohort, and with short RFS and CSS in the subgroup analysis according to age categories (≤65 and >65 years). Multivariate Cox regression analysis showed that preoperative GNRI, as a continuous or categorical variable, was an independent predictor of RFS and CSS.Conclusion: Malnutrition as assessed by the preoperative GNRI is associated with aggressive tumor characteristics and poor survival in patients with surgically treated ccRCC.

Intraoperative allogeneic blood transfusion is associated with adverse oncological outcomes in patients with surgically treated non-metastatic clear cell renal cell carcinoma.

BACKGROUND: The objective of this study was to provide more definitive information about the prognostic impact of perioperative blood transfusion (PBT) on patients with surgically treated renal cell carcinoma (RCC). METHODS: A database of 4019 patients with clear cell RCC, all of whom underwent radical or partial nephrectomy as primary therapy as part of a multi-institutional Korean collaboration between 1988 and 2015, was analyzed retrospectively. PBT was defined as transfusion of allogeneic red blood cells during surgery or postsurgical period. Receipt of a PBT, as well as the amount and time of blood transfusion (BT), was compared. RESULTS: Overall, 335 (8.3%) patients received a PBT: 84 received postoperative BT, 202 received intraoperative BT, and 49 received both intraoperative and postoperative BT. Patients receiving a PBT had a poor preoperative immuno-nutritional status, and aggressive tumor characteristics. Multivariate analyses identified PBT as an independent predictor of recurrence-free survival and cancer-specific survival. Prognostic impact of PBT was restricted to those with locally advanced stage (pT3-4), and who underwent radical nephrectomy. Among patients who received a PBT, intraoperative (but not postoperative) BT was a prognostic factor for survival. Among patients who received intraoperative BT, those receiving three or more transfusion units had a significantly worse survival. CONCLUSION: Receipt of a PBT was an independent predictor of RFS and CSS in patients with surgically treated RCC, specifically locally advanced disease. Regarding the prognostic impact of timing or dose of PBT on survival, intraoperative BT and ≥ 3 pRBC units were associated with adverse oncological outcomes.

Urinary cell-free microRNA biomarker could discriminate bladder cancer from benign hematuria.

The most common symptom of bladder cancer (BC) is hematuria. However, not all patients with hematuria are diagnosed with BC. Here, we explored a novel method to discriminate BC from hematuria under nonmalignant conditions by measuring differences in urinary cell-free microRNA (miRNA) expression between patients with BC and those with hematuria. A multicenter study was performed using 543 urine samples obtained from the National Biobank of Korea, including 326 BC, 174 hematuria and 43 pyuria without cancer. The urinary miR-6124 to miR-4511 ratio was considerably higher in BC than in hematuria or pyuria, and enabled the discrimination of BC from patients with hematuria at a sensitivity of >90% (p < 0.001). Conclusively, the proposed noninvasive diagnostic tool based on the expression ratio of urinary cell-free miR-6124 to miR-4511 can reduce unnecessary cystoscopies in patients with hematuria undergoing evaluation for BC, with a minimal loss in sensitivity for detecting cancer.

National practice patterns and direct medical costs for prostate cancer in Korea across a 10 year period: a nationwide population-based study using a national health insurance database.

BACKGROUND: A complete enumeration study was conducted to evaluate trends in national practice patterns and direct medical costs for prostate cancer (PCa) in Korea over a 10-year retrospective period using data from the Korean National Health Insurance Service. METHODS: Reimbursement records for 874,924 patients diagnosed between 2002 and 2014 with primary PCa according to the International Classification of Disease (ICD) 10th revision code C61 were accessed. To assess direct medical costs for patients newly diagnosed after 2005, data from 68,596 patients managed between January 2005 and 31 December 2014 were evaluated. RESULTS: From 2005 to 2014, the total number of PCa patients showed a 2.6-fold increase. Surgery and androgen deprivation therapy were the most common first-line treatment, alone or within the context of combined therapy. Surgery as a monotherapy was performed in 23.5% of patients in 2005, and in 39.4% of patients in 2014. From 2008, the rate of robot-assisted RP rose sharply, showing a similar rate to open RP in 2014. Average total treatment costs in the 12 months post-diagnosis were around 10 million Korean won. Average annual treatment costs thereafter were around 5 million Korean won. Out-of-pocket expenditure was highest in the first year post-diagnosis, and ranged from 12 to 17% thereafter. CONCLUSIONS: Between 2005 and 2014, a substantial change was observed in the national practice pattern for PCa in Korea. The present data provide a reliable overview of treatment patterns and medical costs for PCa in Korea.

Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma.

BACKGROUND: Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC). The aim of this study was to identify prognostic methylation markers in surgically treated clear cell RCC (ccRCC). METHODS: Methylation patterns were assayed using the Infinium HumanMethylation450 BeadChip array on pairs of ccRCC and normal tissue from 12 patients. Using quantitative PSQ analysis, tumor-specific hypermethylated genes were validated in 25 independent cohorts and their clinical relevance was also verified in 152 independent cohorts. RESULTS: Using genome-wide methylation array, Zinc finger protein 278 (ZNF278), Family with sequence similarity 155 member A (FAM155A) and Dipeptidyl peptidase 6 (DPP6) were selected for tumor-specific hypermethylated genes in primary ccRCC. The promoter methylation of these genes occurred more frequently in ccRCC than normal kidney in independent validation cohort. The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC. During median follow-up of 39.2 (interquartile range, 15.4-79.1) months, 22 (14.5%) patients experienced distant metastasis. Multivariate analysis identified the methylation status of these three genes, either alone, or in a combined risk score as an independent predictor of distant metastasis. CONCLUSION: The promoter methylation of ZNF278, FAM155A and DPP6 genes are associated with aggressive tumor phenotype and early development of distant metastasis in patients with surgically treated ccRCC. These potential methylation markers, either alone, or in combination, could provide novel targets for development of individualized therapeutic and prevention regimens.

Prognostic Impact of Nutritional Status Assessed by the Controlling Nutritional Status (CONUT) Score in Patients with Surgically Treated Renal Cell Carcinoma.

PURPOSE: The prognostic role of the controlling nutritional status (CONUT) score in renal cell carcinoma (RCC) has not been evaluated. The aim of the current study was to clarify the prognostic significance of the CONUT score in Korean patients with surgically treated RCC. MATERIALS AND METHODS: A database of 1,881 patients with surgically treated RCC from a multiinstitutional Korean collaboration between 1999 and 2015 was analyzed. The preoperative CONUT score was calculated from serum albumin, total cholesterol concentrations, and total lymphocyte count. Clinicopathological variables and survival rates were compared between the CONUT score groups. RESULTS: A high CONUT score was associated with older age, lower body mass index, lower preoperative prognostic nutritional index, and presence of diabetes or hypertension (each P < 0.001). Regarding pathologic features, a high CONUT score was associated with aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, and sarcomatous differentiation (each P < 0.001). Multivariate Cox regression analysis indicated that a high CONUT score (≥ 2) was an independent predictor of cancer-specific mortality (hazard ratio, 1.892; 95% CI: 1.118-3.201; P = 0.018). CONCLUSION: The CONUT score, an easily measurable immune-nutritional biomarker, may provide useful prognostic information in patients with surgically treated RCC.

Low preoperative serum cholesterol level is associated with aggressive pathologic features and poor cancer-specific survival in patients with surgically treated renal cell carcinoma.

BACKGROUND: The prognostic implications of preoperative serum total cholesterol (TC) level in patients with renal cell carcinoma (RCC) remain poorly understood. We investigated the prognostic role of preoperative serum TC in patients with surgically treated RCC from a large, multi-institutional Korean collaboration. PATIENTS AND METHODS: A database of 3064 patients with RCC who underwent radical or partial nephrectomy between 1999 and 2011 at eight academic centers was analyzed. Preoperative serum TC levels were measured in fasting blood samples. RESULTS: Low preoperative serum TC level was associated with aggressive tumor characteristics, including large tumor size, advanced stage, high nuclear grade, lymph node involvement, and sarcomatous differentiation (all P < 0.001). Low TC level was associated with poor recurrence-free or cancer-specific survival (CSS) in the entire cohort, whereas the significance of the association changed after stratification by disease stage and histologic subtype. Multivariate Cox regression analysis showed that preoperative TC, as a continuous or categorical variable, was an independent predictor of CSS. CONCLUSIONS: Preoperative low serum TC level was associated with aggressive tumor characteristics and poor CSS in patients with surgically treated RCC. Preoperative TC may provide additional guidance regarding the choice of therapeutic strategies to improve prognosis.

Outcomes After Double-Bundle Anterior Cruciate Ligament Reconstruction.

PURPOSE: To identify the risk factors predicting unsatisfactory postoperative clinical outcomes after double-bundle (DB) anterior cruciate ligament (ACL) reconstruction using multivariate logistic regression. METHODS: Inclusion criteria were consecutive DB ACL reconstructions from January 2006 to September 2012 with a minimum 3-year follow-up. Exclusion criteria included (1) a delay to surgery from initial injury of more than 4 years (210 weeks); (2) contralateral knee pathology; (3) the lack of postoperative 3-dimensional computed tomography; (4) single-bundle ACL reconstruction; (5) revision ACL reconstruction; (6) meniscus allograft transplantation after total or subtotal meniscectomy; (7) multiple ligament surgeries. According to the overall International Knee Documentation Committee (IKDC) rating at the last follow-up, we sorted all enrolled subjects into superior (IKDC grade A or B) and inferior outcome groups (IKDC grade C or D). Multivariate logistic regression was used to analyze risk factors, including age, gender, body mass index, time from injury to surgery, posterior tibial slope, notch width index, cartilage injury, meniscus injury, and femoral and tibial tunnel positions. RESULTS: In comparison between the superior outcome group (n = 240) and inferior outcome group (n = 50), anterior (adjusted odds ratio [OR]: 0.902, 95% confidence interval [CI]: 0.846-0.962) or distal (adjusted OR: 1.025, 95% CI: 1.006-1.060) femoral anteromedial tunnel position was a significant risk factor for the inferior outcomes. Partial meniscectomy of medial (adjusted OR: 49.002, 95% CI: 7.047-340.717) or lateral (adjusted OR: 14.974, 95% CI: 2.181-102.790) meniscus and delayed time from injury to surgery (adjusted OR: 1.062, 95% CI: 1.023-1.102) were also a significant predictor. CONCLUSION: Anterior or distal anteromedial femoral tunnel position, partial meniscectomy of medial or lateral meniscus, and prolonged surgical delay of more than 11.5 weeks from injury were significant risk factors for the inferior clinical outcomes after DB ACL reconstruction. LEVEL OF EVIDENCE: Level III, retrospective therapeutic case series.

The Within-Group Discrimination Ability of the Cancer of the Prostate Risk Assessment Score for Men with Intermediate-Risk Prostate Cancer.

BACKGROUND: Significant clinical heterogeneity within contemporary risk group is well known, particularly for those with intermediate-risk prostate cancer (IRPCa). Our study aimed to analyze the ability of the Cancer of the Prostate Risk Assessment (CAPRA) score to discern between favorable and non-favorable risk in patients with IRPCa. METHODS: We retrospectively reviewed the data of 203 IRPCa patients who underwent extraperitoneal robot-assisted radical prostatectomy (RARP) performed by a single surgeon. Pathologic favorable IRPCa was defined as a Gleason score ≤ 6 and organ-confined stage at surgical pathology. The CAPRA score was compared with two established criteria for the within-group discrimination ability. RESULTS: Overall, 38 patients (18.7% of the IRPCa cohort) had favorable pathologic features after RARP. The CAPRA score significantly correlated with established criteria I and II and was inversely associated with favorable pathology (all P < 0.001). The area under the receiver operating characteristic curve for the discriminative ability between favorable and non-favorable pathology was 0.679 for the CAPRA score and 0.610 and 0.661 for established criteria I and II, respectively. During a median 37.8 (interquartile range, 24.6-60.2) months of follow-up, 66 patients (32.5%) experienced biochemical recurrence (BCR). Cox regression analysis revealed that the CAPRA score, as a continuous sum score model or 3-group risk model, was an independent predictor of BCR after RARP. CONCLUSION: The within-group discrimination ability of preoperative CAPRA score might help in patient counseling and selecting optimal treatments for those with IRPCa.

CDC6 mRNA Expression Is Associated with the Aggressiveness of Prostate Cancer.

BACKGROUND: Cell division cycle 6 (CDC6) is an essential regulator of DNA replication and plays important roles in the activation and maintenance of the checkpoint mechanisms in the cell cycle. CDC6 has been associated with oncogenic activities in human cancers; however, the clinical significance of CDC6 in prostate cancer (PCa) remains unclear. Therefore, we investigated whether the CDC6 mRNA expression level is a diagnostic and prognostic marker in PCa. METHODS: The study subjects included 121 PCa patients and 66 age-matched benign prostatic hyperplasia (BPH) patients. CDC6 expression was evaluated using real-time polymerase chain reaction and immunohistochemical (IH) staining, and then compared according to the clinicopathological characteristics of PCa. RESULTS: CDC6 mRNA expression was significantly higher in PCa tissues than in BPH control tissues (P = 0.005). In addition, CDC6 expression was significantly higher in patients with elevated prostate-specific antigen (PSA) levels (> 20 ng/mL), a high Gleason score, and advanced stage than in those with low PSA levels, a low Gleason score, and earlier stage, respectively. Multivariate logistic regression analysis showed that high expression of CDC6 was significantly associated with advanced stage (≥ T3b) (odds ratio [OR], 3.005; confidence interval [CI], 1.212-7.450; P = 0.018) and metastasis (OR, 4.192; CI, 1.079-16.286; P = 0.038). Intense IH staining for CDC6 was significantly associated with a high Gleason score and advanced tumor stage including lymph node metastasis stage (linear-by-linear association, P = 0.044 and P = 0.003, respectively). CONCLUSION: CDC6 expression is associated with aggressive clinicopathological characteristics in PCa. CDC6 may be a potential diagnostic and prognostic marker in PCa patients.

Ca2+ Regulation of Cav3.3 T-type Ca2+ Channel Is Mediated by Calmodulin.

Calcium-dependent inactivation of high voltage-activated Ca2+ channels plays a crucial role in limiting rises in intracellular calcium (Ca2+i). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming α subunit. In contrast, little is known about how Ca2+i can regulate low voltage-activated T-type Ca2+ channels. Using whole cell patch clamp, we examined the biophysical properties of Ca2+ current through the three T-type Ca2+ channel isoforms, Cav3.1, Cav3.2, or Cav3.3, comparing internal solutions containing 27 nM and l µM free Ca2+ Both activation and inactivation kinetics of Cav3.3 current in l µM Ca2+i solution were more rapid than those in 27 nM Ca2+i solution. In addition, both activation and steady-state inactivation curves of Cav3.3 were negatively shifted in the higher Ca2+i solution. In contrast, the biophysical properties of Cav3.1 and Cav3.2 isoforms were not significantly different between the two internal solutions. Overexpression of CaM1234 (a calmodulin mutant that doesn't bind Ca2+) occluded the effects of l µM Ca2+i on Cav3.3, implying that CaM is involved in the Ca2+i regulation effects on Cav3.3. Yeast two-hybrid screening and co-immunoprecipitation experiments revealed a direct interaction of CaM with the carboxyl terminus of Cav3.3. Taken together, our results suggest that Cav3.3 T-type channel is potently regulated by Ca2+i via interaction of Ca2+/CaM with the carboxyl terminus of Cav3.3.