Population pharmacokinetics and pharmacodynamic target attainment analysis of cefazolin using total and unbound serum concentration in patients with prostatectomy or nephrectomy.

The aim of this study was to analyze the population pharmacokinetics of total and unbound concentrations of prophylactic cefazolin (CFZ) in patients with prostatectomy or nephrectomy. We also aimed to calculate a pharmacodynamics target unbound concentration that exceeded the minimum inhibitory concentration (MIC), to design an effective dosing regimen. Briefly, 614 total concentration and 610 unbound concentration samples from 152 individuals were evaluated, using a nonlinear mixed-effects model. The obtained pharmacodynamics index target value reflected the probability of maintaining CFZ unbound trough concentrations exceeding MIC90, 0.5 mg/L, and MIC50, and 1.0 mg/L, to account for methicillin-susceptible Staphylococcus aureus (MSSA) or Escherichia coli. Population pharmacokinetics were estimated using a two-compartment model with nonlinear protein binding. Unbound systemic clearance (CL) was significantly associated with creatinine clearance, while the maximum protein-binding constant was significantly associated with albumin levels. The probability of achieving an unbound concentration exceeding the MIC50 for E. coli or MIC90 for MSSA in a patient with normal renal function following a 1 g CFZ infusion over 15 min was above 90% at 3 h after the initial dose. Our findings indicated that population pharmacokinetic parameters are useful for determining unbound CFZ pharmacokinetics and evaluating intraoperative CFZ redosing intervals.

Real-world data on the comprehensive genetic profiling test for Japanese patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: comprehensive genomic profiling test has been covered by Japanese health insurance since June 2019. However, no real-world data on the test have been reported with a focus on Japanese patients with prostate cancer. METHODS: we retrospectively reviewed the data of 45 consecutive patients with metastatic castration-resistant prostate cancer, who underwent the comprehensive genomic profiling tests at Kitasato University Hospital between August 2019 and December 2022. Patients' characteristics, prevalence of gene alterations and therapeutic impact of genotype-matched therapy were assessed. RESULTS: genomic data were obtained using a tissue-based test (n = 32) and liquid-based test (n = 13). Actionable genomic alternations were identified in 51.1% of patients, and 22.2% were treated with genotype-matched therapy. The main reason for not receiving genotype-matched therapy was disease progression, accounting for 46.2% (6/13). Kaplan-Meier analysis showed significantly longer overall survival after the comprehensive genomic profiling tests in patients with genotype-matched therapy under public insurance (17.8%, n = 8) than those without it (median: not reached vs. 18.1 months; P = 0.003). Five (62.5%) out of the eight patients with genotype-matched therapy under public insurance had BRCA1 or 2 deleterious alteration. Multivariate analyses showed that BRCA deleterious alteration (17.8%, n = 8) was an independent risk factor for shorter time to castration-resistant prostate cancer (hazard ratio: 2.46, 95% confidence interval: 1.04-5.87; P = 0.041), and no patients with the alteration had ≤5 bone metastases. CONCLUSIONS: the results of this study showed the promising survival outcomes in patients with genotype-matched therapy under public insurance, even in the castration-resistant prostate cancer setting. Further detection of promising therapeutic target gene is expected to increase the number of patients who reach genotype-matched therapies.

Effect of water glass treatment for zirconia and silane coupling on bond strength of resin cement.

OBJECTIVE: To evaluate the ability of the water glass treatment to penetrate zirconia and improve the bond strength of resin cement. MATERIAL AND METHODS: Water glass was applied to zirconia specimens, which were then sintered. The specimens were divided into water-glass-treated and untreated zirconia (control) groups. The surface properties of the water-glass-treated specimens were evaluated using surface roughness and electron probe micro-analyser (EPMA) analysis. A resin cement was used to evaluate the tensile bond strength, with2 and without a silane-containing primer. After 24 h in water storage at 37 °C and thermal cycling, the bond strengths were statistically evaluated with t-test, and the fracture surfaces were observed using SEM. RESULTS: The water glass treatment slightly increased the surface roughness of the zirconia specimens, and the EPMA analysis detected the water glass penetration to be 50 µm below the zirconia surface. The application of primer improved the tensile bond strength in all groups. After 24 h, the water-glass-treated zirconia exhibited a tensile strength of 24.8 ± 5.5 MPa, which was significantly higher than that of the control zirconia (17.6 ± 3.5 MPa) (p < 0.05). After thermal cycling, the water-glass-treated zirconia showed significantly higher tensile strength than the control zirconia. The fracture surface morphology was mainly an adhesive pattern, whereas resin cement residue was occasionally detected on the water-glass-treated zirconia surfaces. CONCLUSION: The water glass treatment resulted in the formation of a stable silica phase on the zirconia surface. This process enabled silane coupling to the zirconia and improved the adhesion of the resin cement.

Patients with gastroesophageal reflux disease (both reflux oesophagitis and non-erosive reflux disease): Prevalence and severity of erosive tooth wear and saliva properties.

BACKGROUND: The prevalence between erosive tooth wear (ETW) in association with reflux oesophagitis (RO) has been reported. However, the severity of both diseases and the relationship between ETW and non-erosive reflux disease (NERD) is unclear. OBJECTIVES: The prevalence and severity of ETW were investigated in RO, NERD and healthy controls. METHODS: 135 patients with RO, 65 with NERD and 40 healthy controls were recruited for this case-control study. A modified tooth wear index was used to evaluate the prevalence and severity of ETW. Salivary secretion and buffer capacity were assessed prior to endoscopy. The prevalence and severity of ETW, saliva properties among each group were analysed using Pearson's chi-squared test. RESULTS: A total of 135 cases (56.3%) were categorised as the patient with ETW (55 with mild RO, 49 with severe RO and 31 with NERD). There was a significant relationship between the prevalence of RO and ETW, while there was no significant correlation between the prevalence of NERD and ETW. There was a significant difference related to the severity between RO and ETW. For salivary secretion, there was a significant difference between with and without ETW in patients with mild RO, severe RO and NERD. There was a significant difference between with and without ETW for salivary buffer capacity in patients with mild and severe RO. CONCLUSION: There was a significant association of the prevalence and severity between RO and ETW. Clinical signs such as ETW and salivary buffer capacity depended on the severity of RO.

Factors associated with prevalence and severity of erosive tooth wear in patients with reflux oesophagitis.

BACKGROUND: Extrinsic factors for erosive tooth wear (ETW) have been widely reported, but the intrinsic factors for wear remain unclear. OBJECTIVES: The aim of this study was to evaluate the factors associated with the prevalence of ETW in patients with reflux oesophagitis (RO). To prevent severe ETW with RO, factors associated with severity of ETW were also evaluated. METHODS: A total of 270 patients with RO were recruited. A modified tooth wear index was used to evaluate the prevalence and severity of ETW. Salivary secretion and buffering capacity were assessed prior to endoscopy. Subjects were asked to complete a medical condition and oral self-care questionnaire. Univariate and multivariate analyses were employed to identify factors collectively associated with the prevalence and severity of ETW. RESULTS: A total of 212 cases were categorized as patients with ETW (148 with mild ETW and 64 with severe ETW). Multivariate analyses indicated that saliva secretion, severity of RO and proton pump inhibitor (PPI) resistance were associated with the prevalence of ETW, whereas age, BMI and severity of RO were associated with the severity of ETW. The odds ratio of saliva secretion and BMI were less than 1, meaning that higher saliva secretion resulted in a lower prevalence of ETW and lower BMI was associated with severe ETW. CONCLUSION: Saliva secretion, severity of RO and PPI resistance were associated with the prevalence of ETW, whereas age, BMI and severity of RO were associated with the severity of ETW. Lower saliva secretion and BMI were significant factors for ETW.

Questionnaire survey on hands-on simulation training using a dental humanoid robot (SIMROID®).

INTRODUCTION: A dental humanoid robot, SIMROID®, is able to replicate the actions characteristic of human beings and enable training for communicating with patients and coping with unexpected situations. This study assessed user experiences via a survey questionnaire following hands-on training on the SIMROID®. MATERIALS AND METHODS: A total of 112 participants, consisting of 50 high school students who visited AUSD (Asahi University School of Dentistry) to participate in open campus events, 42 fourth-year students at AUSD and 20 dental students from Mexico State Autonomy University, University of Siena and Peking University took the survey. The participants observed the movements and reactions of a SIMROID® robot placed on a dental unit for approximately 20 min after which they completed a questionnaire survey. Both Japanese and English versions of the questionnaire were prepared for local and visiting foreign dental students. The questionnaire comprised 8 items, with a further two items for those undertaking dental training and an open comment field. RESULTS: All participants who observed the SIMROID® completed the questionnaire giving a 100% response rate. Generally, simulation training with SIMROID® was highly appreciated by all participants. The comprehensive evaluation score for SIMROID® was 4.56 ± 0.50 points for high school students, 4.05 ± 0.82 points for students at AUSD and 4.70 ± 0.47 points for foreign dental students, showing all participants had a very positive experience and impression of the SIMROID®. CONCLUSIONS: Therefore, simulation training using SIMROID® seems beneficial learning tool.

Proton Pump Inhibitor Treatment Has Little Effects on Secretion of Saliva in Patients with Proton Pump Inhibitor-Responsive Mild Reflux Esophagitis and Non-Erosive Reflux Disease.

INTRODUCTION: The secretion of saliva, which is triggered by acid reflux into the esophagus via the esophagosalivary reflex, plays a crucial role in the defensive mechanisms of the esophagus. The volume of saliva secreted in patients with gastroesophageal reflux disease (GERD) is reduced. However, the effects of proton pump inhibitors (PPI) on the secretion of saliva have rarely been reported. Therefore, the present study investigated changes in the volume and pH of saliva after the cessation of PPI. MATERIALS AND METHODS: We retrospectively reviewed the records of consecutive patients previously diagnosed with mild reflux esophagitis (RE) or non-erosive reflux disease (NERD) controlled with PPI (including vonoprazan) who performed the salivary secretion test before and after a 2-week cessation of PPI. The volume, pH, and pH after acid loading (buffering capacity) of saliva were compared before and after the cessation of PPI. RESULTS: Thirty-two patients (25 NERD, 7 mild RE) were included. The second saliva test was performed a median interval of 14 months [12.0-15.3] after the first test. No significant differences were observed in the volume of saliva secreted before and after the cessation of PPI (before 4.0 mL [2.7-6.0] vs. after 4.0 mL [2.3-5.9], p = 0.894). No significant differences were noted in pH or changes in pH after acid loading before and after the cessation of PPI (pH: before 7.1 ± 0.24 vs. after 7.0 ± 0.24, p = 0.1. Delta pH after acid loading: before 1.0 [0.8-1.2] vs. after 1.0 [0.8-1.2], p = 0.844). CONCLUSION: The cessation of PPI did not appear to affect the volume, pH, or buffering capacity of saliva in patients with PPI-responsive mild RE and NERD.

Patients with Non-Muscle-Invasive Bladder Cancer Previously Treated with Nephroureterectomy Have a High Risk of Recurrence after Bacillus Calmette-Guérin Intravesical Instillation Therapy.

BACKGROUND: There is a high incidence of intravesical recurrence after transurethral resection of bladder tumor for non-muscle-invasive bladder cancer (NMIBC). Intravesical instillation of bacillus Calmette-Guérin (BCG) is widely used to prevent recurrence and progression. There are two types of NMIBC: primary NMIBC and subsequent NMIBC after radical nephroureterectomy (RNU). We compared the clinical outcomes of BCG intravesical instillation therapy between the two types of NMIBC. PATIENTS AND METHODS: This study included a total of 357 patients, who received BCG intravesical instillation therapy to prevent recurrence of NMIBC (pTa/pT1) between 1991 and 2019. Among them, 34 patients had subsequent NMIBC after RNU, and the remaining 323 patients had primary NMIBC. This retrospective study analyzed 68 patients extracted by propensity score matching. Survival curves were estimated using the Kaplan-Meier method, and independent prognostic factors for survival were examined by the Cox proportional hazards model. RESULTS: The 3-year recurrence-free survival (RFS) rates in patients with primary NMIBC and subsequent NMIBC after RNU were 70.7% and 54.8%, respectively (p = 0.036). However, there were no significant differences between the two groups in progression-free survival and cancer-specific survival. Multivariate analysis of RFS showed that only a previous history of upper tract urothelial carcinoma was an independent prognostic and predictive factor. CONCLUSION: Patients with subsequent NMIBC after RNU treated with BCG intravesical instillation therapy have a higher risk of recurrence than those with primary NMIBC. Thus, stringent follow-up is necessary for patients with subsequent NMIBC after RNU.

Efficacy of Intravesical Instillation Therapy with Low-Dose Tokyo-172 Bacillus Calmette-Guérin to Prevent Recurrence of Non-Muscle-Invasive Bladder Cancer and Treat Carcinoma in situ: A Multi-Institutional Retrospective Study.

INTRODUCTION: There are various doses, durations, and strains of bacillus Calmette-Guérin (BCG) intravesical instillation therapy, but optimal treatment has not yet been established. We retrospectively investigated the efficacy and safety of low-dose BCG therapy for non-muscle-invasive bladder cancer (NMIBC) and carcinoma in situ (CIS) in a multicenter study. METHODS: From 1991 to 2019, 323 patients who received BCG therapy to prevent recurrence of NMIBC were analyzed as group A. Similarly, 147 patients who received BCG therapy for the treatment of CIS were analyzed as group B. Patients received low- or full-dose Tokyo-172 strain or full-dose Connaught strain, and the three strains were compared. Survival curves were estimated by the Kaplan-Meier method, and independent risk factors for intravesical recurrence were examined by multivariate logistic regression. RESULTS: Recurrence-free survival (RFS) in group A was significantly better for the Connaught strain than the low-dose Tokyo-172 strain (p = 0.026), but not between the low- and full-dose Tokyo-172 strains (p = 0.443). RFS of group B, cancer-specific survival, and progression-free survival in both groups did not show statistically significant differences. Logistic analysis of group A showed that for intravesical recurrence, only pT1 was a significant risk factor, and there were no differences between the BCG strain and dose and no significant factors in group B. There were also no differences in the completion rate in both groups, but adverse events such as urinary frequency and feeling of residual urine were significantly lower with the low-dose Tokyo-172 strain. CONCLUSION: There was no difference in efficacy between the low- and full-dose Tokyo-172 strains, but to minimize adverse events, the low-dose Tokyo-172 strain may be worth considering.

Expression of S100A16 Is Associated with Biological Aggressiveness and Poor Prognosis in Patients with Bladder Cancer Who Underwent Radical Cystectomy.

S100 calcium binding protein A16 (S100A16) is expressed in various cancers; however, there are few reports on S100A16 in bladder cancer (BC). We retrospectively investigated clinical data including clinicopathological features in 121 patients with BC who underwent radical cystectomy (RC). Immunohistochemical staining was performed to evaluate S100A16 expression in archived specimens. Cases with >5% expression and more than moderate staining intensity on cancer cells were considered positive. S100A16 expression was observed in 54 patients (44.6%). Univariate analysis showed that S100A16 expression was significantly associated with age, pT stage, recurrence, and cancer-specific death. Kaplan-Meier analyses showed that patients with S100A16 expression had shorter overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) than those without S100A16 expression. In multivariate analysis, pT stage was an independent prognostic factor for OS and lymph node metastasis for CSS and RFS. S100A16 expression may be a biomarker of a biologically aggressive phenotype and poor prognosis in patients with BC who underwent RC. The PI3k/Akt signaling pathway is probably associated with S100A16 and may be a therapeutic target.

Surface roughness and shear bond strength to composite resin of additively manufactured interim restorative material with different printing orientations.

STATEMENT OF PROBLEM: Additive manufacturing (AM) is a technology that has been recently introduced into dentistry for fabricating dental devices, including interim restorations. Printing orientation is one of the important and influential factors in AM that affects the accuracy, surface roughness, and mechanical characteristics of printed objects. However, the optimal print orientation for best bond strength to 3D-printed interim restorations remains unclear. PURPOSE: The purpose of this in vitro study was to evaluate the effect of printing orientation on the surface roughness, topography, and shear bond strength of AM interim restorations to composite resin. MATERIAL AND METHODS: Disk-shaped specimens (Ø20×10 mm) were designed by a computer-aided design software program (Geomagic freeform), and a standard tessellation language (STL) file was obtained. The STL file was used for the AM of 60 disks in 3 different printing orientations (0, 45, and 90 degrees) by using E-Dent 400 C&B material. An autopolymerizing interim material (Protemp 4) was used as a control group (CNT), and specimens were fabricated by using the injecting mold technique (n=20). Surface roughness (Sa, Sz parameters) was measured by using a 3D-laser scanning confocal microscope (CLSM) at ×20 magnification. For shear bond testing, the specimens were embedded in polymethylmethacrylate autopolymerized resin (n=20). A flowable composite resin was bonded by using an adhesive system. The specimens were stored in distilled water at 37 °C for 1 day and thermocycled 5000 times. The shear bond strength (SBS) was measured at a crosshead speed of 1 mm/min. The data were analyzed by 1-way ANOVA, followed by the Tukey HSD test (α=.05). RESULTS: The 45-degree angulation printing group reported the highest Sa, followed by the CNT and the 90-degree and 0-degree angulations with significant difference between them (P<.001). The CNT showed the highest Sz, followed by the 45-degree, 90-degree, and 0-degree angulations. The mean ±standard deviation SBS was 28.73 ±5.82 MPa for the 90-degree, 28.21 ±10.69 MPa for the 45-degree, 26.21 ±11.19 MPa for the 0-degree angulations and 25.39 ±4.67 MPa for the CNT. However, no statistically significant difference was found in the SBS among the groups (P=.475). CONCLUSIONS: Printing orientation significantly impacted the surface roughness of 3D-printed resin for interim restorations. However, printing orientation did not significantly affect the bond strength with composite resin.

Shear bond strength of porcelain to milled and stereolithography additively manufactured zirconia with and without surface treatment: An in vitro study.

STATEMENT OF PROBLEM: Delamination of veneering ceramic is one of the most common challenges relating to veneered zirconia restorations. Additive manufacturing (AM) is a fast-expanding technology that has gained widespread acceptance in dentistry and is increasingly being used to produce dental restorations. However, information about bonding of porcelain to AM zirconia is lacking. PURPOSE: The purpose of this in vitro study was to investigate the shear bond strength (SBS) of porcelain to milled and additively manufactured zirconia, and the effect of surface treatment on bond strength. MATERIAL AND METHODS: A Ø12×5-mm disk was designed virtually to fabricate all specimens, which were divided into 2 groups according to the manufacturing technique: additively manufactured or milled zirconia. The effect of airborne-particle abrasion and a zirconia liner before porcelain application was investigated in both groups. Veneering porcelain was fired into an alumina ring mold on the zirconia surface. SBS was measured by using a universal testing machine at a crosshead speed of 1 mm/min before and after aging (n=10). SBS data were analyzed with 3-way ANOVA (α=.05) RESULTS: A significant difference was found between milled and AM zirconia. The SBS of porcelain to milled zirconia was significantly higher (1.38 MPa) than to AM zirconia (0.68 MPa) (P<.001). The surface treatment of zirconia had no significant effect on porcelain SBS in either group (P=.254), whereas thermocycling significantly reduced the SBS of porcelain to zirconia in both milled and AM groups (P=.001). CONCLUSIONS: Porcelain bonding to milled zirconia was better than to AM zirconia. Pretreating the zirconia substrate before porcelain application did not improve the porcelain bond.

High-resolution manometry with additional maneuvers using the Starlet system: normative thresholds and diagnostic yields for relevant esophagogastric junction outflow disorders.

BACKGROUND: Chicago classification version 4.0 suggests additional maneuvers, such as upright testing, multiple rapid swallows (MRS), and the rapid drink challenge (RDC), for high-resolution manometry (HRM) to minimize ambiguity in the diagnosis of esophageal motility disorders. The present study investigated normative thresholds for these new metrics using the Starlet system as well as their diagnostic yields for relevant esophagogastric outflow disorders (EGJOD). METHODS: In study 1, 30 asymptomatic volunteers prospectively performed HRM including MRS and RDC in the supine/upright positions. We calculated normative thresholds for the new metrics, such as upright integrated relaxation pressure (IRP), upright intrabolus pressure (IBP), and IRP during RDC (RDC-IRP). In study 2, we retrospectively analyzed the HRM tracings of 82 patients who underwent HRM in both positions at our hospital to assess the diagnostic yields of HRM metrics. RESULTS: Based on the results of study 1, we adopted the following normative thresholds: upright IRP < 20 mmHg, upright IBP < 21 mmHg, and RDC-IRP < 16 mmHg. In study 2, 45 patients with dysphagia or chest pain were included in the analysis to identify predictive factors for clinically relevant esophagogastric outflow disorders (true EGJOD). Supine/upright IRP, RDC-IRP, and pan-esophageal pressurization > 20 mmHg during RDC (RDC-PEP) predicted true EGJOD with RDC-PEP with the highest sensitivity of 91.7%. CONCLUSIONS: HRM with additional maneuvers may facilitate the diagnosis of clinically relevant EGJOD.

Impact of salvage cytotoxic chemotherapy on prognosis in patients with recurrence after radical cystectomy: a multi-institutional retrospective study.

BACKGROUND: In patients experiencing disease recurrence after radical cystectomy (RC) for bladder cancer, data about the impact of clinicopathologic factors, including salvage treatment using cytotoxic chemotherapy, on the survival are scarce. We investigated the prognostic value of clinicopathologic factors and the treatment effect of salvage cytotoxic chemotherapy (SC) in such patients. METHODS: In this retrospective study, we evaluated the clinical data for 86 patients who experienced recurrence after RC. Administration of SC or of best supportive care (BSC) was determined in consultation with the urologist in charge and in accordance with each patient's performance status, wishes for treatment, and renal function. Statistical analyses explored for prognostic factors and evaluated the treatment effect of SC compared with BSC in terms of cancer-specific survival (CSS). RESULTS: Multivariate analyses showed that liver metastasis after RC (hazard ratio [HR] 2.13; 95% confidence interval [CI] 1.17 to 3.85; P = 0.01) and locally advanced disease at RC (HR 1.92; 95% CI 1.06 to 3.46; P = 0.03) are independent risk factors for worse CSS in patients experiencing recurrence after RC. In a risk stratification model, patients were assigned to one of two groups based on liver metastasis and locally advanced stage. In the high-risk group, which included 68 patients with 1-2 risk factors, CSS was significantly better for patients receiving SC than for those receiving BSC (median survival duration: 9.4 months vs. 2.4 months, P = 0.005). The therapeutic effect of SC was not related to a history of adjuvant chemotherapy. CONCLUSIONS: The present study indicated the potential value of 1st-line SC in patients experiencing recurrence after RC even with advanced features, such as liver metastasis after RC and locally advanced disease at RC.

The effects of different silicatization and silanization protocols on the bond durability of resin cements to new high-translucent zirconia.

OBJECTIVE: The aim of this study was to assess the influence of different silicatization protocols with various silane treatment methods on the bond performance to high-translucent zirconia. MATERIALS AND METHODS: High-translucent zirconia specimens were assigned to five groups according to mechanical surface pretreatment: as-sintered (Con), 0.2 MPa alumina sandblasting (AB2), tribochemical silica coating (TSC), 0.2 and 0.4 MPa glass bead air abrasion (GB2) and (GB4). Each group was subjected to 4 different cementation protocols: Panavia SA Universal (SAU), Panavia SA plus (SAP), silane + SAP (S-SAP), and Universal adhesive + SAP (U-SAP). Tensile bond strength (TBS) was measured after 24 h and 10,000 thermocycling (TC). Surface topography, surface energy, and elemental composition of the abraded zirconia surface analyses were completed. TBS data was analyzed using the Weibull analysis method. Surface roughness and surface energy were compared by one-way ANOVA analysis of variance (α = 0.05). RESULTS: After 24 h, higher TBS was achieved with all cementation protocols in AB2 and TSC, also, in GB2 with all protocols except U-SAP, and in GB4 with SAU and S-SAP. After aging, GB4/S-SAP, GB2/S-SAP, AB2/U-SAP, and TSC/S-SAP showed the highest bond strength. GB groups showed the lowest surface roughness and highest surface energy. CONCLUSION: Glass bead abrasion achieved the durable bond strength to high-translucent zirconia using a separate silane coupling agent while altered surface chemistry, surface energy, and roughness without effect on morphology. CLINICAL RELEVANCE: Glass bead air abrasion is an alternative to alumina sandblasting and tribochemical silica coating and improves bond strength to high translucent zirconia.

Progression of non-carious cervical lesions: 3D morphological analysis.

OBJECTIVES: This longitudinal study aimed to investigate morphologically and quantitatively the progression of non-carious cervical lesions (NCCLs) using a confocal laser scanning microscope (CLSM) and replica models. MATERIALS AND METHODS: The samples examined comprised sets of replicas annually obtained from 83 lesions in 16 participants over 3 to 5 years. All lesions were visually categorized as wedge-shaped, saucer-shaped, or mixed-shaped lesions. CLSM images of the replicas were analyzed in terms of axial depth, occlusogingival width (height) in the buccolingual cross-section, and estimated volume using a custom code of the image analysis software to estimate the progression of the NCCLs over time. The morphological characteristics of the NCCLs were also objectively divided into three groups according to the depth to height ratio (D/H ratio). Fisher's exact test and the Cochran-Armitage trend test were used for statistical analysis. RESULTS: Saucer-shaped lesions progressed mainly in height, whereas wedge-shaped lesions increased both in height and depth. Annual progression in depth and volume significantly increased as the D/H ratio increased. More than half of the NCCLs with a small D/H ratio progressed 50 µm or more in height, whereas none of them progressed more than 50 µm in depth. Annual progression in depth significantly increased as the lesion depth at baseline increased. CONCLUSIONS: Progression patterns significantly differed between NCCLs of different shapes. Most NCCLs progressed slowly in depth regardless of their shape. Moreover, NCCLs may progress through active and inactive stages.

Diagnostic Potential of Circulating Tumor Cells, Urinary MicroRNA, and Urinary Cell-Free DNA for Bladder Cancer: A Review.

Early detection of primary bladder cancer (BCa) is vital, because stage and grade have been generally accepted not only as categorical but also as prognostic factors in patients with BCa. The widely accepted screening methods for BCa, cystoscopy and urine cytology, have unsatisfactory diagnostic accuracy, with high rates of false negatives, especially for flat-type BCa with cystoscopy and for low-risk disease with urine cytology. Currently, liquid biopsy has attracted much attention as being compensatory for that limited diagnostic power. In this review, we survey the literature on liquid biopsy for the detection of BCa, focusing on circulating tumor cells (CTCs), urinary cell-free DNA (ucfDNA), and urinary microRNA (umiRNA). In diagnostic terms, CTCs and umiRNA are determined by quantitative analysis, and ucfDNA relies on finding genetic and epigenetic changes. The ideal biomarkers should be highly sensitive in detecting BCa. Currently, CTCs produce an unfavorable result; however, umiRNA and ucfDNA, especially when analyzed using a panel of genes, produce promising results. However, given the small cohort size in most studies, no conclusions can yet be drawn about liquid biopsy's immediate application to clinical practice. Further large studies to validate the diagnostic value of liquid biopsy for clinical use are mandatory.

Gemcitabine-Paclitaxel Chemotherapy for Patients with Advanced Urothelial Cancer Refractory to Cisplatin-Based Chemotherapy: Predictive Role of PGK1 for Treatment Response to Cytotoxic Chemotherapy.

An investigation of alternatives to immune checkpoint inhibitors for advanced urothelial cancer (aUC), with biologic information, is urgently needed. Clinical data for 53 patients who received gemcitabine-paclitaxel therapy (GP) as 2nd-line chemotherapy for aUC refractory to platinum-based chemotherapy were retrospectively reviewed. The efficacy and tolerability of GP were evaluated, and the predictive value of phosphoglycerate kinase 1 (PGK1) immunostained in surgical specimens was investigated for treatment outcomes in 1st- and 2nd-line chemotherapy. GP was associated with an objective response rate of 35.8% and a median overall survival duration of 12.3 months. Multivariate analysis showed that PS2 and 1st- and 2nd-line non-response are independent predictors of worse progression-free survival and that PS2 and 1st-line non-response are independent predictors of worse overall survival. Adverse events were manageable, and no therapy-related deaths occurred. Non-response rates to 1st-line chemotherapy were significantly higher in patients with a high expression of PGK1 in the nucleus than in those with low expression (p = 0.006). Our study demonstrates the efficacy and tolerability of 2nd-line GP for patients with aUC who are refractory to platinum-based chemotherapy. Moreover, PGK1 in the nucleus was predictive values for resistance to platinum-based chemotherapy in aUC.

Perforated Hydrogels Consisting of Cholesterol-Bearing Pullulan (CHP) Nanogels: A Newly Designed Scaffold for Bone Regeneration Induced by RANKL-Binding Peptides and BMP-2.

The receptor activator of NF-κB ligand (RANKL)-binding peptide, OP3-4, is known to stimulate bone morphogenetic protein (BMP)-2-induced bone formation, but peptides tend to aggregate and lose their bioactivity. Cholesterol-bearing pullulan (CHP) nanogel scaffold has been shown to prevent aggregation of peptides and to allow their sustained release and activity; however, the appropriate design of CHP nanogels to conduct local bone formation needs to be developed. In the present study, we investigated the osteoconductive capacity of a newly synthesized CHP nanogel, CHPA using OP3-4 and BMP-2. We also clarified the difference between perforated and nonperforated CHPA impregnated with the two signaling molecules. Thirty-six, five-week-old male BALB/c mice were used for the calvarial defect model. The mice were euthanized at 6 weeks postoperatively. A higher cortical bone mineral content and bone formation rate were observed in the perforated scaffold in comparison to the nonperforated scaffold, especially in the OP3-4/BMP-2 combination group. The degradation rate of scaffold material in the perforated OP3-4/BMP-2 combination group was lower than that in the nonperforated group. These data suggest that perforated CHPA nanogel could lead to local bone formation induced by OP3-4 and BMP-2 and clarified the appropriate degradation rate for inducing local bone formation when CHPA nanogels are designed to be perforated.

Additive effects of touch-activated polymerization and extended irradiation time on bonding of light-activated adhesives to root canal dentin.

STATEMENT OF PROBLEM: The bonding of light-activated adhesives to root canal dentin with an additional touch-polymerization activator has been insufficiently examined. PURPOSE: The purpose of this in vitro study was to investigate the effect of touch-polymerization activators and extended light-irradiation time on the microtensile bond strength (µTBS) of light-activated adhesives. MATERIAL AND METHODS: Post cavities were prepared in 50 extracted mandibular premolars and bonded using Prime&Bond Universal (PBU); PBU+Self Cure Activator (SCA); Clearfil SE Bond 2 (SEB); SEB+Clearfil DC Activator (DCA); or Clearfil Universal Bond Quick ER (UBQ). After light-irradiation for 10 or 20 seconds, the post cavities were filled with dual-activated resin core materials. Eight beams were prepared per specimen and subjected to the µTBS test. The µTBS data were analyzed by using 3-way ANOVAs with the Bonferroni correction (α=.05). RESULTS: The 3-way ANOVAs indicated that the use of touch-polymerization activators (SCA and DCA) significantly increased the µTBS of PBU and SEB in both the coronal (P=.015) and apical (P=.001) regions. The extension of light-irradiation time to 20 seconds significantly improved their µTBS in the apical region (P<.001), but not in the coronal region (P=.09). Light-irradiation for 20 seconds increased the µTBS of UBQ significantly in the coronal region (P=.014). CONCLUSIONS: Touch-polymerization activators improved the bond strength of light-activated adhesives to root canal dentin, especially when combined with an extended light-irradiation time.