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Patients with prostate cancer who have high-risk biochemical recurrence have an increased risk of progression. The efficacy and safety of enzalutamide plus androgen-deprivation therapy and enzalutamide monotherapy, as compared with androgen-deprivation therapy alone, are unknown. In this phase 3 trial, we enrolled patients with prostate cancer who had high-risk biochemical recurrence with a prostate-specific antigen doubling time of 9 months or less. Patients were randomly assigned, in a 1:1:1 ratio, to receive enzalutamide (160 mg) daily plus leuprolide every 12 weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group). The primary end point was metastasis-free survival, as assessed by blinded independent central review, in the combination group as compared with the leuprolide-alone group. A key secondary end point was metastasis-free survival in the monotherapy group as compared with the leuprolide-alone group. Other secondary end points were patient-reported outcomes and safety. A total of 1068 patients underwent randomization: 355 were assigned to the combination group, 358 to the leuprolide-alone group, and 355 to the monotherapy group. The patients were followed for a median of 60.7 months. At 5 years, metastasis-free survival was 87.3% (95% confidence interval [CI], 83.0 to 90.6) in the combination group, 71.4% (95% CI, 65.7 to 76.3) in the leuprolide-alone group, and 80.0% (95% CI, 75.0 to 84.1) in the monotherapy group. With respect to metastasis-free survival, enzalutamide plus leuprolide was superior to leuprolide alone (hazard ratio for metastasis or death, 0.42; 95% CI, 0.30 to 0.61; P<0.001); enzalutamide monotherapy was also superior to leuprolide alone (hazard ratio for metastasis or death, 0.63; 95% CI, 0.46 to 0.87; P = 0.005). No new safety signals were observed, with no substantial between-group differences in quality-of-life measures. In patients with prostate cancer with high-risk biochemical recurrence, enzalutamide plus leuprolide was superior to leuprolide alone with respect to metastasis-free survival; enzalutamide monotherapy was also superior to leuprolide alone. The safety profile of enzalutamide was consistent with that shown in previous clinical studies, with no apparent detrimental effect on quality of life. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.).

Background: Descriptive epidemiologists have repeatedly reported that males are more susceptible to head and neck cancers. However, most published data are those of cross-sectional studies, and no population-based cohort study has yet been published. The aim of this study was to compare the prevalence of head and neck cancers in healthy males with females. Methods: A retrospective cohort study using the Korean National Health Insurance Service database on 9,598,085 individuals who underwent regular health checkups from 1 January to 31 December 2009. We sought head and neck cancers developed during the 10-year follow-up. Results: A total of 10,732 (incidence rate (IR) per 1000 person-years 0.25) individuals were newly diagnosed with head and neck cancer among the 9,598,085 individuals during the 10-year follow-up. The IR was 0.19 in males (8500 affected) and 0.06 in females (2232 affected). Notably, the male–female ratio increased with age below 70 years but decreased thereafter. The male–female difference was most apparent for laryngeal cancer; the male IR was 11-fold higher in the 40 s and 20-fold higher in the 60 s, followed by hypopharyngeal cancer (6.8- and 24.2-fold). Males smoked more and drank more alcohol than females (p < 0.0001 *, p < 0.0001 *). When never-smokers/-drinkers (only) were compared, males remained at a 2.9-fold higher risk of head and neck cancer than females. The hazard ratios for head and neck cancers in males tended to increase in the lower part of the upper aerodigestive tract: larynx (13.9) > hypopharynx (10.9) > oropharynx (4.4) > nasopharynx (2.9) > sinonasal region (1.8) > oral (1.6). Only the salivary gland cancer incidence did not differ between the sexes; the gland is not in the upper aerodigestive tract. Conclusion: Males are much more susceptible to head and neck cancers than females regardless of whether they drink alcohol or smoke tobacco. Sex differences in the incidence of head and neck cancer are most evident in the 60 s in the lower part of the upper aerodigestive tract, such as the larynx and hypopharynx.

Vocal fold scarring is a major cause of dysphonia. Vocal fold fibroblasts (VFFs) and the TGF-β signaling pathway play important roles in scar formation. Eupatilin, a chromone derivative of the Artemisia species, is a traditional folk remedy for wound healing. However, until recently, few studies investigated the therapeutic effects of eupatilin. We investigated the antifibrogenic effects of eupatilin on TGF-β1-treated human vocal fold fibroblasts (hVFFs). The optimal concentration of eupatilin was determined by a cell viability assay. Western blotting was used to measure the expression of alpha-smooth muscle actin during myofibroblast differentiation, fibronectin (FN), collagen type I (Col I), and collagen type III (Col III) extracellular matrix proteins, and Smad2, Smad3, and p38 in the fibrotic pathway. Measurements were made before and after eupatilin treatment. Eupatilin at 100 nM was shown to be safe for use in hVFFs. TGF-β1 induced hVFFs to proliferate and differentiate into myofibroblasts and increased Col III and FN synthesis in a time- and dose-dependent manner. Eupatilin suppressed TGF-β1-induced hVFF proliferation and differentiation into myofibroblasts through the Smad and p38 signaling pathways. Furthermore, eupatilin inhibited TGF-β1-induced FN, Col I, and Col III synthesis in hVFFs. Our in vitro findings show that eupatilin effectively suppressed TGF-β1-induced fibrotic changes in hVFFs via the Smad and p38 signaling pathways. Thus, eupatilin may be considered a novel therapeutic agent for the treatment of vocal fold fibrosis.

Polycyclic aromatic hydrocarbons (PAHs) are toxicants in particulate matter (PM). The vocal fold, part of the larynx and a key structure for voicing, is always in contact with air. In recent epidemic studies, PM was shown to cause laryngitis; however, the basic mechanism has not been evaluated. In the present study, intracellular reactive oxygen species (ROS) and proinflammatory cytokine levels were analyzed after exposing human vocal fold fibroblasts (hVFFs) to PM standard reference material (SRM 2786). Expression levels of the aryl hydrocarbon receptor (AhR) and Cytochrome P450 Family 1 Subfamily A Member 1 (CYP1A1) were also evaluated. PM induced ROS formation and proinflammatory cytokines via the AhR CYP1A1 pathway and caused lipid peroxidation and DNA damage. Blocking AhR or CYP1A1 production using siRNAs significantly decreased ROS production and IL-6 and IL-9 expression in PM-exposed hVFFs, thus protecting the cells against oxidative stress. These results confirm that PAHs in PM play an important role in cell damage and inflammation, confirming a basic pathophysiologic relationship between PM exposure and laryngitis.

Objectives To evaluate the impact of prostate-specific antigen (PSA) screening on prostate cancer (PCa) characteristics and survival outcomes in a contemporary cohort, amidst evolving PSA screening practices. Methods We retrospectively analyzed clinicopathologic data of 5,437 men diagnosed with PCa via prostate biopsy at our institution between 2006 and 2018. Patients were categorized as PSA-detected (PCa detected by PSA testing in asymptomatic individuals) or Symptom-detected (PCa detected after PSA testing prompted by symptoms). Temporal trends in PSA screening and cancer characteristics were assessed using correlation and time-series analyses. Multivariable Cox regression evaluated the effect of PSA screening on overall and cancer-specific survival. Results The PSA screening rate in our cohort increased from 46.4% in 2006 to 63.1% in 2018 ( p  < 0.001). Greater PSA screening uptake was associated with an increasing proportion of Gleason score 7 tumors ( r  = 0.608, p  = 0.028), more localized-stage disease ( r  = 0.757, p  = 0.003), and fewer cases of distant metastasis at diagnosis ( r = -0.605, p  = 0.028). The detection of clinically insignificant (low-risk) cancer rose modestly over time ( r  = 0.437, p  = 0.136) but was not significantly influenced by PSA screening rates ( r  = 0.496, p  = 0.085). On multivariate analysis, PSA screening was an independent predictor of improved overall survival (hazard ratio [HR] 0.54, p  < 0.001) and cancer-specific survival (HR 0.46, p  < 0.001). Conclusions Increasing utilization of PSA screening correlated with a stage migration toward localized disease and a reduction in metastatic presentations, without a substantial increase in the detection of clinically insignificant cancer, as defined by Epstein criteria. PSA screening was an independent prognostic factor for better survival outcomes.

Segmentation is fundamental to medical image analysis. Recent advances in fully convolutional networks has enabled automatic segmentation; however, high labeling efforts and difficulty in acquiring sufficient and high-quality training data is still a challenge. In this study, a cascaded 3D U-Net with active learning to increase training efficiency with exceedingly limited data and reduce labeling efforts is proposed. Abdominal computed tomography images of 50 kidneys were used for training. In stage I, 20 kidneys with renal cell carcinoma and four substructures were used for training by manually labelling ground truths. In stage II, 20 kidneys from the previous stage and 20 newly added kidneys were used with convolutional neural net (CNN)-corrected labelling for the newly added data. Similarly, in stage III, 50 kidneys were used. The Dice similarity coefficient was increased with the completion of each stage, and shows superior performance when compared with a recent segmentation network based on 3D U-Net. The labeling time for CNN-corrected segmentation was reduced by more than half compared to that in manual segmentation. Active learning was therefore concluded to be capable of reducing labeling efforts through CNN-corrected segmentation and increase training efficiency by iterative learning with limited data.

The advent of three-dimensional printing (3DP) technology has enabled the creation of a tangible and complex 3D object that goes beyond a simple 3D-shaded visualization on a flat monitor. Since the early 2000s, 3DP machines have been used only in hard tissue applications. Recently developed multi-materials for 3DP have been used extensively for a variety of medical applications, such as personalized surgical planning and guidance, customized implants, biomedical research, and preclinical education. In this review article, we discuss the 3D reconstruction process, touching on medical imaging, and various 3DP systems applicable to medicine. In addition, the 3DP medical applications using multi-materials are introduced, as well as our recent results.

A multiple receptor tyrosine kinase inhibitor, sunitinib, is a first-line therapy for clear cell renal cell carcinoma (CCRCC). Unfortunately, it has the major challenges of low initial response rate and resistance after about one year of treatment. Here we evaluated a microRNA (miRNA) and its target responsible for sunitinib resistance. Using miRNA profiling, we identified miR-96-5p upregulation in tumors from sunitinib-resistant CCRCC patients. By bioinformatic analysis, PTEN was selected as a potential target of miR-96-5p, which showed low levels in tumors from sunitinib-resistant CCRCC patients. Furthermore, PTEN and miR-96-5p levels were negatively correlated in a large The Cancer Genome Atlas kidney renal clear cell carcinoma cohort and high miR-96 and low PTEN represented poor prognosis in this cohort. Additionally, four-week sunitinib treatment increased miR-96-5p and decreased PTEN only in tumors from a sunitinib-resistant patient-derived xenograft model. We found a novel miR-96-5p binding site in the PTEN 3′ UTR and confirmed direct repression by luciferase reporter assay. Furthermore, we demonstrated that repression of PTEN by miR-96-5p increased cell proliferation and migration in sunitinib-treated cell lines. These results highlight the direct suppression of PTEN by miR-96-5p and that high miR-96-5p and low PTEN are partially responsible for sunitinib resistance and poor prognosis in CCRCC.

Prostate cancer (PCa) is the second most prevalent malignancy among men worldwide. However, current screening tools such as serum prostate-specific antigen (PSA) tests and digital rectal examination (DRE) are limited by low specificity and high false-positive rates, often leading to unnecessary biopsies and overtreatment. To address this clinical challenge, we developed a novel diagnostic framework termed PCASSO (Prostate CAncer diagnosis using Sensitive and Sophisticated ML classifiers based on nOn-invasive urinary RNA biomarkers), which integrates machine learning (ML) algorithms with non-invasive urinary RNA biomarker profiles obtained from DRE-free whole urine. A total of 163 urine samples (112 PCa, 51  benign prostatic hyperplasia [BPH]) were analyzed using quantitative PCR for 20 RNA biomarkers, including 2 long noncoding RNAs, 1 fusion gene, and 17 miRNAs. Among six ML classifiers evaluated, a Gradient Boosting model using an optimized 9-biomarker panel achieved the highest diagnostic performance (AUC: 0.99), with robust cross-validation results (Stratified-K-Fold: 0.912; LOOCV: 0.890). Notably, this classifier retained high accuracy in patients within the PSA gray zone (3–10 ng/mL), where clinical decision-making is often ambiguous. Our results demonstrate that ML-based classifiers using DRE-free urinary RNA biomarkers showed improved performance through robust internal validation, providing a basis for future validation studies.

Background and Objectives: Damage to the vocal folds frequently results in fibrosis, which can degrade vocal quality due to the buildup of collagen and modifications in the extracellular matrix (ECM). Conventional treatments have shown limited success in reversing fibrotic changes. Hepatocyte growth factor (HGF) and c-Met-targeting antibodies are promising due to their potential to inhibit fibrosis and promote regeneration. This research examines the effectiveness of injections containing c-Met agonistic antibodies relative to HGF in reducing fibrosis within a rat model of vocal fold injury. Materials and Methods: Forty-five Sprague Dawley rats were divided into three groups, which were HGF, c-Met agonistic antibody, and the control (PBS). The right vocal folds were injured and treated with HGF or c-Met agonistic antibody injections. RNA isolation and quantitative real-time PCR were performed to assess mRNA levels of fibrosis-related markers at 1 and 2 weeks post-injury. Histopathological analysis was conducted at 3 weeks to evaluate collagen and hyaluronic acid (HA) deposition. Results: Both the HGF and c-Met groups demonstrated reduced type III collagen mRNA expression compared to the PBS group. The c-Met group uniquely maintained fibronectin levels closer to normal. Additionally, the c-Met group showed significantly upregulated expression of hyaluronan synthase (HAS) 1 and HAS 3 at 2 weeks post-injury, indicating enhanced HA synthesis. Histological analysis showed significantly lower collagen deposition and higher HA in the c-Met group than in PBS, confirming superior anti-fibrotic effects and ECM restoration. Conclusions: c-Met agonistic antibody injections outperformed HGF in reducing fibrosis, upregulating HAS expression, and promoting HA deposition in injured vocal folds, highlighting its potential as a superior therapeutic approach for preventing fibrosis and enhancing ECM quality in vocal fold injuries. Further research on functional outcomes in larger models is recommended to validate these findings.