Discovery of TCP-(MP)-caffeic acid analogs as a new class of agents for treatment of osteoclastic bone loss.

Inhibition of LSD1 was proposed as promising and attractive therapies for treating osteoporosis. Here, we synthesized a series of novel TCP-(MP)-Caffeic acid analogs as potential LSD1 inhibitors to assess their inhibitory effects on osteoclastogenesis by using TRAP-staining assay and try to explore the preliminary SAR. Among them, TCP-MP-CA (11a) demonstrated osteoclastic bone loss both in vitro and in vivo, showing a significant improvement in the in vivo effects compared to the LSD1 inhibitor GSK-LSD1. Additionally, we elucidated a mechanism that 11a and its precursor that 11e directly bind to LSD1/CoREST complex through FAD to inhibit LSD1 demethylation activity and influence its downstream IκB/NF-κB signaling pathway, and thus regulate osteoclastic bone loss. These findings suggested 11a or 11e as potential novel candidates for treating osteoclastic bone loss, and a concept for further development of TCP-(MP)-Caffeic acid analogs for therapeutic use in osteoporosis clinics.

Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer.

PURPOSE: This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer. MATERIALS AND METHODS: Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2-3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded. RESULTS: The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4-5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates. CONCLUSION: This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT.

Deep learning model for differentiating nasal cavity masses based on nasal endoscopy images.

BACKGROUND: Nasal polyps and inverted papillomas often look similar. Clinically, it is difficult to distinguish the masses by endoscopic examination. Therefore, in this study, we aimed to develop a deep learning algorithm for computer-aided diagnosis of nasal endoscopic images, which may provide a more accurate clinical diagnosis before pathologic confirmation of the nasal masses. METHODS: By performing deep learning of nasal endoscope images, we evaluated our computer-aided diagnosis system's assessment ability for nasal polyps and inverted papilloma and the feasibility of their clinical application. We used curriculum learning pre-trained with patches of nasal endoscopic images and full-sized images. The proposed model's performance for classifying nasal polyps, inverted papilloma, and normal tissue was analyzed using five-fold cross-validation. RESULTS: The normal scores for our best-performing network were 0.9520 for recall, 0.7900 for precision, 0.8648 for F1-score, 0.97 for the area under the curve, and 0.8273 for accuracy. For nasal polyps, the best performance was 0.8162, 0.8496, 0.8409, 0.89, and 0.8273, respectively, for recall, precision, F1-score, area under the curve, and accuracy. Finally, for inverted papilloma, the best performance was obtained for recall, precision, F1-score, area under the curve, and accuracy values of 0.5172, 0.8125, 0.6122, 0.83, and 0.8273, respectively. CONCLUSION: Although there were some misclassifications, the results of gradient-weighted class activation mapping were generally consistent with the areas under the curve determined by otolaryngologists. These results suggest that the convolutional neural network is highly reliable in resolving lesion locations in nasal endoscopic images.

Comparison of disposable digital single-operator cholangioscopy versus direct peroral cholangioscopy for the diagnosis of intraductal superficial lesions of the bile duct.

BACKGROUND: Disposable digital single-operator cholangioscopy (D-SOC) and direct peroral cholangioscopy (D-POC) using an ultraslim endoscope are established POC modalities for the diagnosis and treatment of various biliary diseases. We compared the usefulness of D-SOC and D-POC for the diagnosis of intraductal superficial lesions of the bile duct (ISL-Bs). METHODS: 38 consecutive patients with suspected biliary diseases who underwent both D-SOC and D-POC were enrolled. The primary outcome was ISL-B detection rate, and the secondary outcomes were technical success of POC and POC-guided forceps biopsy sampling (POC-FB), procedure time, visualization quality, and tissue adequacy. RESULTS: D-SOC had a higher technical success rate than D-POC but the difference was not statistically significant (100% vs. 92.1%, P = 0.25). D-POC had a marginally higher ISL-B detection rate (34.2% vs. 28.9%, P = 0.68) and significantly higher visualization quality (P = 0.03). The mean (SD) procedure time was significantly shorter with D-SOC (11.00 [1.33] vs. 19.03 [2.95] minutes, P<0.001). The technical success rate of POC-FB and tissue adequacy did not differ between the two techniques (D-SOC vs. D-POC: 81.8% vs. 84.6%, P = 0.69 and 77.8% vs. 90.9%, P = 0.57, respectively). CONCLUSIONS: Both POC systems were safe and useful for the detection, characterization, and diagnosis of minute ISL-Bs. While D-SOC displayed a shorter procedure time and a tendency for higher technical success rate, D-POC provided superior visualization quality, allowing detailed observation of the surface structure and microvascular patterns.

Impact of temperature-controlled endobiliary radiofrequency ablation for inoperable hilar cholangiocarcinoma: A propensity score-matched analysis.

Background and study aims Endobiliary radiofrequency ablation (RFA) can be an effective palliative treatment, but few studies have evaluated its outcomes for malignant obstruction in the hilar bile duct, which has a thin wall and complex duct-vascular contacts. We evaluated the efficacy and safety of temperature-controlled endobiliary RFA, which can reduce the risk of unintentional thermal injury by maintaining the temperature of the ablation segment, in the treatment of inoperable hilar cholangiocarcinoma (CCA). Patients and methods After propensity score matching, 64 patients with inoperable hilar CCA were categorized to the RFA + stent group (endobiliary RFA with stenting; n=32) or stent-only group (stenting only; n=32). The evaluated outcomes were the median time to recurrent biliary obstruction (RBO), overall survival (OS), and adverse events (AEs). Results Technical success was achieved in all patients. The clinical success rate was 93.8% in the RFA + stent group and 87.5% in the stent-only group ( P =0.672). The median time to RBO was 242 days in the RFA + stent group and 168 days in the stent-only group ( P =0.031). The median OS showed a non-significant tendency to be higher in the RFA + stent group (337 versus 296 days; P =0.260). Overall AE rates were comparable between the two groups (12.5% vs 9.4%, P =1.000). Conclusions Temperature-controlled endobiliary RFA resulted in favorable stent patency without increasing the rate of AEs but it did not significantly increase OS in patients with inoperable hilar CCA (Clinical trial registration number: KCT0008576).

Androgen deprivation alone versus combined with pelvic radiation for adverse events and quality of life in clinically node-positive prostate cancer.

The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.

Hypofractionated radiation therapy combined with androgen deprivation therapy for high-risk localized prostate cancer.

INTRODUCTION: This study aimed to analyse the treatment outcomes of moderately hypofractionated radiation therapy (RT) combined with androgen deprivation therapy (ADT) and the prognostic implications of prostate-specific antigen (PSA) kinetics in high-risk localized prostate cancer. METHODS: The medical records of 140 patients who underwent definitive RT (70 Gy in 28 fractions) combined with ADT were retrospectively reviewed. ADT consists of a gonadotropin-releasing hormone agonist and an anti-androgen. Clinical outcomes included the biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS) and prostate cancer-specific survival (PCSS). The BFR and CFR were stratified by the PSA nadir and the time to the PSA nadir, respectively. Acute and late genitourinary and gastrointestinal adverse events were also recorded. RESULTS: The 5-year BFR, CFR, OS and PCSS rates were 9.8%, 4.5%, 90.2% and 98.7%, respectively. Ninety-five (67.9%) patients achieved a PSA nadir of 0.01 ng/mL. Patients with a PSA nadir >0.01 ng/mL had a significantly higher BFR and CFR (BFR, P = 0.001; CFR, P = 0.027), even after adjusting for other prognostic factors [per 0.1 ng/mL; BFR, hazard ratio (HR) 4.440, P < 0.001; CFR, HR 4.338, P = 0.001]. However, the time to the PSA nadir and pre-RT PSA were not significantly associated with the BFR and CFR. Six patients (4.3%) reported grade 3 late adverse events, mostly haematuria and haematochezia. CONCLUSION: Definitive RT with moderate hypofractionation combined with long-term ADT showed good efficacy for high-risk localized prostate cancer. The lowest PSA nadir was significantly associated with a low recurrence rate, indicating the importance of PSA follow-up.

Clinical Outcomes in Adenoid Cystic Carcinoma of the Nasal Cavity and Paranasal Sinus: A Comparative Analysis of Treatment Modalities.

This study aimed to present the treatment patterns and outcomes for adenoid cystic carcinoma (ACC) arising in the nasal cavity and paranasal sinus. Sixty-one sinonasal ACC patients were retrospectively reviewed: 31 (50.8%) underwent surgery followed by postoperative radiation therapy (S+PORT), and 30 (49.2%) received definitive radiation therapy (D(C)RT). T4 disease was significantly more frequent in the D(C)RT group (25.8% vs. 80.0%, p < 0.001), where all T4b disease patients underwent D(C)RT. The 5-year local failure-free survival (LFFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival were 61.8% versus 37.8% (p = 0.003), 64.8% versus 38.1% (p = 0.036), 52.6% versus 19.3% (p = 0.010), and 93.2% versus 73.4% (p = 0.001) in the S+PORT and D(C)RT groups, respectively. The absolute differences in 5-year rates of LFFS, DMFS, and PFS between the two groups were smaller in the T3-4 subgroup. The univariate analysis showed that T4b disease, neurologic symptoms, longest diameter of tumor, radiological evidence of nerve involvement, and undergoing D(C)RT were associated with worse clinical outcomes, but the significance disappeared in the multivariate analysis, except for in the case of radiological evidence of nerve involvement. In conclusion, most patients with extensive disease underwent upfront D(C)RT and generally exhibited inferior clinical outcomes when compared to those with less extensive disease and who underwent S+PORT.

Analysis of the Effectiveness of Anterior Septal Reconstruction in Asians.

Background: Although anterior septal reconstruction (ASR) is effective, it is less commonly employed in Asian patients compared with the septal extension graft technique, even in cases of severe antero-caudal septal deviation. Objective: To compare airflow and patient perceptions after ASR in patients of Korean descent with caudal septal deviations and external nasal deformities, we considered the potential tendency of their septal cartilage to be smaller and less robust compared with that of Caucasians. The measurements were conducted using acoustic rhinometry and patient-reported outcomes. Methods: We analyzed 103 patients using preoperative and 3-month postoperative assessments: Korean version of the Standardized Cosmesis and Health Nasal Outcomes Survey (K-SCHNOS), obstructive (SCHNOS-O), and cosmetic (SCHNOS-C) scores, and minimal cross-sectional area (MCA) measured by acoustic rhinometry. Results: Among 103 patients (mean age 33.36 years, median age 32 years, age range 17-70 years, 77 men [75%], and 26 women [25%]), the average follow-up period for the patients was 264.6 days (median 202 days and range 13-1540 days), SCHNOS-O scores improved significantly from 64.02 ± 4.89 to 19.31 ± 4.45 after ASR (p < 0.001), as did SCHNOS-C scores, improving from 60.61 ± 7.71 to 14.25 ± 4.66 (p < 0.001). MCA increased from 0.30 ± 0.16 cm2 to 0.56 ± 0.38 cm2 (p < 0.001). Conclusions: As measured by MCA and SCHNOS scores at 3 months postoperatively, ASR proves valuable for correcting antero-caudal septal deviations and nasal deformities in Asians, despite the tendency of their septal cartilage to be smaller and less strong compared with that of Caucasians.

Discovery of a novel homoisoflavonoid derivative 5g for anti-osteoclastic bone loss via targeting FGFR1.

Several flavonoids have been shown to exert anti-osteoporosis activity. However, the structure-activity relationship and the mechanism of anti-osteoporosis activity of flavonoids remain unknown. In this study, we prepared a series of novel homoisoflavonoid (HIF) derivatives to evaluate their inhibitory effects on osteoclastogenesis using TRAP-activity in vitro assay. Then, the preliminary structure-activity relationship was studied. Among the evaluated novel flavonoids, derivative 5g exerted the most inhibitory bioactivity on primary osteoclast differentiation without interfering with osteogenesis. It was hence selected for further in vitro, in vivo and mechanism of action investigation. Results show that 5g likely directly binds to the fibroblast growth factor receptor 1 (FGFR1), decreasing the activation of ERK1/2 and IκBα/NF-κB signaling pathways, which in turn blocks osteoclastogenesis in vitro and osteoclastic bone loss in vivo. Our study shows that homoisoflavonoid (HIF) derivatives 5g can serve as a potential novel candidate for treating osteoporosis via inhibition of FGFR1.

A meta-analysis comparing efficacy and safety between proton beam therapy versus carbon ion radiotherapy.

BACKGROUND: This study aimed to compare the outcomes of proton beam therapy (PBT) and carbon ion radiotherapy (CIRT) by a systematic review and meta-analysis of the existing clinical evidence. METHODS: A systematic literature search was performed to identify studies comparing the clinical outcomes of PBT and CIRT. The included studies were required to report oncological outcomes (local control [LC], progression-free survival [PFS], or overall survival [OS]) or adverse events. RESULTS: Eighteen articles comprising 1857 patients (947 treated with PBT and 910 treated with CIRT) were included in the analysis. The pooled analysis conducted for the overall population yielded average hazard ratios of 0.690 (95% confidence interval (CI), 0.493-0.967, p = 0.031) for LC, 0.952 (95% CI, 0.604-1.500, p = 0.590) for PFS, and 1.183 (0.872-1.607, p = 0.281) for OS with reference to CIRT. The subgroup analyses included patients treated in the head and neck, areas other than the head and neck, and patients with chordomas and chondrosarcomas. These analyses revealed no significant differences in most outcomes, except for LC in the subgroup of patients treated in areas other than the head and neck. Adverse event rates were comparable in both groups, with an odds ratio (OR) of 1.097 (95% CI, 0.744-1.616, p = 0.641). Meta-regression analysis for possible heterogeneity did not demonstrate a significant association between treatment outcomes and the ratio of biologically effective doses between modalities. CONCLUSION: This study highlighted the comparability of PBT and CIRT in terms of oncological outcomes and adverse events.

Usefulness of Direct Peroral Cholangioscopy Using a Multibending Ultraslim Endoscope for the Management of Intrahepatic Bile Duct Lesions (with Videos).

Background/Aims: : Peroral cholangioscopy (POC) has been used to assess intrahepatic duct (IHD) lesions but with a limited role. A new multibending (MB) ultraslim endoscope has been designed to improve POC performance. We evaluated the usefulness of POC using the MB ultraslim endoscope for the management of IHD lesions. Methods: : Between March 2017 and March 2020, 22 patients underwent direct POC using the MB ultraslim endoscope for IHD lesions documented by previous imaging or cholangiopancreatography. The primary outcome was technical success of POC, and secondary outcomes were technical success of POC-guided interventions, median procedure time, and POC-related adverse events. Results: : The technical success rate for POC using the MB ultraslim endoscope for IHD lesions was 95.5% (21/22). Free-hand insertion was successful in 95.2% (20/21). The overall technical success rate for POC-guided intervention was 100% (21/21), including nine diagnostic and 12 therapeutic procedures (eight direct stone removal and four intraductal lithotripsies). The median procedure time was 29 minutes (range, 9 to 79 minutes). There were no procedure-related adverse events. Conclusions: : Direct POC using the MB ultraslim endoscope allows direct visualization of IHD lesions and may be useful for diagnosis and therapeutic management in selected patients.

Patients with diabetes in regions with population decline and likelihood of receiving diabetes management education and screenings for related complications in Korea.

OBJECTIVE: Many municipal districts in Korea face population decline owing to overall population decreases and aging. We investigated the association between geographic rurality and likelihood of receiving diabetes management education and diabetic retinopathy and diabetes-related kidney disease screenings among adults with diabetes. METHODS: Patient data were obtained from the 2021 Korea Community Health Survey (27,391 individuals; aged ≥19 years and physician-diagnosed with diabetes mellitus). Geographic rurality was categorized based on population decline as follows: with, at risk of, or without population decline. The association between geographic rurality and likelihood of receiving diabetes management education and diabetic retinopathy and diabetes-related kidney disease screenings was examined using multilevel logistic regression analyses. RESULTS: Among 27,391 patients with diabetes, 31.1% received diabetes education; 40.0% and 46.4% were screened for diabetic retinopathy and diabetes-related kidney disease, respectively. Individuals residing in regions with population decline were less likely to receive diabetes education (odds ratio [OR] 0.62, 95% CI 0.50-0.75) and diabetic retinopathy (OR 0.79, 95% CI 0.70-0.90) and diabetes-related kidney disease (OR 0.64, 95% CI 0.55-0.75) screenings, as compared with their counterparts. CONCLUSIONS: Our findings highlight the importance of increased monitoring and providing diabetes education and screenings for patients with diabetes living in rural areas.

Quantitative assessment of breast volume changes after whole-breast irradiation for breast cancer using breast auto-segmentation.

PURPOSE: This study aimed to quantitatively estimate the changes in breast volume associated with radiotherapy in patients undergoing breast-conserving surgery and whole-breast irradiation (WBI). METHODS: Pre-WBI simulation computed tomography (CT) scans and post-WBI follow-up chest CT scans from a total of 1,151 breast cancer patients were analyzed using a deep-learning-driven auto-segmentation approach. The CT-based asymmetry index (CTAI) was calculated by dividing the volume of the irradiated breast by the volume of the contralateral breast. Significant breast shrinkage was defined as a CTAI < 0.85. To quantify changes in CTAI over the follow-up period, the CTAI ratio was determined as the post-WBI CTAI divided by the pre-WBI CTAI. A multivariate logistic regression analysis was conducted to identify potential variables associated with post-WBI significant breast shrinkage. RESULTS: The median CTAI values for pre- and post-WBI CT scans were 0.973 (interquartile range: 0.887-1.069) and 0.866 (interquartile range: 0.773-0.967), respectively. The difference between them was statistically significant (p < 0.001). Following WBI, there was an increase in the rate of significant breast shrinkage from 16.3 to 44.8%. The CTAI ratio showed a negative association with the time interval (p < 0.001, Pearson r = - 0.310). In the multivariate logistic regression analysis, lower pre-WBI CTAI, younger age, and longer interval between CT scans were found to be significantly associated with a higher occurrence of post-WBI significant breast shrinkage. CONCLUSION: Breast volume decreases following WBI, and this decrease is correlated with an increased duration after WBI. These findings highlight the long-term consequences of WBI on breast asymmetry.

Implication of Pre- and Post-radiotherapy ctDNA Dynamics in Patients with Residual Triple-Negative Breast Cancer at Surgery after Neoadjuvant Chemotherapy: Findings from a Prospective Observational Study.

PURPOSE: This study aims to determine the association between pre- and postoperative radiotherapy (PORT) circulating tumor DNA (ctDNA) dynamics and oncological outcomes in patients with residual triple-negative breast cancer who underwent surgery after neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Between March 2019 and July 2020, 11 nonmetastatic patients with residual disease who underwent surgery after NAC were prospectively enrolled. In each patient, tumor specimens obtained during surgery and blood samples collected at three time points during PORT (T0: pre-PORT, T1: 3 weeks after PORT, T2: 1 month after PORT) were sequenced, targeting 38 cancer-related genes. Disease-free survival (DFS) was evaluated and the association between DFS and ctDNA dynamics was analyzed. RESULTS: At T0, ctDNA was detected in three (27.2%) patients. The ctDNA dynamics were as follows: two showed a decreasing ctDNA variant allele frequency (VAF) and reached zero VAF at T2, while one patient exhibited an increasing VAF during PORT and maintained an elevated VAF at T2. After a median follow-up of 48 months, two patients experienced distant metastasis without any locoregional failures. All failures occurred in patients with ctDNA positivity at T0 and a decreased VAF after PORT. The 4-year DFS rates according to the T0 ctDNA status were 67% (positive ctDNA) and 100% (negative ctDNA) (p=0.032). CONCLUSION: More than a quarter of the patients with residual disease after post-NAC surgery exhibited pre-PORT ctDNA positivity, and ctDNA positivity was associated with poor DFS. For patients with pre-PORT ctDNA positivity, the administration of a more effective systemic treatment should be considered.

Assessment of Bone Marrow Involvement in Extranodal NK/T-Cell Lymphoma: Positron Emission Tomography versus Bone Marrow Biopsy, and the Significance of Minimal Involvement by EBV+ Cells (KROG 18-09).

PURPOSE: This study aims to investigate the diagnostic significance of positron emission tomography/computed tomography (PET/CT) in assessing bone marrow (BM) involvement through a comparison of PET/CT findings with BM biopsy in extranodal natural killer/T-cell lymphoma. MATERIALS AND METHODS: The medical records of 193 patients were retrospectively reviewed. Patients were categorized as having early-stage (PET-ES) or advanced-stage (PET-AS) disease based on PET/CT results. The BM involvement was classified into three groups according to BM biopsy: gross BM involvement, minimal BM involvement (defined as the presence of a limited number of Epstein-Barr virus-positive cells in BM), and no involvement. Calculations of the accuracy of PET/CT in detecting BM involvement and analysis of the clinical outcomes (progression-free survival [PFS] and overall survival [OS]) according to the BM biopsy status were performed. RESULTS: PET/CT exhibited a sensitivity of 64.7% and a specificity of 96.0% in detecting gross BM involvement. For detecting any (both gross and minimal) BM involvement, the sensitivity was 30.4%, while the specificity was 99.0%. Only one patient (0.7%) demonstrated gross BM involvement among the PET-ES group. Survival outcomes of the PET-ES group with minimal BM involvement (3-year PFS, 55.6%; OS, 77.0%) were closer to those of the PET-ES group with no BM involvement (3-year PFS, 62.2%; OS, 80.6%) than to those of the PET-AS group (3-year PFS, 20.1%; OS, 29.9%). CONCLUSION: PET/CT exhibits high specificity, but moderate and low sensitivity in detecting gross and minimal BM involvement, respectively. The clinical significance of minimal BM involvement for patients in the PET-ES group may be limited.