Photodynamic diagnosis-assisted transurethral resection of bladder tumor for high-risk non-muscle invasive bladder cancer improves intravesical recurrence-free survival (BRIGHT study).

OBJECTIVES: In a primary analysis of data from the BRIGHT study (UMIN000035712), photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) using oral 5-aminolevulinic acid hydrochloride reduced residual tumors in high-risk non-muscle invasive bladder cancer (NMIBC). We aimed to evaluate the effectiveness of PDD-TURBT for intravesical recurrence after a second transurethral resection for high-risk NMIBC. METHODS: High-risk NMIBC patients initially treated with PDD-TURBT (PDD group) were prospectively registered between 2018 and 2020. High-risk patients with NMIBC who were initially treated with white-light TURBT (WL group) were retrospectively registered. Intravesical recurrence-free survival after the second transurethral resection was compared between the PDD and WL groups using propensity score matching analysis. RESULTS: In total, 177 patients were enrolled in the PDD group, and 306 patients were registered in the WL group. After propensity score matching (146 cases in each group), intravesical recurrence within 1 year was significantly less frequent in the PDD group than in the WL group (p = 0.004; hazard ratio [HR] 0.44, 95% confidence interval [CI]: 0.25-0.77). In subgroup analysis, PDD-TURBT showed a particularly high efficacy in reducing intravesical recurrence within 1 year, especially in cases of tumors measuring less than 3 cm (p = 0.003; HR 0.31, 95% CI: 0.14-0.67), absence of residual tumor at second transurethral resection (p = 0.020; HR 0.37, 95% CI: 0.16-0.86), and no postoperative intravesical Bacillus Calmette-Guérin therapy (p < 0.001; HR 0.27, 95% CI: 0.13-0.58). CONCLUSIONS: PDD-TURBT may reduce short-term intravesical recurrence in patients with high-risk NMIBC.

Development of an Artificial Intelligence Diagnostic System Using Linked Color Imaging for Barrett's Esophagus.

Background: Barrett's esophagus and esophageal adenocarcinoma cases are increasing as gastroesophageal reflux disease increases. Using artificial intelligence (AI) and linked color imaging (LCI), our aim was to establish a method of diagnosis for short-segment Barrett's esophagus (SSBE). Methods: We retrospectively selected 624 consecutive patients in total at our hospital, treated between May 2017 and March 2020, who experienced an esophagogastroduodenoscopy with white light imaging (WLI) and LCI. Images were randomly chosen as data for learning from WLI: 542 (SSBE+/- 348/194) of 696 (SSBE+/- 444/252); and LCI: 643 (SSBE+/- 446/197) of 805 (SSBE+/- 543/262). Using a Vision Transformer (Vit-B/16-384) to diagnose SSBE, we established two AI systems for WLI and LCI. Finally, 126 WLI (SSBE+/- 77/49) and 137 LCI (SSBE+/- 81/56) images were used for verification purposes. The accuracy of six endoscopists in making diagnoses was compared to that of AI. Results: Study participants were 68.2 ± 12.3 years, M/F 330/294, SSBE+/- 409/215. The accuracy/sensitivity/specificity (%) of AI were 84.1/89.6/75.5 for WLI and 90.5/90.1/91.1/for LCI, and those of experts and trainees were 88.6/88.7/88.4, 85.7/87.0/83.7 for WLI and 93.4/92.6/94.6, 84.7/88.1/79.8 for LCI, respectively. Conclusions: Using AI to diagnose SSBE was similar in accuracy to using a specialist. Our finding may aid the diagnosis of SSBE in the clinic.

Randomised controlled, patient-blinded, multicentre, superiority trial to evaluate the efficacy of the line-attached sheath-type traction device for endoscopic submucosal dissection in patients with superficial gastric neoplasms.

INTRODUCTION: EndoTrac is a line-attached sheath-type traction device that enables us to control the direction and the force of traction during endoscopic submucosal dissection (ESD). The efficacy of EndoTrac for gastric ESD has not been fully verified. METHODS AND ANALYSIS: The G-Trac study is a multicentre (nine general hospitals and two university hospitals in Japan) collaborative trial assessing the efficacy of EndoTrac for gastric ESDs. Patients with superficial gastric neoplasms will be enrolled and randomly assigned to undergo either conventional ESD or EndoTrac ESD. Allocation will be stratified according to tumour location, operator experience and tumour diameter at an allocation rate of 1:1. The type of endoknife used will be confirmed before randomisation. The primary outcome, procedure time, will be compared between the groups in both intention-to-treat and per-protocol analyses using the Wilcoxon rank sum test. The efficacy-related, safety-related and device-related outcomes will be assessed in the secondary analysis. The planned sample size of the 142 patients in the two groups will enable us to detect a difference with a power of 80% by using the Wilcoxon rank sum test, assuming an effect size of 0.54, asymptotic relative efficiency of 0.864 and a two-sided type 1 error rate of 5%. ETHICS AND DISSEMINATION: This trial was approved by the certified review board of Kobe University (22 December 2022). The results from this trial will be disseminated through peer-review journals, presentations at national and international conferences, and data sharing with other researchers. TRIAL REGISTRATION NUMBER: jRCT1052220166.

Objective Evaluation of Gaze Location Patterns Using Eye Tracking During Cystoscopy and Artificial Intelligence-Assisted Lesion Detection.

Background: The diagnostic accuracy of cystoscopy varies according to the knowledge and experience of the performing physician. In this study, we evaluated the difference in cystoscopic gaze location patterns between medical students and urologists and assessed the differences in their eye movements when simultaneously observing conventional cystoscopic images and images with lesions detected by artificial intelligence (AI). Methodology: Eye-tracking measurements were performed, and observation patterns of participants (24 medical students and 10 urologists) viewing images from routine cystoscopic videos were analyzed. The cystoscopic video was captured preoperatively in a case of initial-onset noninvasive bladder cancer with three low-lying papillary tumors in the posterior, anterior, and neck areas (urothelial carcinoma, high grade, and pTa). The viewpoint coordinates and stop times during observation were obtained using a noncontact type of gaze tracking and gaze measurement system for screen-based gaze tracking. In addition, observation patterns of medical students and urologists during parallel observation of conventional cystoscopic videos and AI-assisted lesion detection videos were compared. Results: Compared with medical students, urologists exhibited a significantly higher degree of stationary gaze entropy when viewing cystoscopic images (p < 0.05), suggesting that urologists with expertise in identifying lesions efficiently observed a broader range of bladder mucosal surfaces on the screen, presumably with the conscious intent of identifying pathologic changes. When the participants observed conventional and AI-assisted lesion detection images side by side, contrary to urologists, medical students showed a higher proportion of attention directed toward AI-detected lesion images. Conclusion: Eye-tracking measurements during cystoscopic image assessment revealed that experienced specialists efficiently observed a wide range of video screens during cystoscopy. In addition, this study revealed how lesion images detected by AI are viewed. Observation patterns of observers' gaze may have implications for assessing and improving proficiency and serving educational purposes. To the best of our knowledge, this is the first study to utilize eye tracking in cystoscopy. University of Tsukuba Hospital, clinical research reference number R02-122.

Patient characteristics correlate with diagnostic performance of photodynamic diagnostic assisted transurethral resection of bladder tumors: A retrospective, single-center study.

BACKGROUND: Identification of patient subclasses that correlate with the diagnostic performance of photodynamic diagnostic (PDD)-assisted transurethral resection of bladder tumors (TURBT) may improve outcomes. METHODS: Data were extracted from patients that underwent PDD-assisted TURBT at the University of Tsukuba Hospital between 2018 and 2023. Sensitivity and specificity were evaluated based on PDD findings (excluding WL findings) and pathology results. Cluster analysis using uniform manifold approximation and projection and k-means methods was performed, focusing on patients with malignant lesions. RESULTS: A total of 267 patients and 2082 specimens were extracted. Sensitivity was lowest with regard to BCG treatment (53.7 %), followed by flat lesions (57.2 %), urine cytology class ≥ III (62.9 %), and recurrent tumors (64.5 %). In the cluster analysis of 231 patients with malignant lesions, two showed lower sensitivity: Cluster 3 (62.4 %), consisting of patients with recurrent tumors and post-BCG treatment, and Cluster 4 (55.7 %), consisting of patients with primary tumors and urine cytology class ≥ III. Clusters 1 and 2, consisting of patients without BCG treatment and patients with lower urine cytology classes, exhibited higher sensitivities (94.4 % and 87.7 %). Among all clusters, Cluster 4 had the highest proportion of specimens which were negative for both PDD and white light (WL) findings but actually had malignant lesions (20.8 %). CONCLUSIONS: PDD-assisted TURBT sensitivity was lower in subclasses after BCG treatment or with cytology class III or higher. Random biopsy for PDD/WL double-negative lesions may improve diagnostic accuracy in these subclasses.

Risk Factors for Mucosal Redness in the Duodenal Bulb as Detected via Linked Color Imaging.

Linked color imaging (LCI) for image-enhanced endoscopy (IEE) highlights mucosal color differences. We investigated risk factors associated with mucosal redness of the duodenal bulb using LCI. Consecutive patients were retrospectively selected after their duodenal bulbs were observed via LCI. A symptom questionnaire (Izumo scale) was completed. The LCI of the duodenal bulb was subjectively evaluated on whether redness was present and objectively evaluated based on L* a* b* color values. The clinical characteristics of the 302 study participants were: male/female, 120/182; mean age, 70.9 years. Twenty-one cases (7.0%) were in the redness (+) group. After multiple regression analysis, independent predictors for the red component (a*) of the duodenal bulb using LCI were: age (ß = -0.154, p < 0.01), female (ß = -0.129, p < 0.05), body mass index (BMI; ß = -0.136, p < 0.05), Helicobacter pylori eradication (ß = 0.137, p < 0.05), endoscopic gastric mucosal atrophy score (EGAS; ß = -0.149, p < 0.05), and constipation-related quality of life (QOL) (ß = -0.122, p < 0.05) scores. Lower age, lower BMI, lower EGAS, a constipation-related QOL score, post-H. pylori eradication, and being male were associated with mucosal redness in the duodenal bulb with IEE using LCI.

Pulsed Field Ablation Index-Guided Ablation for Lesion Formation: Impact of Contact Force and Number of Applications in the Ventricular Model.

BACKGROUND: The effect of contact force (CF) on lesion formation is not clear during pulsed field ablation (PFA). The aim of this study was to evaluate the impact of CF, PFA, and their interplay through the PFA index (PF index) formula on the ventricular lesion size in swine. METHODS: PFA was delivered through the CF-sensing OMNYPULSE catheter. Predefined PFA applications (×3, ×6, ×9, and ×12) were delivered maintaining low (5-25 g), high (26-50 g), and very high (51-80 g) CFs. First, PFA lesions were evaluated on necropsy in 11 swine to investigate the impact of CF/PFA-and their integration in the PF index equation-on lesion size (study characterization). Then, 3 different PF index thresholds-300, 450, and 600-were tested in 6 swine to appraise the PF index accuracy to predict the ventricular lesion depth (study validation). RESULTS: In the study characterization data set, 111 PFA lesions were analyzed. CF was 32±17 g. The average lesion depth and width were 3.5±1.2 and 12.0±3.5 mm, respectively. More than CF and PFA dose alone, it was their combined effect to impact lesion depth through an asymptotically increasing relationship. Likewise, not only was the PF index related to lesion depth in the study validation data set (r2=0.66; P<0.001) but it also provided a prediction accuracy of the observed depth of ±2 mm in 69/73 lesions (95%). CONCLUSIONS: CF and PFA applications play a key role in lesion formation during PFA. Further studies are required to evaluate the best PFA ablation settings to achieve transmural lesions.

Usefulness of tissue Doppler-derived left ventricular isovolumic contraction velocity in patients with heart failure with preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a group of diseases classified by left ventricular (LV) EF, a measure of pump function. However, LVEF does not reflect LV contractility. Previous studies have shown that tissue Doppler-derived LV isovolumic contraction velocity (IVCv) correlates well with the LV peak dP/dt, an index of LV contractility. We explored whether LV IVCv is associated with 1-year post-discharge outcomes in HFpEF. METHODS: We enrolled 113 patients (median age, 86 years, 45 male) with HFpEF (EF on admission ≥ 50%) who were admitted to our hospital for the treatment of acute HF. Clinical characteristics including echocardiographic data were obtained before discharge. IVCv was obtained from the tissue Doppler waveforms of both the septal and lateral mitral annulus of the apical 4-chamber view and averaged data were used. Primary outcomes were all-cause death or unplanned hospitalization due to HF within the first year. RESULTS: Among all patients, median LVEF was 61%, left atrial diameter was 47 mm, E/e' was 17.5, and IVCv was 4.5 cm/sec; mean tricuspid regurgitation velocity was 2.6 m/sec. Regarding laboratory data, the median plasma B-type natriuretic peptide level was 185 pg/mL. Thirty-four events occurred (15 deaths, 19 unplanned hospitalizations due to HF) within the first year. In multivariate Cox proportional hazards analyses, IVCv was significantly associated with outcomes (hazard ratio .68, 95% confidence interval .50-.89, p = .0095), independent of general characteristics, echocardiographic measures and pertinent laboratory parameters. CONCLUSION: LV IVCv was independently associated with 1-year outcomes in patients with HFpEF.

Instantaneous normal modes of glass-forming liquids during the athermal relaxation process of the steepest descent algorithm.

Understanding glass formation by quenching remains a challenge in soft condensed matter physics. Recent numerical studies on steepest descent dynamics, which is one of the simplest models of quenching, revealed that quenched liquids undergo slow relaxation with a power law towards mechanical equilibrium and that the late stage of this process is governed by local rearrangements of particles. These advances motivate the detailed study of instantaneous normal modes during the relaxation process because the glassy dynamics is considered to be governed by stationary points of the potential energy landscape. Here, we performed a normal mode analysis of configurations during the steepest descent dynamics and found that the dynamics is driven by almost flat directions of the potential energy landscape at long times. These directions correspond to localized modes and we characterized them in terms of their statistics and structure using methods developed in the study of local minima of the potential energy landscape.

A Tricyclic Aromatic Polyketide Isolated from the Marine-Derived Fungus Curvularia aeria.

A novel tricyclic polyketide, curvulanone (1), was isolated from the marine-derived fungus Curvularia aeria. The structure of 1 was determined by NMR and single-crystal X-ray crystallography. 1 had a cyclopentabenzopyranone with 3-acetic acid structure that is rarely found in natural compounds. Monoamine oxidase and sirtuin 1 inhibitory test was exhibited and 1 showed their inhibitory activity.

Delivery of external proteins into the cytoplasm using protein capsules modified with IgG on the surface, created from the amphiphilic two helix-bundle protein OLE-ZIP.

This study explores a new method for delivering therapeutic proteins into specific cells using OLE-ZIP capsules that present IgG. OLE-ZIP capsules is a spherical caspules prepared from amphihilic dimetic coiled-coil peptide, OLE-ZIP. Upon presenting cetuximab, these capsules showed preferential uptake in A431 cells and increased cytotoxicity when loaded with RNase A.

The prognostic impact of treatment centralization in patients with testicular germ cell tumors: analysis of hospital-based cancer registry data in Japan.

BACKGROUND: To identify the prognostic impact of treatment centralization in patients with testicular germ cell tumors (TGCT). METHODS: We used a hospital-based cancer registry data in Japan to extract seminoma and non-seminoma cases that were diagnosed in 2013, histologically confirmed, and received the first course of treatment. To compare the 5-years overall survival (OS) rates of patients stratified by institutional care volume, we performed a Cox proportional hazards regression analysis using inverse probability of treatment weighting (IPTW) method to adjust patient backgrounds. RESULTS: A total of 1767 TGCT patients were identified. The 5-years OS rates for stage II and III TGCT patients treated at low-volume institutions (< 7 cases) were significantly worse than high-volume institutions (≥ 7 cases) (91.2% vs. 83.4%, p = 0.012). Histological stratification revealed that 5-year OS rates for stage II and III seminoma patients in the low-volume group were significantly worse than the high-volume group (93.5% vs. 84.5%, p = 0.041). Multivariate OS analysis using an IPTW-matched cohort showed that institutional care volume was an independent prognostic factor (hazard ratio 2.13 [95% confidence interval: 1.23-3.71], p = 0.0072). CONCLUSION: Our results indicate that stage II and III TGCT patients experience lower survival rates at low-volume institutions and would benefit from treatment centralization.

Outcomes of endoscopic submucosal dissection for esophageal cancer with segmental absence of intestinal musculature.

BACKGROUND AND AIMS: Perforation during esophageal endoscopic submucosal dissection (ESD) typically results from electrical damage. However, there are cases in which perforation occurs because of segmental absence of intestinal musculature (SAIM) without iatrogenic muscular injury. We investigated the occurrence rate and clinical course of SAIM during esophageal ESD. METHODS: We conducted a retrospective review of esophageal ESDs performed between 2013 and 2019 at 10 centers in Japan. RESULTS: Five of 1708 (0.29%) patients received ESD for esophageal cancer and had SAIM. The median muscular defect size was 20 mm. All lesions were resected without discontinuation. After resection, 3 patients were closed with Endoloop. Four patients had mediastinal emphysema. All patients were managed conservatively. CONCLUSIONS: SAIM is a very rare condition that is usually only diagnosed during ESD. Physicians performing esophageal ESD should be aware of SAIM. When SAIM is detected, the ESD technique should be modified to prevent full-thickness perforation.

Effects of Contact Force on Lesion Size During Pulsed Field Catheter Ablation: Histochemical Characterization of Ventricular Lesion Boundaries.

BACKGROUND: Effects of contact force (CF) on lesion formation during pulsed field ablation (PFA) have not been well validated. The purpose of this study was to determine the relationship between average CF and lesion size during PFA using a swine-beating heart model. METHODS: A 7F catheter with a 3.5-mm ablation electrode and CF sensor (TactiCath SE, Abbott) was connected to a PFA system (CENTAURI, Galvanize Therapeutics). In 5 closed-chest swine, biphasic PFA current was delivered between the ablation electrode and a skin patch at 40 separate sites in right ventricle (28 Amp) and 55 separate sites in left ventricle (35 Amp) with 4 different levels of CF: (1) low (CF range of 4-13 g; median, 9.5 g); (2) moderate (15-30 g; median, 21.5 g); (3) high (34-55 g; median, 40 g); and (4) no electrode contact, 2 mm away from the endocardium. Swine were sacrificed at 2 hours after ablation, and lesion size was measured using triphenyl tetrazolium chloride staining. In 1 additional swine, COX (cytochrome c oxidase) staining was performed to examine mitochondrial activity to delineate reversible and irreversible lesion boundaries. Histological examination was performed with hematoxylin and eosin and Masson trichrome staining. RESULTS: Ablation lesions were well demarcated with triphenyl tetrazolium chloride staining, showing (1) a dark central zone (contraction band necrosis and hemorrhage); (2) a pale zone (no mitochondrial activity and nuclear pyknosis, indicating apoptosis zone); and a hyperstained zone by triphenyl tetrazolium chloride and COX staining (unaffected normal myocardium with preserved mitochondrial activity, consistent with reversible zone). At constant PFA current intensity, lesion depth increased significantly with increasing CF. There were no detectable lesions resulting from ablation without electrode contact. CONCLUSIONS: Acute PFA ventricular lesions show irreversible and reversible lesion boundaries by triphenyl tetrazolium chloride staining. Electrode-tissue contact is required for effective lesion formation during PFA. At the same PFA dose, lesion depth increases significantly with increasing CF.

Cleft Lip With Ankyloblepharon Filiforme Adnatum: A Case Report.

Ankyloblepharon filiforme adnatum (AFA) is a rare, benign congenital anomaly. Notably, it is characterized by the adhesion of the ciliary edges of the upper and lower eyelids at the trabecular line. AFA is usually a solitary malformation of sporadic occurrence; however, it can occur in conjunction with other congenital diseases. Herein, we report a case of cleft lip with AFA. A patient was referred to the ophthalmology department of our hospital. The ophthalmic diagnosis was AFA in both the eyes. The left eye was observed to have a fibrous adhesion in the center, and she underwent surgery to excise the fibrous adhesion of tissue with scissors. The right eye was observed to have a fibrous adhesion in the external canthus and was excised during lip plasty. After surgery, her eyes were able to fully open, and no other apparent disease was diagnosed. AFA is thought to be caused by an ectodermal-derived developmental abnormality. Notably, cases of AFA with a cleft lip are rare. Diagnosis and surgery should be performed promptly to minimize any risk of amblyopia and for the early detection of congenital diseases, including glaucoma.

Safety and stable survival of stem-cell-derived retinal organoid for 2 years in patients with retinitis pigmentosa.

Transplantation of induced pluripotent stem cell (iPSC)-derived retinal organoids into retinal disease animal models has yielded promising results, and several clinical trials on iPSC-derived retinal pigment epithelial cell transplantation have confirmed its safety. In this study, we performed allogeneic iPSC-derived retinal organoid sheet transplantation in two subjects with advanced retinitis pigmentosa (jRCTa050200027). The primary endpoint was the survival and safety of the transplanted retinal organoid sheets in the first year post-transplantation. The secondary endpoints were the safety of the transplantation procedure and visual function evaluation. The grafts survived in a stable condition for 2 years, and the retinal thickness increased at the transplant site without serious adverse events in both subjects. Changes in visual function were less progressive than those of the untreated eye during the follow-up. Allogeneic iPSC-derived retinal organoid sheet transplantation is a potential therapeutic approach, and the treatment's safety and efficacy for visual function should be investigated further.

Water Solubilization and Guest Molecule-Induced Fluorescence Changes of Porous Host Molecules via Complexing with Polysaccharide or Polypeptide.

To detect small aromatic molecules in water, we prepared functional host molecules based on water-soluble N,N'-bis(2-aminobenzophenone)-1,4,5,8-naphthalenetetracarboxylic diimide (1) and a solubilizing agent using a high-speed vibration milling apparatus. The fluorescence response of host 1-solubilizing agent complexes before and after extraction of small aromatic guest molecules was large and the fluorescence maxima were dependent on the small aromatic guest molecules.

Complete Response to Cetuximab Plus Paclitaxel Therapy in Nivolumab-Refractory Patients in Distant Metastasis of Squamous Cell Carcinoma of the Tongue: A Report of Two Cases.

Herein, we report two cases of patients diagnosed with nivolumab-refractory distant metastatic squamous cell carcinoma of the tongue who were successfully treated with a combination of paclitaxel and cetuximab. Case 1 had controllable local recurrence and distant metastasis. Case 2 had controllable distant metastatic disease. Thus, demonstrating that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy.

Successful treatment with nivolumab in a patient with unresectable oral squamous cell carcinoma following ineffective chemoradiotherapy.

Key clinical message: Nivolumab has been clinically successful in prolonging the overall survival of patients with recurrent and metastatic head and neck cancer, complete remission is rare. Synergistic combinations of immunotherapy and conventional cancer treatments, such as radiotherapy or chemotherapy, are likely to be the most viable strategies for improving patient responses. Abstract: Immune checkpoint inhibitors have revolutionized recurrent, metastatic oral cancer treatment; however complete remission in advanced stages is unusual. We present a case of complete remission of advanced oral squamous cell carcinoma for >4 years in a 64-year-old Japanese woman, that responded poorly to chemoradiotherapy but well to subsequent nivolumab treatment.

Novel Iron Chelators, Super-Polyphenols, Show Antimicrobial Effects against Cariogenic Streptococcus mutans.

Dental caries are an oral infectious disease that can affect human health both orally and systemically. It remains an urgent issue to establish a novel antibacterial method to prevent oral infection for a healthy life expectancy. The aim of this study was to evaluate the inhibitory effects of novel iron chelators, super-polyphenols (SPs), on the cariogenic bacterium Streptococcus mutans, in vitro. SPs were developed to reduce the side effects of iron chelation therapy and were either water-soluble or insoluble depending on their isoforms. We found that SP6 and SP10 inhibited bacterial growth equivalent to povidone-iodine, and viability tests indicated that their effects were bacteriostatic. These results suggest that SP6 and SP10 have the potential to control oral bacterial infections such as Streptococcus mutans.