Spontaneous differentiation of human induced pluripotent stem cells to odorant-responsive olfactory sensory neurons.

Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells (iPSCs), can differentiate into almost all cell types and are anticipated to have significant applications in the field of regenerative medicine. However, there are no reports of successfully directing iPSCs to become functional olfactory sensory neurons (OSNs) capable of selectively receiving odorant compounds. In this study, we employed dual SMAD inhibition and fibroblast growth factor 8 (FGF-8, reported to dictate olfactory fates) along with N-2 and B-27 supplements in the culture medium to efficiently induce the differentiation of iPSCs into neuronal cells with olfactory function through olfactory placode. Temporal gene expression and expression of OSN-specific markers during differentiation indicated that the expression of olfactory marker proteins and various olfactory receptors (ORs), which are markers of mature OSNs, was observed after approximately one month of differentiation culture, irrespective of the differentiation cues, suggesting differentiation into OSNs. Cells that exhibited specific responses to odorant compounds were identified after administering odorant compounds to differentiated iPSC-derived OSNs. This suggests the spontaneous generation of functional OSNs expressing diverse ORs that respond to odorant compounds from iPSCs.

Protecting-Group-Free Synthesis of ADP-Ribose and Dinucleoside Di-/Triphosphate Derivatives via P(V)-P(V) Coupling Reaction.

Biomolecules containing adenosine di- or triphosphate (ADP or ATP) are crucial for diverse biological processes. Synthesis of these biomolecules and development of their chemical probes are important to elucidate their functions. Enabling reproducible and high-yielding access to these ADP- and ATP-containing molecules via conventional P(III)-P(V) and P(V)-P(V) coupling reactions is challenging owing to water content in highly polar phosphate-containing substrates. Herein, we report an efficient and reliable method for protecting-group-free P(V)-P(V) coupling reaction through in situ activation of phosphates using hydrolysis-stable 2-[N-(2-methylimidazoyl)]-1,3-dimethylimidazolinium chloride (2-MeImIm-Cl), providing the corresponding electrophilic P(V) intermediates for subsequent nucleophilic attack using their coupling partners. This P(V)-P(V) coupling reaction proceeded even in a wet reaction medium and showed a broad substrate scope, accommodating protecting-group-free synthesis of ADP-ribose and nicotinamide adenine diphosphate analogs, ATP-containing biomolecules, and ADP-ribosyl peptides.

Analysis of anti-tumor effect and mechanism of GLS1 inhibitor CB-839 in colorectal cancer using a stroma-abundant tumor model.

BACKGROUND: Glutaminase 1 (GLS1), a key enzyme in glutamine metabolism in cancer cells, acts as a tumor promoter and could be a potential therapeutic target. CB-839, a GLS1-specific inhibitor, was developed recently. Herein, we aimed to elucidate the anti-tumor effects and mechanism of action of CB-839 in colorectal cancer (CRC). METHODS: Using the UCSC Xena public database, we evaluated GLS1 expression in various cancers. Immunostaining for GLS1 was performed on 154 surgically resected human CRC specimens. Subsequently, we examined the GLS1 mRNA expression levels in eight CRC cell lines and evaluated the association between GLS1 expression and CB-839 efficacy. To create a reproducible CRC model with abundant stroma and an allogeneic immune response, we co-transplanted CT26 and stem cells into BALB/c mice and treated them with CB-839. Finally, RNA sequencing of mouse tumors was performed. RESULTS: Database analysis showed higher GLS1 expression in CRC tissues than in normal colon tissues. Clinical samples from 114 of the 154 patients with CRC showed positive GLS1 expression. GLS1 expression in clinical CRC tissues correlated with vascular invasion. CB-839 treatment inhibited cancer cell proliferation depending on GLS1 expression in vitro and inhibited tumor growth and metastasis in the CRC mouse model. RNA sequencing revealed that CB-839 treatment inhibited stromal activation, tumor growth, migration, and angiogenesis. These findings were validated through in vitro and in vivo experiments and clinical specimen analysis. CONCLUSIONS: GLS1 expression in CRC plays important roles in tumor progression. CB-839 has inhibitory effects on cancer proliferation and the tumor microenvironment.

Predictive factors for esophageal stenosis in patients receiving prophylactic steroid therapy after endoscopic submucosal dissection for esophageal squamous cell carcinoma.

BACKGROUND: Methods to prevent esophageal stenosis (ES) after endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) have received increasing attention. Although steroid administration is a prophylactic treatment, the risk factors for ES during prophylactic steroid therapy remain unknown. Therefore, this study aimed to retrospectively evaluate the risk factors for refractory ES in patients administered prophylactic steroids after ESD for ESCC. METHODS: Among 795 patients with ESCC (854 lesions), 180 patients (211 lesions) administered local triamcinolone acetonide (TrA) and/or oral prednisolone were recruited for this study. We compared the total number of endoscopic balloon dilatation (EBD) procedures performed for post-ESD ES and clinical findings (tumor size, ESD history or chemoradiation therapy [CRT], entire circumferential resection, muscle layer damage, supplemental oral prednisolone administration, EBD with TrA injection, and additional CRT) between patients with refractory and non-refractory ES. EBD was continued until dysphagia resolved. We categorized cases requiring ≥ 8 EBD procedures as refractory postoperative stenosis and divided the lesions into two groups. RESULTS: Multivariate logistic regression analysis revealed that factors such as ESD history, CRT history, tumor size, and entire circumferential resection were independently associated with the development of refractory ES. The withdrawal rates of EBD at 3 years were 96.1% (52/53) and 58.5% (39/59) in the non-refractory and refractory groups, respectively. CONCLUSIONS: Our data suggest that entire circumferential resection and CRT history are risk factors for refractory post-ESD ES in ESCC, even with prophylactic steroid administration.

Long-term prognosis after endoscopic submucosal dissection for esophageal cancer in older adult patients.

BACKGROUND: The validity of endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) in older individuals with comorbidities remains unclear. Therefore, this study evaluated the safety and efficacy of ESD and additional treatment for ESCC in older adult patients. METHODS: The clinicopathological characteristics and clinical outcomes of 398 consecutive older adult patients (≥ 65 years) with 505 lesions who underwent ESD for ESCC at the Hiroshima University Hospital between September 2007 and December 2019 were retrospectively evaluated. Additionally, the prognoses of 381 patients who were followed up for > 3 years were assessed. RESULTS: The mean patient age and procedure time were 73.1 ± 5.8 years and 77.1 ± 43.5 min, respectively. The histological en bloc resection rate was 98% (496/505). Postoperative stenosis, perforation, pneumonia, and delayed bleeding were conservatively treated in 82 (16%), 19 (4%), 15 (3%), and 5 (1%) patients, respectively. The 5-year overall and disease-specific survival rates were 78.9% and 98.0%, respectively (mean follow-up time: 71.1 ± 37.3 months). Multivariate analysis showed that age and the American Society of Anesthesiologists classification of physical status class ≥III (hazard ratio: 1.27; 95% confidence interval: 1.01-1.59, p = 0.0392) were independently associated with overall survival. A significantly lower overall survival rate was observed in the high-risk follow-up group than in the low-risk follow-up and high-risk additional treatment groups (p < 0.01). However, no significant difference in disease-specific survival was observed among the three groups. CONCLUSIONS: ESD is safe for ESCC treatment in patients aged ≥ 65 years. However, additional treatments should be considered based on the patient's general condition.

Long-term outcomes of patients with obscure gastrointestinal bleeding after negative capsule endoscopy.

BACKGROUND AND AIM: Although small-bowel capsule endoscopy (CE) is widely used for obscure gastrointestinal bleeding (OGIB), long-term outcomes for OGIB patients after negative CE remain unclear. Herein, we defined negative CE as P0 (no bleeding potential) or P1 (less likely to bleed), based on the P classification using CE. We aimed to clarify long-term outcomes of patients with OGIB after negative CE. METHODS: This single-center observational study enrolled 461 consecutive patients with OGIB who underwent CE from March 2014 to October 2021 and were followed up for >1 year. We examined rebleeding rates and predictive factors. RESULTS: Two hundred and twenty-four (49%) patients had P0, and 237 (51%) had P1 findings. Rebleeding occurred in 9% and 16% of patients in the P0 and P1 groups, respectively. Two patients in the P0 group and 15 in the P1 group showed rebleeding from the small bowel. The rate of small-bowel rebleeding was significantly lower in the P0 group than that in the P1 group (1% vs 6%, P = 0.002), as was the cumulative rebleeding rate (P = 0.004). In the multivariate analysis, history of endoscopic hemostasis (hazard ratio [HR] = 15.958, 95% confidence interval [CI]:4.950-51.447, P < 0.001) and P1 CE findings (HR = 9.989, 95% CI: 2.077-48.030, P = 0.004) were independently predicted small-bowel rebleeding. CONCLUSIONS: OGIB with P0 CE findings rarely showed rebleeding from the small bowel. Rebleeding may occur in patients with OGIB. Patients with history of endoscopic hemostasis for small-bowel lesions or P1 CE findings should be followed up intensively.

Usefulness and Educational Benefit of a Virtual Scale Endoscope in Measuring Colorectal Polyp Size.

INTRODUCTION: The virtual scale endoscope (VSE) is a newly introduced endoscope that helps endoscopists in measuring colorectal polyp size (CPS) during colonoscopy by displaying a virtual scale. This study aimed to determine the usefulness of the VSE for CPS measurement and the educational benefit of using VSE images to improve CPS estimation accuracy. METHODS: This study included 42 colorectal polyps in 26 patients treated at Hiroshima University Hospital. In study 1, CPS measured using a VSE before endoscopic mucosal resection was compared with CPS measured on resected specimens, and the agreement between the two measurement methods was evaluated via Bland-Altman analysis. In study 2, 14 endoscopists (5 beginners, 5 intermediates, and 4 experts) took a pre-test to determine the size of 42 polyps. After the pre-test, a lecture on CPS measurement using VSE images was given. One month later, the endoscopists took a post-test to compare CPS accuracy before and after the lecture. RESULTS: In study 1, Bland-Altman analysis revealed no fixed or proportional errors. The mean bias ±95% limits of agreement (±1.96 standard deviations) of the measurement error was -0.05 ± 0.21 mm, indicating that the agreement between two measurement methods was sufficient. In study 2, the accuracy of CPS measurement was significantly higher among beginners (59.5% vs. 26.7%, p < 0.01) and intermediates (65.2% vs. 44.3%, p < 0.05) in the post-test than in the pre-test. CONCLUSION: The VSE accurately measures CPS before resection, and its images are useful teaching tools for beginner and intermediate endoscopists.

Characteristics and Prognosis of Sporadic Neoplasias Detected in Patients with Ulcerative Colitis.

INTRODUCTION: Patients with ulcerative colitis (UC) develop not only UC-associated neoplasias but also sporadic neoplasias (SNs). However, few studies have described the characteristics of SNs in patients with UC. Therefore, this study aimed to evaluate the clinical features and prognosis of SNs in patients with UC. METHODS: A total of 141 SNs in 59 patients with UC, detected by surveillance colonoscopy at Hiroshima University Hospital between January 1999 and December 2021, were included. SNs were diagnosed based on their location, endoscopic features, and histopathologic findings along with immunohistochemical staining for Ki67 and p53. RESULTS: Of the SNs, 91.5% were diagnosed as adenoma and 8.5% were diagnosed as carcinoma (Tis carcinoma, 3.5%; T1 carcinoma, 5.0%). 61.0% of the SNs were located in the right colon, 31.2% were located in the left colon, and 7.8% were located in the rectum. When classified based on the site of the lesion, 70.9% of SNs occurred outside and 29.1% within the affected area. Of all SNs included, 95.7% were endoscopically resected and 4.3% were surgically resected. Among the 59 patients included, synchronous SNs occurred in 23.7% and metachronous multiple SNs occurred in 40.7% during surveillance. The 5-year cumulative incidence of metachronous multiple SNs was higher in patients with synchronous multiple SNs (54.2%) than in those without synchronous multiple SNs (46.4%). CONCLUSION: Patients with UC with synchronous multiple SNs are at a higher risk of developing metachronous multiple SNs and may require a closer follow-up by total colonoscopy than patients without synchronous SNs.

Current Status of Diagnosis and Treatment of Colorectal Cancer in Asian Countries: A Questionnaire Survey.

INTRODUCTION: Diagnostic and therapeutic methods for colorectal cancer (CRC) have advanced; however, they may be inaccessible worldwide, and their widespread use is challenging. This questionnaire survey investigates the current status of diagnosis and treatment of early-stage CRC in Asian countries. METHODS: Responses to the questionnaire were obtained from 213 doctors at different institutions in 8 countries and regions. The questionnaire consisted of 39 questions on the following four topics: noninvasive diagnosis other than endoscopy (6 questions), diagnosis by magnification and image-enhanced endoscopy (IEE) including artificial intelligence (AI) (10 questions), endoscopic submucosal dissection (ESD), proper use among other therapeutic methods (11 questions), and pathologic diagnosis and surveillance (12 questions). RESULTS: Although 101 of 213 respondents were affiliated with academic hospitals, there were disparities among countries and regions in the dissemination of advanced technologies, such as IEE, AI, and ESD. The NICE classification is widely used for the diagnosis of colorectal tumors using IEE, while the JNET classification with magnification was used in countries such as Japan (65/70, 92.9%) and China (16/22, 72.7%). Of the 211 respondents, 208 (98.6%) assumed that en bloc resection should be achieved for carcinomas, and 180 of 212 (84.9%) believed that ESD was the most suitable in cases with a diameter larger than 2 cm. However, colorectal ESD is not widespread in countries such as Thailand, the Philippines, and Indonesia. CONCLUSION: The promotion of advanced technologies and education should be continual to enable more people to benefit from them.

Hybrid endoscopic submucosal dissection as a salvage option for difficult colorectal conventional endoscopic submucosal dissection.

BACKGROUND: When total submucosal dissection is difficult to achieve during conventional colorectal endoscopic submucosal dissection (C-ESD), the lesion can be resected by final snaring through salvage hybrid ESD (SH-ESD). This study aimed to examine the outcomes of SH-ESD and identify its indications that could achieve en bloc resection. METHODS: We recruited 1039 consecutive patients with colorectal lesions that underwent ESD at Hiroshima University Hospital between January 2015 and December 2020. C-ESD was attempted thoroughly in 924 lesions (C-ESD group, including 9 lesions in which ESD was discontinued), and SH-ESD was performed owing to some difficulties in 115 lesions (SH-ESD group). Risk factors for incomplete resection by SH-ESD and ESD discontinuation were evaluated using multivariate analysis. The outcomes were compared between cases with remaining undissected submucosa of < 20 mm in diameter in the SH-ESD and C-ESD groups, using propensity score matching. RESULTS: Multivariate analysis revealed that a procedure time > 80 min and remaining undissected submucosa ≥ 20 mm in diameter were significant risk factors for incomplete resection after SH-ESD and ESD discontinuation. By propensity score matching analysis, procedure time was significantly shorter in the SH-ESD group with remaining undissected submucosa < 20 mm in diameter than in the C-ESD group (71 min vs. 90 min, p = 0.0053), although no significant difference was found in the en bloc resection rate (94% vs. 87%, p = 0.0914). CONCLUSION: SH-ESD can be an alternative surgical method when conventional ESD is difficult to continue in cases in which the remaining undissected submucosa is < 20 mm in diameter.

Comparison of the specimen quality of endobronchial ultrasound-guided intranodal forceps biopsy using standard-sized forceps versus mini forceps for lung cancer: A prospective study.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic procedure with adequate performance; however, its ability to provide specimens of sufficient quality and quantity for treatment decision-making in advanced-stage lung cancer may be limited, primarily due to blood contamination. The use of a 0.96-mm miniforceps biopsy (MFB) permits true histological sampling, but the resulting small specimens are unsuitable for the intended applications. Therefore, we introduced a 1.9-mm standard-sized forceps biopsy (SFB) and compared its utility to that of MFB. METHODS: We prospectively enrolled patients from three institutions who presented with hilar/mediastinal lymphadenopathy and suspected advanced-stage lung cancer, or those who were already diagnosed but required additional tissue specimens for biomarker analysis. Each patient underwent MFB followed by SFB three or four times through the tract created by TBNA using a 22-gauge needle on the same lymph node (LN). Two pathologists assessed the quality and size of each specimen using a virtual slide system, and diagnostic performance was compared between the MFB and SFB groups. RESULTS: Among the 60 enrolled patients, 70.0% were diagnosed with adenocarcinoma. The most frequently targeted sites were the lower paratracheal LNs, followed by the interlobar LNs. The diagnostic yields of TBNA, MFB and SFB were 91.7%, 93.3% and 96.7%, respectively. The sampling rate of high-quality specimens was significantly higher in the SFB group. Moreover, the mean specimen size for SFB was three times larger than for MFB. CONCLUSION: SFB is useful for obtaining sufficient qualitative and quantitative specimens.

CRISPR/Cas9-mediated knockout of NYC1 gene enhances chlorophyll retention and reduces tillering in Zoysia matrella (L.) Merrill.

KEY MESSAGE: Genome editing by CRISPR/Cas9 can be applied to Z. matrella 'Wakaba', and knockout mutants of ZmNYC1 gene exhibited stay-green phenotype and reduced tillering. Zoysia matrella is a widely used C4 warm-season turfgrass for landscaping, golf courses, and sports fields. Here, we used the CRISPR/Cas9 system to target the Non-Yellow Coloring1 (ZmNYC1) gene in the highly heterozygous allotetraploid Z. matrella 'Wakaba', aiming to generate a novel stay-green variety. Of 441 Agrobacterium-infected calli, 22 (5.0%) were transformed, and 14 of these (63.6%) showed targeted mutations through cleaved amplified polymorphic sequences analysis. Sequencing analysis revealed mutations mostly consisting of 1 or 2 bp indels, occurring 2 to 4 bp upstream of the PAM sequence. Regenerated plants exhibited five ZmNYC1 target locus genotypes, including homozygous mutants with a complete knockout of all four alleles in the T0 generation. Under dark treatment, ZmNYC1-mutated plants displayed suppressed chlorophyll b (Chl b) degradation, leading to higher chlorophyll content and Chl b, with a lower chlorophyll a/chlorophyll b ratio compared to the wild type (WT). However, the ZmNYC1 mutation also inhibited plant growth in homozygous mutant genotypes, exhibiting reduced tillering compared to WT. Additionally, during winter simulation, mutant with a complete knockout retained greenness longer than the WT. This is the first successful use of CRISPR/Cas9 genome editing in zoysiagrass. The mutants of the ZmNYC1 gene would serve as valuable breeding material for developing improved zoysiagrass varieties that can maintain their green color for longer periods, even during winter dormancy.

An integrative epigenomic approach identifies ELF3 as an oncogenic regulator in ASCL1-positive neuroendocrine carcinoma.

Neuroendocrine carcinoma (NEC) is a highly aggressive subtype of the neuroendocrine tumor with an extremely poor prognosis. We have previously conducted a comprehensive genomic analysis of over 100 cases of NEC of the gastrointestinal system (GIS-NEC) and unraveled its unique and organ-specific genomic drivers. However, the epigenomic features of GIS-NEC remain unexplored. In this study, we have described the epigenomic landscape of GIS-NEC and small cell lung carcinoma (SCLC) by integrating motif enrichment analysis from the assay of transposase-accessible chromatin sequencing (ATAC-seq) and enhancer profiling from a novel cleavage under targets and tagmentation (CUT&Tag) assay for H3K27ac and identified ELF3 as one of the super-enhancer-related transcriptional factors in NEC. By combining CUT&Tag and knockdown RNA sequencing for ELF3, we uncovered the transcriptional network regulated by ELF3 and defined its distinctive gene signature, including AURKA, CDC25B, CLDN4, ITGB6, and YWAHB. Furthermore, a loss-of-function assay revealed that ELF3 depletion led to poor cell viability. Finally, using gene expression of clinical samples, we successfully divided GIS-NEC patients into two subgroups according to the ELF3 signature and demonstrated that tumor-promoting pathways were activated in the ELF3 signature-high group. Our findings highlight the transcriptional regulation of ELF3 as an oncogenic transcription factor and its tumor-promoting properties in NEC.

Fluorescent GD2 analog for single-molecule imaging.

Ganglioside GD2 is associated with the proliferation and migration of breast cancer cells. However, the precise role of GD2 is unclear because its tendency to form dynamic and transient domains in cell plasma membranes (PMs), called lipid rafts, makes it difficult to observe. Previously, we developed fluorescent analogs of gangliosides (e.g., GM3 and GM1), which enabled the observation of lipid raft formation for the first time using single-molecule imaging. In this report, we describe the first chemical synthesis of a fluorescent ganglioside, GD2. A biophysical analysis of the synthesized analog revealed its raft-philic character, suggesting its potential to aid single-molecule imaging-based investigations into raft-associated interactions.

The Limiting Dynamics of SGD: Modified Loss, Phase-Space Oscillations, and Anomalous Diffusion.

In this work, we explore the limiting dynamics of deep neural networks trained with stochastic gradient descent (SGD). As observed previously, long after performance has converged, networks continue to move through parameter space by a process of anomalous diffusion in which distance traveled grows as a power law in the number of gradient updates with a nontrivial exponent. We reveal an intricate interaction among the hyperparameters of optimization, the structure in the gradient noise, and the Hessian matrix at the end of training that explains this anomalous diffusion. To build this understanding, we first derive a continuous-time model for SGD with finite learning rates and batch sizes as an underdamped Langevin equation. We study this equation in the setting of linear regression, where we can derive exact, analytic expressions for the phase-space dynamics of the parameters and their instantaneous velocities from initialization to stationarity. Using the Fokker-Planck equation, we show that the key ingredient driving these dynamics is not the original training loss but rather the combination of a modified loss, which implicitly regularizes the velocity, and probability currents that cause oscillations in phase space. We identify qualitative and quantitative predictions of this theory in the dynamics of a ResNet-18 model trained on ImageNet. Through the lens of statistical physics, we uncover a mechanistic origin for the anomalous limiting dynamics of deep neural networks trained with SGD. Understanding the limiting dynamics of SGD, and its dependence on various important hyperparameters like batch size, learning rate, and momentum, can serve as a basis for future work that can turn these insights into algorithmic gains.

A lexical approach for identifying behavioural action sequences.

Animals display characteristic behavioural patterns when performing a task, such as the spiraling of a soaring bird or the surge-and-cast of a male moth searching for a female. Identifying such recurring sequences occurring rarely in noisy behavioural data is key to understanding the behavioural response to a distributed stimulus in unrestrained animals. Existing models seek to describe the dynamics of behaviour or segment individual locomotor episodes rather than to identify the rare and transient sequences of locomotor episodes that make up the behavioural response. To fill this gap, we develop a lexical, hierarchical model of behaviour. We designed an unsupervised algorithm called "BASS" to efficiently identify and segment recurring behavioural action sequences transiently occurring in long behavioural recordings. When applied to navigating larval zebrafish, BASS extracts a dictionary of remarkably long, non-Markovian sequences consisting of repeats and mixtures of slow forward and turn bouts. Applied to a novel chemotaxis assay, BASS uncovers chemotactic strategies deployed by zebrafish to avoid aversive cues consisting of sequences of fast large-angle turns and burst swims. In a simulated dataset of soaring gliders climbing thermals, BASS finds the spiraling patterns characteristic of soaring behaviour. In both cases, BASS succeeds in identifying rare action sequences in the behaviour deployed by freely moving animals. BASS can be easily incorporated into the pipelines of existing behavioural analyses across diverse species, and even more broadly used as a generic algorithm for pattern recognition in low-dimensional sequential data.

Endoscopic submucosal dissection for tumors involving the ileocecal valve with extension into the terminal ileum: a multicenter study from the Hiroshima GI Endoscopy Research Group.

BACKGROUND: The efficacy and safety of endoscopic submucosal dissection (ESD) for tumors extending into the terminal ileum remain obscure. We aimed to evaluate the outcomes of ESD for tumors involving the ileocecal valve (ICV) with extension into the terminal ileum. METHODS: Sixty-eight patients (40 men; mean age, 67 years) with 68 tumors involving the ICV that were resected by ESD between December 2013 and December 2018 were included and classified into Group A (21 tumors with extension into the terminal ileum) and Group B (47 tumors without extension). ESD outcomes were compared between groups. RESULTS: The clinical features of the patients and tumors were not significantly different between the groups. There were no significant differences in en bloc resection rate (95% and 94%, respectively; p = 0.79), R0 resection rate (90% and 89%, respectively; p = 0.89), procedure time (95 ± 54 min and 94 ± 69 min, respectively; p = 0.64), postoperative bleeding rate (5% and 3%, respectively; p = 0.79), intraoperative perforation rate (0% and 4%, respectively; p = 0.34), delayed perforation rate (0% and 0%, respectively), or postoperative symptomatic stenosis rate (0% and 0%, respectively) between Groups A and B. No specific factors related to the outcomes of ESD were found by subgroup analysis according to the dominance and degree of circumference of the ICV. Local recurrence was observed in 1 patient in Group A who was retreated using ESD. CONCLUSIONS: ESD for tumors involving the ICV with extension into the terminal ileum is safe and effective.

[Two Cases of the Significant Liver Damage by Regorafenib].

There is a liver damage in a serious side effect of regorafenib. Case 1 was a 54-year-old woman, and she had an operation of rectal cancer and metastasized to multiple organs afterwards and started regorafenib as third-line. Erythema exudativum multiform developed on the 8th day after a start and regorafenib was canceled once and reduced on the 21st day when a skin symptom was relieved and restarted. However, because a significant rise of AST, ALT, T -Bil was recognized afterwards, regorafenib was canceled on the 27th day and enforced steroid pulse therapy and was relieved afterwards. Case 2 was a 61-year-old woman, and she had an operation of ascending colon cancer, ovarian metastasis and peritoneum dissemination. Regorafenib was started by frequent occurrence lung metastasis, cancerous pleurisy afterwards as fifth-line. Dissemination erythema developed on the 16th day and a liver damage developed on the 22nd day. Because a rise of AST, ALT went and was prolonged, liver biopsy was enforced in a cause close inspection purpose on the 45th day. A medicamentosus liver damage was diagnosed. The liver enzyme decreased afterwards. It may be easy to make the liver damage by regorafenib serious, and attention is necessary.

Outcomes of endoscopic submucosal dissection in patients who develop metachronous superficial esophageal squamous cell carcinoma close to a post-endoscopic submucosal dissection scar.

BACKGROUND: The presence of post-endoscopic submucosal dissection (ESD) scars renders complete metachronous superficial esophageal squamous cell carcinoma resection difficult. We aimed to identify the risk factors for incomplete resection of metachronous esophageal squamous cell carcinoma close to the post-ESD scar by ESD. METHODS: We enrolled patients who developed post-ESD superficial esophageal squamous cell carcinoma at Hiroshima University Hospital between January 2006 and March 2020. We analyzed the outcomes and risk factors of incomplete resection between patients whose lesions were close to (close-to group) and away from (away-from group) the post-ESD scar. RESULTS: We included 111 patients with 212 lesions. The close-to group had a significantly lower complete resection rate (88.6% [62/70] vs. 98.6% [69/70], p = 0.033), longer procedure time (80.2 ± 47.2 min vs. 60.4 ± 29.3 min, p < 0.01), higher proportion of lesions with severe fibrosis (72.9% [51/70] vs. 5.7% [4/70], p < 0.01), and higher intraoperative bleeding rate (78.6% [55/70] vs. 60.0% [42/70], p = 0.027) than the away-from group. There was no significant difference in the rate of local recurrence, muscle injury, perforation, and stenosis as well as the pathological tumor depth between the groups. Of the 92 lesions in the close-to group, the proportion of lesions located on the oral side of the post-ESD scar significantly affected the incidence of incomplete resection (91.7% [11/12] vs. 53.8% [43/80], p = 0.013). CONCLUSIONS: Complete resection was more difficult for lesions located on the oral side of the post-ESD scar.

Endoscopic findings suggestive of a high risk of non-radical cure after definitive chemoradiotherapy for cT1bN0M0 esophageal squamous cell carcinoma.

BACKGROUND: Definitive chemoradiotherapy (DCRT) is a curative treatment option for cT1bN0M0 esophageal squamous cell carcinoma (ESCC); however, local residual disease and recurrence after complete remission may occur. We aimed to identify endoscopic findings associated with the risk of non-radical cure (local remnant or recurrence) after DCRT for cT1bN0M0 ESCC. METHODS: We retrospectively analyzed 40 consecutive patients with cT1bN0M0 ESCC who had undergone DCRT between January 2007 and December 2017. We examined the endoscopic findings in patients with residual or recurrent (RR) disease (RR group) and those without RR disease [non-RR (NRR) group] after DCRT. We also evaluated outcomes after DCRT for each endoscopic finding. RESULTS: There were 10 patients in the RR group and 30 patients in the NRR group. The RR group had a significantly larger tumor size and a higher proportion of lesions with type 0-I. The 5-year relapse-free survival rate was significantly lower in type 0-I and in the presence of B3 vessels. Endoscopic findings in 15 patients with cT1bN0M0 ESCC, type 0-I, who underwent DCRT revealed significantly more reddish lesions in the RR group compared to the NRR group. CONCLUSIONS: cT1bN0M0 ESCC large size, with B3 vessels, and type 0-I has a high risk of non-radical cure after DCRT, especially the reddish type 0-I, which may need to be considered for treatment similar to advanced cancer, including surgery with preoperative DCRT.