Potential for expanding indications and curability criteria of endoscopic resection for early gastric cancer in elderly patients: results from a Japanese multicenter prospective cohort study.

BACKGROUND AND AIMS: Evidence for endoscopic resection (ER) in elderly patients with early gastric cancer (EGC) is limited. We assessed its clinical outcomes, and explored new indications and curability criteria. METHODS: We analyzed data from a Japanese multicenter prospective cohort study. Patients aged ≥75 years with EGC treated with ER were included. We classified "eCuraC-2 (corresponding to noncurative ER, defined in the Japanese gastric cancer treatment guidelines)" into "elderly-high (EL-H)" (>10% estimated metastatic risk) and "elderly-low (EL-L)" (≤10%). RESULTS: In total, 3,371 patients with 3,821 EGCs were included; endoscopic submucosal dissection (ESD) was the prominent treatment choice. Among them, 3,586 lesions met the guidelines' ER indications and 235 did not. The proportions of en bloc and R0 resections and perforations were 98.9%, 94.4%, and 0.8%, respectively, in EGCs within the indications. In EGCs beyond the indications, they were 99.5%, 85.4%, and 5.9%, respectively, for lesions diagnosed as ≤3 cm, and 96.0%, 64.0%, and 18.0% for those >3 cm. Curative ER ("eCuraA/B") and EL-L were observed in 83.6% and 6.2% of lesions within the indications, respectively, and in 44.2% and 16.8% of lesions <3 cm beyond the indications, respectively. The 5-year cumulative gastric cancer death rates following eCuraA/B and EL-H were 0.3% (95% CI, 0.2-0.6) and 3.5% (2.0-5.7), respectively. Following EL-L, the rate was 0.9% (0.2-3.5) even without subsequent treatment. CONCLUSIONS: Usefulness of ESD for elderly EGC patients was confirmed by their clinical outcomes. Lesions ≤3 cm and EL-L emerged as new ER indication and curability criterion, respectively.

Evaluating false-positive detection in a computer-aided detection system for colonoscopy.

BACKGROUND AND AIM: Computer-aided detection (CADe) systems can efficiently detect polyps during colonoscopy. However, false-positive (FP) activation is a major limitation of CADe. We aimed to compare the rate and causes of FP using CADe before and after an update designed to reduce FP. METHODS: We analyzed CADe-assisted colonoscopy videos recorded between July 2022 and October 2022. The number and causes of FPs and excessive time spent by the endoscopist on FP (ET) were compared pre- and post-update using 1:1 propensity score matching. RESULTS: During the study period, 191 colonoscopy videos (94 and 97 in the pre- and post-update groups, respectively) were recorded. Propensity score matching resulted in 146 videos (73 in each group). The mean number of FPs and median ET per colonoscopy were significantly lower in the post-update group than those in the pre-update group (4.2 ± 3.7 vs 18.1 ± 11.1; P < 0.001 and 0 vs 16 s; P < 0.001, respectively). Mucosal tags, bubbles, and folds had the strongest association with decreased FP post-update (pre-update vs post-update: 4.3 ± 3.6 vs 0.4 ± 0.8, 0.32 ± 0.70 vs 0.04 ± 0.20, and 8.6 ± 6.7 vs 1.6 ± 1.7, respectively). There was no significant decrease in the true positive rate (post-update vs pre-update: 95.0% vs 99.2%; P = 0.09) or the adenoma detection rate (post-update vs pre-update: 52.1% vs 49.3%; P = 0.87). CONCLUSIONS: The updated CADe can reduce FP without impairing polyp detection. A reduction in FP may help relieve the burden on endoscopists.

Clinical outcomes and learning curve of Tip-in endoscopic mucosal resection for 15-25 mm colorectal neoplasms among non-experts.

BACKGROUND AND AIM: Tip-in endoscopic mucosal resection (EMR) has a high en bloc resection rate for large colorectal neoplasms. However, non-experts' performance in Tip-in EMR has not been investigated. We investigated whether Tip-in EMR can be achieved effectively and safely even by non-experts. METHODS: This retrospective study included consecutive patients who underwent Tip-in EMR for 15-25 mm colorectal nonpedunculated neoplasms at a Japanese tertiary cancer center between January 2014 and December 2020. Baseline characteristics, treatment outcomes, learning curve of non-experts, and risk factors of failing self-achieved en bloc resection were analyzed. RESULTS: A total of 597 lesions were analyzed (438 by experts and 159 by non-experts). The self-achieved en bloc resection (69.8% vs 88.6%, P < 0.001) and self-achieved R0 resection (58.3% vs 76.5%, P < 0.001) rates were significantly lower in non-experts with <10 cases of experience than in experts, but not in non-experts with >10 cases. Adverse event (P = 0.165) and local recurrence (P = 0.892) rates were not significantly different between experts and non-experts. Risk factors of failing self-achieved en bloc resection were non-polypoid morphology (OR 3.4, 95% CI 1.6-7.3, P = 0.001), lesions with an underlying semilunar fold (OR 3.6, 95% CI 1.6-7.3, P < 0.001), positive non-lifting sign (OR 3.1, 95% CI 1.2-8.0, P = 0.023), and non-experts with an experience of ≤10 cases (OR 3.6, 95% CI 2.1-6.3, P < 0.001). CONCLUSION: The clinical outcomes of Tip-in EMR for 15-25 mm lesions performed by non-experts were favorable.

A novel low-power pure-cut hot snare polypectomy for 10-14 mm colorectal adenomas: An ex vivo and a clinical prospective feasibility study (SHARP trial).

BACKGROUND AND AIM: Hot snare polypectomy using blend or coagulation current is widely used; however, it causes deeper tissue heat injury, leading to adverse events. We hypothesized that hot polypectomy using low-power pure cut current (PureCut, effect 1 10 W) could reduce deeper tissue heat injury. We conducted animal experiments to evaluate the deeper tissue heat injury and conducted a prospective clinical study to examine its cutting ability. METHODS: In a porcine rectum, hot polypectomy using Blend current (EndoCut, effect 3 40 W) and low-power pure cut current was performed. The deepest part of heat destruction and thickness of the non-burned submucosal layer were evaluated histologically. Based on the results, we performed low-power pure cut current hot polypectomy for 10-14 mm adenoma. The primary endpoint was complete resection defined as one-piece resection with negative for adenoma in quadrant biopsies from the defect margin. RESULTS: In experiments, all low-power pure-cut resections were limited within the submucosal layer whereas blend current resections coagulated the muscular layer in 13% (3/23). The remaining submucosal layer was thicker in low-power pure cut current than in blend current resections. In the clinical study, low-power pure-cut hot polypectomy removed all 100 enrolled polyps. For 98 pathologically neoplastic polyps, complete resection was achieved in 84 (85.7%, 95% confidence interval, 77-92%). The lower limit of the 95% confidence interval was not more than 15% below the pre-defined threshold of 86.6%. No severe adverse events occurred. CONCLUSIONS: A novel low-power pure-cut hot polypectomy may be feasible for adenoma measuring 10-14 mm. (UMIN000037678).

Randomized controlled trial of remimazolam compared with placebo in Japanese patients undergoing upper gastrointestinal endoscopy: Phase III investigator-initiated clinical trial.

OBJECTIVES: To assess the effectiveness of remimazolam against normal saline (placebo) as a sedative agent for endoscopy in a multicenter, randomized, double-blind, investigator-initiated phase III controlled trial. METHODS: We included 48 Japanese patients undergoing upper gastrointestinal endoscopy. For the procedure, an initial remimazolam dose of 3 mg and additional doses of 1 mg were administered, as determined in the phase II clinical study. The primary study end-point was the successful sedation rate during gastrointestinal endoscopy, determined as a Modified Observer's Assessment of Alertness/Sedation score ≤4 before the start of endoscopy, the completion of gastrointestinal endoscopy, and two or fewer additional doses per 6 min. RESULTS: The successful endoscopy sedation rates were 91.9% and 9.1% in the remimazolam and placebo groups, respectively (P < 0.01). The time from the end of endoscopy to arousal was 0.0 (0.0-0.0) min for both groups. The number of additional doses required to achieve sedation was lower in the remimazolam group than that in the placebo group (P < 0.01). CONCLUSIONS: Remimazolam demonstrated a significantly higher sedation effect during upper gastrointestinal endoscopy in Japanese patients with safe and fast recovery compared with placebo.

Ketamine as an Alternative Anesthetic for Augmenting Seizure Durations During Electroconvulsive Therapy: A Retrospective Observational Study.

OBJECTIVE: Electroconvulsive therapy (ECT) is highly effective for severe psychiatric disorders; however, short seizure durations may lead to ineffective therapy. This retrospective study aimed to examine the risks and benefits of switching to ketamine anesthesia to augment seizure durations during an acute course of ECT. METHODS: We included 33 patients who underwent ketamine anesthesia due to suboptimal seizures during an acute course of ECT. We assessed seizure duration, stimulus dose, hemodynamic variability, and postseizure complications before and after switching to ketamine. RESULTS: Age was significantly associated with suboptimal seizures during ECT ( P = 0.040). After switching to ketamine, 32 patients (97%) experienced prolonged seizure duration. Ketamine significantly prolonged both electroencephalogram and motor seizure durations with a mean difference of 34.6 seconds (95% confidence interval [CI], 26.4-42.7 seconds; P < 0.001) and 26.6 seconds (95% CI, 19.6-33.6 seconds; P < 0.001), respectively. It also significantly reduced stimulus dose (mean difference, -209.5 mC [95% CI, -244.9 to -174.1 mC]; P < 0.001). In addition, maximum changes in systolic blood pressure and heart rate during ECT sessions significantly increased with ketamine (mean difference, 27.2 mm Hg [95% CI, 12.0-42.4 mm Hg; P = 0.001]; 25.7 beats per minute [95% CI, 14.5-36.8 beats per minute; P < 0.001], respectively). Patients reported more headaches with ketamine ( P = 0.041). CONCLUSIONS: Our results provide evidence that ketamine as an alternative anesthetic can augment seizure durations in specific patients experiencing suboptimal seizures during an acute course of ECT. However, its use requires greater attention to circulatory management and postseizure complications.

Iron links endogenous and exogenous nanoparticles.

Current progress in biology and medical science is based on the observation at the level of nanometers via electron microscopy and computation. Of note, the size of most cells in higher species exists in a limited range from 5 to 50 µm. Recently, it was demonstrated that endogenous extracellular nanoparticles play a role in communication among various cellular types in a variety of contexts. Among them, exosomes in serum have been established as biomarkers for human diseases by analyzing the cargo molecules. No life on the earth can survive without iron. However, excess iron can be a risk for carcinogenesis in rodents and humans. Nano-sized molecules may cause unexpected bioeffects, including carcinogenesis, which is a process to establish cellular iron addiction with ferroptosis-resistance. Asbestos and carbon nanotubes are the typical examples, leading to carcinogenesis by the alteration of iron metabolism. Recently, we found that CD63, one of the representative markers of exosomes, is under the regulation of iron-responsive element/iron-regulatory protein system. This is a safe strategy to share excess iron in the form of holo-ferritin between iron-sufficient and -deficient cells. On the other hand, damaged cells may secrete holo-ferritin-loaded exosomes as in the case of macrophages in ferroptosis after asbestos exposure. These holo-ferritin-loaded exosomes can cause mutagenic DNA damage in the recipient mesothelial cells. Thus, there is an iron link between exogenous and endogenous nanoparticles, which requires further investigation for better understanding and the future applications.

Matrigel-based organoid culture of malignant mesothelioma reproduces cisplatin sensitivity through CTR1.

Organoids are a three-dimensional (3D) culture system that simulate actual organs. Therefore, tumor organoids are expected to predict precise response to chemotherapy in patients. However, to date, few studies have studied the drug responses in organoids of malignant mesothelioma (MM). The poor prognosis of MM emphasizes the importance of establishing a protocol for generating MM-organoid for research and clinical use. Here, we established murine MM organoids from p53+/- or wild-type C57BL/6 strain by intraperitoneal injection either with crocidolite or carbon nanotube. Established MM-organoids proliferated in Matrigel as spheroids. Subcutaneous injection assays revealed that the MM-organoids mimicked actual tissue architecture and maintained the original histological features of the primary MM. RNA sequencing and pathway analyses revealed that the significant expressional differences between the 2D- and 3D-culture systems were observed in receptor tyrosine kinases, including IGF1R and EGFR, glycosylation and cholesterol/steroid metabolism. MM-organoids exhibited a more sensitive response to cisplatin through stable plasma membrane localization of a major cisplatin transporter, copper transporter 1/Slc31A1 (Ctr1) in comparison to 2D-cultures, presumably through glycosylation and lipidation. The Matrigel culture system facilitated the localization of CTR1 on the plasma membrane, which simulated the original MMs and the subcutaneous xenografts. These results suggest that the newly developed protocol for MM-organoids is useful to study strategies to overcome chemotherapy resistance to cisplatin.

Endoscopic causes and characteristics of missed gastric cancers after endoscopic submucosal dissection.

BACKGROUND AND AIMS: Because endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) preserves the entire stomach, missed gastric cancers (MGCs) are often found in the remaining gastric mucosa. However, the endoscopic causes of MGCs remain unclear. Therefore, we aimed to elucidate the endoscopic causes and characteristics of MGCs after ESD. METHODS: From January 2009 to December 2018, all patients undergoing ESD for initially detected EGC were enrolled. According to a review of EGD images before ESD, we identified the endoscopic causes (perceptual, exposure, sampling errors, and inadequate preparation) and characteristics of MGC in each endoscopic cause. RESULTS: Of 2208 patients who underwent ESD for initial EGC, 82 patients (3.7%) had 100 MGCs. The breakdown of endoscopic causes of MGCs was as follows: 69 (69%) perceptual errors, 23 (23%) exposure errors, 7 (7%) sampling errors, and 1 (1%) inadequate preparation. Logistic regression analysis showed that the risk factors for perceptual error were male sex (odds ratio [OR], 2.45; 95% confidence interval [CI], 1.16-5.18), isochromatic coloration (OR, 3.17; 95% CI, 1.47-6.84), greater curvature (OR, 2.31; 95% CI, 1.121-4.40), and lesion size ≤12 mm (OR, 1.74; 95% CI, 1.07-2.84). The sites of exposure errors were around the incisura angularis (11 [48%]), posterior wall of the gastric body (6 [26%]), and antrum (5 [21%]). CONCLUSIONS: We identified MGCs in 4 categories and clarified their characteristics. Quality improvements in EGD observation, with attention to the risks of perceptual and site of exposure errors, can potentially prevent missing EGCs.

Clinical outcomes of endoscopic submucosal dissection for superficial circumferential esophageal squamous cell carcinoma.

BACKGROUND AND AIMS: Our aim was to elucidate the clinical outcomes of endoscopic submucosal dissection (ESD) for superficial circumferential esophageal squamous cell carcinoma (cESCC). METHODS: Consecutive patients who underwent ESD for cESCC between 2009 and 2020 were retrospectively reviewed. Short-term outcomes were en-bloc resection, R0 resection, procedure time, and adverse events, whereas long-term outcomes were overall survival (OS), disease-specific survival (DSS), cumulative recurrence rate (CRR), and clinical course. RESULTS: Fifty-two patients with 52 cESCCs (median tumor length, 5.0 cm; interquartile range [IQR], 4.0-6.3) were evaluated. The en-bloc resection and R0 resection rates were 100% (95% confidence interval [CI], 94.4-100) and 69.2% (95% CI, 54.9-81.3), respectively. The median procedure time was 112 minutes (IQR, 87-162). Intraoperative perforations and delayed bleeding occurred in 4 (7.7%) and 1 (1.9%) patients, respectively. Among the 42 patients who underwent ESD alone, 36 (85.7%) experienced esophageal strictures. Within a median follow-up of 49.1 months (IQR, 25.7-74.7), the 4-year OS, DSS, and CRR were 86.2% (95% CI, 71.6-93.6), 95.5% (95% CI, 83.1-98.9), and 11.5% (95% CI, 4.1-23.1), respectively. There was no significant difference in the OS between patients with low-risk cESCC (pT1a, negative lymphovascular invasion, and negative vertical margin) and high-risk lesions, regardless of undergoing additional treatment (P = .93). In 31 patients with low-risk cESCC who were treated with ESD alone, the 4-year OS, DSS, and CRR were 93.2%, 100%, and 0%, respectively. CONCLUSIONS: ESD is a highly curative treatment for cESCC with favorable long-term outcomes, especially in low-risk patients. Stricture-prevention techniques should be improved to optimize the benefits of ESD for cESCC.

Diagnostic performance of endoscopy for subsquamous extension of superficial adenocarcinoma of the esophagogastric junction.

OBJECTIVES: Extension of adenocarcinoma of the esophagogastric junction under the squamous epithelium may lead to errors when determining lateral margins. However, the characteristics of subsquamous extension are unclear. Herein, we evaluated the prevalence and characteristics of subsquamous extension of adenocarcinoma of the esophagogastric junction and the diagnostic performance of endoscopy for this condition. METHODS: Eighty-nine consecutive patients with superficial adenocarcinoma of the esophagogastric junction who underwent endoscopic or surgical resection at a tertiary cancer center between January 2010 and December 2017 were retrospectively evaluated. Endoscopic subsquamous extension was defined as a submucosal tumor-like elevation covered by squamous epithelium and/or a brownish area with abnormal microvessels on the squamous epithelium observed using narrow-band imaging. The diagnostic performance of endoscopy for subsquamous extension was evaluated using histological subsquamous extension as gold standard. RESULTS: Thirty-nine patients (44%) had histological subsquamous extension. Proton pump inhibitor use was significantly associated with histological subsquamous extension [odds ratio: 4.65; 95% confidence interval (CI): 1.77-12.2]. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of endoscopic subsquamous extension were 56% (95% CI: 40-72%), 96% (86-99%), 92% (73-99%), 74% (62-84%) and 79% (69-87%), respectively. The median length difference between histological and endoscopic subsquamous extension was 2 mm (range: -6 to 9 mm). CONCLUSIONS: The sensitivity of endoscopic diagnosis of subsquamous extension was unsatisfactory. The endoscopic length of subsquamous extension tended to be underestimated. An oral safety margin of one centimeter is reasonable during endoscopic resection of adenocarcinoma of the esophagogastric junction.IMPACT STATEMENT This study will contribute significantly to the literature because this is the first study to determine the difference between the lengths of subsquamous extension detected endoscopically and histologically. This study determines the prevalence of subsquamous extension and identifies characteristics associated with subsquamous extension. An understanding of the risk of subsquamous extension is important when choosing a treatment strategy and planning the resection margins in patients with adenocarcinoma of the esophagogastric junction. This study provides patients with subsquamous extension characteristics and suggests a method for accurately diagnosing this condition.

Complete endoscopic removal rate of detected colorectal polyps in a real world out-patient practical setting.

OBJECTIVES: Colonoscopy with adenomatous polypectomy reduces the incidence and mortality of colorectal cancer. We introduced a strategy of removing all neoplastic polyps in single-session out-patient colonoscopy using cold polypectomy. We aimed to investigate the achievement of single-session complete removal rate of detected colorectal polyps in clinical practice. MATERIALS AND METHODS: This retrospective study included colonoscopy-scheduled 40-79-year-old outpatients, with at least one colorectal neoplasm, between January 2015 and December 2016. Exclusion criteria were: colorectal neoplasms 21 mm or larger in size; pre-examination for colorectal surgery or endoscopic submucosal dissection; colonoscopy performed by health check program; ongoing antithrombotic treatment; inflammatory bowel disease; familial adenomatous polyposis. We defined 'clean colon' as the removal of all detected neoplastic polyps in a single-session colonoscopy. We evaluated clean colon rate, factors relating to clean colon failure and complications. RESULTS: We evaluated 2527 patients (mean age 68 years; 799 women) with 8203 colorectal polyps (7675 adenomas, 423 serrated lesions, 105 Tis and T1 cancers). In 1-4 mm polyps, cold snare polypectomy (CSP; 51.8%) and cold forceps polypectomy (CFP; 45.8%) were applied. Clean colon rates were 95.1% per patient and 97.1% per lesion. The significant factors denoting clean colon failure were inadequate bowel preparation, ≥5 lesions, and the most advanced estimated histology of adenocarcinoma, on multivariate analyses. Post-polypectomy bleeding requiring endoscopic hemostasis occurred in five patients (0.2%) who had undergone endoscopic mucosal resection (EMR) or hot snare polypectomy (HSP). Perforation occurred in one patient (0.04%) with EMR. CONCLUSIONS: The clean colon rates were satisfactory in single-session out-patient colonoscopy using cold polypectomy.

Local recurrence risk of esophageal squamous cell carcinoma due to intralesional damage during endoscopic submucosal dissection.

BACKGROUND AND AIM: It is unclear whether additional treatment should be considered given the recurrence risk after endoscopic submucosal dissection (ESD) for esophageal squamous cell carcinoma (ESCC) when the vertical margin is positive or unclear (VM1/VMX) due to intralesional damage. This study aimed to elucidate the local recurrence risk of ESCC caused by intralesional damage during ESD. METHODS: Among consecutive patients with pT1a ESCCs initially treated by ESD at our institution between January 2006 and December 2018, ESCCs diagnosed as VM1/VMX were retrospectively reviewed. Exclusion criteria were piecemeal resection and any additional treatment after ESD. Intralesional damage included the following three types: a macroscopic hole inside the lesion, an incision from the lateral margin of the specimen into the lesion, and crushing injury or burn effect into the deepest area of the lesion without an obvious hole. The local recurrence rate after ESD was primarily analyzed. RESULTS: Of 1174 pT1a ESCCs initially treated using ESD, 22 lesions were histopathologically diagnosed as VM1/VMX due to intralesional damage (1.9%; 95% confidence interval [CI], 1.2-2.8%). At a median follow-up period of 60.0 (interquartile range, 15.0-84.0) months, no local recurrence was observed (0.0%; 95% CI, 0.0-13.3%) among 21 lesions finally evaluated. CONCLUSIONS: The impact of intralesional damage during ESD for ESCC on local recurrence might be negligible. Follow-up without additional treatment may be acceptable even if intralesional damage occurs and results in VM1/VMX after ESD for pT1a ESCCs.

Optimization of endoscopic ultrasound-guided tissue sample acquisition for commercially available comprehensive genome profiling.

BACKGROUND AND AIM: Optimal tumor samples are crucial for successful analysis using commercially available comprehensive genomic profiling (CACGP). However, samples acquired by endoscopic ultrasound-guided tissue acquisition (EUS-TA) are occasionally insufficient, and no consensus on the optimal number of needle passes required for CACGP exists. This study aimed to explore the optimal number of needle passes required for EUS-TA to procure an ideal sample fulfilling the prerequisite criteria of CACGPs. METHODS: Patients who underwent EUS-TA for solid masses between November 2019 and July 2021 were retrospectively studied. The correlation between the acquisition rate of an ideal sample and the number of needle passes mounted on a microscope slide was evaluated. Additionally, the factors predicting a successful analysis were investigated in patients scheduled for CACGP using EUS-TA-obtained samples during the same period. RESULTS: EUS-TAs using 22- and 19-gauge (G) needles were performed in 336 and 57 patients, respectively. There was a positive correlation between the acquisition rate and the number of passes using a 22-G needle (38.9%, 45.0%, 83.7%, and 100% for 1, 2, 3, and 4 passes, respectively), while no correlation was found with a 19-G needle (84.2%, 83.3%, and 85.0% for 1, 2, and 3 passes, respectively). The analysis success rate in patients with scheduled CACGP was significantly higher with ideal samples than with suboptimal samples (94.1% vs 55.0%, P < 0.01). CONCLUSIONS: The optimal estimated number of needle passes was 4 and 1-2 for 22- and 19-G needles, respectively.

MRI screening for osteonecrosis of the femoral head after COVID-19.

OBJECTIVES: Systemic steroid administration has been suggested for the treatment of coronavirus disease 2019 (COVID-19), but the occurrence of osteonecrosis of the femoral head (ONFH) was one of the concerns for this treatment. This study aimed to use magnetic resonance imaging (MRI) to assess the incidence of ONFH after treatment COVID-19. METHODS: The study included 41 patients who were hospitalized and treated for pneumonia or other COVID-19-induced diseases. We conducted interviews with these patients regarding hip pain and performed MRI screenings for ONFH. The incidence and timing of ONFH after COVID-19 treatment were investigated. RESULTS: Of the 41 patients, one died of pneumonia, and the remaining patients did not complain of hip pain. MRI screening of 26 patients was performed, and asymptomatic ONFH was detected in one patient (3.8%) whose ONFH appeared 1 month after the COVID-19 infection. CONCLUSION: Our MRI screening of ONFH in post-COVID-19 patients revealed asymptomatic ONFH, which would not have been identified without active screening. Physicians should be aware that ONFH may occur in patients after treating COVID-19.

Tip-in EMR as an alternative to endoscopic submucosal dissection for 20- to 30-mm nonpedunculated colorectal neoplasms.

BACKGROUND AND AIMS: Tip-in EMR, which includes anchoring the snare tip, has recently shown a favorable en-bloc and R0 resection rate for colorectal neoplasms. Thus, Tip-in EMR may be an alternative to endoscopic submucosal dissection (ESD). We aimed to compare clinical outcomes between Tip-in EMR and ESD for large colorectal neoplasms. METHODS: This retrospective study evaluated consecutive patients who underwent Tip-in EMR or ESD for 20- to 30-mm nonpedunculated colorectal neoplasms at a Japanese tertiary cancer center between January 2014 and December 2019. Baseline characteristics, treatment results, and long-term outcomes were analyzed using 1:1 propensity score matching. RESULTS: Seven hundred nine lesions were evaluated. The Tip-in EMR group included 1 lesion with a nonlifting sign but no lesions with fold convergence. After propensity score matching, each group included 140 lesions. The ESD group showed significantly higher en-bloc resection rates (99.3% vs 85.0%) and R0 resection rates (90.7% vs 62.9%). Procedure time was significantly shorter in the Tip-in EMR group (8 minutes vs 60 minutes). The Tip-in EMR and ESD groups did not differ significantly with respect to local recurrence rate (2.1% vs 0%). CONCLUSIONS: Tip-in EMR is comparable with ESD with respect to the local recurrence rate but has a shorter procedure time, despite the lower en-bloc and R0 resection rates for 20- to 30-mm nonpedunculated colorectal neoplasms without fold convergence or nonlifting sign. Thus, Tip-in EMR could be a feasible alternative to ESD in these lesions.

Changes in gonadotropin-releasing hormone in the cerebral ganglion of the Manila clam Ruditapes philippinarum during gonadal development.

Gonadotropin-releasing hormone (GnRH) plays an important role in reproduction in both vertebrates and invertebrates; however, little is known about GnRH during gonadal development in bivalves. We developed a time-resolved fluoroimmunoassay (TR-FIA) for Manila clam Ruditapes philippinarum GnRH (rpGnRH) and measured the amount of rpGnRH in the cerebral ganglion (CG) and sex steroid hormones in the hemolymph during gonadal development. The cross-reactivity of the anti-rpGnRH antibody against other forms of GnRH was <0.15%, and the displacement curve obtained for serially diluted CG extracts was parallel to the rpGnRH standard curve, confirming the suitability of the TR-FIA system. Based on histological observation, gonadal development of the clams was classified into early developing (stage 1), late developing (stage 2), ripe (stage 3), and partially spent (stage 4). In female clams, rpGnRH levels in the CG peaked at stage 1, and 17ß-estradiol (E2) levels in the hemolymph peaked at stage 2. The rpGnRH levels in males and hemolymph testosterone levels in both sexes did not differ significantly across stages. Hemolymph E2 levels in males were below the detection limit for the TR-FIA. These results suggest that rpGnRH and E2 secretion in females can activate ovarian development of the Manila clam at the early and late developing stages, respectively.

Iron as spirit of life to share under monopoly.

Any independent life requires iron to survive. Whereas iron deficiency causes oxygen insufficiency, excess iron is a risk for cancer, generating a double-edged sword. Iron metabolism is strictly regulated via specific systems, including iron-responsive element (IRE)/iron regulatory proteins (IRPs) and the corresponding ubiquitin ligase FBXL5. Here we briefly reflect the history of bioiron research and describe major recent advancements. Ferroptosis, a newly coined Fe(II)-dependent regulated necrosis, is providing huge impact on science. Carcinogenesis is a process to acquire ferroptosis-resistance and ferroptosis is preferred in cancer therapy due to immunogenicity. Poly(rC)-binding proteins 1/2 (PCBP1/2) were identified as major cytosolic Fe(II) chaperone proteins. The mechanism how cells retrieve stored iron in ferritin cores was unraveled as ferritinophagy, a form of autophagy. Of note, ferroptosis may exploit ferritinophagy during the progression. Recently, we discovered that cellular ferritin secretion is through extracellular vesicles (EVs) escorted by CD63 under the regulation of IRE/IRP system. Furthermore, this process was abused in asbestos-induced mesothelial carcinogenesis. In summary, cellular iron metabolism is tightly regulated by multi-system organizations as surplus iron is shared through ferritin in EVs among neighbor and distant cells in need. However, various noxious stimuli dramatically promote cellular iron uptake/storage, which may result in ferroptosis.

Homeobox A5 and C10 genes modulate adaptation of brown adipose tissue during exercise training in juvenile rats.

NEW FINDINGS: What is the central question of this study? Exercise can stimulate brown adipose tissue (BAT) with subsequent increase in uncoupling protein 1 expression and mitochondrial biogenesis. In that case, do BAT-specific Hox genes modify BAT functioning and cause uncoupling protein expression changes due to exercise? What is the main finding and its importance? Exercise enhanced brown adipocyte markers, with significant upregulation of HoxA5 and downregulation of HoxC10 mRNA expression in rat BAT. HoxA5 and HoxC10 are thus likely to play distinct roles in exercise-induced changes in BAT markers during the early postnatal period. These findings provide new insight into the mechanisms underlying exercise-induced changes in BAT function. ABSTRACT: Brown adipose tissue (BAT) recruitment is involved in increased energy expenditure associated with cold exposure and exercise training. We explored whether exercise training induced changes in expression levels of brown adipocyte-selective factors and Homeobox (Hox) genes during the post-weaning growth period of male Wistar rats. Relative to total body weight, BAT weights alone were lower in exercise-trained (EX) rats compared to sedentary control (SED) rats. mRNA expression of HoxA5 was higher and that of HoxC10 was lower in EX rats than in SED rats, accompanied by both higher citrate synthase activity and protein expression levels for uncoupling protein 1 (UCP1), peroxisome proliferator-activated receptor (PPAR) α, and PPARγ-coactivator (PGC)-1α. HoxA5 knockdown with siRNA reduced the expression of PR-domain containing 16 (Prdm16), cell death-inducing DNA fragmentation factor-α-like effector A (Cidea) gene, type 2 deiodinase mRNA, and PRDM16 protein. Comparatively, HoxC10 knockdown with siRNA enhanced mRNA expression of Prdm16, Pparα and Pgc1α and protein expression of UCP1, PPARα and PGC1α in brown adipocytes. The stimulation of brown adipocytes with isoproterenol, a ß-adrenoceptor agonist, caused a phenomenon similar to the effect of exercise training on the genes tested: upregulation of HoxA5 mRNA, downregulation of HoxC10 mRNA, and increased protein expression for UCP1 and PGC1α. Collectively, HoxA5 and HoxC10 may have unique functions that contribute to modulating the expression of BAT-selective markers in BAT of juvenile rats during exercise training. The study findings regarding activation and recruitment of BAT during exercise training have implications for anti-obesity management.

Differential effects of dexamethasone and roflumilast on asthma in mice with or without short cigarette smoke exposure.

Appropriate drug treatment for smoking asthmatics is uncertain because most smokers with asthma are less sensitive to treatment with glucocorticoids compared with non-smokers with asthma. We hypothesized that roflumilast (Rof), a selective phosphodiesterases-4 inhibitor regarded as an add-on therapy for chronic obstructive pulmonary disease, might be more effective than glucocorticoids for improving asthma in smokers. To investigate this hypothesis, we compared the therapeutic effects of dexamethasone (Dex) and Rof in a mouse model of ovalbumin-induced asthma with or without concurrent cigarette smoke (CS) exposure for 2 weeks. We found that recurrent asthma attacks increased lung tissue resistance. CS exposure in asthmatic mice decreased the central airway resistance, increased lung compliance, and attenuated airway hyper-responsiveness (AHR). CS exposure in asthmatic mice also increased the number of neutrophils and macrophages in the bronchoalveolar fluid. Treatment with Dex in asthmatic mice without CS exposure reduced airway resistance, AHR and airway eosinophilia. In asthmatic mice with CS exposure, however, Dex treatment unexpectedly increased lung tissue resistance and restored AHR that had been otherwise suppressed. Dex treatment in asthmatic mice with CS exposure inhibited eosinophilic inflammation but conversely exacerbated neutrophilic inflammation. On the other hand, treatment with Rof in asthmatic mice without CS exposure reduced airway resistance and airway eosinophilia, although the inhibitory effect of Rof on AHR was unremarkable. In asthmatic mice with CS exposure, Rof treatment did not exacerbate lung tissue resistance but modestly restored AHR, without any significant effects on airway inflammation. These results suggest that CS exposure mitigates sensitivity to both Dex and Rof. In asthmatic mice with CS exposure, Dex is still effective in reducing eosinophilic inflammation but increases lung tissue resistance, AHR and neutrophilic inflammation. Rof is ineffective in improving lung function and inflammation in asthmatic mice with CS exposure. This study did not support our initial hypothesis that Rof might be more effective than glucocorticoids for improving asthma in smokers. However, glucocorticoids may have a detrimental effect on smoking asthmatics.