Trends of Early Helicobacter pylori-Uninfected Gastric Cancer in an Aging Regional Area.

Background/Objectives: We aimed to determine the trends over time and current status of early Helicobacter pylori-uninfected gastric cancer (HpUIGC) treatment in a region with an aging population. Methods: This retrospective, multi-center observational study was conducted at seven major general hospitals in Kagoshima Prefecture. From January 2009 to July 2022, 2091 patients who received endoscopic resection (ER) for early gastric cancer (EGC) were retrospectively enrolled, of which 35 were identified as early HpUIGC cases. Results: The number of ERs for EGC demonstrated a significant increasing trend from 2010 to 2021 (p = 0.01 for trend). Furthermore, the 12-year period from 2010 to 2021 was divided into an early and late phase every 6 years. In the early phase, there were 5 cases (0.7%) of early HpUIGC, while in the late phase, there were 25 cases (2.1%), indicating a significant increase in the proportion of ERs for early HpUIGC cases in the late phase (p = 0.02). Conclusions: The proportion of ERs for early HpUIGC, which are more common in relatively young patients, may be increasing as a proportion of all ERs for GC, even in areas of Japan with an aging population.

Pathologically diagnosed early-stage gastric adenocarcinoma with enteroblastic differentiation after endoscopic submucosal dissection: A case report.

A 77-year-old male patient underwent esophagogastroduodenoscopy at his family doctor, and an easily hemorrhagic depressed lesion was noted near the anterior wall of the gastric antrum. A biopsy revealed moderately differentiated tubular adenocarcinoma > poorly differentiated adenocarcinoma, and the patient was referred to our department for further examination. A 15-mm 0-IIc lesion is seen near the anterior wall of the gastric antrum and narrow band imaging magnifying endoscopy revealed obscured glandular duct structures and corkscrew pattern vascular structures. We diagnosed the patient with early-stage gastric cancer [L, Ant, 15mm, cType0-IIc, cT1(M-SM1), cN0, cM0, cStage IA] after an esopahogastroduodenoscopy examination at our hospital, and endoscopic submucosal dissection was performed. Histopathological images with hematoxylin and eosin staining showed tumor cells with pale cytoplasm and the immunostaining for alpha-fetoprotein, sal-like protein 4, and Glypican3 was positive. The patient was pathologically diagnosed with gastric adenocarcinoma with enteroblastic differentiation, pT1b1 (SM, 0.4 mm), type 0-IIc, 15 mm, UL (-), Ly0, and V0. Gastric adenocarcinoma with enteroblastic differentiation is one of the representative histological types of alpah-fetoprotein-producing gastric cancer. Alpha-fetoprotein-producing gastric cancer is infrequent, accounting for at least 3% of all gastric cancers, and is generally highly malignant. Most cases are already advanced upon diagnosis, and finding them in the early stage is rare. Therefore, pathological findings that may indicate the gastric adenocarcinoma with enteroblastic differentiation should be noted even in early gastric cancer.

A successful case of an endoscopic submucosal dissection using a combination of the pocket-creation method and traction with a spring-and-loop with clip for early gastric cancer with severe ulcer scarring.

Video 1ESD for gastric cancer with severe scarring using PCM and S-O clip.

Usefulness of the aldehyde breath test for predicting metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharyngeal squamous cell carcinoma.

BACKGROUND: The rate of metachronous recurrence after endoscopic submucosal dissection for early-stage esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma is as high (10-15%). The acetaldehyde breath test may detect acetaldehyde dehydrogenase 2 gene polymorphisms. Therefore, we evaluated its usefulness in assessing metachronous recurrence in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. METHODS: A total of 76 patients underwent endoscopic submucosal dissection for esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma and were followed up for at least 3 years (non-recurrence group: 52 patients; recurrence group: 24 patients). The risk factors for carcinogenesis were compared between the recurrence and non-recurrence groups, and the acetaldehyde-to-ethanol ratio was assessed. The cutoff acetaldehyde-to-ethanol ratio that correlated with recurrence was established, and the cumulative recurrence rate was evaluated. RESULTS: The recurrence group had a higher acetaldehyde-to-ethanol ratio, daily alcohol consumption, and Lugol-voiding lesion grade than the non-recurrence group in the univariate analysis. The cutoff acetaldehyde-to-ethanol ratio for recurrence was 28.1 based on the receiver operating characteristic curve. The multivariate analysis revealed an acetaldehyde-to-ethanol ratio of > 28.1 and a Lugol-voiding lesion grade associated with carcinogenesis. Patients with an acetaldehyde-to-ethanol ratio of ≥ 28.1 had a significantly high recurrence rate using the Kaplan-Meier method. CONCLUSIONS: The acetaldehyde-to-ethanol ratio detected using the acetaldehyde breath test could be a novel biomarker of metachronous recurrence after endoscopic submucosal dissection in patients with esophageal squamous cell carcinoma and hypopharynx squamous cell carcinoma. TRIAL REGISTRATION NUMBER: UMIN000040615.

Hepatocyte growth factor ameliorates dextran sodium sulfate­induced colitis in a mouse model by altering the phenotype of intestinal macrophages.

Hepatocyte growth factor (HGF) serves key roles in cell motility, proliferation and immunoregulatory functions. However, the effect of HGF on macrophages is unclear. The present study aimed to elucidate the effect of HGF on the phenotypic alterations of intestinal lamina propria mononuclear cells (LPMCs). Colitis was induced in a mouse model using dextran sodium sulfate (DSS). Subsequently, LPMCs were isolated from the mice with chronic colitis and the expression levels of cytokine­encoding genes in the LPMCs were determined. CD11b­positive macrophages isolated from LPMCs were cultured with HGF, and alterations in the levels of M1 or M2 markers were evaluated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and flow cytometry. In addition, the cytokine levels were assessed using RT­qPCR and ELISA. HGF shifted the phenotype of macrophages from M1 to M2­like, as determined by increased mRNA expression levels of arginase­1, CD206 and IL­10, and reduced mRNA expression levels of CD86 and IL­6 in mice with DSS­induced colitis. Moreover, HGF could ameliorate DSS­induced colitis owing to its immunosuppressive effect on immune cells. These findings indicated that HGF treatment may not only promote the regeneration of epithelial cells but also lead to tissue repair by phenotypic alteration of M1 macrophages to M2­like macrophages.

Clinical features of obscure gastrointestinal bleeding undergoing capsule endoscopy: A retrospective cohort study.

BACKGROUND: Capsule endoscopy has been widely used to investigate obscure gastrointestinal bleeding (OGIB) in the small intestine since its approval in 2001. However, the clinical features of OGIB remain unclear. AIM: We retrospectively examined the clinical features and risk factors of OGIB in patients who underwent capsule endoscopy in our hospital. METHODS: We included 420 of the 431 patients who underwent capsule endoscopy from June 2014 to May 2021, in whom the small intestine could be observed. We retrospectively compared the clinical features and treatment of OGIB cases, with or without active small bowel bleeding (n = 173), with other cases (n = 247). Patient sex, age, diabetes mellitus, and heart failure histories were matched for the analysis. RESULTS: The male/female ratio was 247/173 and the average age was 51.54 years. In multivariate analysis, the use of direct oral anticoagulants was significant (P = 0.016), and vascular lesions (P = 0.018) were observed in OGIB cases. When OGIB cases with and without active small bowel bleeding were compared, serum albumin level was lower in cases with active bleeding (P = 0.031). When treatment of OGIB cases were compared, those without vascular lesions could be treated conservatively (P = 0.0047). In the 1:1 propensity score matching analysis, serum creatinine level was elevated in cases of active bleeding (P = 0.029), and cases without vascular lesions were treated conservatively (P = 0.010). CONCLUSIONS: Use of direct oral anticoagulants is frequently associated with OGIB. OGIB patients without vascular lesions may be treated conservatively.

Efficacy of endoscopic ultrasonography in evaluating tumor thickness in patients with superficial pharyngeal carcinoma: A pilot study.

OBJECTIVES: A histopathological tumor thickness of ≥1000 µm has been reported as one of many risk factors for recurrent lymph node metastasis in superficial pharyngeal cancer (SPC). However, methods for assessing this risk factor preoperatively have not yet been established. Hence, the current study aimed to evaluate the efficacy of endoscopic ultrasonography (EUS) in measuring tumor thickness preoperatively in patients with SPC. METHODS: This single-center retrospective study included 44 consecutive patients with 47 lesions who underwent endoscopic submucosal dissection (ESD). Prior to surgery, EUS examination was performed while under general anesthesia. Further, microvascular irregularity in the target lesion was evaluated using the Japan Esophageal Society (JES) magnification endoscopic classification system. RESULTS: A significant correlation was noted between histopathological and EUS tumor thickness (Spearman's correlation r == 0.879, p < 0.001). In tumors ≥1000 µm thick on histopathology, the cutoff value for EUS tumor thickness was 2.6 mm, and the following values were obtained: sensitivity, 100%; specificity, 81.8%; positive predictive value (PPV), 70%; negative predictive value (NPV), 100%; and accuracy, 87.2%. In B2 lesions ≥1000-µm thick, the following values were obtained: sensitivity, 85.7%; specificity, 90.9%; PPV, 80%; NPV, 93.8%; and accuracy, 89.4%. The diagnostic accuracy rate of combined EUS and the JES magnifying endoscopic classification system was 95.7%. CONCLUSIONS: Tumor thickness assessed using EUS was effective in diagnosing histopathological tumor thickness of ≥1000 µm. The combined use of EUS and the JES magnifying endoscopic classification system may be useful for assessing preoperative risk factors for lymph node metastasis in SPC.

Acetaldehyde breath test as a cancer risk marker in patients with esophageal and hypopharyngeal squamous cell carcinoma.

Patients with inactive acetaldehyde dehydrogenase 2 (ALDH2) are at high risk for esophageal squamous cell carcinoma (ESCC) and hypopharyngeal squamous cell carcinoma (HPSCC). The acetaldehyde breath test (ABT) may demonstrate ALDH2 gene polymorphisms. We evaluated the usefulness of the ABT in patients with ESCC and HPSCC. The squamous cell carcinoma (SCC) group consisted of 100 patients who were treated with endoscopic submucosal dissection (ESD) for ESCC or HPSCC, and the control group (HC) consisted of 275 healthy subjects. The SCC group comprised the "single subgroup" (n = 63), in which a single lesion was initially treated with ESD, and the "multiple subgroup" (n = 31), in which multiple lesions were initially treated with ESD. First, we compared the groups' risk factors for carcinogenesis and measured the acetaldehyde-to-ethanol (A/E) ratio. Then we tested the groups' differences in the abovementioned carcinogenic risk factors. We found that the proportion of individuals in the SCC group with inactive ALDH2 (A/E ratio ≥ 23.3) was significantly higher than that in the HC group (p = 0.035), as was the A/E ratio (p < 0.001). Also, the proportion of individuals with inactive ALDH2 in the multiple subgroup was significantly higher than that in single subgroup (p = 0.015), as was the A/E ratio (p = 0.008). In conclusion, ABT may be a potential screening tool for detecting people at risk of ESCC and HPSCC. In addition, it could be a useful tool in detecting patients at risk of multiple or double carcinomas among patients with ESCC and HPSCC. Trial registration: Trial Registration number: UMIN000040615 [https://rctportal.niph.go.jp/en/detail?trial_id=UMIN000040615], Data of Registration: 01 46 June 2020, retrospectively registered.

Robust closure of post-endoscopic submucosal dissection perforation by microparticle-based wound dressing.

Endoscopic submucosal dissection (ESD) has been used as a minimally invasive cancer treatment for early-stage gastrointestinal cancer. However, cancer dissection in thin tissues, such as the duodenum and large intestine, often cause post-ESD and delayed perforation, which elicit severe complications. In this study, we report a microparticle-based wound dressing with hydrophobically-modified gelatin that can close the perforation after ESD. Hydrophobized microparticles were prepared using a coacervation method in a water/ethanol mixed solvent. The optimized alkyl chain length and degree of substitution of hydrophobic groups improved the mechanical strength of the hydrogel formed by hydration and fusion of the microparticles. The hydrogels formed on tissue defects revealed higher burst strength in ex vitro perforation models using duodenum, large intestine, and stomach under wet conditions compared with hydrogels without hydrophobic modification. The particle fusion was determined to be a crucial step to yield a high burst strength. An in vivo degradability evaluation showed that microparticle hydrogels subcutaneously implanted in rats degraded within 14 days. The microparticle wound dressing is expected to be applicable to post-ESD perforation and prevent delayed perforation.

Covering Post-Endoscopic Submucosal Dissection Ulcers in Miniature Swine with Hexanoyl (Hx:C6) Group-Modified Alkaline-Treated Gelatin Porous Film (HAG) Induces Proper Healing by Decreasing Inflammation and Fibrosis.

BACKGROUND AND AIMS: Hexanoyl (Hx:C6) group-modified alkaline-treated gelatin porous film (HAG) is a newly developed degradable hydrogel characterized by strong adhesiveness and high affinity for vascular endothelial growth factor (VEGF). The aim of this study was to clarify the effect of HAG sheets on the healing process of post-endoscopic submucosal dissection (ESD) porcine gastric artificial ulcers. METHODS: (1) To evaluate the adhesiveness of HAG sheets over time, we performed ESD to create 1 artificial ulcer and covered the lesion with 1 HAG sheet using 1 miniature swine. We observed 2 ulcers by endoscopic and microscopic examinations. (2) To examine the effect of HAG sheets on post-ESD ulcer healing, we performed ESD using 5 miniature swine. The artificial ulcers were covered with HAG sheets, or left uncovered after ESD (day 0), followed by macroscopic and microscopic examinations. On days 7 and 14, we observed 2 ulcers by endoscopic examinations. On day 14, the animals were sacrificed, and histological examination was performed on the 3 stomachs that could be extirpated. RESULTS: (1) On day 7, adhesion of HAG sheets was observed. (2) Gastric ulcer area on day 7 was significantly larger in the covered ulcers than in the non-covered ulcers (p = 0.046). On day 14, although there was no significant difference in ulcer area irrespective of covering (p = 0.357), the covered ulcers tended to repair less fold convergence than non-covered ulcers. The covered ulcer sheets significantly decreased inflammatory cell infiltration (p = 0.011), but significantly increased the abundance of macrophages (p = 0.033), in submucosal layers. Also, the abundance of alpha-smooth muscle actin-positive cells in submucosal layers of the covered ulcers was significantly reduced (p = 0.044), leading to a decrease in collagen accumulation. In addition, fibrosis and atrophy of the muscularis propria were significantly lower for covered ulcers than for non-covered ulcers. Furthermore, microvessels and VEGF-positive cells were significantly more abundant in the submucosal layers of the covered ulcers (p < 0.001 and p = 0.024, respectively). CONCLUSIONS: HAG sheets induced post-ESD ulcer healing with less submucosal inflammation and muscularis propria injury and have the potential to decrease excess scarring.

Perirectal abscess with dysuria.

Perirectal abscesses often occur in the dorsal portion of the perirectal tissues. We report a patient who presented with fever, pain on defecation, and dysuria. He was found to have a perirectal abscess in the anterior perineum pressing on the urethra. After emergency surgery to drain the abscess, the symptoms improved.

Multifunctional Hydrophobized Microparticles for Accelerated Wound Healing after Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection (ESD) provides strong therapeutic benefits for early gastrointestinal cancer as a minimally invasive treatment. However, there is currently no reliable treatment to prevent scar contracture resulting from ESD which may lead to cicatricial stricture. Herein, a multifunctional colloidal wound dressing to promote tissue regeneration after ESD is demonstrated. This sprayable wound dressing, composed of hydrophobized microparticles, exhibits the multifunctionality necessary for wound healing including tissue adhesiveness, blood coagulation, re-epithelialization, angiogenesis, and controlled inflammation based on hydrophobic interaction with biological systems. An in vivo feasibility study using swine gastric ESD models reveals that this colloidal wound dressing suppresses fibrosis and accelerates wound healing. Multifunctional colloidal and sprayable wound dressings have an enormous therapeutic potential for use in a wide range of biomedical applications including accelerated wound healing after ESD, prevention of perforation, and the treatment of inflammatory diseases.

Hepatocyte Growth Factor Facilitates Esophageal Mucosal Repair and Inhibits the Submucosal Fibrosis in a Rat Model of Esophageal Ulcer.

BACKGROUND/AIMS: Esophageal mucosal damage often causes scar tissue, leading to refractory stricture. The aim of this study was to clarify the effect of hepatocyte growth factor (HGF) on esophageal mucosal repair and fibrosis leading to stricture in a rat model of esophageal ulcer. METHODS: Esophageal ulcers were induced in rats by topical exposure of the lower esophageal serosa to acetic acid, followed by intraperitoneal administration of HGF (200 µg/day) using an osmotic pump for 7 days. The effect of HGF on esophageal mucosal injury was investigated macroscopically and microscopically. The effect of HGF on epithelial cell proliferation and the expression of genes closely associated with the development of fibrosis were also examined. RESULTS: The administration of HGF for 7 days led to a significant reduction in the ulcerative area and enhanced the proliferation of esophageal epithelial cells. HGF treatment significantly decreased the fibrosis, and subsequently attenuated not only the foreshortening but also the narrowing of the esophagus. The expression levels of tissue inhibitor of metalloproteinase (TIMP)-1, -2, and matrix metalloproteinase (MMP)-2, -9 were significantly decreased among rats treated with HGF. CONCLUSION: HGF facilitates the repair of esophageal mucosal injury and may also ameliorate the esophageal fibrosis, possibly through enhanced re-epithelization.

[A case of postoperative recurrent gastric cancer resembling esophageal achalasia diagnosed by staging laparoscopy].

A 65-year-old man underwent subtotal gastrectomy for advanced gastric cancer. The histological type of the cancer was signet-ring cell carcinoma, and the clinical stage was stage IB (T2N0M0). Three years after surgery, the patient had the following symptoms:dysphagia, odynophagia, and weight loss. Esophageal endoscopy and esophagography revealed a circular stenosis covered with the normal mucosa between the middle esophagus and the esophagogastric junction. Histologically, the samples obtained by staging laparoscopy revealed signet-ring cell carcinoma. Tucker's criteria are an important tool for differentiating secondary achalasia from primary achalasia with clinical value. Therefore, we suggest that staging laparoscopy is useful for the histological diagnosis of recurrent gastric cancer.