A machine learning model for predicting the lymph node metastasis of early gastric cancer not meeting the endoscopic curability criteria.

BACKGROUND: We developed a machine learning (ML) model to predict the risk of lymph node metastasis (LNM) in patients with early gastric cancer (EGC) who did not meet the existing Japanese endoscopic curability criteria and compared its performance with that of the most common clinical risk scoring system, the eCura system. METHODS: We used data from 4,042 consecutive patients with EGC from 21 institutions who underwent endoscopic submucosal dissection (ESD) and/or surgery between 2010 and 2021. All resected EGCs were histologically confirmed not to satisfy the current Japanese endoscopic curability criteria. Of all patients, 3,506 constituted the training cohort to develop the neural network-based ML model, and 536 constituted the validation cohort. The performance of our ML model, as measured by the area under the receiver operating characteristic curve (AUC), was compared with that of the eCura system in the validation cohort. RESULTS: LNM rates were 14% (503/3,506) and 7% (39/536) in the training and validation cohorts, respectively. The ML model identified patients with LNM with an AUC of 0.83 (95% confidence interval, 0.76-0.89) in the validation cohort, while the eCura system identified patients with LNM with an AUC of 0.77 (95% confidence interval, 0.70-0.85) (P = 0.006, DeLong's test). CONCLUSIONS: Our ML model performed better than the eCura system for predicting LNM risk in patients with EGC who did not meet the existing Japanese endoscopic curability criteria. We developed a neural network-based machine learning model that predicts the risk of lymph node metastasis in patients with early gastric cancer who did not meet the endoscopic curability criteria.

Diagnostic value of endoscopic ultrasonography for the depth of gastric cancer suspected of submucosal invasion: a multicenter prospective study.

BACKGROUND: Although the combination of conventional endoscopy (CE) and endoscopic ultrasonography (EUS) is useful for predicting the depth of early gastric cancer (EGC), the diagnostic value of EUS for submucosal (SM) invasive cancer has not been fully investigated. METHODS: We conducted a multicenter prospective study from May 2017 to January 2021 to evaluate the validity of a diagnostic strategy combining CE and EUS and to clarify the additional value of EUS for EGC suspected of SM invasion. In each case, the diagnosis was first made using CE, followed by EUS, and finally confirmed using a combination algorithm. RESULTS: A total of 180 patients with EGC were enrolled from 10 institutions, of which 175 were analyzed. The histopathological depths were M, SM1, SM2, and ≥ MP in 72, 16, 64, and 23 lesions, respectively. Treatment included 92 endoscopic submucosal dissection cases and 83 surgical cases. The overall diagnostic accuracy classified by M-SM1 or SM2-MP was 58.3% for CE, 75.7% for EUS, and 78.9% for the combination of CE and EUS; the latter two were significantly higher than that of CE alone (P < 0.001). The CE, EUS, and combination accuracy rates in 108 differentiated-type lesions were 51.9%, 77.4%, and 79.6%, respectively; the latter two were significantly higher than CE alone (P < 0.001). A significant additive effect of EUS was observed in CE-SM2 low-confidence lesions but not in CE-M-SM1 lesions or in CE-SM2 high-confidence lesions. Among the nine CE findings, irregular surface, submucosal tumor-like elevation, and non-extension signs were significant independent markers of pSM2-MP. Poorly delineated EUS lesions were misdiagnosed. CONCLUSIONS: EUS provides additional value for differentiated-type and CE-SM2 low-confidence EGCs in diagnosing invasion depth. CLINICAL REGISTRATION NUMBER: UMIN000025862.

Geriatric nutritional risk index as a prognostic indicator in elderly patients with early colorectal cancer undergoing endoscopic submucosal dissection.

OBJECTIVES: Data on the long-term outcomes of endoscopic submucosal dissection (ESD) performed in elderly patients with early colorectal cancer (CRC) are limited. We analyzed the prognosis of elderly CRC patients, not only from the viewpoint of treatment curability but also from the patients' baseline physical condition assessed by several indexes. METHODS: A retrospective analysis of 729 patients aged ≥75 years who underwent ESD for Tis/T1 CRC in 16 institutions was conducted. The patients were classified into three groups based on curability: curative ESD (Group A, n = 582), non-curative ESD with additional surgery (Group B, n = 60), and non-curative ESD without additional surgery (Group C, n = 87). Overall survival (OS) was compared among the groups, and factors associated with reduced OS were investigated. RESULTS: The median follow-up periods in Groups A, B, and C were 41, 49, and 46 months, respectively (P = 0.62), during which 92 patients died. Two patients (0.3%) in Group A, none (0%) in Group B, and three (3.4%) in Group C died of CRC. Three-year OS rates in Groups A, B, and C were 93.9%, 96.1%, and 90.1%, respectively, without a significant difference (P = 0.07). Multivariate analysis indicated low (<96.3) geriatric nutritional risk index (GNRI) as the sole independent predictor for reduced OS (hazard ratio 3.37; 95% confidence interval 2.18-5.22; P < 0.0001). CONCLUSIONS: Low GNRI, but not the curability attained by ESD, was independently associated with reduced OS in patients with early CRC aged ≥75 years.

Vascular endothelial growth factor-A is an Immunohistochemical biomarker for the efficacy of bevacizumab-containing chemotherapy for duodenal and jejunal adenocarcinoma.

BACKGROUND: The efficacy and safety of bevacizumab-containing chemotherapy for patients with metastatic duodenal and jejunal adenocarcinoma (mDJA) are unclear. The present study aimed to evaluate the efficacy of bevacizumab and to explore immunohistochemical markers that can predict the efficacy of bevacizumab for patients with mDJA. METHODS: This multicentre study included patients with histologically confirmed small bowel adenocarcinoma who received palliative chemotherapy from 2008 to 2017 at 15 hospitals. Immunostaining was performed for vascular endothelial growth factor-A (VEGF-A), TP53, Ki67, ß-catenin, CD10, MUC2, MUC5AC, MUC6, and mismatch repair proteins. RESULTS: A total of 74 patients were enrolled, including 65 patients with mDJA and 9 with metastatic ileal adenocarcinoma. Patients with mDJA who received platinum-based chemotherapy with bevacizumab as first-line treatment tended to have a longer progression-free survival and overall survival than those treated without bevacizumab (P = 0.075 and 0.077, respectively). Multivariate analysis extracted high VEGF-A expression as a factor prolonging progression-free survival (hazard ratio: 0.52, 95% confidence interval: 0.30-0.91). In mDJA patients with high VEGF-A expression, those who received platinum-based chemotherapy with bevacizumab as a first-line treatment had significantly longer progression-free survival and tended to have longer overall survival than those treated without bevacizumab (P = 0.025 and P = 0.056, respectively), whereas no differences were observed in mDJA patients with low VEGF-A expression. CONCLUSION: Immunohistochemical expression of VEGF-A is a potentially useful biomarker for predicting the efficacy of bevacizumab-containing chemotherapy for patients with mDJA.

Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice.

UNLABELLED: Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. In APAP-induced acute liver failure, hepatocyte death and subsequent liver regeneration determines the prognosis of patients, making it necessary to identify suitable therapeutic targets based on detailed molecular mechanisms. Grb2-associated binder 1 (Gab1) adaptor protein plays a crucial role in transmitting signals from growth factor and cytokine receptors to downstream effectors. In this study, we hypothesized that Gab1 is involved in APAP-induced acute liver failure. Hepatocyte-specific Gab1 conditional knockout (Gab1CKO) and control mice were treated with 250 mg/kg of APAP. After APAP treatment, Gab1CKO mice had significantly higher mortality and elevated serum alanine aminotransferase levels compared to control mice. Gab1CKO mice had increased hepatocyte death and increased serum levels of high mobility group box 1, a marker of hepatocyte necrosis. In addition, Gab1CKO mice had reduced hepatocyte proliferation. The enhanced hepatotoxicity in Gab1CKO mice was associated with increased activation of stress-related c-Jun N-terminal kinase (JNK) and reduced activation of extracellular signal-regulated kinase and AKT. Furthermore, Gab1CKO mice showed enhanced mitochondrial translocation of JNK accompanied by an increase in the release of mitochondrial enzymes into the cytosol, which is indicative of increased mitochondrial dysfunction and subsequent nuclear DNA fragmentation. Finally, in vitro experiments showed that Gab1-deficient hepatocytes were more susceptible to APAP-induced mitochondrial dysfunction and cell death, suggesting that hepatocyte Gab1 is a direct target of APAP-induced hepatotoxicity. CONCLUSION: Our current data demonstrate that hepatocyte Gab1 plays a critical role in controlling the balance between hepatocyte death and compensatory hepatocyte proliferation during APAP-induced liver injury.

Increased expression of Forkhead box M1 transcription factor is associated with clinicopathological features and confers a poor prognosis in human hepatocellular carcinoma.

AIM: Forkhead Box M1 (FoxM1) is a proliferation-specific transcription factor. In this study, we aimed to elucidate the clinicopathological and prognostic values of FoxM1 expression in human hepatocellular carcinoma (HCC) and correlate FoxM1 expression with various etiologies of liver diseases. We also investigated its therapeutic value in HCC. METHODS: We investigated the expression of FoxM1 in tumor tissues and adjacent non-tumor tissues of 79 Japanese HCC patients by quantitative real-time reverse transcription-polymerase chain reaction analysis. Depletion by siRNA or specific inhibition by siomycin A were also used to investigate the effect of FoxM1 inhibition on stem-like features of human HCC cells. RESULTS: Quantitative real-time reverse transcription-polymerase chain reaction analysis showed that tumor tissues displayed an approximately 14-fold increase in FoxM1 expression compared with adjacent non-tumor tissues. Interestingly, the expression levels of FoxM1in tumor tissues did not depend on the etiology of liver disease. The expression of FoxM1 in tumor tissues was associated with serum α-fetoprotein level, maximum tumor size, histological grade, TNM staging, and portal involvement. Kaplan-Meier analysis indicated that the high FoxM1 expression (≥median) group had a poor prognosis compared with the low FoxM1 expression (

Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice.

Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 (Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.

Secreted frizzled-related protein 5 (Sfrp5) decreases hepatic stellate cell activation and liver fibrosis.

BACKGROUND & AIMS: Obesity-related adipocytokine dysregulation is known to accelerate liver fibrosis progression. Recently, a natural Wnt5a inhibitor, secreted frizzled-related protein 5 (Sfrp5), was identified as a novel adipocytokine that has reduced expression in obese adipose tissue in both rodents and human. In addition, hepatic gene expression of Wnt5a and its receptor frizzled 2 (Fz2) is elevated during fibrosis progression. Therefore, Sfrp5 could have biological significance in liver fibrosis. METHODS: We first investigated the effects of Sfrp5 on primary cultured mouse hepatic stellate cells (HSCs) in vitro. Next, to elucidate the roles of Sfrp5 in liver fibrosis, we investigated a carbon-tetrachloride (CCl4 )-induced liver fibrosis model using Sfrp5 knockout (KO) and wild type (WT) mice in vivo. Each mouse was injected intraperitoneally with CCl4 (0.5 ml/kg) or olive oil as a single dose (acute liver injury model), or twice a week for 6 weeks (liver fibrosis model). RESULTS: In in vitro studies, Wnt5a enhanced both proliferation and migration of HSCs, and these effects could be completely blocked by Sfrp5. Moreover, siRNA knockdown of Fz2 in HSCs could block the effects of Wnt5a on both HSC proliferation and migration. In in vivo studies, there were no differences in the CCl4 -induced liver injury between KO and WT mice. Hepatic Wnt5a gene expression and plasma Wnt5a levels significantly increased after a single CCl4 injection in both mice. Sfrp5 knockout significantly enhanced CCl4 -induced liver fibrosis. CONCLUSIONS: Our findings demonstrate that Sfrp5 may ameliorate mouse liver fibrosis through inhibition of Wnt5a/Fz2 signalling.

A novel artificial intelligence-based endoscopic ultrasonography diagnostic system for diagnosing the invasion depth of early gastric cancer.

BACKGROUND: We developed an artificial intelligence (AI)-based endoscopic ultrasonography (EUS) system for diagnosing the invasion depth of early gastric cancer (EGC), and we evaluated the performance of this system. METHODS: A total of 8280 EUS images from 559 EGC cases were collected from 11 institutions. Within this dataset, 3451 images (285 cases) from one institution were used as a development dataset. The AI model consisted of segmentation and classification steps, followed by the CycleGAN method to bridge differences in EUS images captured by different equipment. AI model performance was evaluated using an internal validation dataset collected from the same institution as the development dataset (1726 images, 135 cases). External validation was conducted using images collected from the other 10 institutions (3103 images, 139 cases). RESULTS: The area under the curve (AUC) of the AI model in the internal validation dataset was 0.870 (95% CI: 0.796-0.944). Regarding diagnostic performance, the accuracy/sensitivity/specificity values of the AI model, experts (n = 6), and nonexperts (n = 8) were 82.2/63.4/90.4%, 81.9/66.3/88.7%, and 68.3/60.9/71.5%, respectively. The AUC of the AI model in the external validation dataset was 0.815 (95% CI: 0.743-0.886). The accuracy/sensitivity/specificity values of the AI model (74.1/73.1/75.0%) and the real-time diagnoses of experts (75.5/79.1/72.2%) in the external validation dataset were comparable. CONCLUSIONS: Our AI model demonstrated a diagnostic performance equivalent to that of experts.

Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice.

Our aims were to evaluate the involvement of heparin-binding EGF-like growth factor (HB-EGF) in liver fibrogenesis of humans and mice and to elucidate the effect of HB-EGF deficiency on cholestatic liver fibrosis using conditional HB-EGF knockout (KO) mice. We first demonstrated that gene expression of HB-EGF had a positive significant correlation with that of collagen in human fibrotic livers, and was increased in bile duct ligation (BDL)-induced fibrotic livers in mouse. We then generated conditional HB-EGF knockout (KO) mice using the interferon inducible Mx-1 promoter driven Cre recombinase transgene and wild type (WT) and KO mice were subjected to BDL. After BDL, KO mice exhibited enhanced liver fibrosis with increased expression of collagen, compared with WT mice. Finally, we used mouse hepatic stellate cells (HSCs) to examine the role of HB-EGF in the activation of these cells and showed that HB-EGF antagonized TGF-ß-induced gene expression of collagen in mouse primary HSCs. Interestingly, HB-EGF did not prevent the TGF-ß-induced nuclear accumulation of Smad3, but did lead to stabilization of the Smad transcriptional co-repressor TG-interacting factor. In conclusion, our data suggest a possible protective role of HB-EGF in cholestatic liver fibrosis.

Pitavastatin ameliorated the progression of steatohepatitis in ovariectomized mice fed a high fat and high cholesterol diet.

AIM: Many studies indicate an accelerated progression of non-alcoholic steatohepatitis (NASH) in postmenopausal women. Very recently, we reported that estrogen deficiency enhanced the progression of steatohepatitis in mice fed a high fat and high cholesterol (HFHC) diet. Hypercholesterolemia is often observed in postmenopausal women, and recent studies indicate it to be an important risk factor for the progression of NASH. Statins can slow NASH progression in the estrogen-deficient state but the precise mechanisms of their effects are still unclear. METHODS: We investigated the effects of pitavastatin on steatohepatitis progression using ovariectomized (OVX) mice fed a HFHC diet or HFHC + pitava diet (containing 5 p.p.m. pitavastatin) for 6 weeks. RESULTS: Serum alanine aminotransferase and cholesterol levels significantly decreased in mice fed the HFHC + pitava diet compared with mice fed the HFHC diet. Real-time reverse transcription polymerase chain reaction representing hepatic inflammatory gene expressions significantly decreased in mice fed the HFHC + pitava diet compared with the HFHC-fed mice. Pitavastatin treatment also decreased both hepatic macrophage infiltration and hepatocyte chemokine (C-C motif) ligand 2 expression and improved the liver fibrosis condition when compared with the mice fed the HFHC diet. In addition, the enhanced spleen monocyte chemokine (C-C motif) receptor 2 expression in ovariectomized mice fed the HFHC diet was also decreased by pitavastatin administration. CONCLUSION: Our study demonstrated that the exacerbated steatohepatitis progression in OVX mice fed a HFHC diet could be attenuated by pitavastatin treatment at least through inhibition of hepatic macrophage infiltration. We concluded that statins should be useful for treating NASH in postmenopausal women.

Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice.

AIM: We previously demonstrated that heparin-binding epidermal growth factor-like growth factor (HB-EGF) is induced in response to several liver injuries. Because the HB-EGF knockout (KO) mice die in utero or immediately after birth due to cardiac defects, the loss of function study in vivo is limited. Here, we generated liver-specific HB-EGF conditional knockout mice using the interferon-inducible Mx-1 promoter driven cre recombinase transgene and investigated its role during acute liver injury. METHODS: We induced acute liver injury by a single i.p. injection of carbon tetrachloride (CCl4 ) in HB-EGF KO mice and wild-type mice and liver damage was assessed by biochemical and immunohistochemical analysis. We also used AML12 mouse hepatocyte cell lines to examine the molecular mechanism of HB-EGF-dependent anti-apoptosis and wound-healing process of the liver in vitro. RESULTS: HB-EGF KO mice exhibited a significant increase of alanine aminotransferase level and also showed a significant increase in the number of apoptotic hepatocytes assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining at 24 h after CCl4 injection. We also demonstrated that HB-EGF treatment inhibited tumor necrosis factor-α-induced apoptosis of AML12 mouse hepatocytes and promoted the wound-healing response of these cells. CONCLUSION: This study showed that HB-EGF plays a protective role during acute liver injury.

Adiponectin negatively correlates with alcoholic and non-alcoholic liver dysfunction: Health check-up study of Japanese men.

AIM: Central obesity, insulin resistance and alcohol consumption are thought to be major risk factors for fatty liver formation. Adiponectin (APN) prevents fatty liver formation, and its serum levels are lower in subjects with central obesity and/or insulin resistance. The aim of this study was to explore the association among serum APN levels, central obesity, insulin resistance and liver dysfunction with or without fatty liver classified by alcohol consumption in healthy subjects. METHODS: A total of 5588 Japanese male subjects who underwent a health check-up were classified into three groups according to alcohol consumption: non- or light drinkers (15 g/day ≥ ethanol); mild drinkers (15 g/day < ethanol ≤ 30 g/day); and moderate- or heavy drinkers (30 g/day < ethanol). Central obesity and insulin resistance were assessed by waist circumference (WC) and Homeostasis Model of Assessment - Insulin Resistance (HOMA-IR), respectively. RESULTS: WC was significantly increased, while HOMA-IR was significantly decreased according to the extent of alcohol consumption. Serum alanine aminotransferase levels were significantly lower and serum APN levels were significantly higher in mild drinkers than in the other two groups. Multiple linear regression analysis showed that serum APN level served as the significant and independent determinant for liver dysfunction in the subjects with fatty liver, irrespective of alcohol consumption. However, WC became a non-significant determinant of liver dysfunction as alcohol consumption increased. CONCLUSION: Hypoadiponectinemia is a significant determinant for steatotic dysfunction for all levels of alcohol consumption, but central obesity was not a significant determinant for alcoholic fatty liver-induced liver dysfunction.

Protective role of adiponectin against ethanol-induced gastric injury in mice.

Adiponectin is an anti-inflammatory molecule released from adipocytes, and serum adiponectin concentrations are reduced in obesity. We previously reported that gastric erosion occurs in association with obesity and low serum adiponectin levels. In the present study, we examined adiponectin-knockout (APN-KO) mice to elucidate the role of adiponectin in gastric mucosal injury. Gastric injury was induced by oral administration of ethanol in wild-type (WT) and APN-KO mice. Ethanol treatment induced severe gastric injury in APN-KO mice compared with WT mice. In APN-KO mice, increased apoptotic cells and decreased expression of prostaglandin E(2) (PGE(2)) were detected in the injured stomach. We next assessed the effect of adiponectin on the cellular response to ethanol treatment and wound repair in rat gastric mucosal cells (RGM1). Adiponectin induced the expression of PGE(2) and cyclooxygenase 2 (COX-2) in ethanol-treated RGM1 cells. RGM1 cells exhibited efficient wound repair accompanied by increased PGE(2) expression in the presence of adiponectin. Coadministration of adiponectin with celecoxib, a COX-2 inhibitor, inhibited efficient wound repair. These findings indicate that adiponectin has a protective role against ethanol-induced gastric mucosal injury in mice. This effect may be partially mediated by the efficient wound repair of epithelial cells via increased PGE(2) expression.

Elderly onset age is associated with low efficacy of first anti-tumor necrosis factor treatment in patients with inflammatory bowel disease.

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns.

Estrogen deficiency worsens steatohepatitis in mice fed high-fat and high-cholesterol diet.

Recent studies indicate an accelerated progression of nonalcoholic steatohepatitis (NASH) in postmenopausal women. Hypercholesterolemia, an important risk factor for NASH progression, is often observed after menopause. This study examined the effects of estrogen on NASH in ovariectomized (OVX) mice fed a high-fat and high-cholesterol (HFHC) diet. To investigate the effects of estrogen deficiency, OVX mice and sham-operated (SO) mice were fed normal chow or HFHC diet for 6 wk. Next, to investigate the effects of exogenous estrogen replenishment, OVX mice fed with HFHC diet were treated with implanted hormone release pellets (containing 17ß-estradiol or placebo vehicle) for 6 wk. OVX mice on the HFHC diet showed enhanced liver injury with increased liver macrophage infiltration and elevated serum cholesterol levels compared with SO-HFHC mice. Hepatocyte monocyte chemoattractant protein-1 (MCP1) protein expression in OVX-HFHC mice was also enhanced compared with SO-HFHC mice. In addition, hepatic inflammatory gene expressions, including monocytes chemokine (C-C motif) receptor 2 (CCR2), were significantly elevated in OVX-HFHC mice. Estrogen treatment improved serum cholesterol levels, liver injury, macrophage infiltration, and inflammatory gene expressions in OVX-HFHC mice. Moreover, the elevated expression of liver CCR2 and MCP1 were decreased by estrogen treatment in OVX-HFHC mice, whereas low-density lipoprotein dose dependently enhanced CCR2 expression in THP1 monocytes. Our study demonstrated that estrogen deficiency accelerated NASH progression in OVX mice fed HFHC diet and that this effect was improved by estrogen therapy. Hypercholesterolemia in postmenopausal women would be a potential risk factor for NASH progression.

[Bronchogenic cyst in the abdomen--a case report].

A man in his thirties with epigastric pain was referred to our hospital for detailed examinations. Abdominal computed tomography showed an abdominal cystic lesion with a longest dimension of 7 cm, located behind the stomach. Endoscopic ultrasonography through the stomach showed a cystic lesion and the wall of the lesion revealed continuity to the proper muscle layer of the gastric wall. Therefore, gastric duplication was suspected and the cystic lesion was resected because of the possibility of malignancy and also for a definitive diagnosis. The cystic lesion consisted of columnar ciliated epithelium, seromucous glands, smooth muscle and cartilage and was diagnosed as a bronchogenic cyst. Bronchogenic cysts are sometimes encountered in the thoracic or mediastinal area, but abdominal bronchogenic cysts, such as the present case, are extremely rare.

Efficacy of an endo-knife with a water-jet function (Flushknife) for endoscopic submucosal dissection of superficial colorectal neoplasms.

OBJECTIVES: Endoscopic submucosal dissection (ESD) is currently not a common treatment for colorectal neoplasms because it is time consuming and technically difficult. Flushknife--an electrosurgical endo-knife with a water-jet function--is expected to reduce the difficulty of colorectal ESD. The objective of this study was to investigate the efficacy of a water-jet function for colorectal ESD. METHODS: This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. A total of 49 patients, with a total of 51 superficial colorectal neoplasms (median tumor size of 30 mm), were enrolled and randomly assigned to undergo ESD using either the Flexknife (electrosurgical endo-knife without a water-jet function) or the Flushknife. Tumors were resected by ESD using each endo-knife. The procedures were conducted by two endoscopists. Operation time was defined as the main outcome measure. RESULTS: En bloc resection was achieved in 23 out of 26 (88%) lesions in the Flexknife group and in 24 out of 24 (100%) lesions in the Flushknife group. The mean operation time (95% confidence interval) was 87.3 (71.3-103.4) min in the Flexknife group and 61.0 (49.3-72.7) min in the Flushknife group (P=0.02). The Flushknife reduced the number of endoscopic device changes (P=0.001), the number of submucosal injections (P=0.001), and the mean amount of injected hyaluronate sodium (P=0.001) compared with the Flexknife. No severe adverse events were observed in either group. CONCLUSIONS: Without increasing adverse events, the endo-knife with a water-jet function efficiently reduced the operation time of colorectal ESD in patients with large superficial colorectal neoplasms. (University hospital Medical Information Network Clinical Trials Registry number UMIN000001302).

Endoscopic Doppler US for the prevention of ulcer bleeding after endoscopic submucosal dissection for early gastric cancer: a preliminary study (with video).

BACKGROUND: After endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), delayed bleeding occurs in 1.7% to 38% of cases. Routine coagulation of all nonbleeding visible vessels (NBVVs) in post-ESD ulcers is currently performed as standard practice, but it cannot eliminate bleeding. An endoscopic Doppler US (DOP-US) probe system has possible benefits for the prediction of recurrent bleeding in peptic ulcer hemorrhage. OBJECTIVE: To establish optimum use and evaluate feasibility of DOP-US for post-ESD ulcers. DESIGN: Case series study. SETTING: Cancer referral center. PATIENTS: Eight patients with mucosal EGC larger than 2 cm without ulceration or scarring and 2 patients with EGC less than 3 cm with scarring. INTERVENTIONS: We searched for a positive DOP-US signal (DOP-US+), which was defined as pulsatile sound at a depth of 1.5 mm, and NBVVs or areas with DOP-US+ were coagulated with hemostatic forceps. A multibending, double-channel videoendoscope that was fitted with a transparent hood was used. MAIN OUTCOME MEASUREMENTS: Detectability of DOP-US signals in post-ESD ulcers. RESULTS: One of 13 oozing bleeding sites, 24 (18%) of 136 NBVVs, and 7 areas without any bleeding stigmata had DOP-US+ and were coagulated until the signal became silent. One hundred twelve NBVVs (82%) and 8 adherent clots without DOP-US signals were left untreated. No delayed bleeding was experienced at 30 days. Median time required for Doppler examination was 34 minutes, but it improved to 18 and 19 minutes in patients 9 and 10, respectively. CONCLUSIONS: DOP-US might be helpful in the endoscopic management of post-ESD ulcers in EGC. Our setting and maneuver warrant further investigation to clarify whether DOP-US can reduce delayed bleeding and avoid unnecessary coagulation for NBVVs in post-ESD ulcers.

Autofluorescence imaging with a transparent hood for detection of colorectal neoplasms: a prospective, randomized trial.

BACKGROUND: Colonoscopy is one of the most reliable methods for detection of colorectal neoplasms, but conventional colonoscopy can miss some lesions. OBJECTIVE: To evaluate the efficacy of autofluorescence imaging (AFI) with a transparent hood (TH) for detection of colorectal neoplasms. DESIGN: A 2 × 2 factorial designed, prospective, randomized, controlled trial. SETTING: This study was conducted at the Osaka Medical Center for Cancer and Cardiovascular Diseases, a tertiary cancer center. PATIENTS: A total of 561 patients. INTERVENTIONS: Patients were allocated to 1 of 4 groups: (1) white light imaging (WLI) alone--colonoscopy using WLI without a TH; (2) WLI+TH--colonoscopy using WLI with a TH; (3) AFI alone--colonoscopy using AFI without a TH; and (4) AFI+TH--colonoscopy using AFI with a TH. Eight colonoscopists used each allocated method. MAIN OUTCOME MEASUREMENT: The difference in neoplasm detection rate (number of detected neoplasms per patient) between the WLI alone and AFI+TH groups. RESULTS: Neoplasm detection rate (95% confidence interval) in the AFI+TH group was significantly higher than in the WLI alone group (1.96 [1.50-2.43] vs 1.19 [0.93-1.44]; P = .023, Tukey-Kramer multiple comparison test). Relative detection ratios (95% confidence interval) for polypoid neoplasms based on Poisson regression model were significantly increased by mounting a TH (1.69 [1.34-2.12], P < .001), and relative detection ratios for flat neoplasms were significantly increased by AFI observation (1.83 [1.24-2.71], P = .002). LIMITATIONS: Open trial performed in single cancer referral center. CONCLUSION: AFI colonoscopy with a TH detected significantly more colorectal neoplasms than did conventional WLI colonoscopy without a TH.