A Case of Esophageal MALT Lymphoma Mimicking a Subepithelial Tumor.

Mucosa-associated lymphoid tissue (MALT) lymphoma, also known as extranodal marginal zone lymphoma, is a low-grade B-cell lymphoma that can develop in the mucosal layer of various organs, including the gastrointestinal tract, salivary glands, lungs, and skin. The most common site is the gastrointestinal tract, particularly the stomach. On the other hand, primary esophageal lymphomas are extremely rare. MALT lymphomas can undergo histological transformation into more aggressive B-cell lymphomas, such as diffuse large B-cell lymphoma, resulting in a poor prognosis. This paper reports a rare case of primary esophageal MALT lymphoma mimicking a subepithelial tumor located in the lower esophagus that was treated successfully with radiotherapy. MALT lymphoma should be included in a differential diagnosis when subepithelial tumors are found in the esophagus, particularly if endoscopic ultrasonography reveals the tumor to be located in the deep mucosal and submucosal layers. Following the precise diagnosis, accurate staging and appropriate treatment are crucial. Regular follow-up is necessary to assess the possibility of recurrence or transformation to high-grade lymphoma.

Single-nucleotide polymorphisms link gout with health-related lifestyle factors in Korean cohorts.

Gout-a very painful inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints-is influenced by several factors. We identified the association of single- nucleotide polymorphisms (SNPs) that link gout with health-related lifestyle factors using genomic data from the Korean Genome and Epidemiology Study. We conducted a genome-wide association study (GWAS) on 18,927 samples of 438 Korean patients with gout and 18,489 controls for the discovery stage. For the replication stage, another batch containing samples of 326 patients with gout and 2,737 controls were analyzed. Lastly, a meta-analysis was performed using these two cohorts. We analyzed the effects of health-related lifestyle factors, including eating habits, physical activity, drinking behavior, and smoking behavior, on gout. After identifying the association between GWAS-derived SNPs and health-related lifestyle factors, we confirmed the interaction between the polygenic risk score (PRS) and health-related lifestyle factors. We identified 15 SNPs related to gout, among which rs1481012 of ABCG2 located on chromosome 4 has been newly discovered (P = 2.46e-11). On examining the interaction between SNPs and health-related lifestyles, rs3109823-located in ABCG2-was found to be associated with smoking status. In addition, rs11936395-located in SLC2A9-was significantly associated with the average momentum of exercise per session, whereas rs11066325 located in PTPN11, showed a significant association with the number of exercise sessions per week, smoking status, drinking status, and amount of soju drink per session. rs9421589-located in FAM35A-was significantly associated with the duration of smoking. In addition, we verified that the association between PRS and duration of smoking affects gout. Thus, in this study, we identified novel SNPs that link gout with health-related lifestyle factors in the Korean population.

Efficacy of Tegoprazan in Patients with Laryngopharyngeal Reflux Disease: A Preliminary Feasibility Study.

Tegoprazan is a novel, potent, and highly selective potassium-competitive acid blocker that inhibits gastric acid secretion with rapid onset of action and prolonged control of gastric acidity. We performed a preliminary feasibility study to evaluate whether tegoprazan could control symptoms more effectively than a placebo in patients with laryngopharyngeal reflux disease (LPRD). In this double-blind, randomized, placebo-controlled trial, 35 patients with LPRD were randomly assigned to two groups: tegoprazan 50 mg daily and placebo. The primary endpoint was the complete resolution rate of LPRD symptoms after 8 weeks of medication, and the secondary endpoints were the complete resolution rate of LPRD symptoms after 4 weeks of medication and changes in the reflux symptom index (RSI) and reflux finding score (RFS) from baseline at 4 and 8 weeks of medication. There was no difference in the complete symptom resolution rates at 8 weeks between the tegoprazan and placebo groups (29.4% [5/17] vs. 27.8% [5/18], p = 1.000). Moreover, there was no significant difference in the complete symptom resolution rates at 4 weeks between the two groups. Compared with the baseline, both tegoprazan and placebo significantly reduced the total RSI and RFS scores after 4 and 8 weeks of medication; however, tegoprazan was not superior to the placebo. In conclusion, tegoprazan (50 mg daily) administration improved LPRD symptoms and signs. However, tegoprazan did not show superiority over placebo. Considering the potential effectiveness of tegoprazan as an acid-suppressing therapy and the possibility of type II error due to a low number of included patients herein, prospective, large-scale, multi-center studies with a higher dose of tegoprazan for a prolonged duration are required to elucidate the efficacy of tegoprazan in patients with LPRD. (ClinicalTrials.gov: NCT05871398).

Associations between the Genetic Heritability of Dyslipidemia and Dietary Patterns in Korean Adults Based on Sex Differences.

Dyslipidemia can be defined as an abnormality in serum lipid levels that is substantially linked to genetic variations and lifestyle factors, such as diet patterns, and has distinct sex-specific characteristics. We aimed to elucidate the genetic impact of dyslipidemia according to sex and explore the associations between genetic variants and dietary patterns in large-scale population-based cohorts. After performing genome-wide association studies (GWASs) in male, female, and entire cohorts, significant single nucleotide polymorphisms (SNPs) were identified in the three groups, and genetic risk scores (GRSs) were calculated by summing the risk alleles from the selected SNPs. After adjusting for confounding variables, the risk of dyslipidemia was 2.013-fold and 2.535-fold higher in the 3rd quartile GRS group in the male and female cohorts, respectively, than in the 1st quartile GRS group. While instant noodle and soft drink intake were significantly associated with GRS related to hyperlipidemia in male cohorts, coffee consumption was substantially related to GRS related to hyperlipidemia in female cohorts. Considering the influence of genetic factors and dietary patterns, the findings of this study suggest the potential for implementing sex-specific strategic interventions to avoid dyslipidemia.

Magnifying Endoscopy with Narrow-Band Imaging for Duodenal Neuroendocrine Tumors.

Duodenal neuroendocrine tumors (NETs) are rare subepithelial tumors that arise from the neuroendocrine cells beneath the epithelial layer. However, an accurate histopathological diagnosis is difficult when tissue samples are obtained using conventional endoscopic forceps biopsy alone. This study aimed to evaluate the magnifying endoscopy with narrow-band imaging (ME-NBI) findings of duodenal NETs. We retrospectively analyzed a database of 22 duodenal NETs from 21 patients who underwent ME-NBI between January 2011 and June 2022. The ME-NBI, endosonographic, and histopathologic findings of duodenal NETs were analyzed. Nineteen lesions were located in the bulb, two were located in the superior duodenal angle, and one was located in the second portion of the duodenum. Eighteen lesions (82%) had IIa morphology, and nine (41%) had central depression on the surface. On endoscopic ultrasonography, almost all lesions (20/22, 91%) were located in the second and/or third layers, and the median tumor size was 6 mm. During ME-NBI, the microsurface pattern was regular in 18 lesions (82%) and absent in 4 (18%). The microvascular pattern was regular in 17 lesions (77%), irregular in 4 (18%), and absent in 1 (5%). Thickened subepithelial vessels were observed in 15 (68%) lesions. There was no difference in tumor size according to the presence or absence of thickened subepithelial vessels (6.1 ± 1.8 mm vs. 5.9 ± 3.8 mm, p = 0.860). In conclusion, the characteristic ME-NBI findings of duodenal NETs were regular microsurface and microvascular patterns and the presence of thickened subepithelial vessels. These ME-NBI features may be useful for differentiating duodenal NETs from other duodenal subepithelial lesions.

Sex-related differences in single nucleotide polymorphisms associated with dyslipidemia in a Korean population.

BACKGROUND: The prevalence of dyslipidemia has increased steadily in Korea, and the incidence of dyslipidemia differs by sex. In this study, we identified single nucleotide polymorphisms (SNPs) related to dyslipidemia in Korean cohorts through genome-wide association study (GWAS) analysis. METHODS: Genotyping was conducted to determine the genotypes of 72,298 participants and investigate genotypes for 7,079,946 SNPs. Sex, age, and BMI were set as covariates for GWAS, and significant SNPs were identified in the discovery and replication stages using logistic regression. RESULTS: GWAS of the entire cohort revealed a total of five significant SNPs: rs117026536 (LPL), rs651821 (APOA5), rs9804646 (APOA5), rs9926440 (CETP), and rs429358 (APOE). GWAS of the male subjects revealed a total of four significant SNPs. While rs9804646 (APOA5) and rs429358 (APOE) were significant for all the subjects, rs662799 (APOA5) and rs56156922 (CETP) were significant only for the male subjects. GWAS of the female subjects revealed two significant SNPs, rs651821 (APOA5) and rs9804646 (APOA5), both of which were significant in all the subjects. CONCLUSION: This is the first study to identify sex-related differences in genetic polymorphisms in Korean populations with dyslipidemia. Further studies considering environmental variables will be needed to elucidate these sex-related genetic differences in dyslipidemia.

Randomized Controlled Trial Comparing the Efficacy of Sustained-Release Formula of Mosapride-Plus-Esomeprazole Combination Therapy to Esomeprazole Monotherapy in Patients with Gastroesophageal Reflux Disease.

We aimed to evaluate whether adding a sustained-release (SR) formula of mosapride to proton-pump inhibitors (PPIs) would be more effective in controlling symptoms than PPI alone in patients with gastroesophageal reflux disease (GERD). Sixty patients with heartburn and/or regurgitation were randomly assigned to two groups: mosapride SR 15 mg combined with esomeprazole 20 mg once daily (ME group) and esomeprazole 20 mg once daily alone (E group). The primary endpoint was the complete-resolution rate of GERD symptoms after eight-week medication, and the secondary endpoints were the complete-resolution rate of GERD symptoms after four-week medication, symptom-improvement rates ≥ 50% after four- and eight-week medication, and change in reflux-disease-questionnaire (RDQ) and GERD-health-related quality-of-life (GERD-HRQL) scores from baseline at four- and eight-week medication. No significant differences in complete-symptom-resolution rates at eight weeks and four weeks or in the changes in RDQ and GERD-HRQL scores from baseline at four- and eight-week medication were observed between the ME and E groups. The symptom-improvement rate of ≥50% after four and eight weeks was comparable between both groups. Adding mosapride SR to esomeprazole in patients with GERD provides no additional benefits in controlling GERD symptoms.

Anti-Tumor Effects of Wee1 Kinase Inhibitor with Radiotherapy in Human Cervical Cancer.

Although the concurrent use of a chemotherapeutic agent and radiotherapy improves survival in patients with locally advanced or recurrent cervical cancer, severe side effects related to chemotherapy are frequent and may result in a low quality of life for the patients. In this study, we investigated the effects of a combination of Wee1 inhibitor (AZD1775) and irradiation in cervical cancer. In vitro effects of AZD1775 with irradiation in human cervical cancer cells were assessed by clonogenic survival and apoptosis assays. The effects on DNA damage response signaling and the cell cycle were also explored. Tumor growth delay was evaluated to investigate the in vivo effects of AZD1775 with irradiation in cervical cancer mouse models, including xenografts and patient-derived xenografts (PDXs). The co-treatment of AZD1775 and irradiation significantly decreased clonogenic survival and increased apoptosis in cervical cancer cells. These effects were associated with G2 checkpoint abrogation which resulted in persistent DNA damage. Both in the xenografts and the PDXs, the co-treatment significantly decreased tumor growth compared tothe irradiation alone (p < 0.05). These results demonstrate that the Wee1 inhibitor (AZD1775) can be considered as a potential alternative as a radiosensitizer in cervical cancer instead of a chemotherapeutic agent such as cisplatin.

Clinical Application of Circulating Tumor Cells in Gastric Cancer.

Early detection and accurate monitoring of cancer is important for improving clinical outcomes. Endoscopic biopsy and/or surgical resection specimens are the gold standard for diagnosing gastric cancer and are also useful for selecting therapeutic strategies based on the analysis of genomic/immune parameters. However, these approaches cannot be easily performed because of their invasiveness and because these specimens do not always reflect tumor dynamics and drug sensitivities during therapeutic processes, especially chemotherapy. Accordingly, many researchers have tried to develop noninvasive novel biomarkers that can monitor real-time tumor dynamics for early diagnosis, prognostic evaluation, and prediction of recurrence and therapeutic efficacy. Circulating tumor cells (CTCs) are metastatic cells that are released from the primary tumors into the blood stream and comprise a crucial step in hematogenous metastasis. CTCs, as a liquid biopsy, have received a considerable amount of attention from researchers since they are easily accessible in peripheral blood, avoiding the invasiveness associated with traditional biopsy techniques; they can also be used to derive clinical information for monitoring disease status. In this review, with respect to CTCs, we summarize the metastatic cascade, detection methods, clinical applications, and prospects for patients with gastric cancer.

Continuous Infusion versus Intermittent Dosing with Pantoprazole for Gastric Endoscopic Submucosal Dissection.

Background/Aims: Proton pump inhibitors are widely used to prevent gastric endoscopic submucosal dissection (ESD)-related bleeding, but no standard administration regimens have been established. We aimed to prospectively compare the effects of continuous infusion and intermittent dosing with pantoprazole on preventing gastric ESD-related bleeding. Additionally, we analyzed the risk factors for bleeding. Methods: From April 2012 to May 2013, patients with a gastric epithelial neoplasm scheduled for ESD in the Pusan National University Hospital were randomly assigned to one of two groups according to the pantoprazole administration regimen (continuous infusion or intermittent dosing). The primary outcomes measured were intra- and postprocedural bleeding events. Results: The final analysis included 401 patients. The rate of significant intraprocedural bleeding was 25.4% in the C group and 24.0% in the I group, with no significant difference (p=0.419). In addition, there was no significant difference in the postprocedural bleeding rate between the C and I groups (11.7% vs 10.2%, p=0.374). Multivariate analysis showed that intraprocedural bleeding was associated with the proximal tumor location, the presence of fibrosis, and the size of the resected specimen, whereas postprocedural bleeding was associated with the size of the resected specimen and the procedure/coagulation time. Conclusions: Intermittent dosing with pantoprazole is sufficient and cost-effective for the prevention of gastric ESD-related bleeding. Operators should consider tumor characteristics when planning ESD to minimize the risk of intraprocedural bleeding, and patients with large iatrogenic ulcers should be carefully monitored for postprocedural bleeding.

Case of Bleeding Ileal Varices after a Colectomy Diagnosed by Capsule Endoscopy.

We report a case of bleeding ileal varices associated with intra-abdominal adhesions after colectomy which was successfully diagnosed using capsule endoscopy. A 77-year-old woman visited the emergency department for several episodes of melena. She had a medical history of neoadjuvant chemo-radiation therapy and subsequent surgery for rectal cancer 6 years previously. Conventional diagnostic examinations including upper endoscopy, colonoscopy, and abdominal computed tomography could not detect any bleeding focus, however, following capsule endoscopy revealed venous dilatations with some fresh blood in the distal ileum, indicating bleeding ileal varices. The patient underwent exploratory laparotomy and the affected ileum was successfully resected. No further gastrointestinal bleeding occurred during the 6 months follow-up. Small intestinal varices are important differential for obscure gastrointestinal bleeding especially in patients with a history of abdominal surgery in the absence of liver cirrhosis, and capsule endoscopy can be a good option for diagnosing small intestinal varices.

Magnifying endoscopy with narrow-band imaging for gastric heterotopic pancreas.

BACKGROUND AND STUDY AIMS: Heterotopic pancreas is a common subepithelial lesion in the stomach. However, its histological diagnosis is difficult when tissue samples are obtained with a conventional biopsy forceps. This study aimed to describe the magnifying endoscopy with narrow-band imaging (ME-NBI) features of gastric heterotopic pancreas. PATIENTS AND METHODS: We retrospectively analyzed a database of all patients who underwent endoscopic ultrasonography (EUS) at Pusan National University Hospital from January 2010 to December 2010. Thirty-six patients with endosonographically diagnosed heterotopic pancreas who underwent ME-NBI and endoscopic ultrasonography (EUS) simultaneously were studied. The ME-NBI features of their lesions were analyzed. RESULTS: Thirty lesions were located in the antrum and six in the body. Six lesions (17 %) showed umbilication or central dimpling on the surface, and nine (25 %) had a macroscopic opening on the surface. On ME-NBI, a microscopic opening was identified in 22 (81 %) of 27 lesions wherein a macroscopic opening was not observed during conventional endoscopy. Macroscopic or microscopic opening was observed in 31 lesions (86 %). The frequency of macroscopic or microscopic opening was higher in lesions with anechoic duct-like structures than in lesions without such structures on EUS (91 % [29/32] vs 50 % [2/4], P  = 0.027). Focal loss of microsurface structure and presence of a thickened submucosal vessel were observed in 6 (17 %) and 5 lesions (14 %), respectively. CONCLUSIONS: The characteristic ME-NBI feature of heterotopic pancreas is presence of a microscopic opening on its surface. This ME-NBI feature is potentially useful for differentiating heterotopic pancreas from other gastric subepithelial tumors.

Endoscopic submucosal dissection for esophagogastric junction tumors: a single-center experience.

BACKGROUND: Surgical resection for esophagogastric junction (EGJ) tumors is more aggressive and worsens the quality of life of the patients and leads to poor prognosis even after surgery compared with tumors in other sites of the stomach. Endoscopic submucosal dissection (ESD) is a widely accepted treatment modality for premalignant lesions and early cancers in the stomach. However, EGJ tumor is one of the most technically difficult lesions to resect by ESD. Therefore, this study aimed to evaluate the therapeutic outcomes of ESD for EGJ epithelial neoplasms and to assess the predictive factors for incomplete resection. METHODS: We conducted a retrospective observational study of 48 patients who underwent ESD for adenomas and early cancers of the EGJ between March 2006 and November 2015 at the Pusan National University Hospital. Therapeutic outcomes of ESD and procedure-related adverse events were analyzed. RESULTS: En bloc resection, complete resection, and curative resection rates were 96, 77, and 71%, respectively. Multivariate analyses showed that the presence of ulceration was an independent predictive factor for incomplete resection (odds ratio 21.3, 95% confidence interval 1.51-298.49; p = 0.023). The procedure-related bleeding, perforation, and stenosis rates were 8, 4, and 0%, respectively; none of the adverse events required surgical intervention. During a median follow-up period of 25 months (range 6-72 months), local recurrence occurred in four patients with incomplete resection. CONCLUSION: ESD is an effective, safe, and feasible treatment for EGJ epithelial neoplasms. However, the complete resection rate decreases for tumors with ulceration.

Long-term outcome of endoscopic submucosal dissection is comparable to that of surgery for early gastric cancer: a propensity-matched analysis.

BACKGROUND: Data concerning the long-term outcomes of endoscopic submucosal dissection (ESD) versus surgery for early gastric cancer (EGC) are limited. We aimed to compare the long-term outcomes of ESD and surgery for patients with EGC. METHODS: Data were reviewed from patients treated by ESD or surgery for EGC in 2005-2010. The primary outcome was overall survival (OS). Secondary outcomes were disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), treatment-related complications, and hospital stay duration. RESULTS: Among 617 patients, 342 underwent ESD and 275 underwent surgery. The 5-year OS rates were similar between the ESD group and the surgery group (96.9% vs 98.1%, P = 0.581). In a propensity-score-matched analysis of 117 pairs, there were no significant differences in the OS rates (96.5% vs 99.1%, P = 0.125) and DSS rates (100% vs 99.1%, P = 0.317) between the ESD group and the surgery group. The ESD group had a significantly lower DFS rate (90.3% vs 98.0%, P = 0.002), a significantly lower RFS rate (95.1% vs 98.0%, P = 0.033), a significantly higher early complication rate (6.7% vs 1.5%, P < 0.001), a significantly lower late complication rate (0% vs 9.1%, P < 0.001), and a significantly shorter median hospital stay (3 days vs 10 days, P < 0.001) than the surgery group. CONCLUSIONS: ESD and surgery have comparable OS rates in patients with EGC. ESD has benefits, including a lower late complication rate and shorter hospital stay. However, RFS and DFS rates might be lower after ESD than after surgery.

Analysis of computed tomographic findings according to gastroesophageal flap valve grade.

BACKGROUND/AIMS: The gastroesophageal junction is an important barrier against gastroesophageal ref lux. Endoscopic grading of gastroesophageal f lap valve is simple, reproducible, and may predict reflux activity. We investigated the correlation between gastroesophageal flap valve grade and the gastroesophageal junction's structural properties using abdominal computed tomography. METHODS: A total of 138 patients with early gastric cancer who underwent both pre-treatment esophagogastroduodenoscopy and water-distended stomach two-phase computed tomography were enrolled. Endoscopic gastroesophageal f lap valve grade and abdominal computed tomography findings were analyzed to assess anatomical factors including the gastroesophageal junction and related organs. RESULTS: The angle of His increased significantly with gastroesophageal flap valve grade (grade I, 65.2˚ ± 19.6˚; grade II, 66.6˚ ± 19.8˚; grade III, 76.7˚ ± 11.9˚; grade IV, 120.0˚ ± 30.3˚; p < 0.001), as did the size of the diaphragmatic hiatus (grade I, 213.0 ± 53.8 mm2 ; grade II, 232.6 ± 71.0 mm2 ; grade III, 292.3 ± 99.2 mm2 ; grade IV, 584.4 ± 268.3; p < 0.001). The length of the abdominal esophagus decreased as gastroesophageal flap valve grade increased (grade I, 34.6 ± 5.8 mm; grade II, 32.0 ± 6.5 mm; grade III, 24.6 ± 7.8 mm; grade IV, -22.6 ± 38.2 mm; p < 0.001). There was no significant relationship between gastroesophageal flap valve grade and visceral and subcutaneous fat areas (p = 0.877 and p = 0.508, respectively). CONCLUSIONS: Endoscopic grading of the gastroesophageal flap valve is well correlated with anatomical changes around the gastroesophageal junction on abdominal computed tomography, and it can provide useful information about the anti-reflux barrier.

Endoscopic submucosal dissection for undifferentiated-type early gastric cancer: short- and long-term outcomes.

BACKGROUND AND AIMS: Application of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancers (EGCs) remains controversial owing to limited data regarding long-term outcomes. We aimed to evaluate the feasibility of ESD for undifferentiated-type EGCs that meet the expanded criteria (EC). METHODS: We performed a retrospective analysis of 66 patients who underwent ESD for undifferentiated-type EGC between January 2005 and December 2014. We evaluated the rates of en bloc, complete, and curative resections along with overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS). RESULTS: Of the 66 patients, the EC group included 38 patients and the beyond-EC group included 28 patients. The overall rates of en bloc, complete, and curative resection of the 66 lesions were 92.4% (61/66), 65.2% (43/66), and 48.5% (32/66), respectively. Of the 34 patients with non-curative resection, 18 underwent additional surgery. Local remnant cancer was detected in 1 patient (1/18, 5.6%), and none of the 18 patients had lymph node metastasis. On multivariate analysis, tumors > 2 cm [odd ratio (OR) 6.183, 95% confidence interval (CI) 1.279-29.880, p = 0.023) and submucosal invasion depth (OR 6.226, 95% CI 1.881-20.606, p = 0.003) were independent predictors of incomplete resection. All 26 patients with more than 1 year of follow-up after curative resection survived without any evidence of local or distant recurrences over a median follow-up period of 36 months. The OS, DSS, and RFS rates of patients with curative ESD were 93.8, 100, and 100%, respectively. CONCLUSIONS: ESD may have favorable long-term outcomes in patients with undifferentiated-type EGC after curative resection.

A Rare Case of Early Gastric Cancer Combined with Underlying Heterotopic Pancreas.

Heterotopic pancreas in the stomach is usually asymptomatic and benign. Here, we presented a rare case of an early gastric cancer overlying a heterotopic pancreas. A 48-year-old woman underwent esophagogastroduodenoscopy, which revealed a subepithelial mass measuring 2.0×1.5 cm on the gastric antrum with a 1-cm erosive erythematous discoloration on the surface. A biopsy specimen showed moderately differentiated tubular adenocarcinoma. Endosonography showed a heterogeneous hypoechoic mass measuring 1.3×0.6 cm, with indistinct margins in the second and third layers of the gastric wall; anechoic tubular structures within the mass were suggestive of heterotopic pancreas. Distal gastrectomy was performed, which confirmed an early gastric cancer confined to the mucosa, and a separate underlying heterotopic pancreas. Although heterotopic pancreas is most likely benign, careful endoscopic observation of the mucosal surface is necessary to avoid overlooking a coincident early gastric cancer.

The anti-cancer effects of itraconazole in epithelial ovarian cancer.

We assessed the anti-proliferative activity of itraconazole using an EOC cell line (SKOV3ip1) and endothelial cell lines (HUVEC & SVEC4-10). We also examined angiogenesis (VEGFR2, p-ERK, p-PLCr1/2), hedgehog (Gli1, Ptch1, SMO), and mTOR (pS6K1) signaling pathways to determine the mechanism of action of itraconazole. Furthermore, we evaluated the synergistic effects of itraconazole and paclitaxel using orthotopic mouse models with established EOC cells (SKOV3ip1 or HeyA8) as well as patient-derived xenografts (PDXs). Itraconazole treatment inhibited proliferation of endothelial cells in a dose-dependent manner, but had no effect on EOC cells. The endothelial cell antiproliferative effect was associated with inhibition of hedgehog, and mTOR pathways and angiogenesis. In xenograft models of EOC using SKOV3ip1 or HeyA8, mice treated with the combination of itraconazole and paclitaxel had significantly decreased tumor weight than the control, paclitaxel-alone, or itraconazole-alone groups. Tissue derived from these tumors had significantly lower microvessel density than tissue from the other groups as well as hedgehog and mTOR pathway inhibition. We confirmed those effects in two EOC PDX models. These results suggest that itraconazole selectively inhibits endothelial cells rather than cancer cells by targeting multiple pathways including hedgehog, and mTOR pathways and angiogenesis.

New magnifying endoscopic classification for superficial esophageal squamous cell carcinoma.

AIM: To assess the accuracy of a new magnifying endoscopy (ME) classification for predicting depth of invasion of superficial esophageal squamous cell carcinoma (SESCC). METHODS: This study included a total of 70 lesions in 69 patients with SESCC who underwent ME with narrow-band imaging (ME-NBI) before resection from August 2010 to July 2016. Accuracy of ME-NBI for predicting depth of invasion of SESCC was analyzed by using a new ME classification proposed by the Japan Esophageal Society (JES), and interobserver agreement was assessed. RESULTS: Overall accuracy of ME-NBI for estimating depth of invasion of SESCC was 78.6%. Sensitivity and specificity of type B1 for tumors limited to the epithelial layer (m1) or invading into the lamina propria (m2) were 71.4% and 100%, respectively. Sensitivity and specificity of type B2 for tumors invading into the muscularis mucosa (m3) or superficial submucosa (≤ 200 µm, sm1) were 94.4% and 73.1%, respectively, while those of type B3 for tumors invading into the deep submucosa (> 200 µm, sm2) were 75.0% and 97.8%, respectively. Interobserver agreement was excellent (κ = 0.86, 95%CI: 0.76-0.95). CONCLUSION: The recently developed JES ME classification is useful for predicting depth of invasion of SESCC, with reliable interobserver agreement.