Usefulness of the S-O clip for duodenal endoscopic submucosal dissection: a propensity score-matched study.

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) for superficial non-ampullary duodenal tumors (SNADETs) is associated with a high rate of en bloc resection. However, the technique for ESD remains challenging. Recent studies have demonstrated the effectiveness of S-O clips in colonic and gastric ESD. We evaluated the efficacy and safety of duodenal ESD using an S-O clip for SNADETs. METHODS: Consecutive patients who underwent ESD for SNADETs between January 2011 and December 2021 were retrospectively enrolled. Propensity score matching analysis was used to compare patients who underwent duodenal ESD with the S-O clip (S-O group) and those who underwent conventional ESD (control group). Intraoperative perforation rate was the primary outcome, while procedure time and R0 resection rate were the secondary outcomes. RESULTS: After propensity score matching, 16 pairs were created: 43 and 17 in the S-O and control groups, respectively. The intraoperative perforation rate in the S-O group was significantly lower than that in the control group (p=0.033). A significant difference was observed in the procedure time between the S-O and control groups (39±9 vs. 82±30 minutes, respectively; p=0.003). CONCLUSION: The S-O clip reduced the intraoperative perforation rate and procedure time, which may be useful and effective in duodenal ESD.

Post-menopausal ovarian fibroma associated with steroid hormone synthesis: A case report.

OBJECTIVE: Ovarian fibromas are benign, sex cord-stromal tumors occurring in both peri- and post-menopausal women. Generally, these tumors are non-functional and do not produce hormones. However, this case report proves the first case of steroid hormone synthesis in an ovarian fibroma by immunohistochemistry. CASE REPORT: A 77-year-old post-menopausal woman presented with a left ovarian tumor, abnormal endometrial thickness, and high levels of estradiol (E2). The tumor was found to be a fibroma, which was positive for alpha-inhibin. We examined estrogen-producing enzymes using immunohistochemistry. The tumor was positive for estrogen receptor, progesterone receptor, 17ß-hydroxysteroid dehydrogenase (HSD)-1, adrenal 4 binding protein/steroidogenic factor 1, 17ß-HSD-5, steroid sulfatase, and P450c17. CONCLUSION: This case study shows that E2 can be locally produced from circulating inactive steroids, by estrogen-producing enzymes. This is the first report of steroid hormone synthesis in an ovarian fibroma.

[A Case of Hepatic Undifferentiated Embryonal Sarcoma in an Adult].

A 20-year-old woman was admitted with abdominal pain and a cystic liver tumor. A hemorrhagic cyst was suspected. Contrast-enhanced computed tomography(CT)and magnetic resonance imaging(MRI)revealed a space-occupying solid mass in the right lobule. Positron emission tomography(PET)-CT revealed 18F-fluorodeoxyglucose uptake in the tumor. We performed a right hepatic lobectomy. Histopathological evaluation of the resected tumor revealed an undifferentiated embryonal sarcoma of the liver(UESL). The patient refused adjuvant chemotherapy but showed no recurrence 30 months postoperatively. UESL is a rare malignant mesenchymal tumor that occurs in infants and children. It is extremely rare and is associated with poor prognosis in adults. In this report, we described a case of adult UESL.

Muscular metastasis of superficial esophageal squamous cell carcinoma: a rare case of recurrence after endoscopic submucosal dissection with additional chemoradiotherapy.

Esophageal cancer after endoscopic treatment may recur depending on the risk. We present a case of a rare T1b esophageal cancer after endoscopic treatment plus chemoradiotherapy (CRT) that recurred with metastasis of the dorsal muscles. A 70-year-old man was referred for treatment of early-stage esophageal carcinoma. Endoscopic submucosal dissection (ESD) was performed and histopathology showed a poorly differentiated squamous cell carcinoma with invasion to the submucosal layer (sm2) with INFc-type invasion and positive venous invasion. After subsequent CRT, the patient was monitored every 6 months, using computed tomography (CT) and endoscopy. Fifteen months after the treatment, contrast CT revealed a spherical mass with 9 cm ring enhancement within the right erector spinae, that had squamous cell carcinoma confirmed by CT-guided biopsy. Radiation and systemic chemotherapy were initiated for the metastasis of the esophageal carcinoma. However, he died of respiratory failure due to rapid pleural effusion 26 months after ESD. Pathological autopsy showed diffuse squamous cell carcinoma invasion of the cystic wall, forming a lumbar mass, and absence of cancer cell remnants or recurrences in the esophagus. This case report emphasizes the need for systemic observation of superficial esophageal cancer after treatment with a high risk of recurrence.

Which factors make Barrett's esophagus lesions difficult to diagnose?

Background and study aims Although the Japan Esophageal Society's magnifying endoscopic classification for Barrett's epithelium (JES-BE) offers high diagnostic accuracy, some cases are challenging to diagnose as dysplastic or non-dysplastic in daily clinical practice. Therefore, we investigated the diagnostic accuracy of this classification and the clinicopathological features of Barrett's esophagus cases that are difficult to diagnose correctly. Patients and methods Five endoscopists with experience with fewer than 10 cases of magnifying observation for superficial Barrett's esophageal carcinoma reviewed 132 images of Barrett's mucosa or carcinoma (75 dysplastic and 57 non-dysplastic cases) obtained using high-definition magnification endoscopy with narrow-band imaging (ME-NBI). They diagnosed each image as dysplastic or non-dysplastic according to the JES-BE classification, and the diagnostic accuracy was calculated. To identify risk factors for misdiagnosed images, images with a correct rate of less than 40 % were defined as difficult-to-diagnose, and those with 60 % or more were defined as easy-to-diagnose. Logistic regression analysis was performed to identify risk factors for difficult-to-diagnose images. Results The sensitivity, specificity and overall accuracy were 67 %, 80 % and 73 %, respectively. Of the 132 ME-NBI images, 34 (26 %) were difficult-to-diagnose and 99 (74 %) were easy-to-diagnose. Logistic regression analysis showed low-grade dysplasia (LGD) and high-power magnification images were each significant risk factors for difficult-to-diagnose images (OR: 6.80, P  = 0.0017 and OR: 3.31, P  = 0.0125, respectively). Conclusions This image assessment study suggested feasibility of the JES-BE classification for diagnosis of Barrett's esophagus by non-expert endoscopists and risk factors for difficult diagnosis as high-power magnification and LGD histology. For non-experts, high-power magnification images are better evaluated in combination with low-power magnification images.

Anti-nuclear antibody and a granuloma could be biomarkers for iCIs-related hepatitis by anti-PD-1 treatment.

It has been reported that various kinds of immune checkpoint inhibitors (iCIs) could induce immune-related liver damage. We should focus on the programmed cell death-receptor-1 (PD-1) antibody and non-small cell lung cancer (NSCLC) to analyze the characteristics of hepatitis related to iCIs and find factors that could be useful biomarkers for the diagnosis. A single-center retrospective study of 252 NSCLC patients who received PD-1 antibody (nivolumab or pembrolizumab). Some of the biochemical markers and immunological markers were analyzed during PD-1-antibody treatment with or without ALT elevation. Histopathological features were reviewed by a single expert of hepatic pathology focusing on the following features: fibrosis, portal inflammation, lobular inflammation, lobular necrosis. The formation of macro- and micro-granulomas was also evaluated. The frequency of liver damage induced by nivolumab including grade 1 to 4 (ALT) was 41.9% (78/186 patients). The positive rate of anti-nuclear antibody in the nivolumab group with iCIs-related hepatitis was significantly higher than that in the nivolumab group without iCIs-related hepatitis (p = 0.00112). Granulomatous changes were significantly increased in patients with iCIs-related hepatitis compared with DILI and AIH patients (p < 0.05). The ratios of inflammatory cells CD4/CD8, and CD138/CD3 in ICIs-related hepatitis were significantly lower than those in AIH or DILI patients (p < 0.05). We demonstrated that the pre-existing ANA and characteristic liver histology including CD8+ cells dominancy and granulomatous hepatitis could be biomarkers for the diagnosis of iCIs-related hepatitis in the NSCLC with anti-PD-1 therapy.

Cancer of unknown primary inside the gastric wall identified by endoscopic submucosal dissection.

We report the rare and interesting case of cancer of unknown primary (CUP) detected by endoscopic submucosal dissection (ESD). A 67-year-old man with a gastric adenoma was referred to our hospital for endoscopic treatment. Esophagogastroduodenoscopy revealed a 15-mm submucosal tumor (SMT) at the lesser curvature of the lower gastric body, near the gastric adenoma. Both lesions were resected by ESD. Pathological examination showed that the SMT was a poorly differentiated adenocarcinoma with lymphatic tissue. Additional surgical resection was performed, and the lymph nodes were found to have the same pathological findings as the SMT. These lesions were diagnosed as CUP because the obvious primary site was not detected with additional examination. The patient has been followed up for 24 months without recurrence.

A Remarkable Clinical Response to Pembrolizumab in a Rare Spindle Cell Carcinoma of the Lung.

Spindle cell carcinoma of the lung consists of only spindle-shaped tumor cells, and accounts for approximately 13.3% of all sarcomatoid carcinomas (SCs), which are a rare subtype of poorly differentiated non-small cell lung cancer (NSCLC). Spindle cell carcinoma of the lung has very poor prognosis owing to resistance to chemotherapy and radiotherapy. This case report describes a 76-year-old man who presented with complaints of dry cough and right-sided neck pain and was later diagnosed with spindle cell carcinoma of the lung. He had a medical history of type 2 diabetes, angina pectoris, atrial fibrillation, hypertension, hyperlipidemia, and hepatitis B and a 20 pack-year history of smoking. A computed tomography (CT) scan revealed a mass with a thick-walled cavity in the right upper lobe of the lung. His neck pain was consistent with PET-CT images, indicating metastases due to invasion of lung cancer cells. The expression of PD-L1 in more than 90% of the tumor cells of the lung biopsy tissue led to the administration of pembrolizumab. The lung and metastatic tumors dramatically decreased in size after 9 weeks, and no tumor regrowth was observed over 11 courses of pembrolizumab administration. To the best of our knowledge, there are no previous reports describing the use of pembrolizumab for spindle cell carcinoma of the lung. This case report suggests that immunotherapy could be a promising treatment option for rare types of lung cancers, including spindle cell carcinoma.

Preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma.

BACKGROUND: The subcategory "solid component of tumor" is a new criterion of tumor categories in the updated eighth edition of the TNM classification. Nevertheless, the predictors of lymph node metastasis among patients with clinical T1 adenocarcinoma, based on the TNM classification 8th edition, remain unclear. This study aimed to identify the preoperative predictors of lymph node metastasis in clinical T1 adenocarcinoma by comparing clinicopathological characteristics between the groups with and without lymph node metastasis. METHODS: We performed a retrospective observational single-center study at the Sendai Kousei Hospital. From January 2012 to September 2019, we included 515 patients who underwent curative lobectomy or segmentectomy and mediastinal lymph node dissection among those with clinical T1 adenocarcinoma according to the UICC-TNM staging 8th edition. They were divided into two groups: those with lymph node metastasis (positive group) and those without (negative group). The clinicopathological factors were retrospectively analyzed and compared between the groups. RESULTS: In univariate analysis, carcinoembryonic antigen (>5.0 ng/mL) (P=0.0007), maximum standardized uptake (>3.5) (P<0.0001), clinical T factor (T1c) (P<0.0001), and consolidation tumor ratio (>0.85) (P<0.0001) were significant predictors of lymph node metastasis. Multivariate analysis revealed that maximum standardized uptake SUVmax (>3.5) (odds ratio =10.4, P<0.0001) was independently associated with lymph node metastasis. In univariate analysis, carcinoembryonic antigen (>5.0) (P=0.048) was the only predictor of lymph node metastasis among patients of cT1b, while no parameters were identified as significant predictors among patients of cT1c. CONCLUSIONS: SUVmax and CEA are useful preoperative predictors of lymph node metastases in patients with clinical T1 adenocarcinoma, stratified to T1b and T1c, based on the 8th TNM classification.

Secondary aortoenteric fistula possibly associated with continuous physical stimulation: a case report and review of the literature.

BACKGROUND: Secondary aortoenteric fistula is a rare but fatal complication after reconstructive surgery for an aortic aneurysm characterized by abdominal pain, fever, hematochezia, and hematemesis, and the mortality rate is high. It has been suggested that it arises due to either continuous physical stimulation or prosthesis infection during primary surgery. We describe an aortoenteric fistula following reconstructive surgery for an abdominal aortic aneurysm together with postmortem pathological findings. CASE PRESENTATION: A 59-year-old Japanese man who had undergone reconstructive surgery for an abdominal aortic aneurysm 20 months earlier presented with the chief complaint of hematochezia and malaise. Esophagogastroduodenoscopy and total colonoscopy revealed only colon diverticula with no bleeding. Contrast-enhanced computed tomography revealed gas within the aneurysm sac and adhesion between the replaced aortic graft and intestinal tract, suggesting a graft infection. After 18 days of antibiotic treatment, he suddenly went into a state of shock, with massive fresh bloody stool and hematemesis, followed by cardiac arrest. An autopsy revealed communication between the artery and the ileum through an ulcerative fistula at the suture line between the left aortic graft branch and the left common iliac artery. Pathological analysis revealed tight adherence between the arterial and intestinal walls, but no marked sign of infection around the fistula, suggesting that the fistula had arisen due to physical stimuli. CONCLUSIONS: Pathological analysis suggested that the present secondary aortoenteric fistula arose due to physical stimuli. This reaffirms the importance of keeping reconstructed aortas isolated from the intestine after abdominal aortic aneurysm surgery.

3ßHSD and CYB5A double positive adrenocortical cells during adrenal development/aging.

Androstenedione is a common precursor of sex steroids produced and secreted in the human adrenal gland and produced by 3ß-hydroxysteroid dehydrogenase (3ßHSD), 17ß-hydroxylase/17,20-lyase (CYP17) and cytochrome b5 (CYB5A). 3ßHSD is expressed in the zona glomerulosa (ZG) and fasciculata (ZF), CYP17 in the ZF and zona reticularis (ZR) and CYB5A in the ZR, respectively. We previously demonstrated the presence of cortical parenchymal cells co-expressing 3ßHSD and CYB5A with hybrid features of both ZF and ZR in human adrenal cortex and hypothesized that these cells may play an important role in androstenedione production in human adrenal gland. Age-related morphologic development of these hybrid cells has, however, not been studied. Therefore, in this study, 48 human adrenal specimens from various age groups were retrieved. Double-immunohistochemical analyses were used in order to study the correlation between this hybrid cell type and age. In both male and female adrenal cortex, the means of total adrenocortical area, the area positive for CYB5A and its ratio reached highest peak in the 21-40-year-old (y.o.) group. The greatest overlap between 3ßHSD and CYB5A in both total and relative area was present in the 13-20 y.o. group. For all the markers mentioned above, statistically significant differences were detected among the different age groups examined (p < 0.05). These findings indicated that both area and ratio of 3ßHSD and CYB5A double positive cells, which could represent the hybrid cells of ZF and ZR, are correlated with human adrenal development and could subsequently influence age-related serum androstenedione levels.

Decreased expression of 14-3-3σ is predictive of poor prognosis for patients with human uterine papillary serous carcinoma.

Uterine papillary serous carcinoma (UPSC) morphologically resembles ovarian serous carcinoma and is categorized as a type II endometrial cancer. UPSC comprises about 10% of all types of endometrial cancer and has an aggressive clinical course and a poor prognosis. The 14-3-3σ gene was originally discovered as a p53-inducible gene; its expression is induced by DNA damage in a p53-dependent manner, which leads to G2 arrest and repair of damaged DNA. Moreover, it has been reported that expression of 14-3-3σ is frequently lost in various types of human cancer, including ovarian cancer. We therefore examined the association between 14-3-3σ expression determined by immunohistochemistry and clinical outcomes of 51 patients with UPSC. UPSC was considered positive for 14-3-3σ when > 30% of tumor cells were stained with a specific antibody. Of these patients, 29 (58.7%) showed positive immunoreactivity for 14-3-3σ and 22 (41.3%) had decreased 14-3-3σ staining. Decreased immunoreactivity for 14-3-3σ was associated with stage (P = 0.001) and lymphovascular space involvement (P = 0.005). Moreover, decreased 14-3-3σ expression was an independent risk factor for reduced overall survival (P = 0.0416) in multivariate analysis. Direct bisulfite sequencing was performed to evaluate the methylation status of the 27 CpG islands in the promoter region and first exon of the 14-3-3σ gene. These CpG islands were hypermethylated in 30% of 14-3-3σ-positive UPSC and 80% of 14-3-3σ-negative UPSC, although the difference was not statistically significant. These findings suggest that decreased expression of immunoreactive 14-3-3σ may be a predictor of poor prognosis in patients with UPSC.

Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma.

We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-α, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas.

Aromatase inhibitor treatment of breast cancer cells increases the expression of let-7f, a microRNA targeting CYP19A1.

Aromatase inhibitors (AIs) are considered the gold standard of endocrine therapy for oestrogen receptor-positive postmenopausal breast cancer patients. AI treatment was reported to result in marked alterations of genetic profiles in cancer tissues but its detailed molecular mechanisms have not been elucidated. Therefore, we profiled miRNA expression before and after treatment with letrozole in MCF-7 co-cultured with primary breast cancer stromal cells. Letrozole significantly altered the expression profiles of cancer miRNAs in vitro. Among the elevated miRNAs following letrozole treatment, computational analysis identified let-7f, a tumour-suppressor miRNA which targeted the aromatase gene (CYP19A1) expression. Quantitative real-time PCR assay using MCF-7 and SK-BR-3 cells as well as clinical specimens of a neoadjuvant study demonstrated a significant inverse correlation between aromatase mRNA and let-7f expression. In addition, high let-7f expression was significantly correlated with low aromatase protein levels evaluated by both immunohistochemistry and the western blotting method in breast cancer cases. Results of 3'UTR luciferase assay also demonstrated the actual let-7f binding sites in CYP19A1, indicating that let-7f directly targets the aromatase gene. Subsequent WST-8 and migration assays performed in let-7f-transfected MCF-7 and SK-BR-3 cells revealed a significant decrement of their proliferation and migration. These findings all demonstrated that let-7f, a tumour suppressor miRNA in breast cancer, directly targeted the aromatase gene and was restored by AI treatment. Therefore, AIs may exert tumour-suppressing effects upon breast cancer cells by suppressing aromatase gene expression via restoration of let-7f.

Synergistic anti-tumor effects of RAD001 with MEK inhibitors in neuroendocrine tumors: a potential mechanism of therapeutic limitation of mTOR inhibitor.

Mammalian target of rapamycin (mTOR) inhibitors have been clinically used as anticancer agents in several types of human malignancies including neuroendocrine tumor (NET) but the development of clinical resistances or their therapeutic limitations have been also reported. This clinical resistance has been proposed to be partly due to a compensatory activation of an mTOR upstream factor Akt and MEK/ERK pathway in NET cells but its details have not necessarily been reported. Therefore, in this study, we examined the effects of mTOR inhibitors on these activations and of the concomitant treatment of mTOR and MEK inhibitors in two NET cell lines, NCI-H727 and COLO320. We evaluated the effects of RAD001, mTOR inhibitor, and U0126, MEK inhibitor, on cell proliferation and migration of these cells. In addition, an alteration of the factors involved in Akt/mTOR and MEK/ERK pathways was also examined under administration of these agents. RAD001 and U0126 treatment significantly inhibited cell proliferation and their combined treatment synergistically decreased it in both cell lines. Additionally, these treatments above decreased the expression of cell cycle-related factors, suggestive of an involvement of cell cycle arrest in therapeutic effects. The combined treatment also inhibited the cell migration in NCI-H727 via the decrement of MMP2 and 9 in an additive manner. We demonstrated the potential synergistic/combined effects of inhibitors of mTOR and MEK on cell proliferation and migration. These results suggest the potential therapeutic efficacy of the combined therapy of mTOR and MEK inhibitors or a dual inhibitor for the treatment of NET patients.