Similarity of oncogenic protein expression in KRASG12D gene delivery-based rat pancreatic cancer model to that of human pancreatic cancer.

BACKGROUND: The development of effective therapies and biomarkers for pancreatic cancer is an unmet clinical need. To address this, we have developed an easy-to-use pancreatic cancer rat animal model via pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes. Our study aimed to determine the molecular similarity between the pancreatic tumor in the rat model and human pancreatic cancer. METHODS: KRASG12D gene-expressing plasmid was delivered to the pancreas of wild type rats via pancreas-targeted hydrodynamic gene delivery as previously reported. Tissue samples were collected at 5 weeks after the first gene delivery. The tumors developed in the rats were assessed for the expression of oncogenic proteins that are involved in human pancreatic cancer development. RESULTS: The development of a tumor mimicking pancreatic ductal adenocarcinoma was confirmed. The expression levels of Cyclin D1, c-Jun, IL-33, and Zip4 proteins in the tumor were immunohistochemically assessed and the correlation of the proteins was confirmed. The expression pattern showed similarity to that of surgically resected human pancreatic cancer tissues. CONCLUSIONS: Our study findings showing a similar pattern of oncogenic protein expression in novel KRASG12D gene-induced rat pancreatic cancer model and human pancreatic cancer will be useful for establishing novel tumor markers and therapeutic options for pancreatic cancer.

Visceral Adipose Tissue Index and Hepatocellular Carcinoma Are Independent Predictors of Outcome in Patients with Cirrhosis Having Endoscopic Treatment for Esophageal Varices.

BACKGROUND: The relationship between the amount of adipose tissue and advanced-stage liver cirrhosis with esophageal varices (EV) is unknown. We aimed to reveal the prognostic significance of adipose tissues in patients with liver cirrhosis. METHODS: We enrolled 87 patients with EV who received initial endoscopic treatment and underwent scheduled treatments in our hospital. Computed tomography (CT) images were obtained of a 5-mm slice at the umbilical level. We evaluated the effect of mortality based on the visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue ratio (VSR). RESULTS: Cox hazard multivariate analysis showed that the presence of hepatocellular carcinoma (HCC; hazard ratio [HR]: 4.650, 95% confidence interval [CI]: 1.750-12.353, p = 0.002), γ-GTP (HR: 1.003, 95% CI: 1.001-1.006, p = 0.026), and VATI (HR: 1.057, 95% CI: 1.030-1.085, p < 0.001) significantly affected mortality. Cox hazard multivariate analysis for liver-related death was also significantly affected by HCC (HR: 1.057, 95% CI: 1.030-1.085, p < 0.001) and VATI (HR: 1.052, 95% CI: 1.019-1.086, p = 0.002). The difference between the Child-Pugh scores 12 months after treatment and that during initial treatment were significantly positively correlated with VATI (r = 0.326, p = 0.027). Patients with high VATI had a significantly higher frequency of HCC after EV treatment by Kaplan-Meier analysis (p = 0.044). CONCLUSION: Our findings suggest that VATI measured by CT could significantly predict mortality in cirrhosis patients through decreasing liver function and increasing HCC frequency, and appropriately controlling VATI could improve their prognosis.

Change in body composition in patients with achalasia before and after peroral endoscopic myotomy.

BACKGROUND AND AIM: Patients with achalasia experience weight loss because of dysphagia caused by impaired relaxation of the lower esophageal sphincter. This study aimed to use dual bioelectrical impedance analysis (BIA) to determine the change in bodyweight and body composition in patients with achalasia before and after peroral endoscopic myotomy (POEM). METHODS: Patients with achalasia who underwent POEM from 2013 to 2018 (n = 72) were retrospectively analyzed for change in bodyweight before and after 3 months. Additionally, change in body composition was prospectively investigated in the final 10 of 72 patients using non-radiation dual BIA. RESULTS: Twenty patients (27.8%) were underweight (body mass index < 18.5) before undergoing POEM. No clinical parameters were identified to be associated with the underweight condition before POEM and be predictive of an increase in bodyweight after POEM. Low visceral fat volume observed on dual BIA correlated closely with the result obtained using computed tomography (Pearson correlation coefficient: r = 0.850, P < 0.01). Patients with achalasia had a statistically significant increase in visceral (P < 0.01) and subcutaneous fat volumes (P < 0.01) after POEM. Skeletal muscle mass index slightly increased (P = 0.02), although the value after POEM was still low. No blood biomarkers were indicators for low bodyweight or low visceral fat volume. CONCLUSIONS: Dual BIA is an effective non-invasive tool to evaluate the change in body composition of underweight patients with achalasia. Skeletal muscle volume was not enough after POEM, although a rapid increase in the intra-abdominal fat volume was observed. Additional studies are warranted to understand the pathological implications.

Management decision based on lymphovascular involvement leads to favorable outcomes after endoscopic treatment of esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) invading the muscularis mucosae (MM) and submucosa up to 200 µm (SM1) has a risk of metastasis. The aims of this study were to investigate the long-term outcome of endoscopic submucosal dissection (ESD) for MM/SM1 ESCC and to assess the management after ESD in our hospital. METHODS: This was a retrospective cohort study conducted at a single institution. Patients with MM or SM1 ESCC who were treated with ESD were included. Additional prophylactic therapy was added if lymphovascular involvement (LVI) was noted in the ESD specimens. RESULTS: A total of 102 patients were analyzed. The median length of follow-up was 71.5 months (range 9 - 144 months) and the median number of CTs was 6 (range 0 - 24). LVI was found in 21 patients (20.6 %), and 12 patients underwent additional prophylactic therapy. The 5-year overall survival, disease-specific survival, and tumor-free survival rates were 84.1 %, 97.5 %, and 82.1 %, respectively. A total of 26 patients died, but only 2 of them died from ESCC. The cumulative metastasis rate was 11.8 %, and LVI was a significant predictor of metastasis (hazard ratio 5.42, 95 % confidence interval 1.39 - 21.18; P = 0.02). There were no differences between patients with MM ESCC and those with SM1 ESCC. CONCLUSIONS: The long-term outcome after ESD for MM/SM1 ESCC was favorable with additional prophylactic therapy and strict adherence to follow-up. These results indicate that our management decision based on LVI is a valid approach and that ESD can be offered as a therapeutic option to MM/SM1 ESCCs.

The factors influencing long-term outcomes of stenting for malignant colorectal obstruction in elderly group in community medicine.

PURPOSE: Malignant bowel obstruction is a complication of colorectal carcinoma or metastasis from other carcinoma, and it causes significant damage on the condition of elderly patients; however, the self-expandable metallic stents (SEMSs) have been effectively used either for palliation or for bridging to the surgical procedure for this condition. The aim of this study was to investigate the factors influencing long-term outcomes of old-aged patients with SEMS for large bowel obstruction to develop the strategy for those patients in the community medicine. METHODS: We performed a retrospective review of 42 patients with a median age of 83.0 years (range, 65-99 years), who underwent SEMS placement for malignant colorectal obstruction between 2006 and 2015 in our hospital. Univariate and multivariate logistic regressions were performed on data from the patients to assess the factors affecting 6-month survival without stent dysfunction. RESULTS: The study population comprised 24 females (57.1%) and 18 males (42.9%). Of these, 38 patients (90.5%) received SEMS as palliation, whereas 4 patients (9.5%) underwent subsequent surgery. SEMSs were successfully inserted in 97.6% of patients. The median duration of follow-up was 205.0 days (range, 20-1377 days). On multivariate analysis, shorter stents (< 10 cm) yielded better outcomes than longer stents (≥ 10 cm) (P = 0.041), and the Cox proportional hazard model also indicated that shorter stents (P = 0.036) predicted longer event-free survival. CONCLUSIONS: Elderly patients with malignant bowel obstruction receiving shorter stents had longer event-free survival after stenting with better general condition.

[Successful treatment with bortezomib in a patient with systemic primary AL amyloidosis manifesting severe gastrointestinal bleeding].

We present a systemic primary AL amyloidosis patient with severe gastrointestinal bleeding for whom treatment with bortezomib and dexamethasone was very effective. An 83-year-old woman was admitted to our hospital suffering from multiple gastric ulcers with bleeding. She had monoclonal protein (IgG, λ) in her serum. Systemic primary AL amyloidosis was diagnosed. She was also suspected of having amyloid deposition in cardiac muscle, as well as her bladder and intestinal mucosa. However, we were unable to carry out other invasive examinations due to her bleeding tendency. She was treated with bortezomib and dexamethasone. Her bleeding tendency gradually diminished. After one year, the bleeding tendency had completely resolved. However, she still had amyloid deposition in her gastric mucosa and skin.

Two rare pancreatic parenchymal hemorrhagic lesions associated with acute pancreatitis in acute liver failure: a case report and literature review.

Acute pancreatitis is an uncommon occurrence in acute liver failure. Furthermore, such cases are rarely complicated by parenchymal hemorrhages. Herein, we report the case of a 69-year-old male patient with multiple pancreatic parenchymal hemorrhages concomitant with acute liver failure. The patient underwent conservative treatment for acute liver failure caused by hepatitis B virus infection. Plain computed tomography on the 30th day revealed two high-density mass lesions in the pancreatic body and tail, which were suspected to be multiple pancreatic parenchymal hemorrhages. Despite restarting gabexate mesylate, the patient died of multiple organ failure on the 49th day. The clinical information of the present case and our literature review of 61 similar cases in 43 case reports identified via a systematic keyword search of the PubMed database, which described acute pancreatitis concomitant with acute hepatitis and acute liver failure, will aid physicians in the diagnosis and treatment of this rare condition.

Solid pseudopapillary neoplasm in a woman presenting with acute pancreatitis: a case report and review of literature.

Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that typically affects young women in the body and tail of the pancreas. SPN is often asymptomatic in the early stages, so it is initially discovered as a large tumor. In this report, we experienced a case of a relatively small SPN discovered in the setting of acute pancreatitis. Because there have been few reports of SPN being discovered in the situation like our case, we report this case based on a review of the literature.

Machine learning prediction model for treatment responders in patients with primary biliary cholangitis.

Background and Aim: Treatment response to ursodeoxycholic acid may predict the prognosis of patients with primary biliary cholangitis (PBC). Recent studies have suggested the benefits of using machine learning (ML) to forecast complex medical predictions. We aimed to predict treatment response in patients with PBC using ML and pretreatment data. Methods: We conducted a single-center retrospective study and collected data from 194 patients with PBC who were followed up for at least 12 months after treatment initiation. Patient data were analyzed with five ML models, namely random forest, extreme gradient boosting (XGB), decision tree, naïve Bayes, or logistic regression, to predict treatment response using the Paris II criteria. The established models were assessed using an out-of-sample validation. The area under the curve (AUC) was used to evaluate the efficacy of each algorithm. Overall survival and liver-related deaths were analyzed using Kaplan-Meier analysis. Results: Compared to logistic regression (AUC = 0.595, P = 0.0219, 0.031 models), ML analyses showed significantly high AUC in the random forest (AUC = 0.84) and XGB (AUC = 0.83) models; however, the AUC was not significantly high for decision tree (AUC = 0.633) or naïve Bayes (AUC = 0.584) models. Kaplan-Meier analysis showed significantly improved prognoses in patients predicted to achieve the Paris II criteria by XGB (log-rank = 0.005 and 0.007). Conclusion: ML algorithms could improve treatment response prediction using pretreatment data, which could lead to better prognoses. In addition, the ML model using XGB could predict the prognosis of patients before treatment initiation.

A Rare Case of Ulcerative Colitis with Severe Pneumocystis jirovecii Pneumonia and Cytomegalovirus Colitis: A Case Report and Literature Review.

Pneumocystis jirovecii pneumonia (PJP) and cytomegalovirus (CMV) colitis are opportunistic infections that occur during immunosuppressive treatments for ulcerative colitis (UC). The prognosis of PJP and CMV colitis is very poor. We herein report a rare case of a 74-year-old UC patient with PJP and CMV colitis that was successfully treated with intensive therapy. PJP progresses rapidly, so the timing and choice of treatment are critical. Furthermore, a literature review of similar cases suggested that prophylactic therapy for opportunistic infections might be important, especially in the elderly. This case will serve as a reference for successful treatment in future cases.

Establishment of a pancreatic cancer animal model using the pancreas-targeted hydrodynamic gene delivery method.

This research developed an easy-to-use, reproducible pancreatic cancer animal model utilizing pancreas-targeted hydrodynamic gene delivery to deliver human pancreatic cancer-related genes to the pancreas of wild-type rats. KRAS G12D -induced pancreatic intraepithelial neoplasia lesions showed malignant transformation in the main pancreatic duct at 4 weeks and developed acinar-to-ductal metaplasia, which led to pancreatic ductal adenocarcinoma within 5 weeks, and the gene combination of KRAS G12D and YAP enhanced these effects. The repeat hydrodynamic gene delivery of KRAS G12D  + YAP combination at 4 weeks showed acinar-to-ductal metaplasia in all rats and pancreatic ductal adenocarcinoma in 80% of rats 1 week later. Metastatic tumors in the liver, lymph nodes, and subcutaneous lesions and nervous invasion were confirmed. KRAS G12D and YAP combined transfer contributes to the E- to N-cadherin switch in pancreatic ductal adenocarcinoma cells and to tumor metastases. This pancreatic cancer model will speed up pancreatic cancer research for novel treatments and biomarkers for early diagnosis.

Utility of autologous fecal microbiota transplantation and elucidation of microbiota in diversion colitis.

Objectives: Diversion colitis (DC) is an inflammatory disorder caused by interruption of the fecal stream and subsequent nutrient deficiency from luminal bacteria. The utility of fecal microbiota transplantation (FMT) for DC was recently investigated; however, the precise pathogenesis of this condition remains unclear. This study aimed to evaluate the utility of autologous FMT in DC and to determine the related changes in the intestinal microbiota. Methods: Autologous FMT was performed to reestablish the intestinal microbiota in five patients (average age, 64.6 ± 8.3 years) with DC. They underwent double-ended colostomy. We assessed the diverted colon by endoscopy and evaluated the microbiota before and after FMT using the 16S rRNA gene sequencing method. Results: All five patients had mild inflammation (ulcerative colitis endoscopic index of severity [UCEIS] 2-3) in the diverted colon based on the colonoscopic findings. Three patients presented with symptoms, such as tenesmus, mucoid stool, and bloody stool. With FMT treatment, all patients achieved endoscopic remission (UCEIS score of 0 or 1) and symptomatic improvement. We observed a significantly decreased α-diversity in DC patients compared to healthy controls. The frequency of aerobic bacteria, such as Enterobacteriaceae, in the diverted colon decreased after autologous FMT. Conclusions: This study was the first to show that the microbiota in the diverted colon was significantly affected by autologous FMT. Since interruption of the fecal stream is central to the development of DC, FMT can be considered a promising treatment.

Choledochocele observed on direct peroral cholangioscopy using an ultra-slim endoscope.

Highlight Ikarashi and colleagues report a case of choledococele treated by endoscopic sphincterotomy and observed on direct peroral cholangioscopy. Histological examination reveals duodenum-like mucosa without atypical changes in the choledochocele. Direct peroral cholangioscopy using an ultra-slim endoscope may be a useful technique for diagnosis and surveillance of choledochocele.

Rare paraneoplastic syndromes in digestive systems caused by lung cancer.

We observed a rare case of two different digestive paraneoplastic syndromes that improved with the treatment of the neoplasms. The first syndrome was chronic intestinal pseudo-obstruction (CIPO), which is a subtype of paraneoplastic syndromes called a paraneoplastic neurological syndrome (PNS). The second was Stauffer's syndrome, which is a unique paraneoplastic syndrome characterised by non-metastatic intrahepatic cholestasis associated with neoplasms. Here, we report the case of a 55-year-old man who presented with two concurrent paraneoplastic syndromes in the digestive system. The intestinal pseudo-obstruction and elevated biliary enzyme levels improved as the lung cancer responded to chemotherapy. In this case, CIPO as a PNS led to the detection of lung cancer. To our knowledge, this is the first report of Stauffer's syndrome caused by lung adenocarcinoma.

Novel Strategy for Diagnosis of Focal Nodular Hyperplasia Using Gadolinium Ethoxybenzyl Diethylenetriaminepentaacetic Acid: Enhanced Magnetic Resonance Imaging and Magnetic Resonance Elastography.

Focal nodular hyperplasia (FNH) is the second most frequent benign liver tumor, and it is a fiber-rich stiff lesion. Typically, FNH can be diagnosed by imaging without biopsy. However, liver biopsy and diagnostic resection may be required to differentiate atypical FNH from other liver tumors, such as hepatocellular adenoma (HCA). Therefore, improved noninvasive diagnostic methods are needed. We experienced 2 cases where combination of magnetic resonance elastography (MRE) and gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) helped diagnose FNH. A 36-year-old woman and 17-year-old boy with liver tumors measuring 40 mm in diameter each showed hypointense nodule centers, indicating a central scar, surrounded by hyperintense signals during the hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI. To rule out HCA, we performed MRE and liver biopsy. On MRE, the mean stiffness of the mass was 11.6 kPa (mean stiffness of the background liver was 1.7 kPa) and 11.1 kPa (mean stiffness of the background liver was 2.4 kPa) in the first and second patients, respectively. Histological examination of both specimens showed CK7-positive bile-ductular proliferations, abundant fibrous tissue, and few Ki-67-positive cells. Based on these results, we diagnosed these tumors as FNH. Combination of Gd-EOB-DTPA-enhanced MRI and MRE can evaluate the character and stiffness of lesion and help in the diagnosis of FNH.

Rapid decline in visceral adipose tissue over 1 month is associated with poor prognosis in patients with unresectable pancreatic cancer.

BACKGROUND: Involuntary weight loss related to cachexia is common in patients with advanced cancer, but the association between body composition changes and survival is still unclear in pancreatic cancer. METHODS: We retrospectively reviewed the clinical outcomes of 55 patients with advanced pancreatic cancer undergoing palliative therapy or best supportive care (BSC). The skeletal muscle index (SMI), visceral adipose tissue index (VATI), subcutaneous adipose tissue index (SATI), and visceral to subcutaneous adipose tissue area ratio (VSR) were calculated based on the cross-sectional area on two sets of computed tomography images obtained at cancer diagnosis and 1 month later before treatment. The prognostic value of body composition indexes at diagnosis and the changes in those indexes over 1 month was then evaluated. RESULTS: In total, 45 patients (81.8%) received chemotherapy, chemoradiation, or radiation therapy, whereas the remaining patients underwent BSC. There were 27 patients (49.1%) who had low SMI at cancer diagnosis. Univariate analysis showed no significant associations between the baseline body composition indexes including SMI, VATI, SATI, and VSR and survival. Meanwhile, male sex (HR, 2.79; 95% CI, 1.16-6.71, p = 0.022) and higher decrease in VATI over 1 month (HR, 2.41; 95% CI, 1.13-5.13, p = 0.023) were identified as independent risk factors for mortality in multivariate analysis. CONCLUSION: Rapid decline in VAT over 1 month is closely associated with poorer survival in unresectable advanced pancreatic cancer. A short-term assessment of body composition changes may be a rational approach to predict prognosis in these patients.

Comparison of Oral and Esophageal Microbiota in Patients with Achalasia Before and After Peroral Endoscopic Myotomy.

BACKGROUND/AIMS: Patients with achalasia have a high incidence of esophageal squamous cell carcinoma (ESCC), which may be associated with alterations in oral and esophageal microbiota caused by food stasis. This study compared the oral and esophageal microbiota of patients with achalasia before and after peroral endoscopic myotomy (POEM). It also compared patients with achalasia to those with ESCC. MATERIALS AND METHODS: The study prospectively examined 6 patients with achalasia and 14 with superficial ESCC. Oral samples obtained from the buccal mucosa using a swab and esophageal samples obtained from the mid-esophagus using a brush via endoscopy were analyzed by 16S rRNA metagenome sequencing. Additionally, endoscopic and histological findings of patients with achalasia before and after POEM were prospectively compared. RESULTS: In patients with achalasia, Streptococcus was most abundant in both the oral and the esophageal microbiota, and these microbiota were significantly different. Although the overall structure of the oral and esophageal microbiota did not change after POEM, the relative abundance rate of Haemophilus and Neisseria increased in the esophagus, and endoscopic findings of inflammation improved after POEM (P = .04). The relative abundance of microbiota was not different among patients with achalasia from those with ESCC. CONCLUSIONS: The oral and esophageal microbiota were significantly different in patients with achalasia, and some of the composition of the esophageal microbiota changed after POEM. However, these findings and disease-specific microbiota should be further evaluated in large-scale studies.

Immunoglobulin therapy for successful management of prolonged, recurrent jaundice in a young adult male with combined immunodeficiency.

Jaundice may be persistent in drug-induced liver injury associated with vanishing bile duct syndrome. However, recurrent jaundice is atypical, following bile flow restoration. Here, we report a 28-year-old man with prolonged, recurrent jaundice (more than 300 days) and combined immunodeficiency (CID) of B-cells, T-cells, and natural killer (NK) cells. Hypogammaglobulinemia was observed throughout his hospitalization, and peripheral blood flow cytometry detected a few B-cells (2% of CD19 + cells and 2% of CD20 + cells). We further detected the dysfunction of T-cells and NK cells. Based on these findings, CID was diagnosed. We presumed that hypogammaglobulinemia was related to the jaundice. After regular injections of intravenous immunoglobulin (IVIG), the stool color gradually turned brown. However, the color returned to white as IgG levels decreased. The brown-to-white stool pattern was repeated with another IVIG administration, suggesting that the patient's serum immunoglobulin levels were related to the jaundice. On follow-up, IVIG was performed every two to three weeks, and his total bilirubin improved gradually. Immunoglobulin replacement therapy could be one of the treatment choices for jaundice with CID.