Association of CD4-positive cell infiltration with response to vedolizumab in patients with ulcerative colitis.

Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4ß7) integrin, suppresses immune cell migration by blocking the interaction between α4ß7 integrin and mucosal addressin cell adhesion molecule 1. Reports about histological features that predict vedolizumab efficacy are scarce. So, we examined the association between histological features and vedolizumab efficacy. This was a multicenter, retrospective study of patients with UC treated with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified. We enrolled 42 patients. Patients with a high CD4+ infiltration showed a better response to vedolizumab [odds ratio (OR) = 1.44, P = 0.014]. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR = 0.11, P = 0.008 and OR = 0.50, P = 0.009, respectively). Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

[A case of gastric follicular lymphoma with rapid deterioration and transformation].

A 79-year-old male patient underwent esophagogastroduodenoscopy, which revealed a reddish lesion, 10mm in diameter, presenting as a surface recess in the angular incisure. He was diagnosed with gastric follicular lymphoma. Positron emission tomography-computed tomography revealed metastasis to the mediastinal lymph node, although the tumor size was small. Hence, we did not administer any treatment and continued following up. After 8 months, multiple enlarged lymphoma lesions in the stomach and a mass with ulceration on the oral side of the duodenal papilla were observed. The tumor had transformed into diffuse large B-cell lymphoma; therefore, chemotherapy was initiated. The patient has remained recurrence-free for 55 months after treatment.

[A case of anaplastic pancreatic carcinoma with tumor infiltration into the main pancreatic duct].

A 57-year-old man with fatigue was admitted to our hospital. Abdominal contrast computed tomography indicated the presence of a 35mm tumor in the pancreatic head and dilation of the main pancreatic duct from its body to the tail. Endoscopic ultrasonography revealed that the tumor had infiltrated and occupied the main pancreatic duct, and endoscopic retrograde pancreatography confirmed that the tumor was present in the main pancreatic duct. Tumor biopsy via endoscopic retrograde cholangiopancreatography demonstrated the proliferation of spindle and pleomorphic cells. Therefore, the patient was diagnosed with anaplastic pancreatic carcinoma and underwent subtotal stomach-preserving pancreaticoduodenectomy. Histological analysis showed the prevalence of adenocarcinoma and anaplastic carcinoma cells in the pancreatic parenchyma and main pancreatic duct, respectively. Anaplastic carcinoma cells showed a decrease in E-cadherin staining. In conclusion, tumor cell proliferation and lack of cell adhesion may have caused the infiltration into the main pancreatic duct.

Folinic Acid, Fluorouracil, and Oxaliplatin Therapy for Recurrent Esophageal Cancer with Syndrome of Inadequate Antidiuretic Hormone Secretion (SIADH) After Preoperative Cisplatin/5-Fluorouracil Therapy.

BACKGROUND Cisplatin/5-fluorouracil therapy is the standard therapy for unresectable and recurrent esophageal cancer. Cisplatin-based chemotherapy often causes adverse effects, such as nausea, vomiting, and renal dysfunction, which may necessitate dose modification or treatment prolongation. Therefore, novel combination therapies are urgently needed to improve the efficacy and overcome drug toxicity in this setting. CASE REPORT A 77-year-old man with advanced esophageal cancer received cisplatin/5-fluorouracil therapy as neoadjuvant chemotherapy. On day 8 of administration, the patient had lightheadedness, diaphoresis, and nausea and became unconscious and developed severe hyponatremia. We diagnosed the patient with cisplatin-induced syndrome of inadequate antidiuretic hormone secretion (SIADH). Subsequently, water restriction was started, and treatment with a salt-added diet and 3% hypertonic saline infusion was initiated. The hyponatremia improved and the patient was discharged on day 16 of administration. Therefore, neoadjuvant chemotherapy was discontinued, and surgical treatment was performed. However, the tumor recurred and chemotherapy was required. The patient developed severe hyponatremia while receiving neoadjuvant chemotherapy; hence, folinic acid, fluorouracil, and oxaliplatin therapy (FOLFOX) were administered as an alternative treatment. The patient completed the FOLFOX therapy without developing SIADH. CONCLUSIONS The cisplatin/5-fluorouracil therapy is currently the standard chemotherapy regimen for esophageal cancer. However, SIADH is a known adverse effect when using cisplatin. In patients with esophageal cancer, oxaliplatin appears to have a lower risk of SIADH than cisplatin, suggesting that oxaliplatin can be a therapeutic option for patients with esophageal cancer who are at high risk of SIADH.

[An autopsy case of anaplastic pancreatic carcinoma with diffuse liver metastases in acute hepatic failure].

A 76-year-old man presented to our hospital with continuous abdominal pain and vomiting. The results of the computed tomography indicated a pancreatic head mass with multiple liver metastatic tumors. Multiple liver tumors progressed rapidly, and the patient died of the resulting acute hepatic failure approximately 1 month after the onset of symptoms. The results of the postmortem examination indicated anaplastic pancreatic carcinoma (pleomorphic type) with multiple liver metastases. The tumor cells in the primary pancreatic lesion and liver metastases were replaced with normal tissue, and they showed a decrease in stainability by E-cadherin staining. Overall, the pathological findings suggested that the inhibition of E-cadherin may be related to the proliferation and infiltration of anaplastic cancer cells.

Successful Treatment of Bouveret Syndrome by Electrohydraulic Lithotripsy and Double Balloon Endoscopy.

BACKGROUND Bouveret syndrome is a rare complication of cholelithiasis that often leads to symptoms of gastric outlet obstruction. CASE REPORT An 84-year-old woman developed acute abdominal symptoms due to impaction of a gallstone in the horizontal part of the duodenum. The diagnosis was supported by abdominal computed tomography and double balloon endoscopy. Considering her advanced age and the position of the calcified gallstone, we decided to perform electrohydraulic lithotripsy using double balloon endoscopy for treatment. Finally, the impacted stone was removed with reduced size. She was discharged home 10 days after admission without recurrence. CONCLUSIONS This case illustrates that electrohydraulic lithotripsy using double balloon endoscopy is very effective, especially for treatment of Bouveret syndrome caused by gallstone impaction in the horizontal part of the duodenum.

Acute Pancreatitis Caused by Ampullary Duodenum Adenoma in a Patient with Adenomatous Polyposis Coli with Billroth II Reconstruction After Distal Gastrectomy.

BACKGROUND Adenomatous polyposis coli is an autosomal dominant hereditary disorder. Duodenal adenocarcinoma and adenoma, which are extracolonic lesions, not only affect the prognosis of patients but also cause acute pancreatitis. CASE REPORT We present the case of a 73-year-old male. He had undergone proctocolectomy for familial adenomatous polyposis and distal gastrectomy (Billroth II reconstruction with Braun anastomosis) for gastric ulcer; he presented with acute pancreatitis caused by ampullary duodenum adenoma. Double-balloon endoscopy showed 2 adenomatous polyps in the major papilla and descending limb of the duodenum. Based on the findings of endoscopy and biopsy, the duodenal polyps were diagnosed as adenomas and classified as Spigelman stage II. CONCLUSIONS Our case report suggests that duodenal surveillance is necessary for patients with adenomatous polyposis coli. In addition, surveillance using double-balloon endoscopy is useful for patients with an altered gastrointestinal anatomy.

[A case of intracholecystic papillary neoplasm of the gallbladder (ICPN) examined using contrast-enhanced endoscopic ultrasonography].

A 78-year-old woman was found to have gallbladder wall thickening on ultrasonography during a routine health check-up and was referred to our clinic. On contrast-enhanced endoscopic ultrasonography, a papillary lesion measuring 14mm was detected in the fundus, which showed a heterogeneous enhancement at the early phase. She underwent cholecystectomy and gallbladder bed resection. Histological examination revealed that the tumor consisted of mucinous atypical cells, regularly arranged in a high-papillary architecture with delicate fibrovascular cores, which led to the diagnosis of intracholecystic papillary neoplasm of the gallbladder.

A case of esophageal mucosa-associated lymphoid tissue lymphoma diagnosed using endoscopic ultrasound-guided fine-needle aspiration.

A 65-year-old man presenting with an esophageal lesion underwent esophagogastroduodenoscopy and computed tomography and an upper esophageal submucosal mass was found. Endoscopic ultrasound-guided fine-needle aspiration led to the diagnosis of mucosa-associated lymphoid tissue lymphoma of the esophagus. Positron emission tomography showed abnormal uptake in the internal iliac lymph nodes, and laparoscopic biopsy findings confirmed the diagnosis of esophageal cancer. The patient declined treatment of any kind and has been followed up for 39 months with no progression of the lymphoma.

A novel gas chromatography mass spectrometry-based serum diagnostic and assessment approach to ulcerative colitis.

BACKGROUND & AIMS: To improve the clinical course of ulcerative colitis (UC), more accurate serum diagnostic and assessment methods are required. We used serum metabolomics to develop diagnostic and assessment methods for UC. METHODS: Sera from UC patients, Crohn's disease (CD) patients, and healthy volunteers (HV) were collected at multiple institutions. The UC and HV were randomly allocated to the training or validation set, and their serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS). Using the training set, diagnostic and assessment models for UC were established by multiple logistic regression analysis. Then, the models were assessed using the validation set. Additionally, to establish a diagnostic model for discriminating UC from CD, the CD patients' data were used. RESULTS: The diagnostic model for discriminating UC from HV demonstrated an AUC of 0.988, 93.33% sensitivity, and 95.00% specificity in the training set and 95.00% sensitivity and 98.33% specificity in the validation set. Another model for discriminating UC from CD exhibited an AUC of 0.965, 85.00% sensitivity, and 97.44% specificity in the training set and 83.33% sensitivity in the validation set. The model for assessing UC showed an AUC of 0.967, 84.62% sensitivity, and 88.23% specificity in the training set and 84.62% sensitivity, 91.18% specificity, and a significant correlation with the clinical activity index (rs=0.7371, P<0.0001) in the validation set. CONCLUSIONS: Our models demonstrated high performance and might lead to the development of a novel treatment selection method based on UC condition.

A novel serum metabolomics-based diagnostic approach to pancreatic cancer.

BACKGROUND: To improve the prognosis of patients with pancreatic cancer, more accurate serum diagnostic methods are required. We used serum metabolomics as a diagnostic method for pancreatic cancer. METHODS: Sera from patients with pancreatic cancer, healthy volunteers, and chronic pancreatitis were collected at multiple institutions. The pancreatic cancer and healthy volunteers were randomly allocated to the training or the validation set. All of the chronic pancreatitis cases were included in the validation set. In each study, the subjects' serum metabolites were analyzed by gas chromatography mass spectrometry (GC/MS) and a data processing system using an in-house library. The diagnostic model constructed via multiple logistic regression analysis in the training set study was evaluated on the basis of its sensitivity and specificity, and the results were confirmed by the validation set study. RESULTS: In the training set study, which included 43 patients with pancreatic cancer and 42 healthy volunteers, the model possessed high sensitivity (86.0%) and specificity (88.1%) for pancreatic cancer. The use of the model was confirmed in the validation set study, which included 42 pancreatic cancer, 41 healthy volunteers, and 23 chronic pancreatitis; that is, it displayed high sensitivity (71.4%) and specificity (78.1%); and furthermore, it displayed higher sensitivity (77.8%) in resectable pancreatic cancer and lower false-positive rate (17.4%) in chronic pancreatitis than conventional markers. CONCLUSIONS: Our model possessed higher accuracy than conventional tumor markers at detecting the resectable patients with pancreatic cancer in cohort including patients with chronic pancreatitis. IMPACT: It is a promising method for improving the prognosis of pancreatic cancer via its early detection and accurate discrimination from chronic pancreatitis.

A novel serum metabolomics-based diagnostic approach for colorectal cancer.

BACKGROUND: To improve the quality of life of colorectal cancer patients, it is important to establish new screening methods for early diagnosis of colorectal cancer. METHODOLOGY/PRINCIPAL FINDINGS: We performed serum metabolome analysis using gas-chromatography/mass-spectrometry (GC/MS). First, the accuracy of our GC/MS-based serum metabolomic analytical method was evaluated by calculating the RSD% values of serum levels of various metabolites. Second, the intra-day (morning, daytime, and night) and inter-day (among 3 days) variances of serum metabolite levels were examined. Then, serum metabolite levels were compared between colorectal cancer patients (N = 60; N = 12 for each stage from 0 to 4) and age- and sex-matched healthy volunteers (N = 60) as a training set. The metabolites whose levels displayed significant changes were subjected to multiple logistic regression analysis using the stepwise variable selection method, and a colorectal cancer prediction model was established. The prediction model was composed of 2-hydroxybutyrate, aspartic acid, kynurenine, and cystamine, and its AUC, sensitivity, specificity, and accuracy were 0.9097, 85.0%, 85.0%, and 85.0%, respectively, according to the training set data. In contrast, the sensitivity, specificity, and accuracy of CEA were 35.0%, 96.7%, and 65.8%, respectively, and those of CA19-9 were 16.7%, 100%, and 58.3%, respectively. The validity of the prediction model was confirmed using colorectal cancer patients (N = 59) and healthy volunteers (N = 63) as a validation set. At the validation set, the sensitivity, specificity, and accuracy of the prediction model were 83.1%, 81.0%, and 82.0%, respectively, and these values were almost the same as those obtained with the training set. In addition, the model displayed high sensitivity for detecting stage 0-2 colorectal cancer (82.8%). CONCLUSIONS/SIGNIFICANCE: Our prediction model established via GC/MS-based serum metabolomic analysis is valuable for early detection of colorectal cancer and has the potential to become a novel screening test for colorectal cancer.

Regulation of the metabolite profile by an APC gene mutation in colorectal cancer.

Mutation of the APC gene occurs during the early stages of colorectal cancer development. To obtain new insights into the mechanisms underlying the aberrant activation of the Wnt pathway that accompanies APC mutation, we carried out a gas chromatography-mass spectrometry-based semiquantitative metabolome analysis. In vitro experiments comparing SW480 cells expressing normal APC and truncated APC indicated that the levels of metabolites involved in the latter stages of the intracellular tricarboxylic acid cycle, including succinic acid, fumaric acid, and malic acid, were significantly higher in the SW480 cells expressing the truncated APC. In an in vivo study, we found that the levels of most amino acids were higher in the non-polyp tissues of APC(min/+) mice than in the normal tissues of the control mice and the polyp tissues of APC(min/+) mice. Ribitol, the levels of which were decreased in the polyp lesions of the APC(min/+) mice and the SW480 cells expressing the truncated APC, reduced the growth of SW480 cells with the APC mutation, but did not affect the growth of SW480 transfectants expressing full-length APC. The level of sarcosine was found to be significantly higher in the polyp tissues of APC(min/+) mice than in their non-polyp tissues and the normal tissues of the control mice, and the treatment of SW480 cells with 50 µM sarcosine resulted in a significant increase in their growth rate. These findings suggest that APC mutation causes changes in energetic metabolite pathways and that these alterations might be involved in the development of colorectal cancer.

AP1B plays an important role in intestinal tumorigenesis with the truncating mutation of an APC gene.

Recent evidence has suggested that carcinoma is accompanied by the loss of cell polarity. An epithelial cell-specific form of the AP-1 clathrin adaptor complex, AP1B, is involved in the polarized transport of membrane proteins to the basolateral surface of epithelial cells. In our study, we investigated whether AP1B is involved in intestinal tumorigenesis. The cellular polarity of intestinal tumor cells was examined using APC(Min/+) mice as an in vivo model and SW480 cells with a truncating mutation in the adenomatous polyposis coli (APC) gene as an in vitro model by confocal microscopy. Next, the expression of AP1B in intestinal tumor cells was examined by real-time polymerase chain reaction (PCR) and Western blotting. The localization of ß-catenin and the expression of AP1B in the tumor tissue of patients with colorectal cancer were evaluated by confocal microscopy and real-time PCR, respectively, and the relationships among cell polarity, AP1B expression and intestinal tumorigenesis were examined. Cellular polarity was lost in intestinal tumor cells, and the expression of AP1B was downregulated. In addition, the reduction in the expression level of AP1B correlated with the nuclear localization of ß-catenin in human colorectal cancer. Our study indicates the close associations between AP1B, intestinal tumorigenesis and mutations in the APC gene. This is the first report to reveal the relationships among AP1B, cellular polarity and intestinal tumorigenesis, and achieving a detailed understanding of AP1B will hopefully lead to discovery of therapeutic targets and novel biomarkers for intestinal cancer.

Serum metabolomics as a novel diagnostic approach for gastrointestinal cancer.

Conventional tumor markers are unsuitable for detecting carcinoma at an early stage and lack clinical efficacy and utility. In this study, we attempted to investigate the differences in serum metabolite profiles of gastrointestinal cancers and healthy volunteers using a metabolomic approach and searched for sensitive and specific metabolomic biomarker candidates. Human serum samples were obtained esophageal (n = 15), gastric (n = 11), and colorectal (n = 12) cancer patients and healthy volunteers (n = 12). A model for evaluating metabolomic biomarker candidates was constructed using multiple classification analysis, and the results were assessed with receiver operating characteristic curves. Among the 58 metabolites, the levels of nine, five and 12 metabolites were significantly changed in the esophageal, gastric and colorectal cancer patients, respectively, compared with the healthy volunteers. Multiple classification analysis revealed that the variations in the levels of malonic acid and L-serine largely contributed to the separation of esophageal cancer; gastric cancer was characterized by changes in the levels of 3-hydroxypropionic acid and pyruvic acid; and L-alanine, glucuronoic lactone and L-glutamine contributed to the separation of colorectal cancer. Our approach revealed that some metabolites are more sensitive for detecting gastrointestinal cancer than conventional biomarkers. Our study supports the potential of metabolomics as an early diagnostic tool for cancer.

Serum fatty acid profiling of colorectal cancer by gas chromatography/mass spectrometry.

AIMS: Several screening methods have been applied for the early diagnosis of colorectal cancer, but most colorectal cancer patients are not diagnosed at a localized stage. In order to find novel biomarkers for the diagnosis of colorectal cancer, profiling of the serum levels of fatty acids, which are the main components of fats and are important factors for human metabolism, was performed using the sera of colorectal cancer patients. MATERIALS & METHODS: A total of 42 colorectal cancer patients and eight healthy volunteers participated in this study. The serum levels of fatty acids, including free fatty acids and esterified fatty acids, were evaluated by gas chromatography/mass spectrometry. Then, partial least squares discriminant analysis was performed on the basis of the serum fatty acids detected by gas chromatography/mass spectrometry. RESULTS: The serum levels of the nine fatty acids exhibited distinct differences between the colorectal cancer patients and healthy volunteers: the levels of four fatty acids were higher in the colorectal cancer patients than the healthy volunteers, and those of the other five fatty acids were lower. These changes were also observed at a very early clinical stage. Furthermore, the levels of very-long-chain fatty acids had a tendency to be increased in the sera of the colorectal cancer patients. CONCLUSIONS: The pathogenesis of colorectal cancer leads to changes in the composition of serum fatty acids including free fatty acids and esterified fatty acids. These results suggest that serum fatty acid profiling may be used as a novel diagnostic tool for early-stage colorectal cancer.

GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis.

OBJECTIVE: The roles that amino acids play in immunity and inflammation are well defined, and the relationship between inflammatory bowel disease (IBD) and certain amino acids has recently attracted attention. In this study, the levels of amino acids and trichloroacetic acid (TCA) cycle-related molecules in the colonic tissues and sera of patients with ulcerative colitis (UC) were profiled by gas chromatography/mass spectrometry (GC/MS), with the aim of evaluating whether the clinical state induced by UC leads to variations in the amino acid profile. MATERIALS AND METHODS: Colonic biopsy samples from 22 UC patients were used, as well as serum samples from UC patients (n = 13), Crohn's disease (CD) patients (n = 21), and healthy volunteers (n = 17). RESULTS: In the GC/MS-based profiling of amino acids and TCA cycle-related molecules, lower levels of 16 amino acids and 5 TCA cycle-related molecules were observed in the colonic lesion tissues of the UC patients, and the serum profiles of amino acids and TCA cycle-related molecules of the UC patients were different from those of the CD patients and healthy volunteers. CONCLUSIONS: Our study raises the possibility that GC/MS-based profiling of amino acids and TCA cycle-related molecules is a useful early diagnostic tool for UC.