Utility of Combined Use of Transabdominal Ultrasonography and Fecal Immunochemical Test Examinations in Ulcerative Colitis.

This study examined the utility of the combined use of transabdominal ultrasonography (TUS) and fecal immunochemical testing (FIT) to detect mucosal inflammation, vis-a-vis the Mayo endoscopic subscore (MES), in ulcerative colitis (UC). Sixty-three UC patients who underwent TUS and FIT were retrospectively enrolled. For TUS, the colon was divided into five segments, and the bowel wall thickness was measured and evaluated. The accuracy of FIT (> 100 ng/ml) in detecting mucosal inflammation (MES>0) was 0.93, whereas that of TUS (BWT>2 mm) in each segment was 0.84-0.97. The combined use of TUS and FIT may be helpful in noninvasive treatment strategies.

Clinical development of a blood biomarker using apolipoprotein-A2 isoforms for early detection of pancreatic cancer.

BACKGROUND: We have previously reported apolipoprotein A2-isoforms (apoA2-is) as candidate plasma biomarkers for early-stage pancreatic cancer. The aim of this study was the clinical development of apoA2-is. METHODS: We established a new enzyme-linked immunosorbent sandwich assay for apoA2-is under the Japanese medical device Quality Management System requirements and performed in vitro diagnostic tests with prespecified end points using 2732 plasma samples. The clinical equivalence and significance of apoA2-is were compared with CA19-9. RESULTS: The point estimate of the area under the curve to distinguish between pancreatic cancer (n = 106) and healthy controls (n = 106) was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832-0.925] than for CA19-9 (0.849, 95% CI 0.793-0.905) and achieved the primary end point. The cutoff apoA2-ATQ/AT of 59.5 µg/mL was defined based on a specificity of 95% in 2000 healthy samples, and the reliability of specificities was confirmed in two independent healthy cohorts as 95.3% (n = 106, 95% CI 89.4-98.0%) and 95.8% (n = 400, 95% CI 93.3-97.3%). The sensitivities of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) pancreatic cancers were higher than those of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cutoff, 59.5 µg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. The clinical performance of apoA2-is was blindly confirmed by the National Cancer Institute Early Detection Research Network. CONCLUSIONS: The clinical performance of ApoA2-ATQ/AT as a blood biomarker is equivalent to or better than that of CA19-9.

Apolipoprotein A2 isoforms associated with exocrine pancreatic insufficiency in early chronic pancreatitis.

BACKGROUND AND AIM: Apolipoprotein A2 (apoA2) isoforms have been reported to undergo the aberrant processing in pancreatic cancer and pancreatic risk populations compared with that in healthy subjects. This study aimed to clarify whether apoA2 isoforms were as useful as N-benzoyl-p-aminobenzoic acid (BT-PABA) test for exocrine pancreatic dysfunction markers in patients with early chronic pancreatitis (ECP). METHODS: Fifty consecutive patients with functional dyspepsia with pancreatic enzyme abnormalities (FD-P) (n = 18), with ECP (n = 20), and asymptomatic patients with pancreatic enzyme abnormalities (AP-P) (n = 12) based on the Rome IV classification and the Japan Pancreatic Association were enrolled in this study. The enrolled patients were evaluated using endoscopic ultrasonography and endoscopic ultrasonography elastography. Five pancreatic enzymes were estimated. Pancreatic exocrine function was analyzed using the BT-PABA test. Lighter and heavier apoA2 isoforms, AT and ATQ levels were measured by enzyme-linked immunosorbent assay methods. RESULTS: There were no significant differences in clinical characteristics such as age, gender, body mass index, alcohol consumption and smoking among patients with AP-P, FD-P, and ECP. The BT-PABA test and lighter apoA2 isoform, AT level in the enrolled patients had a significant correlation (P < 0.01). The BT-PABA test in patients with ECP was significantly lower (P = 0.04) than that in AP-P. ApoA2-AT level in patients with ECP was lower than that in AP-P, albeit, insignificantly. Interestingly, apo A2-AT level was significantly (P = 0.041) associated with exocrine pancreatic insufficiency by multiple logistic regression analysis. CONCLUSIONS: ApoA2-AT level is a useful tool to evaluate exocrine pancreatic insufficiency in the early stage of chronic pancreatitis.

Development of fluorogenic substrates for colorectal tumor-related neuropeptidases for activity-based diagnosis.

The M3 metalloproteases, neurolysin and THOP1, are neuropeptidases that are expressed in various tissues and metabolize neuropeptides, such as neurotensin. The biological roles of these enzymes are not well characterized, partially because the chemical tools to analyse their activities are not well developed. Here, we developed a fluorogenic substrate probe for neurolysin and thimet oligopeptidase 1 (THOP1), which enabled the analysis of enzymatic activity changes in tissue and plasma samples. In particular, the probe was useful for studying enzyme activities in a single-molecule enzyme assay platform, which can detect enzyme activity with high sensitivity. We detected the activity of neurolysin in plasma samples and revealed higher enzyme activity in the blood samples of patients with colorectal tumor. The result indicated that single-molecule neurolysin activity is a promising candidate for a blood biomarker for colorectal cancer diagnosis.

Usefulness of Intestinal Ultrasound to Detect Small Intestinal Stenosis in Patients With Crohn's Disease.

OBJECTIVES: Double balloon enteroscopy (DBE) with retrograde contrast is useful as a monitoring tool for small intestinal lesions in Crohn's disease (CD), but these are burdensome for patients. Intestinal ultrasound (IUS) can be used with ease in daily clinical practice, but there is less evidence regarding the accuracy of detection of small intestinal stenosis in CD. This study aimed to examine the diagnostic power of IUS for small intestinal stenosis in patients with CD. METHODS: The findings of DBE and IUS in 86 patients with CD with small intestinal lesions were evaluated. Using DBE as the reference standard, we examined the detection rate of IUS for small intestinal stenosis. We evaluated three parameters: luminal narrowing, prestenotic dilation, and to-and-fro movement for determining stenosis using IUS. In addition, we compared the characteristics between the stenosis-detectable and stenosis-undetectable groups by IUS. RESULTS: Of the 86 patients, 30 had small intestinal stenosis. In IUS findings, when lesions that met two or more of the three parameters were judged as stenosis, the detection rate was 70.0% for sensitivity, 98.2% for specificity, and 88.4% for accuracy. Moreover, there were patients with a younger age at diagnosis (P < 0.05) and more ileocolonic disease location (P < 0.05) in the stenosis-detectable group by IUS. The stenoses detected by IUS were significantly longer than those undetected by IUS (14.1 mm versus 5.2 mm, P < 0.05). CONCLUSIONS: IUS delivered reliable results for clinically important small intestinal stenosis of CD with high diagnostic accuracy.

The Colon Wall Thickness Measured Using Transabdominal Ultrasonography Is Useful for Detecting Mucosal Inflammation in Ulcerative Colitis.

Objective Transabdominal ultrasonography (TUS) is a non-invasive procedure that is reportedly useful for managing ulcerative colitis (UC) and assessing bowel wall thickness (BWT), the most common measure of mucosal inflammation. However, the exact range of BWT that reflects disease activity remains undetermined. The present study clarified the BWT due to disease activity by comparing the use of TUS in each segment of the colon versus using colonoscopy (CS) and determined the usefulness of TUS in patients with UC. Methods We divided the colon into five segments and measured the BWT using TUS. The results were then compared to the Mayo endoscopic subscore (MES) classification to determine the accuracy of BWT measurement. Patients Eighty patients with UC who underwent TUS within 14 days of CS were retrospectively registered. Results We evaluated a total of 268 images depicting each segment among 80 patients with UC. The BWT was positively correlated with endoscopic activity (0.69, p<0.0001). In each segment, the relationship between a BWT>2 mm and an MES>0 had the highest sensitivity, specificity, and accuracy (0.85-1.00, 0.67-0.92, and 0.81-0.97, respectively). Conclusion This study concluded that TUS was a useful method of detecting an MES>0, which indicates the presence of inflammation and its location among UC patients. MES>0 was found to be highly accurate when a BWT>2 mm was considered positive. This non-invasive method may help control disease activity in patients with UC.

Noninvasive risk stratification of intraductal papillary mucinous neoplasia with malignant potential by serum apolipoprotein-A2-isoforms.

Intraductal papillary mucinous neoplasms (IPMNs) are premalignant lesions of pancreatic cancer. An accurate serum biomarker, which allows earlier identification of asymptomatic individuals with high-risk for developing cancer, is of urgent need. Apolipoprotein A2-isoforms (apoA2-i) have previously been identified as biomarkers in pancreatic cancer. This study investigates a potential clinical application of the serum apoA2-i for risk stratification of IPMN and associated cancer. The concentrations of apoA2-i were retrospectively determined in 523 patient sera specimen, composed of 305 IPMNs with preinvasive lesions with different grades of dysplasia and invasive cancer, 140 pancreatic ductal adenocarcinoma, 78 with other cystic lesions and healthy controls cohorts, using an apoA2-i enzyme-linked immunosorbent assay kit. The diagnostic performance of serum apoA2-i was assessed and compared to routine clinical marker CA 19-9. ApoA2-i levels were significantly reduced in all IPMN samples regardless of stage compared to healthy controls. Receiver operating characteristic curve analysis of IPMNs with high-grade dysplasia and IPMN with associated carcinoma revealed the area under curve (AUC) of 0.91 and >0.94, respectively. The respective sensitivities were 70% and 83% with a specificity of 95%, and significantly higher than the gold standard biomarker CA 19-9. AUC values of apoA2-i for detecting IPMN-associated carcinoma of colloid and ductal subtypes were 0.990 and 0.885, respectively. ApoA2-i has the potential to early detect the risk of malignancy of patients with IPMN. The serological apoA2-i test in combination with imaging modalities could help improve the diagnosis of IPMN malignancy. Further validation in larger and independent international cohort studies is needed.

Prospective Study Using Plasma Apolipoprotein A2-Isoforms to Screen for High-Risk Status of Pancreatic Cancer.

Apolipoprotein A2-ATQ/AT (apoA2-ATQ/AT) has been identified as a minimally invasive biomarker for detecting pancreatic cancer (PC) and high-risk (HR) individuals for PC. To establish an efficient enrichment strategy for HR, we carried out a plasma apoA2-ATQ/AT level-based prospective screening study among the general population. The subjects for the screening study were recruited at six medical check-up facilities in Japan between October 2015 and January 2017. We evaluated the positive predictive value (PPV) of the plasma apoA2-ATQ/AT level of ≤35 µg/mL for detecting PC and HR. Furthermore, we prospectively confirmed its diagnostic accuracy with another post-diagnosis population in a cross-sectional study. We enrolled 5120 subjects in experimental screening, with 84 subjects (1.3%) showing positive results for apoA2-ATQ/AT. Pancreatic abnormalities were recognized in 26 of the 84 subjects from imaging examinations. Pancreatic abnormalities detected included 1 PC and 15 HR abnormalities, such as cystic lesions including intraductal papillary mucinous neoplasm. The PPV of apoA2-ATQ/AT for detecting PC and HR was 33.3%. Moreover, a combination study with another cross-sectional study revealed that the area under the curve for apoA2-ATQ/AT to distinguish PC from healthy controls was 0.903. ApoA2-ATQ/AT has the potential to enrich PC and HR by increasing the diagnostic probability before imaging examinations.

Prospects for Comprehensive Analyses of Circulating Tumor Cells in Tumor Biology.

The comprehensive analysis of biological and clinical aspects of circulating tumor cells (CTCs) has attracted interest as a means of enabling non-invasive, real-time monitoring of cancer patients and enhancing our fundamental understanding of tumor metastasis. However, CTC populations are extremely small when compared to other cell populations in the blood, limiting our comprehension of CTC biology and their clinical utility. Recently developed proteomic and genomic techniques that require only a small amount of sample have attracted much interest and expanded the potential utility of CTCs. Cancer heterogeneity, including specific mutations, greatly impacts disease diagnosis and the choice of available therapeutic strategies. The CTC population consists primarily of cancer stem cells, and CTC subpopulations are thought to undergo epithelial-mesenchymal transition during dissemination. To better characterize tumor cell populations, we demonstrated that changes in genomic profiles identified via next-generation sequencing of liquid biopsy samples could be expanded upon to increase sensitivity without decreasing specificity by using a combination of assays with CTCs and circulating tumor DNA. To enhance our understanding of CTC biology, we developed a metabolome analysis method applicable to single CTCs. Here, we review-omics studies related to CTC analysis and discuss various clinical and biological issues related to CTCs.

"Pinstripe Pattern" in an Achalasia Patient.

Endoscopic image of achalasia usually shows dilated esophageal cavity with retained liquids and foods. Recently, "pinstripe pattern" (PSP) in the case of achalasia patient was reported as an endoscopic image of the indicator for early detection of achalasia. The typical endoscopic image of PSP can be recognized in this case.

A target-controlled infusion system with bispectral index monitoring of propofol sedation during endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Propofol administration via a target-controlled infusion system with bispectral index monitoring (BIS/TCI system) is expected to prevent complications from sedation during complex and long endoscopic procedures. We evaluated the feasibility of setting the BIS/TCI system for non-anesthesiologist administration of propofol (NAAP) during endoscopic submucosal dissection (ESD). PATIENTS AND METHODS: From May 2009 to February 2013, 250 patients with esophagogastric neoplasms were treated with ESD using the BIS/TCI system with NAAP. In the TCI system, the initial target blood concentration of propofol was set at 1.2 µg/mL. The titration speed of propofol was adjusted according to the BIS score and the movement of the patient. The BIS target level ranged from moderate to deep sedation, at which a stable BIS score between 60 and 80 was obtained. RESULTS: In 80.4 % of patients, it was possible to maintain stable sedation with a blood concentration of propofol of less than 1.6 µg/mL using TCI throughout the ESD procedure. The default setting for ideal blood concentration of propofol was 1.2 µg/mL, because the medians of the lower and upper bounds of blood concentration were 1.2 µg/mL (range 0.6 - 1.8 µg/mL) and 1.4 µg/mL (range 1.0 - 3.8 µg/mL), respectively. Although hypotension occurred in 27 patients (10.8 %), oxygen desaturation occurred in only nine patients (3.6 %), and severe desaturation in only two patients (0.8 %). CONCLUSIONS: Using our settings, it is possible for a non-anesthesiologist to maintain stable sedation during a lengthy endoscopic procedure through propofol sedation with a BIS/TCI system.

[A case of renal salt-wasting syndrome during chemotherapy for advanced gastric cancer].

A 66-year-old woman was admitted to our hospital with heartburn and liver dysfunction. She was diagnosed with advanced gastric cancer. After the initiation of chemotherapy with trastuzumab, capecitabine, and cisplatin, she developed hyponatremia and renal failure with renal salt-wasting syndrome (RSWS). She recovered from these conditions after infusion of hypertonic saline. A diagnosis of RSWS should be considered in patients with hyponatremia who receive cisplatin-based chemotherapy.

Primary follicular lymphoma of the duodenum with erosions as atypical macroscopic features.

A 52-year-old Japanese woman who was eventually diagnosed with primary follicular lymphoma of the duodenum showed atypical endoscopic features, namely, erosions with peripheral whitish edematous mucosa. Initial biopsy specimens taken from the erosions revealed insufficient numbers of lymphoma cells for histological diagnosis. Subsequent biopsy specimens from the peripheral mucosa containing the whitish enlarged villi showed infiltration of the lymphoma cells forming lymphoid follicles, which led us to the appropriate diagnosis. This case indicates that endoscopists should take biopsy samples from the peripheral mucosa with whitish enlarged villi rather than erosions in the rare instances that erosions appear as the main macroscopic feature of intestinal follicular lymphoma.

Peppermint oil solution is useful as an antispasmodic drug for esophagogastroduodenoscopy, especially for elderly patients.

BACKGROUND: Although hyoscine butyl bromide (HB) and glucagon (GL) are often used as antispasmodic drugs during esophagogastroduodenoscopy (EGD), these agents may cause adverse effects. Recently, it was reported that peppermint oil solution (PO) was very effective and had few side effects. AIM: We clarified the efficacy and usefulness of PO as an antispasmodic during upper endoscopy, especially for elderly patients. METHODS: This study was a non-randomized prospective study. The antispasmodic score (1-5, where 5 represents no spasm) was defined according to the degree of spasms of the antrum and difficulty of biopsy. We compared the antispasmodic scores between non-elderly patients (younger than 70) and elderly patients (70 years old or older) according to the antispasmodic agent. RESULTS: A total of 8,269 (Group PO: HB: GL: NO (no antispasmodic) = 1,893: 6,063: 157: 156) EGD procedures were performed. There was no significant difference in the antispasmodic score between Group PO (mean score ± standard deviation: 4.025 ± 0.925) and Group HB (4.063 ± 0.887). Among the non-elderly patients, those in Group PO (n = 599, 3.923 ± 0.935) had a worse antispasmodic score than those in Group HB (n = 4,583, 4.062 ± 0.876, P < 0.001). However, among the elderly patients, those in Group PO (n = 1,294, 4.073 ± 0.917) had similar scores to those in Group HB (n = 1,480, 4.064 ± 0.921, P = 0.83), and significantly better scores than those in Group GL (n = 69, 3.797 ± 0.933, P < 0.05). CONCLUSION: Peppermint oil was useful as an antispasmodic during EGD, especially for elderly patients.

Genomics approach to abscisic acid- and gibberellin-responsive genes in rice.

We used an 8987-EST collection to construct a cDNA microarray system with various genomics information (full-length cDNA, expression profile, high accuracy genome sequence, phenotype, genetic map, and physical map) in rice. This array was used as a probe to hybridize target RNAs prepared from normally grown callus of rice and from callus treated for 6 hr or 3 days with the hormones abscisic acid (ABA) or gibberellin (GA). We identified 509 clones, including many clones that had never been annotated as ABA-or GA-responsive. These genes included not only ABA- or GA-responsive genes but also genes responsive to other physiological conditions such as pathogen infection, heat shock, and metal ion stress. Comparison of ABA- and GA-responsive genes revealed antagonistic regulation for these genes by both hormones except for one defense-related gene, thionin. The gene for thionin was up-regulated by both hormone treatments for 3 days. The upstream regions of all the genes that were regulated by both hormones had cis-elements for ABA and GA response. We performed a clustering analysis of genes regulated by both hormones and various expression profiles that showed three notable clusters (seed tissues, low temperature and sugar starvation, and thionin-gene related). A comparison of the cis-elements for hormone response genes between rice and Arabidopsis thaliana, we identified cis-elements for dehydration-stress response or for expression of amylase gene as Arabidopsis gene-specific or rice gene-specific, respectively.

Visual feature binding in early infancy.

How does the developing brain of the human infant solve the feature-binding problem when visual stimuli consisting of multiple colored objects are presented? A habituation--dishabituation procedure revealed that 1-month-old infants have the ability to discriminate changes in the conjunction of a familiar shape and color in two objects. However, this good earlier performance was followed by poorer performance at 2 months of age. The performance improved again at 3 months of age. Detailed analysis of the oculomotor behaviors revealed that the age of 2 months was a period of drastic transition when the tendency to stay with the fixated objects disappeared and repetitive saccades between the two objects emerged. Our findings suggest that the ability to perceive conjunctions of features is available to infants very early, that the perceptual/neural basis at 1 and at 3 months of age may be fundamentally different, and that feature integration by vigorous eye movements or selective attention may be the key functional difference between the age groups.