Germline Pathogenic Variants in Patients With Pancreatic and Periampullary Cancers.

PURPOSE: Inherited cancer susceptibility is often not suspected in the absence of a significant cancer family history. Pathogenic germline variants in pancreatic cancer are well-studied, and routine genetic testing is recommended in the guidelines. However, data on rare periampullary cancers other than pancreatic cancer are insufficient. We compared the prevalence of germline susceptibility variants in patients with pancreatic cancer and nonpancreatic periampullary cancers. MATERIALS AND METHODS: Six hundred and eight patients who had undergone pancreaticoduodenal resection at a tertiary referral hospital were studied, including 213 with pancreatic ductal adenocarcinoma, 172 with ampullary cancer, 154 with distal common bile duct cancer, and 69 with duodenal adenocarcinoma. Twenty cancer susceptibility and candidate susceptibility genes were sequenced, and variant interpretation was assessed by interrogating ClinVar and PubMed. RESULTS: Pathogenic or likely pathogenic, moderate- to high-penetrant germline variants were identified in 46 patients (7.7%), including a similar percentage of patients with pancreatic (8.5%) and nonpancreatic periampullary cancer (7.1%). Low-penetrant variants were identified in an additional 11 patients (1.8%). Eighty-nine percent of the moderate- to high-penetrant variants involved the major cancer susceptibility genes BRCA2, ATM, BRCA1, CDKN2A, MSH2/MLH1, and PALB2; the remaining 11% involved other cancer susceptibility genes such as BRIP1, BAP1, and MSH6. Almost all pathogenic variant carriers had a family history of cancer. CONCLUSION: Patients with pancreatic and nonpancreatic periampullary cancer have a similar prevalence of pathogenic cancer susceptibility variants. Germline susceptibility testing should be considered for patients with any periampullary cancer.

Using Tumor Marker Gene Variants to Improve the Diagnostic Accuracy of DUPAN-2 and Carbohydrate Antigen 19-9 for Pancreatic Cancer.

PURPOSE: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance. MATERIALS AND METHODS: Using a training/validation study design, FUT2/FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay. RESULTS: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUCPR) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2. CONCLUSION: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

Using a CA19-9 Tumor Marker Gene Test to Assess Outcome After Pancreatic Cancer Surgery.

BACKGROUND: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. Individuals can be grouped into one of four functional FUT groups (FUT3-null, FUT-low, FUT-intermediate, FUT-high), each with its own CA19-9 reference range based on its predicted capacity to produce CA19-9. The authors hypothesized that a FUT variant-based CA19-9 tumor marker gene test could improve the prognostic performance of CA19-9. METHODS: Preoperative and pre-treatment CA19-9 levels were measured, and FUT variants were determined in 449 patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2010 and 2020, including 270 patients who underwent neoadjuvant therapy. Factors associated with recurrence-free and overall survival were determined in Cox proportional hazards models. RESULTS: Higher preoperative CA19-9 levels were associated with recurrence and mortality for patients in the higher-FUT groups (FUT-intermediate, FUT-high for mortality, with adjustment for other prognostic factors; hazard ratio [HR], 1.34 and 1.58, respectively; P < 0.001), but not for those in the lower-FUT groups (FUT3-null, FUT-low). As a tumor marker, CA19-9 levels of 100 U/ml or lower after neoadjuvant therapy and normalization of CA19-9 based on FUT group were more sensitive but less specific predictors of evidence for a major pathologic response to therapy (little/no residual tumor) and of early recurrence (within 6 months). CONCLUSION: Among patients undergoing pancreatic cancer resection, a CA19-9 tumor marker gene test modestly improved the prognostic performance of CA19-9.

Duodenal and pancreatic tissue microbiome profiles of PPI users and non-users.

Factors that influence the pancreas microbiome are not well understood. Regular proton pump inhibitor (PPI) use induces significant alterations in the gut microbiome, including an increase in the abundance of Streptococcus, and may be associated with pancreatic cancer risk. The aim of this study was to examine whether PPI use is associated with pancreatic and duodenal tissue microbiomes. We compared 16S rRNA microbiome profiles of normal pancreatic and duodenal tissue from 103 patients undergoing pancreatic surgery for non-malignant indications, including 34 patients on PPIs, accounting for factors including age, smoking, body mass index and the presence of main pancreatic duct dilation. Histologically normal tissue from the pancreatic head had higher alpha diversity and enrichment of Firmicutes by phylum-level analysis and Streptococcus species compared to normal pancreas body/tail tissues (16.8 % vs 8.8 %, P = .02, and 5.9 % vs 1.4 %, P = .03, respectively). Measures of beta diversity differed significantly between the pancreas and the duodenum, but in subjects with main pancreatic duct dilation, beta diversity of pancreatic head tissue was more similar to normal duodenal tissue than those without pancreatic duct dilation. Duodenal tissue of PPI users had significant enrichment of Firmicute phyla (34.7 % vs. 14.1 %, P = .01) and Streptococcus genera (19.5 % vs. 5.2 %, P = .01) compared to non-users; these differences were not evident in pancreas tissues. By multivariate analysis, PPI use was associated with alpha diversity in the duodenum, but not in the pancreas. However, some differences in pancreas tissue beta diversity were observed between PPI users and non-users. In summary, we find differences in the microbiome profiles of the pancreas head versus the pancreatic body/tail and we find PPI use is associated with alterations in duodenal and pancreatic tissue microbiome profiles.

Endoplasmic stress-inducing variants in carboxyl ester lipase and pancreatic cancer risk.

BACKGROUND: Endoplasmic reticulum (ER) stress-inducing variants in several pancreatic secretory enzymes have been associated with pancreatic disease. Multiple variants in CEL, encoding carboxyl ester lipase, are known to cause maturity-onset diabetes of the young (MODY8) but have not been implicated in pancreatic cancer risk. METHODS: The prevalence of ER stress-inducing variants in the CEL gene was compared among pancreatic cancer cases vs. controls. Variants were identified by next-generation sequencing and confirmed by Sanger sequencing. Variants of uncertain significance (VUS) were assessed for their effect on the secretion of CEL protein and variants with reduced protein secretion were evaluated to determine if they induced endoplasmic reticulum stress. RESULTS: ER stress-inducing CEL variants were found in 34 of 986 cases with sporadic pancreatic ductal adenocarcinoma, and 21 of 1045 controls (P = 0.055). Most of the variants were either the CEL-HYB1 variant, the I488T variant, or the combined CEL-HYB1/I488T variant; one case had a MODY8 variant. CONCLUSION: This case/control analysis finds ER stress-inducing CEL variants are not associated with an increased likelihood of having pancreatic cancer.

Do synbiotics really enhance beneficial synbiotics effect on defecation symptoms in healthy adults?: Randomized, double-blind, placebo-controlled trial.

GOALS: We examined whether synbiotics enhance improvement by probiotics. BACKGROUND: Probiotics, which are beneficial microbacteria, are a nutritional intervention for treatment of functional constipation or its tendency. Prebiotics, meanwhile, can promote the proliferation of probiotics in the gastrointestinal tract and enhance their beneficial effects. Synbiotics, a combination of probiotics and prebiotics, may be superior to probiotics in the treatment of defecation-related symptoms, but this requires elucidation. STUDY: This randomized, double-blind, placebo-controlled study enrolled 69 healthy adults with constipation tendency. Participants were allocated to either control, probiotics, or synbiotics groups and they recorded details of their defecations and their condition. The first 2 weeks were the observation period and the latter 2 weeks were the intervention period, in which participants took test foods. Probiotic foods included Bifidobacterium longum NT strain (1010 CFU/day), synbiotic foods included the NT strain (1010 CFU/day) and galactooligosaccharide (1 g/day). Placebo foods contained the vehicle only. Participants answered questionnaires (Patient Assessment on Constipation Symptoms [PAC-SYM], and one on dietary history) on the last day of each period. RESULTS: Nine participants withdrew consent, and 2 of the remaining 60 had missing data. Age, body mass index, and sex were not significantly different between the 3 groups. Frequency of bowel movements in the fourth week, the primary endpoint, was not increased in the probiotics or synbiotics groups compared with the control group, and the frequency of bowel movements and days with defecation were not changed by probiotics or synbiotics during the intervention period. Probiotics and synbiotics did not improve stool conditions, although incomplete defecation was improved by probiotics but not by synbiotics compared with placebo. PAC-SYM indicated that stool condition and total scores were improved by probiotics but not by synbiotics during the intervention compared with placebo. CONCLUSION: The probiotic strain Bifidobacterium longum NT can improve constipation symptoms, especially stool condition, but it does not increase bowel movement frequency in healthy adults with constipation tendency. Synbiotics treatment seemed to diminish this improvement of constipation induced by probiotics. This study indicates the possibility of attenuation of beneficial effects from probiotics by the use of synbiotics, contrary to synbiotics theory.

Alterations in the Duodenal Fluid Microbiome of Patients With Pancreatic Cancer.

BACKGROUND & AIMS: The tumor microbiome of patients with pancreas ductal adenocarcinoma (PDAC) includes bacteria normally present in the upper gastrointestinal tract. If the predominant source of intratumoral bacteria in patients with PDAC is retrograde migration from the duodenum, duodenal fluid could be a representative biospecimen for determining microbiome profiles of patients with PDAC or at risk of developing PDAC. METHODS: We performed a case-control study comparing bacterial and fungal (16S and 18S rRNA) profiles of secretin-stimulated duodenal fluid collections from 308 patients undergoing duodenal endoscopy including 134 normal pancreas control subjects, 98 patients with pancreatic cyst(s) and 74 patients with PDAC. RESULTS: Alterations in duodenal fluid microbiomes with diminished alpha diversity were significantly associated with age >70 and proton pump inhibitor use. Patients with PDAC had significantly decreased duodenal microbial alpha diversity compared with age-matched control subjects with normal pancreata and those with pancreatic cyst(s). There was evidence of enrichment of Bifidobacterium genera in the duodenal fluid of patients with PDAC compared with control subjects and those with pancreatic cyst(s). There were also enrichment of duodenal fluid Fusobacteria and Rothia bacteria among patients with PDAC with short-term survival. Duodenal fluid microbiome profiles were not significantly different between control subjects and patients with pancreatic cyst(s). CONCLUSION: Patients with PDAC have alterations in their duodenal fluid microbiome profiles compared with patients with pancreatic cysts and those with normal pancreata. ClinicalTrials.gov, Number: NCT02000089.

Serum Carboxypeptidase Activity and Genotype-Stratified CA19-9 to Detect Early-Stage Pancreatic Cancer.

BACKGROUND AND AIMS: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer. METHODS: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated. RESULTS: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%. CONCLUSION: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease.

Utility of Contrast-Enhanced Harmonic Endoscopic Ultrasonography for Early Diagnosis of Small Pancreatic Cancer.

This study aimed to assess whether contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), compared to multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI), is useful for early diagnosis of small pancreatic cancer (PC). Between March 2010 and June 2018, all three imaging modalities and surgery were performed for patients with a pancreatic solid lesion measuring ≤20 mm; diagnostic ability was compared among modalities. Fifty-one of 60 patients were diagnosed with PC (PC size in 41 patients: 11-20 mm; 10 patients: ≤10 mm). The sensitivity, specificity, and accuracy of CH-EUS, MDCT, and MRI for PC (11-20 mm) detection were 95%/83%/94%, 78%/83%/79%, and 73%/33%/68%, respectively. The diagnostic ability of CH-EUS was significantly superior compared with MDCT and MRI (p = 0.002 and p = 0.007, respectively). The sensitivity, specificity, and accuracy of CH-EUS, MDCT, and MRI for PC (≤10 mm) detection were 70%/100%/77%, 20%/100%/38%, and 50%/100%/62%, respectively. The diagnostic ability of CH-EUS tended to be superior to that of MDCT (p = 0.025). The sensitivity of MDCT for PC (≤10 mm) detection was significantly lower than that for PC (11-20 mm) detection (20% vs. 78%; p = 0.001). CH-EUS, compared to MDCT and MRI, is useful for diagnosing small PCs.

Utility of Elastography with Endoscopic Ultrasonography Shear-Wave Measurement for Diagnosing Chronic Pancreatitis.

Background/Aims: Rosemont classification (RC) with endoscopic ultrasonography (EUS) is important for diagnosing chronic pancreatitis (CP) but is based only on subjective judgement. EUS shear wave measurement (EUS-SWM) is a precise modality based on objective judgment, but its usefulness has not been extensively studied yet. This study evaluated the utility of EUS-SWM for diagnosing CP and estimating CP severity by determining the presence of endocrine dysfunction along with diabetes mellitus (DM). Methods: Between June 2018 and December 2018, 52 patients who underwent EUS and EUS-SWM were classified into two groups according to RC: non-CP (indeterminate CP and normal) and CP (consistent and suggestive of CP). The EUSSWM value by shear wave velocity was evaluated with a median value. The EUS-SWM value was compared with RC and the number of EUS features. The diagnostic accuracy and cutoff value of EUS-SWM for CP and DM and its sensitivity and specificity were calculated. Results: The EUS-SWM value significantly positively correlated with the RC and the number of EUS features. The EUS-SWM values that were consistent and suggestive of CP were significantly higher than that of normal. The area under the receiver operating characteristic (AUROC) curve for the diagnostic accuracy of EUS-SWM for CP was 0.97. The cutoff value of 2.19 had 100% sensitivity and 94% specificity. For endocrine dysfunction in CP, the AUROC was 0.75. The cutoff value of 2.78 had 70% sensitivity and 56% specificity. Conclusions: EUS-SWM provides an objective assessment and can be an alternative diagnostic tool for diagnosing CP. EUS-SWM may also be useful for predicting the presence of endocrine dysfunction.

Endoscopic Ultrasound for Early Diagnosis of Pancreatic Cancer.

Detection of small pancreatic cancers, which have a better prognosis than large cancers, is needed to reduce high mortality rates. Endoscopic ultrasound (EUS) is the most sensitive imaging modality for detecting pancreatic lesions. The high resolution of EUS makes it particularly useful for detecting small pancreatic lesions that may be missed by other imaging modalities. Therefore, EUS should be performed in patients with obstructive jaundice in whom computed tomography (CT) or magnetic resonance imaging (MRI) does not identify a definite pancreatic lesion. Interest in the use of EUS for screening individuals at high risk of pancreatic cancer, including those with intraductal papillary mucinous neoplasms (IPMNs) and familial pancreatic cancer is growing. Contrast-enhanced EUS can facilitate differential diagnosis of small solid pancreatic lesions as well as malignant cystic lesions. In addition, EUS-guided fine needle aspiration can provide samples of small pancreatic lesions. Thus, EUS and EUS-related techniques are essential for early diagnosis of pancreatic cancer.

Prediction of treatment outcome and relapse in inflammatory bowel disease.

INTRODUCTION: Prediction of treatment outcome and clinical relapse in patients with inflammatory bowel disease (IBD), either ulcerative colitis (UC) or Crohn's disease (CD), is particularly important because therapeutics for IBD are not always effective and patients in remission could frequently relapse. Because undergoing endoscopy for the purpose is sometimes invasive and burdensome to patients, the performance of surrogate biomarkers has been investigated. Areas covered: We particularly featured the performance of patient symptoms, blood markers including C-reactive protein (CRP), fecal markers including fecal calprotectin (Fcal) and fecal immunochemical test (FIT) for prediction of endoscopic mucosal healing (MH) and prediction of relapse. Studies of other modalities and therapeutic drug monitoring (TDM) have also been explored. Expert opinion: Meticulous evaluation of patient symptoms could be predictive for MH in UC. CRP and Fcal may be accurate in prediction of MH of CD when MH is evaluated throughout the entire intestine including the small bowel. Repeated measurements of fecal markers including Fcal and FIT in patients with clinical remission would raise predictability of relapse. Prediction of treatment outcome by monitoring with blood markers including CRP, fecal markers including Fcal, and TDM has frequently been performed in recent clinical trials and shown to be effective.

Impact of endoscopic ultrasonography on diagnosis of pancreatic cancer.

Accumulated evidence has revealed that endoscopic ultrasonography (EUS) has had a great impact on the clinical evaluation of pancreatic cancers. EUS can provide high-resolution images of the pancreas with a quality regarded as far surpassing that achieved on transabdominal ultrasound (US), computed tomography (CT), or magnetic resonance imaging (MRI). EUS is particularly useful for the detection of small pancreatic lesions, while EUS and its related techniques such as contrast-enhanced EUS (CE-EUS), EUS elastography, and EUS-guided fine needle aspiration (EUS-FNA) are also useful in the differential diagnosis of solid or cystic pancreatic lesions and the staging (T-staging, N-staging, and M-staging) of pancreatic cancers. In the diagnosis of pancreatic lesions, CE-EUS and EUS elastography play a complementary role to conventional EUS. When sampling is performed using EUS-FNA, CE-EUS and EUS elastography provide information on the target lesions. Thus, conventional EUS, CE-EUS, EUS elastography, and EUS-FNA are essential in the clinical investigation of pancreatic cancer.

Radical treatment for walled-off necrosis: Transmural nasocyst continuous irrigation.

BACKGROUND AND AIM: Treatment efficiency of walled-off necrosis (WON) using endoscopic ultrasound-guided drainage (EUS-D) with a double pigtail stent (DPS) is limited. Endoscopic necrosectomy is often carried out if EUS-D fails. However, endoscopic necrosectomy is associated with significant morbidity and mortality. Thus, we developed transmural nasocyst continuous irrigation (TNCCI) as an alternative therapeutic option for WON. This study aimed to evaluate the usefulness of TNCCI therapy for WON. METHODS: Between April 2009 and March 2018, 19 of 39 patients admitted with WON underwent EUS-D. Ten consecutive patients also received TNCCI therapy (TNCCI group) between May 2015 and March 2018. TNCCI was carried out by inserting an external tube from the gastroduodenal lumen into the WON under endoscopic ultrasonography guidance and then continuously irrigating the WON with saline at a rate of 40 ml/h. Nine consecutive patients who underwent EUS-D without TNCCI therapy between April 2009 and April 2015 were used for comparison (control group). Various parameters were compared between the TNCCI and control groups. RESULTS: Time taken to reduce WON (6 vs 32 days, P = 0.001), implementation rate of endoscopic necrosectomy (0% vs 55.6%, P = 0.01), and number of endoscopic necrosectomy sessions per patient (0 vs 0.8 ± 1.0, P = 0.008) were significantly lower in the TNCCI group than in the control group. CONCLUSIONS: Walled-off necrosis can be effectively and safely treated by endoscopic drainage with a DPS and TNCCI. This technique can be an alternative therapeutic option before carrying out endoscopic necrosectomy.

Patient self-reported symptoms using visual analog scales are useful to estimate endoscopic activity in ulcerative colitis.

BACKGROUND/AIMS: In clinical practice, colonoscopy has been regarded as the gold standard for the evaluation of disease severity as well as mucosal healing in ulcerative colitis (UC). Some activity indices incorporating patient symptoms as parameters have been shown to reflect the endoscopic activity of UC. The aim of this study was to examine whether self-reported symptoms with visual analog scales (VAS) can predict endoscopic activity. METHODS: A cross-sectional study of 150 UC patients who underwent colonoscopy with submission of VAS scores of 4 symptoms: general condition, bloody stools, stool form, and abdominal pain (0: no symptoms, 10: the most severe symptoms). Each VAS score was compared with colonoscopic activity assessed with the Mayo endoscopic subscore (MES). RESULTS: All VAS scores were significantly correlated with the endoscopic severity (Spearman correlation coefficients of general condition, bloody stools, stool form, and abdominal pain: 0.63, 0.64, 0.58, and 0.43, respectively). Mucosal healing defined as MES 0 alone was predicted by VAS score <1.5 on general condition or 0 on bloody stools with sensitivity of 0.84 and 0.76 and specificity of 0.66 and 0.76, respectively. Additionally, VAS score <2.5 on stool form predicted active lesions in distal colorectum alone with sensitivity of 0.67 and specificity of 0.66, suggesting that this item could predict the indication of topical therapy. CONCLUSIONS: Self-reported VAS scores on symptoms were correlated with endoscopic activity of UC. To clarify the relationship between VAS and mucosal healing, further validation studies are needed.

Risk of colonic diverticular rebleeding according to endoscopic appearance.

BACKGROUND AND STUDY AIMS: Re-commencement of bleeding (rebleeding) of colonic diverticula after endoscopic hemostasis is a clinical problem. This study aimed to examine whether endoscopic visibility of colonic diverticular bleeding affects the risk of rebleeding after endoscopic hemostasis. PATIENTS AND METHODS: We performed a retrospective review of endoscopic images and medical charts of patients with colonic diverticular bleeding who underwent endoscopic hemostasis. Endoscopic visibility was classified into two types according to visibility of the source of bleeding; source invisibility due to bleeding or attached hematin (type 1), or endoscopically visible responsive vessels (type 2). Rebleeding rates within one year after initial hemostasis were examined. RESULTS: Of 93 patients with successful endoscopic hemostasis, 38 (41 %) showed type 1 visibility, while the remaining presented type 2. All patients received hemostasis with clipping, rebleeding developed in 20 patients (22 %). Type 1 visibility was more likely to be observed in patients with rebleeding (65 % vs. 34 %, P  = 0.013). Multivariate analysis revealed that after endoscopic hemostasis, type 1 visibility (invisible source) was the only independent risk factor for colonic diverticular rebleeding (odds ratio, 3.05; 95 % confidence interval, 1.03 - 9.59, P  = 0.044). Kaplan-Meier curve showed the cumulative incidence of rebleeding was significantly higher in patients with type 1 visibility than those with type 2 visibility ( P  = 0.0033, log-rank test). CONCLUSION: Hemostasis by clipping for colonic diverticular bleeding without definite observation of the source of bleeding may not be sufficiently effective. Other hemostatic methods, including band ligation, should be considered when the source of bleeding is unclear.

Irregular Defects in Hepatocellular Carcinomas During the Kupffer Phase of Contrast-Enhanced Ultrasonography with Perfluorobutane Microbubbles: Pathological Features and Metastatic Recurrence After Surgical Resection.

The present study aimed to elucidate the association between post-vascular-phase (Kupffer-phase) images from contrast-enhanced ultrasonography (CEUS) with perfluorobutane microbubbles and metastatic recurrences after the resection of hepatocellular carcinoma (HCC). The study examined 73 patients with solitary HCC ≤5 cm in diameter who underwent CEUS before resection. HCC was defined as irregular type (including an irregular defect on Kupffer-phase images) or non-irregular type. Intrahepatic metastatic recurrence was defined as >3 intrahepatic recurrences. Metastatic recurrence included both extrahepatic and intrahepatic recurrences. Frequencies of microscopic portal invasion and intrahepatic metastasis were significantly higher in the irregular group than in the non-irregular group. Cumulative 5-y metastatic recurrence rates in the irregular and non-irregular groups were 43% and 7% (p = 0.028), respectively. Multivariate analyses identified Kupffer-phase findings as a factor significantly related to metastatic recurrence. In conclusion, HCCs with an irregular defect during Kupffer-phase CEUS are characterized by more frequent microscopic vascular invasion and intrahepatic metastasis and are significantly associated with metastatic recurrence after resection.

Add-on Pegylated Interferon Alpha-2a Therapy in Chronic Hepatitis B Japanese Patients Treated with Entecavir.

Entecavir requires long-term administration. Pegylated interferon (PEG-IFN) therapy leads to significant reduction of hepatitis B surface antigen (HBs Ag) levels. This study aimed to assess the safety and efficacy of adding PEG-IFN-α-2a to entecavir toward cessation of entecavir. A total of 23 patients treated with entecavir underwent add-on PEG-IFN-α-2a therapy (90 µg per week) for 48 weeks. Viral response (VR) was defined as more than 50% reduction of baseline hepatitis B surface antigen (HBs Ag) level at 72 weeks from the start of therapy. Complete response (CR) was defined as the decline of HBs Ag levels <100 IU/mL. Hepatitis B e antigen (HBe Ag) seroconversion rate was 25% (2/8), and VR rate was 52% (12/23). CR was observed in four patients (17%). However, CR rate in baseline HBs Ag level <2000 IU/mL and HBe Ag negative patients was 50% (4/8). Univariate analysis showed that the percentage of HBs Ag level reduction at week 12 was significantly associated with VR. The area under the curve value was 0.848. Adding PEG-IFN-α-2a to entecavir has limited efficacy. The percentage reduction of HBs Ag level at week 12 may be a useful predictor for VR.

Rapid On-Site Evaluation by Endosonographers during Endoscopic Ultrasonography-Guided Fine-Needle Aspiration for Diagnosis of Gastrointestinal Stromal Tumors.

BACKGROUND/AIMS: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been used to diagnose gastrointestinal submucosal tumors (SMTs). Although rapid on-site evaluation (ROSE) has been reported to improve the diagnostic accuracy of EUS-FNA for pancreatic lesions, on-site cytopathologists are not routinely available. Given this background, the usefulness of ROSE by endosonographers themselves for pancreatic tumors has also been reported. However, ROSE by endosonographers for diagnosis of SMT has not been reported. The aim of this study was to evaluate the diagnostic accuracy of EUS-FNA with ROSE by endosonographers for SMT, focusing on diagnosis of gastrointestinal stromal tumor (GIST), compared with that of EUS-FNA alone. METHODS: Twenty-two consecutive patients who underwent EUS-FNA with ROSE by endosonographers for SMT followed by surgical resection were identified. Ten historical control subjects who underwent EUS-FNA without ROSE were used for comparison. RESULTS: The overall diagnostic accuracy for SMT was significantly higher in cases with than without ROSE (100% vs. 80%, p=0.03). The number of needle passes by FNA with ROSE by endosonographers tended to be fewer, although accuracy was increased (3.3±1.3 vs. 5.9±3.8, p=0.06). CONCLUSIONS: ROSE by endosonographers during EUS-FNA for SMT is useful for definitive diagnosis, particularly for GIST.