A case of refractory immune checkpoint inhibitor-induced colitis improved by the treatment with vedolizumab and granulocyte-monocyte apheresis combination therapy.

A 68-year-old man developed immune-related adverse event (irAE) colitis after the initiation of nivolumab and ipilimumab combination therapy for malignant melanoma. We diagnosed the patient with grade 3 irAE colitis and started prednisolone (1 mg/kg/day). Although the symptom improved once, it worsened along with the tapering of prednisolone. Therefore, we started infliximab (IFX). However, symptoms did not improve after two doses of IFX. We discontinued IFX and initiated vedolizumab (VED). Because VED alone did not improve the symptom, we started granulocyte-monocyte apheresis (GMA). Twelve weeks after the onset, the colitis was in remission. Therefore, in addition to vedolizumab, GMA may be considered in cases refractory to treatment.

Biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced or recurrent colorectal cancer: a phase II, multicenter, clinical trial (TAS-CC4 study).

BACKGROUND: TAS-102 improves overall survival (OS) of patients with refractory colorectal cancer (CRC), resulting in median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, a combination of TAS-102 and bevacizumab was shown to extend median PFS by 3.7 months. However, approximately half of these patients experience grade 3/4 neutropenia. In this study, we evaluated whether biweekly TAS-102 and bevacizumab therapy has efficacy equal to that of conventional TAS-102 and bevacizumab therapy and whether it reduces adverse hematological effects. METHODS: This phase II, investigator-initiated, open-label, single-arm, multicenter study was conducted in Japan. Eligible patients had previously received first- and second-line chemotherapy for metastatic CRC. TAS-102 (35 mg/m2) was given twice daily on days 1-5 and days 15-19 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion for 30 min every 2 weeks. The primary end point was progression-free survival (PFS), and secondary end points were time-to-treatment failure (TTF), response rate (RR), OS, and safety. RESULTS: 44 patients with metastatic colorectal cancer were enrolled in this study. Median PFS was 4.6 months (95% confidence interval [95% CI] 3.6-5.3) and median OS was 10.5 months (95% CI 9.6-11.4). A partial response was observed in 2 patients (4.5%, 95% CI 0.4-16.0%). The most common adverse event above grade 3 was neutropenia (7 patients, 15.9%, 95% CI 7.6-29.7%). CONCLUSIONS: Biweekly TAS-102 and bevacizumab therapy as third-line chemotherapy appears as effective as conventional TAS-102 and bevacizumab therapy, and this approach reduces adverse hematological effects.

Autoimmune Pancreatitis with Gastric Cancer: Some IgG4-related Diseases May Be Paraneoplastic Syndrome.

A 70-year-old man was referred to our department for the treatment of early gastric cancer. Contrast-enhanced computed tomography (CT) incidentally showed diffuse enlargement of the pancreas with a capsule-like rim, and blood tests showed elevated serum IgG4 levels, leading to a diagnosis of autoimmune pancreatitis (AIP). Endoscopic treatment for gastric cancer was performed, and pathological findings showed adenocarcinoma with abundant IgG4-positive plasma cell infiltration. Thereafter, the serum IgG4 levels normalized, and the findings of AIP disappeared on CT without steroid treatment. These findings suggest that the gastric cancer activated an IgG4-related immune response, resulting in the development of AIP.

Endoscopic injection sclerotherapy improves liver function compared with endoscopic variceal ligation.

Liver function is a most important prognostic factor in patients with liver cirrhosis. Also, portal hypertension is a fatal complication of liver cirrhosis and variceal treatment is indispensable. However, changes of liver functions after endoscopic variceal treatments are unknown. The aim of this study was to evaluate prognosis and liver functions after endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL). A total of liver cirrhotic 103 patients who underwent prophylactic EIS and EVL were enrolled. Overall survival rate was higher in EIS group than EVL group (p = 0.03). Multivariate analysis showed that EIS was a negative factor for death (HR: 0.46, 95% confidence interval: 0.24-0.88, p = 0.02). Liver functions were assessed by blood test taken at before and 3 months after treatment. In EIS group, albumin and prothrombin time improved (p < 0.01), leading to improvement of Child-Pugh score, ALBI score and MELD score (p < 0.05). However, these did not improve in EVL group. EIS was a significant factor related to the elevated value of albumin after treatment in linear regression analysis (estimated regression coefficient: 0.17, 95% confidence interval: 0.05-0.29, p = 0.005). These results revealed that EIS could improve liver functions and prognosis.

Impact of the Concomitant Use of Immunomodulator and a Lower Week 8 Partial Mayo Score on the Persistence of Adalimumab in Refractory Ulcerative Colitis.

Objective Real-world data of adalimumab (ADA) in the treatment of ulcerative colitis (UC) are scarce. We aimed to study the ADA response rates and predictors of response in UC treatment. Methods This observational, prospective and multi-center study assessed the clinical outcome of refractory UC patients treated with ADA who previously had an inadequate response to either conventional therapies or other anti-TNF antibodies or tacrolimus. The primary endpoint was the proportion of UC patients achieving a clinical response and remission at 8 and 52 weeks. We also evaluated the parameters which were associated with a clinical response at 8 and 52 weeks. Results A total of 35 patients were enrolled from 11 centers. The clinical responses at 8 and 52 weeks were 60.0% and 51.4%, respectively. The clinical remission rates at 8 and 52 weeks were 45.7% and 48.6%, respectively. Positive predictors for week 52 response were combination of ADA with immunomodulator (IM) (OR: 27.229; 95% CI; 1.897-390.76; p=0.015) and a week 8 lower partial Mayo score (OR: 0.406; 95% CI; 0.204-0.809; p=0.010). A receiver operation characteristic curve analysis revealed the optimal week 8 partial Mayo score to be 2.5, therefore a partial Mayo score of ≤2 was a positive predictor for the continuation of ADA. No malignancy or death occurred during this study. Conclusion ADA was effective for inducing and maintaining both a clinical response and remission in patients with refractory UC. It remains possible that the concomitant use of IM and a week 8 partial Mayo score of ≤2 may predict the long-term response of ADA.

Hepatocyte Growth Factor and Primary Systemic Amyloidosis.

A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24 ng/ml). Because the etiology was unclear, we considered the possibility of amyloidosis. Biopsy of the mucosa of the stomach, duodenum and rectum demonstrated amyloid deposition. From the findings of Congo red staining and immunohistochemical analyses, we made a diagnosis of systemic amyloid light-chain amyloidosis. Unfortunately, the patient died one month after the diagnosis. We considered that serum HGF was useful for the diagnosis and prediction of prognosis of primary systemic amyloidosis.

Meckel's Diverticulum Bleeding Missed by the First but Detected by the Second Capsule Endoscopy.

A 13-year-old boy was admitted to our hospital because of bloody stools. Although a Meckel's diverticulum (MD) was suspected, capsule endoscopy (CE) revealed no remarkable findings. Seven months later, he was admitted again because of rebleeding. CE was performed again and revealed an elevated lesion and fresh blood in the ileum. A single balloon endoscopic examination revealed a diverticulum with an elevated lesion in it. Histologic findings showed ectopic gastric mucosa, thus we diagnosed this patient as having MD. Although CE is useful for the examination of obscure gastrointestinal bleeding, a single CE is not enough to diagnose MD bleeding. The timing in performing CE and the evaluation of other modalities would be valuable for patients suspected of having MD.

Influence of gastroesophageal flap valve on esophageal variceal bleeding in patients with liver cirrhosis.

OBJECTIVES: Esophageal variceal bleeding can be fatal in patients with liver cirrhosis. The aim of this study was to investigate the relationship between gastroesophageal flap valve (GEFV) and esophageal variceal bleeding. METHODS: Subjects were cirrhotic patients with endoscopically diagnosed esophageal varices treated at our hospital between 2005 and 2019, excluding those with F3 form and red color (RC) signs at first endoscopy. Sixty-five patients with normal GEFV (Hill grade I or II) and 42 with abnormal GEFV (Hill grade III or IV) were enrolled. Propensity score matching eliminated the baseline differences, resulting in a sample size of 30 patients per cohort. The primary endpoint was esophageal variceal bleeding, and the secondary endpoint was variceal bleeding or appearance of RC sign. We analyzed the cumulative incidences and predictors of each endpoint. RESULTS: The 3-, 5-, and 10-year cumulative incidences of the primary endpoints were all 3.4% in the normal GEFV group, and 19.0%, 24.6% and 34.0% in the abnormal GEFV group, respectively (log-rank P = 0.011). Cumulative incidence of the secondary endpoint was 13.8%, 33.1% and 39.2% in the normal GEFV group, and 42.2%, 54.6% and 84.9% in the abnormal GEFV group, respectively (log-rank P = 0.001). In multivariate Cox regression analyses, hazard ratios of abnormal GEFV of the primary and secondary endpoints were 12.79 (95% confidence interval 1.331-122.8) and 3.600 (1.653-7.840), respectively. CONCLUSIONS: Abnormal GEFV was an independent risk factor for esophageal variceal bleeding and appearance of RC sign.

Usefulness of magnifying endoscopy and endoscopic ultrasonography for the gastric involvement of follicular lymphoma.

A 61-year-old man received an esophagogastroduodenoscopy for further investigation of mesenteric lymphadenopathy. Esophagogastroduodenoscopy revealed swollen gastric folds and cobble stone mucosa in the gastric body. Magnifying endoscopy with narrow-band imaging showed branched abnormal vessels and the absence or destruction of gastric pits. Endoscopic ultrasonography (EUS) depicted homogeneously hypoechoic thickening of the submucosal layer where the mucosal changes were observed. The patient was diagnosed with follicular lymphoma by biopsy of these lesions. We should recognize that these endoscopic features are consistent with follicular lymphoma involving the stomach and that concurrent EUS is useful for diagnosis and identification of adequate biopsy sites.

Hepatic Inflammatory Pseudotumor Protruding from the Liver Surface and Directly Penetrating the Colon.

A 69-year-old man was diagnosed with a liver abscess and received antibiotics at a local hospital. He was referred to our hospital due to a persistent fever. He had hepatic masses protruding from the liver surface toward the transverse colon. We reached a diagnosis of inflammatory pseudotumor (IPT) by a percutaneous liver biopsy. Colonoscopy showed direct invasion of IPT to the colon. His condition improved by the intravenous administration of antibiotics. Hepatic IPT is often misdiagnosed as a malignant tumor. We should consider IPT when we encounter hepatic tumors, and a percutaneous liver biopsy is useful for avoiding unnecessary excessive treatments.

Performance of laboratory tests for detection for Clostridioides difficile: A multicenter prospective study in Japan.

BACKGROUND: The optimal and practical laboratory diagnostic approach for detection of Clostridioides difficile to aid in the diagnosis of C. difficile infection (CDI) is controversial. A two-step algorithm with initial detection of glutamate dehydrogenase (GDH) or nucleic acid amplification test (NAAT) alone are recommended as a predominant method for C. difficile detection in developed countries. The aim of this study was to compare the performance of enzyme immunoassays (EIA) detecting toxins A and B, NAAT detecting the toxin B gene, and GDH compared to toxigenic culture (TC) for C. difficile as the gold standard, in patients prospectively and actively assessed with clinically significant diarrhea in 12 medical facilities in Japan. METHODS: A total of 650 stool specimens were collected from 566 patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h. EIA and GDH were performed at each hospital, and NAAT and toxigenic C. difficile culture with enriched media were performed at the National Institute of Infectious Diseases. All C. difficile isolates recovered were analyzed by PCR-ribotyping. RESULTS: Compared to TC, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of EIA were 41%, 96%, 75% and 84%, respectively, and for NAAT were 74%, 98%, 91%, and 92%, respectively. In 439 specimens tested with GDH, the sensitivity, specificity, PPV, and NPV were 73%, 87%, 65%, and 91%, and for an algorithm (GDH plus toxin EIA, arbitrated by NAAT) were 71%, 96%, 85%, and 91%, respectively. Among 157 isolates recovered, 75% of isolates corresponded to one of PCR-ribotypes (RTs) 002, 014, 018/018", and 369; RT027 was not isolated. No clear differences in the sensitivities of any of EIA, NAAT and GDH for four predominant RTs were found. CONCLUSION: The analytical sensitivities of NAAT and GDH-algorithm to detect toxigenic C. difficile in this study were lower than most previous reports. This study also found low PPV of EIAs. The optimal method to detect C. difficile or its toxins to assist in the diagnosis of CDI needs further investigation.

Effect of direct-acting antivirals on platelet-associated immunoglobulin G and thrombocytopenia in hepatitis C virus-related chronic liver disease.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been known to cause various extrahepatic autoimmune disorders. The prevalence of platelet-associated immunoglobulin G (PA-IgG) has been high in patients with HCV infection. Because thrombocytopenia in HCV-related liver diseases is a notable problem, we performed prospective study on the effect of direct-acting antivirals (DAAs) treatment on PA-IgG and platelet count. METHODS: A total of 215 patients with HCV-related liver disease were enrolled in this study. The patients who discontinued DAAs or did not undergo adequate laboratory examinations and who did not achieve sustained virologic response were excluded and finally a total of 187 patients were investigated. RESULTS: A total of 171 patients (91.4%) were PA-IgG positive (>46 ng/107 cells) before starting DAAs (baseline). The PA-IgG level elevation was significantly correlated with higher liver inflammation and fibrosis markers (P < 0.05) and lower platelet count (P = 0.000019). The platelet count of the patients with low PA-IgG titer tended to be higher at baseline, end of treatment (EOT), and at 12 and 24 weeks after EOT. The platelet count increased at EOT (P < 0.05) and 24 weeks after EOT (P < 0.01). The PA-IgG levels were significantly decreased at EOT, 12 and 24 weeks after EOT (P < 0.01). Multiple regression analysis found that only platelet count at baseline was closely associated with negative conversion of PA-IgG at 24 weeks after EOT (P = 0.004). CONCLUSIONS: Eradication of HCV by DAAs treatment successfully decreased PA-IgG level and increased platelet count.

Clostridioides (Clostridium) difficile infection burden in Japan: A multicenter prospective study.

Clostridioides (Clostridium) difficile is the leading cause of healthcare-associated infectious diarrhea in the developed world. Retrospective studies have shown a lower incidence of C. difficile infection (CDI) in Japan than in Europe or North America. Prospective studies are needed to determine if this is due lack of testing for C. difficile or a true difference in CDI epidemiology. A prospective cohort study of CDI was conducted from May 2014 to May 2015 at 12 medical facilities (20 wards) in Japan. Patients with at least three diarrheal bowel movements (Bristol stool grade 6-7) in the preceding 24 h were enrolled. CDI was defined by positive result on enzyme immunoassay for toxins A/B, nucleic acid amplification test for the toxin B gene or toxigenic culture. C. difficile isolates were subjected to PCR-ribotyping (RT), slpA-sequence typing (slpA-ST), and antimicrobial susceptibility testing. The overall incidence of CDI was 7.4/10,000 patient-days (PD). The incidence was highest in the five ICU wards (22.2 CDI/10,000 PD; range: 13.9-75.5/10,000 PD). The testing frequency and CDI incidence rate were highly correlated (R2 = 0.91). Of the 146 isolates, RT018/018″ was dominant (29%), followed by types 014 (23%), 002 (12%), and 369 (11%). Among the 15 non-ICU wards, two had high CDI incidence rates (13.0 and 15.9 CDI/10,000 PD), with clusters of RT018/slpA-ST smz-02 and 018"/smz-01, respectively. Three non-RT027 or 078 binary toxin-positive isolates were found. All RT018/018" isolates were resistant to moxifloxacin, gatifloxacin, clindamycin, and erythromycin. This study identified a higher CDI incidence in Japanese hospitals than previously reported by actively identifying and testing patients with clinically significant diarrhea. This suggests numerous patients with CDI are being overlooked due to inadequate diagnostic testing in Japan.

Impact of examining additional deeper sections on the pathological diagnosis of endoscopically resected early gastric cancer.

OBJECTIVES: The pathological diagnosis of endoscopically resected early gastric cancer (EGC) is performed by evaluating a few representative sections from the specimen. We aimed to determine whether evaluating twice as many sections as usual by essentially cutting the original sections in half could improve the pathological diagnosis of EGC. METHODS: We retrospectively investigated 85 EGC in 82 patients who had undergone endoscopic resection at our hospital from August 2008 to October 2012. EGC without indications of curative resection were excluded. We re-examined the original paraffin blocks after shaving away approximately half their original thickness, and evaluated whether the pathological diagnoses were affected. This technique essentially doubled the number of sections examined. RESULTS: Ten pathological diagnoses of 68 EGC (14.7%) were changed from curative resection to non-curative resection when we evaluated twice as many sections as in the standard method. The median tumor size was 25 mm in the changed diagnosis group versus 14.5 mm in the no change group (P = 0.03). The univariate analysis also showed that tumor size was a significant predictor of changed diagnosis (P = 0.015). Both the changed diagnosis group and no change group had no recurrence during follow up. CONCLUSIONS: Histological evaluation of twice as many sections as usual changed the initial pathological diagnosis of EGC, although the clinical implication of an additional deeper section was controversial because there was no recurrence. Our analysis also emphasized the importance of detailed histological evaluation to confirm a radical cure in endoscopic resection, especially in the case of larger EGC.

A Young Adult Patient with Nonalcoholic Steatohepatitis Developed Severe Gastroesophageal Varices Associated with Severe Obesity and Diabetes Mellitus.

Obesity is a major contributor to insulin resistance and nonalcoholic fatty liver disease, which is the most common cause of chronic liver diseases. Nonalcoholic steatohepatitis (NASH) can progress to liver cirrhosis and end-stage liver diseases. Some cases already show severe liver fibrosis at the time of diagnosis. We present the case of a 44-year-old male with overt obesity who was admitted with hematemesis due to the rupture of gastric varices. We diagnosed him with NASH with severe liver fibrosis. This case shows that we should be concerned about the progression of liver fibrosis due to NASH associated with severe obesity even in young patients.

Recombinant Thrombomodulin Used to Successfully Treat Cronkhite-Canada Syndrome with Disseminated Intravascular Coagulation due to Sepsis in a Compromised Patient.

Cronkhite-Canada syndrome (CCS) is a rare non-inherited disease characterized by gastrointestinal polyposis, chronic diarrhea, ectodermal dysplasia, skin hyperpigmentation, hair loss and nail atrophy. Although the efficacy of corticosteroid and immunomodulatory agents has been demonstrated, no standard therapy regimen has been established, and the prognosis of CCS is still poor due to various complications. We here in report a CCS patient complicated with severe sepsis and disseminated intravascular coagulation who was successfully treated by combined modality therapies, including recombinant human soluble thrombomodulin.

[A Case of Acute Superior Mesenteric Artery Occlusion Rescued by Thrombus Aspiration without Bowel Resection].

Acute superior mesenteric artery (SMA) occlusion is rare and associated with high morbidity and mortality.One of the reasons is the difficulty to diagnose the disease soon after the abdominal pain initially occurs. A 79-year-old woman with atrial fibrillation was admitted because of progressive left abdominal pain and nausea. Two hours after the onset, computed tomography revealed an occlusion of the SMA. No signs of intestinal infarction were present. Abdominal angiography revealed complete obstruction from the distal portion of the SMA to the ileocolic artery, so we could have a diagnosis of SMA occlusion early. Continuous per-catheteric thrombus aspiration for the occlusion successfully removed the thrombus and led to complete revascularization laparotomy. We encountered a case of acute mesenteric ischemia due to SMA occlusion with atrial fibrillation. Early diagnosis is necessary to survive without bowel resection.

Serum Albumin Concentrations Predict hypovolaemia Caused by Polyethylene Glycol Plus Ascorbic Acid Prior to Colonoscopy in Elderly Patients.

BACKGROUND: Previous studies have confirmed the safety of polyethylene glycol plus ascorbic acid for healthy middle-aged adults but not for the elderly. The osmotic pressure of polyethylene glycol plus ascorbic acid is approximately twice that of plasma osmolality and may cause dehydration. OBJECTIVE: In this study, we determined whether dehydration was induced in elderly patients by polyethylene glycol plus ascorbic acid, and we analysed the data obtained in order to identify predictors of dehydration. METHODS: This was a prospective, uncontrolled, before-and-after intervention study. All patients older than 65 years who underwent colonoscopies at the Moji Medical Center were administered polyethylene glycol plus ascorbic acid prior to colonoscopy. Clinical variables before and after bowel preparation were measured and analysed statistically. A multiple linear regression analysis was performed to identify predictors of dehydration due to this procedure. RESULTS: Eighty-three patients were assessed for eligibility, and 74 clinical variables were ultimately analysed. A significant increase in the red blood cell count (4.10 versus 4.25 × 10(6)/mm(3)), haemoglobin level (12.4 versus 13.0 g/dL) and haematocrit (38.1% versus 39.4%) suggested the presence of hypovolaemia after the procedure (P < 0.001). The serum concentration of albumin before bowel preparation was identified as the only significant predictor of hypovolaemia (ß = 0.47, P = 0.0001, adjusted R (2) = 0.22). CONCLUSION: The serum concentration of albumin before bowel preparation predicted hypovolaemia caused by polyethylene glycol plus ascorbic acid in elderly patients. Therefore, care is needed in order to prevent hypovolaemia, especially in elderly patients with hypoalbuminaemia. TRIAL REGISTRATION: No. 000015724 (University Hospital Medical Information Network Center).

Usefulness of a novel calibrated hood to determine indications for colon polypectomy: visual estimation of polyp size is not accurate.

PURPOSE: Accurate measurement of polyp size during colonoscopy is important because the size is a surrogate marker of cancer, but a standardized measurement technique to measure polyp size has yet to be determined. We have developed a new device "a novel calibrated hood." We assessed polyp size by visual estimation and measurement using the calibrated hood. METHODS: Patients who underwent polypectomy from November 2012 to September 2013 and who had received screening colonoscopy within 6 months prior to the polypectomy were included in this study. Polypectomy was performed attaching the calibrated hood. The endoscopist measured the polyp size using the calibrated hood. Polyp size was compared between visual estimation and measurement using the calibrated hood. RESULTS: Seventy-five patients with 157 polyps were included. Seventy-seven polyps fulfilled the selection criteria. Mean polyp size by visual estimation was 6.57 ± 2.15, and by using calibrated hood was 5.94 ± 1.73 (p = 0.005). There was a significant difference between measurements using the calibrated hood vs. visual estimation by inexperienced trainees; however, there was no difference in case of well-experienced endoscopists. By visual estimation, 11 of 19 polyps were decided for ≥5 mm despite being less than 5 mm, and 5 of 58 polyps were decided for <5 mm despite being 5 mm or larger in diameter. CONCLUSION: Visual estimation of polyp size is not accurate. It is important to measure the size by an objective way, and the calibrated hood is useful in measuring polyp size, from the standpoint of accurately determining indication for polypectomy.

Endoscopic measurement of polyp size using a novel calibrated hood.

Background. Although the size of colon polyps is an important risk factor for colorectal cancer, a standardized measurement technique has yet to be determined. In clinical practice, most endoscopists estimate polyp size by uncertain visual estimation; however, colonoscopic polypectomy is indicated for adenomatous polyps more than 5 mm in diameter. We have therefore developed a novel calibrated hood that enables accurate measurement of polyp size during colonoscopy. Method. We compared prepolypectomy estimates using the calibrated hood against measurements of preformalin-fixed samples immediately after polypectomy. Results. Sixty-five polyps removed from 44 patients were included in the present study. The mean size of polyps was significantly larger at prepolypectomy (6.06 ± 1.23 mm) than after polypectomy (5.48 ± 1.31 mm, P < 0.05). Conclusion. Accurately measuring the size of polyps during colonoscopy is important, since polyps are shrunk by polypectomy. Attaching the calibrated hood appears useful in the measurement of polyp size to determine indications for polypectomy in patients with colon polyps.