Budesonide Foam for Ulcerative Colitis Patients Experiencing Inadequate Response to Biological Therapy.

BACKGROUND In recent years, a plethora of therapeutic agents for ulcerative colitis (UC), especially novel biologics (Bio), have become available. Although it is now possible to use biological drugs, there should be no need for frequently changing medications. To avoid first-pass metabolism in the liver, thus reducing systemic bioavailability, budesonide foam has been applied as a topical steroid. We therefore evaluated whether budesonide foam has therapeutic value in UC patients who responded inadequately to Bio or to tacrolimus. MATERIAL AND METHODS We enrolled 10 patients who were experiencing an inadequate response to Bio (n=7) or to tacrolimus (n=3) at Juntendo University. We used Lichtiger's index to assess UC activity and clinical response. RESULTS Of the study patients, 4 were receiving adalimumab, 3 golimumab, and 3 tacrolimus. The average Lichtiger's index before budesonide administration was 7.1 (range 13-3), which improved to 3.4 (range 7-0) after budesonide therapy (p=0.01). Notably, 4 of the 6 cases with a Lichtiger's index >4 before budesonide administration achieved improvement of ≥3 points or remission. CONCLUSIONS Although the number of patients was small, budesonide foam had significant efficacy when added to the treatment of patients having an inadequate response to Bio or to tacrolimus. These results suggest that in cases responding poorly to Bio, adding budesonide foam as combination therapy can achieve a clinical remission.

Successful remission of ulcerative colitis flare-up during pregnancy with adsorptive granulomonocytapheresis plus tacrolimus.

Ulcerative colitis (UC) is 1 of the 2 major phenotypes of chronic inflammatory bowel disease (IBD), which afflicts millions of individuals throughout the world with debilitating symptoms that impair function and quality of life. Further, IBD often affects women during childbearing age. Indeed, UC activity frequently increases during pregnancy, and the medications used to induce remission may adversely affect the health of the mother and the unborn child. We report successful induction of a remission in a UC case who experienced a flare-up in the first trimester of pregnancy. Upon relapse, she was treated with steroids and adsorptive granulomonocytapheresis (GMA) with the Adacolumn plus tacrolimus. This combination therapy induced a stable remission that was maintained during her entire pregnancy. She gave birth to a healthy child at 36 weeks of pregnancy with no maternal or fetal complications. Our experience indicates that GMA, as a non-drug therapeutic intervention with a favorable safety profile, plus tacrolimus might be a relevant treatment option for patients with active IBD during pregnancy. A future study of a large cohort of pregnant patients should strengthen our findings.

Efficacy and Acceptability of 1 Liter of Polyethylene Glycol with Ascorbic Acid vs. 2 Liters of Polyethylene Glycol Plus Mosapride and Sennoside for Colonoscopy Preparation.

BACKGROUND [color=black]Bowel preparation is an important factor for an optimal outcome of colonoscopy. Recently, polyethylene glycol (PEG) solution has been in common use for bowel cleansing for colonoscopy, but some patients are intolerant of PEG because of taste or volume. A low-volume PEG administered with ascorbic acid solution (PEG-Asc) was designed to improve tolerability, but the administration of this method is more complex than that with PEG alone. This study aimed to compare bowel cleansing efficacy, safety, and tolerability of 1 L PEG-Asc with a 2 L PEG preparation with use of sennosides and mosapride.[/color] MATERIAL AND METHODS [color=black]This was a prospective, single-center, non-inferiority trial that included 112 patients (PEG-Asc group, 68; PEG group, 44). The primary endpoint was the efficacy of colon cleansing assessed by endoscopists using a validated 4-point scale according to the Aronchick scale and was verified by a blinded investigator. Acceptability, tolerability, and adenoma detection rate (ADR) of these 2 regimens were secondary endpoints.[/color][color=black] [/color] RESULTS [color=black]We found no statistically significant differences between the groups in colon-cleansing efficacy or in the adenoma detection rate (ADR). Moreover, overall, patients significantly favored PEG-Asc over PEG, reflecting better acceptance of PEG-Asc. Additionally, more patients favored PEG-Asc over PEG for a hypothetical future colonoscopy. [/color] CONCLUSIONS [color=black]The alternate 1 L PEG-Asc regimen and standard 2 L PEG regimen were clinically equivalent with respect to cleansing efficacy, safety, and ADR, and more patients favored PEG-Asc than PEG. This alternate regimen may improve patient compliance and acceptance of surveillance colonoscopy.[/color].

Efficacy of cytapheresis for remission induction and dermatological manifestations of ulcerative colitis.

BACKGROUND: In ulcerative colitis (UC) patients, cytapheresis depletes elevated and activated leucocytes, which are known to release inflammatory cytokines including tumor necrosis factor (TNF)-α. Further, there are UC patients who develop erythema nodosum (EN) or pyoderma gangrenosum (PG) as extra-intestinal manifestations of UC. METHODS: Between 2008 and 2015, 181 consecutive patients with active UC received cytapheresis with either a granulocyte and monocyte apheresis (GMA) column or with a leucocyte removal filter (LCAP) as remission induction therapy. Each patient received weekly or intensive (2-3 sessions/week) cytapheresis up to 10 sessions. In 13 patients, UC was complicated by EN or PG. Lichtiger's clinical activity index (CAI) ≤4 meant remission, while ≥3 decrease in CAI meant response to therapy. Prednisolone sparing and the changes in the extra-intestinal manifestations were factored for assessing treatment efficacy. RESULTS: The overall remission and response rates were 52.5% and 71.8%, respectively, CAI fell from 9.4 ± 3.3 to 4.9 ± 3.5 (P < 0.001). The efficacy rates in subgroups on concomitant corticosteroid, anti-TNF or tacrolimus, and those without concomitant medications were not significantly different (P > 0.05). However, in 84 patients on prednisolone, the average daily prednisolone dose was reduced from 18.15 to 12.43 mg/day (P < 0.001) with 21.7% being corticosteroid free. All patients with EN or PG showed favorable response to cytapheresis, notably 2 EN patients achieving remission after just 2 cytapheresis sessions without concomitant medication. CONCLUSIONS: In this retrospective efficacy evaluation, cytapheresis was effective as remission induction therapy with steroid sparing effect and desirable safety profile. Further, patients with EN or PG responded favorably to cytapheresis.

Continuation of antithrombotic therapy may be associated with a high incidence of colonic post-polypectomy bleeding.

BACKGROUND AND AIM: Post-polypectomy bleeding (PPB) is the most common complication of endoscopic procedures. To reduce the risk of thromboembolic incidents, Japanese guidelines for gastroenterological endoscopy were revised to indicate that antithrombotic agents were not to be discontinued for endoscopic treatment. However, carrying out endoscopic procedures under antithrombotic medication potentially increases the incidence of hemorrhagic complications. The present study investigated the impact of the revised guidelines on the frequency of complications after colonoscopic procedures. METHODS: The surveillance period comprised the year before the initiation of the new guidelines (2012), which served as a control period, and 2 years after initiation of the new guidelines (2013 and 2014). During the control period, 3955 cases were examined colonoscopically and 1601 lesions were treated endoscopically. During the 2-year period under the new guidelines, 8749 colonoscopies and 3768 endoscopic treatments were carried out. Changes in treatment methods and rates of complications were compared. RESULTS: PPB rate was not significantly different before and after the revision (0.87% vs 1.01%). With the new guidelines, PPB rates in antithrombotic non-users and users were 0.60% and 3.13%, respectively (OR 5.11, P = 0.000). Multivariable analysis showed that the risks for PPB were as follows: heparin bridging therapy (OR 6.34, P = 0.0002); low-dose aspirin (LDA) continuation (OR 5.30, P = 0.0079); and lesion size (OR 1.06, P < 0.0001). CONCLUSION: The present study showed that the overall PPB rate under the new guidelines was not significantly higher when compared with the previous data obtained before the new guidelines were introduced.

MAIT cells are activated and accumulated in the inflamed mucosa of ulcerative colitis.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic, relapsing and remitting, inflammatory disorder of the large intestine. Mucosal associated invariant T (MAIT) cells are a member of innate-like lymphocytes found abundantly in the mucosal tissue. The contribution of MAIT cells in the pathogenesis of UC is still unclear; therefore, this study aimed at investigating the role of these cells in patients with UC. METHODS: The frequency of MAIT cells, as well as the production of cytokines and expression levels of activation markers by these cells in the peripheral blood of UC patients and healthy controls, was analyzed by flow cytometry. MAIT cells were also quantified in colon biopsies of UC patients using a confocal microscope. RESULTS: There was a significant reduction in MAIT cell frequency in the peripheral blood of UC patients compared with healthy controls (P < 0.0001). MAIT cells from UC patients secreted more interleukin (IL)-17 than healthy controls (P < 0.05). The expression levels of CD69 on these cells were correlated with disease activity and endoscopic scores and plasma levels of IL-18. Furthermore, MAIT cells increased in the inflamed mucosa, and their frequency was correlated with clinical and endoscopic disease activity in UC patients. CONCLUSIONS: The findings from this study indicate that MAIT cells could be associated with UC and may serve as potential biomarkers or therapeutic targets in UC.

Stereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes.

Histology is fundamental to assess two-dimensional intestinal inflammation; however, inflammatory bowel diseases (IBDs) are often indistinguishable microscopically on the basis of mucosal biopsies. Here, we use stereomicroscopy (SM) to rapidly profile the entire intestinal topography and assess inflammation. We examine the mucosal surface of >700 mice (encompassing >16 strains and various IBD-models), create a profiling catalogue of 3D-stereomicroscopic abnormalities and demonstrate that mice with comparable histological scores display unique sub-clusters of 3D-structure-patterns of IBD pathology, which we call 3D-stereoenterotypes, and which are otherwise indiscernible histologically. We show that two ileal IBD-stereoenterotypes ('cobblestones' versus 'villous mini-aggregation') cluster separately within two distinct mouse lines of spontaneous ileitis, suggesting that host genetics drive unique and divergent inflammatory 3D-structural patterns in the gut. In humans, stereomicroscopy reveals 'liquefaction' lesions and hierarchical fistulous complexes, enriched with clostridia/segmented filamentous bacteria, running under healthy mucosa in Crohn's disease. We suggest that stereomicroscopic (3D-SMAPgut) profiling can be easily implemented and enable the comprehensive study of inflammatory 3D structures, genetics and flora in IBD.

A Randomized Prospective Study of Bowel Preparation for Colonoscopy with Low-Dose Sodium Phosphate Tablets versus Polyethylene Glycol Electrolyte Solution.

Optimal bowel preparation is essential for the safety and outcome of colonoscopy. A solution containing polyethylene glycol (PEG) is often used as a bowel cleansing agent, but some patients are intolerant of PEG, and this may lead to discontinuation of colonoscopy. Sodium phosphates (NaP) tablets are designed to improve patient acceptance and compliance. The objective of this study was to compare bowel preparation efficiency and patient acceptance of a 30 NaP tablet preparation (L-NaP) and a 2 L PEG preparation. Patients were randomized into either the L-NaP or PEG group. The primary endpoint was the efficiency of colon cleansing as assessed by a validated four-point scale according to the Aronchick scale by endoscopists and was verified by blinded investigators. The secondary endpoints were patients' tolerability and acceptance. Colon-cleansing efficiency was not significantly different between the two preparations. However, patients' overall judgment was significantly in favor of L-NaP, reflecting better acceptance of L-NaP than PEG. Additionally, more patients favored L-NaP over PEG in a hypothetical future occasion requiring colonoscopy.

Frequent occurrence of fever in patients who have undergone endoscopic submucosal dissection for colorectal tumor, but bacteremia is not a significant cause.

BACKGROUND: We examined the incidence of and factors associated with fever, as well as the frequency of bacteremia, in patients who had undergone endoscopic submucosal dissection (ESD) for colorectal tumor. METHOD: A total of 199 patients (120 male and 79 female) were included. The patients were classified into two groups based on the body temperature on the day after ESD treatment: group A, body temperature <37 °C; and group B, body temperature ≥37 °C. The following factors were analyzed to determine their potential association with post-ESD fever: gender, age, tumor size, form, location, and presence or absence of intraoperative perforation. In addition, blood samples from 50 patients were obtained for blood culture and 16S rRNA gene analysis by polymerase chain reaction. RESULTS: Group A included 106 patients (70 male and 36 female), with a median age of 63 years. Group B included 93 patients (50 male and 43 female), with a median age of 70 years. The incidence of post-ESD fever in the entire cohort was 46.7%. Univariate analysis based on comparison between groups A and B showed that the following factors were significantly associated with post-ESD fever: age [mean ± standard deviation (SD)], 64.5 ± 9.2 versus 68.5 ± 10.8 years, P = 0.006; and tumor size (mean ± SD) 30.6 ± 10.8 versus 39.1 ± 16.6 mm, P < 0.001. Logistic regression analysis for post-ESD fever also found that age {odds ratio 1.04 (95% CI [1.01-1.07], P = 0.009)} and lesion size {odds ratio 1.05 (95% CI [1.03-1.08], P = 0.0002)} were closely associated with post-ESD fever. Of the 50 patients who had blood samples cultured and 16S rRNA gene analyzed, bacteria in blood culture and the 16S rRNA gene were not detectable in any of the samples from the 50 patients. CONCLUSIONS: This study indicated that older patients and patients with large tumors were more likely to develop post-ESD fever, but there was a low probability that bacteremia was the cause of fever.

Phase I clinical trial of peptide vaccination with URLC10 and VEGFR1 epitope peptides in patients with advanced gastric cancer.

Peptide vaccine treatment has attracted attention in recent years as a new therapy option for chemotherapy­resistant, advanced, unresectable cancer. The safety of peptide vaccination with HLA-A*2402-restricted URLC10-A24-177 and VEGFR1-A12-9 1084 epitope peptides (fixed 2-mg dose) was investigated in a phase I clinical trial of patients with advanced gastric cancer who were refractory to chemotherapy. We determined the HLA genotype of the subjects after enrollment, results of which were held by the evaluation committee and kept from both patients and investigators until completion of the study. The primary end­point was safety of the peptide vaccination. The secondary end­points were immunological responses and clinical outcome, which were compared between the HLA-A*2402-positive and HLA-A*2402-negative groups. The peptides were subcutaneously administered on day 1, 8, 15 and 22 within a 28-day treatment cycle. A total of 14 patients was enrolled in this study; 12 of the 14 patients received 4 or more vaccinations (at least 1 course). No patient had a severe treatment-related adverse event. Findings from evaluation of clinical responses after a single course showed that 4 cases had stable disease and 8 cases had progressive disease. The median overall survival time (MST) for the 12 patients was 3.9 months. The MSTs in the HLA-A*2402­positive and HLA-A*2402­negative groups were, 4.2 and 3.6 months (p=0.9164), respectively. The results of this study showed that vaccination with URLC10 and VEGFR1 peptides was a safe treatment for advanced gastric cancer. This trial was registered with University Hospital Medical Information Network (UMIN, no. 000002409).

Flexible colonoscopy in mice to evaluate the severity of colitis and colorectal tumors using a validated endoscopic scoring system.

The use of modern endoscopy for research purposes has greatly facilitated our understanding of gastrointestinal pathologies. In particular, experimental endoscopy has been highly useful for studies that require repeated assessments in a single laboratory animal, such as those evaluating mechanisms of chronic inflammatory bowel disease and the progression of colorectal cancer. However, the methods used across studies are highly variable. At least three endoscopic scoring systems have been published for murine colitis and published protocols for the assessment of colorectal tumors fail to address the presence of concomitant colonic inflammation. This study develops and validates a reproducible endoscopic scoring system that integrates evaluation of both inflammation and tumors simultaneously. This novel scoring system has three major components: 1) assessment of the extent and severity of colorectal inflammation (based on perianal findings, transparency of the wall, mucosal bleeding, and focal lesions), 2) quantitative recording of tumor lesions (grid map and bar graph), and 3) numerical sorting of clinical cases by their pathological and research relevance based on decimal units with assigned categories of observed lesions and endoscopic complications (decimal identifiers). The video and manuscript presented herein were prepared, following IACUC-approved protocols, to allow investigators to score their own experimental mice using a well-validated and highly reproducible endoscopic methodology.

Dysregulated NOD2 predisposes SAMP1/YitFc mice to chronic intestinal inflammation.

Nucleotide-binding oligomerization domain-containing 2 (NOD2) is an intracellular receptor that plays an essential role in innate immunity as a sensor of a component of the bacterial cell wall, muramyl dipeptide (MDP). Crohn's disease (CD)-associated NOD2 variants lead to defective innate immune responses, including decreased NF-κB activation and cytokine production. We report herein that SAMP1/YitFc (SAMP) mice, which develop spontaneous CD-like ileitis in the absence of NOD2 genetic mutations, fail to respond to MDP administration by displaying decreased innate cytokine production and dysregulated NOD2 signaling compared with parental AKR control mice. We show that, unlike in other mouse strains, in vivo administration of MDP does not prevent dextran sodium sulfate-induced colitis in SAMP mice and that the abnormal NOD2 response is specific to the hematopoietic cellular component. Moreover, we demonstrate that MDP fails to enhance intracellular bacterial killing in SAMP mice. These findings shed important light on the initiating molecular events underlying CD-like ileitis.

Response to chemotherapy in a case of gastric adenocarcinoma producing granulocyte colony-stimulating factor.

BACKGROUND: Little is known about the patient characteristics and tumor characteristics associated with a high level of granulocyte colony-stimulating factor (G-CSF) and leukocytosis. Moreover, the prognosis of G-CSF-producing gastric cancer has been extremely poor. CASE REPORT: A 72-year-old man presented with fatigue and body weight loss. Laboratory testing showed pronounced leukocytosis (white blood cell count, 34900×106/L). Bone marrow aspiration biopsy excluded leukemia and metastatic leukemoid reaction. G-CSF-producing cancer was suspected as the cause of the abnormally elevated serum G-CSF level (293 pg/ml). Gastrointestinal endoscopy showed type 3 gastric cancer, and the biopsy specimens were histologically proven to include moderately to well differentiated adenocarcinoma with positive expression of G-CSF. Abdominal computed tomography showed a lymph node lesion and multiple hepatic metastatic lesions. This patient was diagnosed as having stage IV gastric cancer that produced G-CSF. We treated the patient with 3 chemotherapy regimens, and he survived for almost 2 years after diagnosis. CONCLUSIONS: The possibility of a G-CSF-producing tumor should be investigated in patients who present with severe leukocytosis in the absence of infection. This unusual gastric cancer should be treated as soon as possible after diagnosis.

Gastrointestinal hemorrhage as the first manifestation of metastatic extragonadal choriocarcinoma.

Although germ cell tumors are the most common malignancy in young men, extragonadal germ cell tumors are rare. Gastric metastasis presenting initially as upper gastrointestinal hemorrhage is also exceedingly rare. A 27-year-old man presented at our hospital with tarry stool. Gastric fiberscopy images revealed a bleeding gastric polypoid lesion in the anterior wall of the gastric body, from which a biopsy specimen was obtained. Histopathological analysis of the biopsy showed syncytiotrophoblast-like cells with multiple, large nuclei, consistent with choriocarcinoma. Based on these results, our diagnosis was extragonadal retroperitoneal germ cell tumor with gastric metastasis.

Obstructing small bowel bezoars due to an agar diet: diagnosis using double balloon enteroscopy.

Primary small bowel bezoars are rare and may cause acute abdomen due to small bowel obstruction (SBO). A 70-year-old Japanese woman presented to the emergency room with abdominal pain, nausea and vomiting. The patient reported that she had eaten a large amount of highly-concentrated, agar dissolved in boiling water two days prior to presentation. Double balloon enteroscopy (DBE) revealed that white-colored, hard bezoars were clogged in the jejunum. At surgery, many bezoars were found impacted in the distal jejunum, and enterotomy was performed. The bezoars were elastic hard, crystallized objects. These bezoars were considered to have formed from highly-concentrated, dissolvable agar.

Gastrointestinal stromal tumor of the stomach with a giant abscess penetrating the gastric lumen.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. In large GISTs, cystic degeneration, necrosis and focal hemorrhage that occur inside the tumor can result in gastrointestinal bleeding. We describe a case of a 74-year old male with GIST of the stomach accompanied with a giant abscess that penetrated the gastric lumen. The patient experienced undiagnosed fever for two months prior to hospitalization. Gastrointestinal endoscopy, X-ray series and computed tomography of the patient's abdomen revealed a gastric submucosal tumor in the fornix, with a fistula to the gastric lumen that was inundated with a great deal of pus. The mass was diagnosed as a GIST from biopsy specimens. The patient was treated by endoscopic drainage of the abscess and intravenous administration of antibiotics. Eventually, a partial gastrectomy was performed. He was also administered Imanitib mesylate as adjuvant therapy. He was followed up for 2 years and no metastasis or recurrence was recognized at the follow-up examinations. This is the first report of a patient with clearly diagnosed GIST with endoscopic evidence of an abscess penetrating into the gastric lumen.