Novel strategies for the treatment of inflammatory bowel disease: Selective inhibition of cytokines and adhesion molecules

The etiology of inflammatory bowel disease （IBD） has not yet been clarified and immunosuppressive agents which non-specifically reduce inflammation and immunity have been used in the conventional therapies for IBD. Evidence indicates that a dysregulation of mucosal immunity in the gut of IBD causes an overproduction of inflammatory cytokines and trafficking of effector leukocytes into the bowel, thus leading to an uncontrolled intestinal inflammation. Such recent advances in the understanding of the pathogenesis of IBD created a recent trend of novel biological therapies which specifically inhibit the molecules involved in the inflammatory cascade. Major targets for such treatment are inflammatory cytokines and their receptors, and adhesion molecules. A chimeric anti-TNF-α monoclonal antibody, infiiximab, has become a standard therapy for CD and it is also likely to be beneficial for UC. Several anti-TNF reagents have been developed but most of them seem to not be as efficacious as infliximab. A humanized anti-TNF monoclonal antibody, adalimumab may be useful for the treatment of patients who lost responsiveness or developed intolerance to infliximab. Antibodies against IL-12 p40 and IL-6 receptor could be alternative new anti-cytokine therapies for IBD. Antiinterferon-γ and anti-CD25 therapies were developed, but the benefit of these agents has not yet been established. The selective blocking of migration of leukocytes into intestine seems to be a nice approach. Antibodies against α4 integrin and α4β7 integrin showed benefit for IBD. Antisense oligonucleotide of intercellular adhesion molecule 1 （ICAM-1） may be efficacious for IBD. Clinical trials of such compounds have been either recently reported or are currently underway. In this article, we review the efficacy and safety of such novel biological therapies for IBD.

Acute pancreatitis associated with peroral double-balloon enteroscopy: A case report

A 58-year-old Japanese man had tarry stool and severe anemia. Neither upper nor lower gastrointestinal （GI） endoscopy showed any localized lesions. Thus, the source of his GI bleeding was suspected to be in the small intestine, and he underwent peroral double-balloon enteroscopy （DBE） using EN-450T5 （Fujinon-Toshiba ES System Co., Tokyo, Japan）. There were no lesions considered to be the source of GI bleeding. After the procedure, the patient began to experience abdominal pain. Laboratory tests revealed hyperamylasemia and abdominal computed tomography revealed an inflammation of the pancreas and the peripancreas. He was thus diagnosed to have acute pancreatitis. Conservative treatments resulted in both clinical and laboratory amelioration. He had no history of alcohol ingestion, gallstone disease or pancreatitis. Magnetic resonance cholangiopancreatography demonstrated no structural alterations and no stones in the pancreatobiliary ductal system. As his abdominal pain started after the procedure, his acute pancreatitis was thus thought to have been related to the peroral DBE. This is the first reported case of acute pancreatitis probably associated with peroral DBE.

Endoscopic submucosal dissection for superficial esophageal squamous cell neoplasms

Endoscopic resection is an effective treatment for noninvasive esophageal squamous cell neoplasms(ESCNs).Endoscopic mucosal resection(EMR)has been developed for small localized ESCNs as an alternative to surgical therapy because it shows similar effectiveness and is less invasive than esophagectomy.However,EMR is limited in resection size and therefore piecemeal resection is performed for large lesions,resulting in an imprecise histological evaluation and a high frequency of local recurrence.Endoscopic submucosal dissection(ESD)has been developed in Japan as one of the standard endoscopic resection techniques for ESCNs.ESD enables esophageal lesions,regardless of their size,to be removed en bloc and thus has a lower local recurrence rate than EMR.The development of new devices and the establishment of optimal strategies for esophageal ESD have resulted in fewer complications such as perforation than expected.However,esophageal stricture after ESD may occur when the resected area is larger than three-quarters of the esophageal lumen or particularly when it encompasses the entire circumference;such a stricture requires multiple sessions of endoscopic balloon dilatation.Recently,oral prednisolone has been reported to be useful in preventing post-ESD stricture.In addition,a combination of chemoradiotherapy(CRT)and ESD might be an alternative therapy for submucosal esophageal cancer that has a risk of lymph node metastasis because esophagectomy is extremely invasive;CRT has a higher local recurrence rate than esophagectomy but is less invasive.ESD is likely to play a central role in the treatment of superficial esophageal squamous cell neoplasms in the future.

Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome

The pathogenesis of irritable bowel syndrome (IBS) is considered to be multifactorial and includes psychosocial factors, visceral hypersensitivity, infection, microbiota and immune activation. It is becoming increasingly clear that low-grade inflammation is present in IBS patients and a number of biomarkers have emerged. This review describes the evidence for low-grade inflammation in IBS and explores its mechanism with particular focus on gastrointestinal motor dysfunction. Understanding of the immunological basis of the altered gastrointestinal motor function in IBS may lead to new therapeutic stra- tegies for IBS.

Promising biological therapies for ulcerative colitis: A review of the literature

Ulcerative colitis(UC) is a chronic lifelong condition characterized by alternating flare-ups and remission. There is no single known unifying cause, and the pathogenesis is multifactorial, with genetics, environmental factors, microbiota, and the immune system all playing roles. Current treatment modalities for UC include 5-aminosalicylates, corticosteroids, immunosuppressants(including purine antimetabolites, cyclosporine, and tacrolimus), and surgery. Therapeutic goals for UC are evolving. Medical treatment aims to induce remission and prevent relapse of disease activity. Infliximab, an anti-tumor necrosis factor(TNF)-α monoclonal antibody, is the first biological agent for the treatment of UC. Over the last decade, infliximab and adalimumab(anti-TNF-α agents) have been used for moderate to severe UC, and have been shown to be effective in inducing and maintaining remission. Recent studies have indicated that golimumab(another anti-TNF-α agent), tofacitinib(a Janus kinase inhibitor), and vedolizumab and etrolizumab(integrin antagonists), achieved good clinical remission and response rates in UC. Recently, golimumab and vedolizumab have been approved for UC by the United States Food and Drug Administration. Vedolizumab may be used as a first-line alternative to anti-TNF-α therapy in patients with an inadequate response to corticosteroids and/or immunosuppressants. Here, we provide updated information on various biological agents in the treatment of UC.

Safety advantage of endocut mode over endoscopic sphincterotomy for choledocholithiasis

AIM： To evaluate whether an automatically controlled cut system （endocut mode） could reduce the complication rate of endoscopic sphincterotomy （EST） and serum hyperamylasemia after EST compared to the conventional blended cut mode. METHODS： From January 2001 to October 2003, 134 patients with choledocholithiasis were assigned to either endocut mode group or conventional blended cut mode group at the time of sphincterotomy. The two groups were retrospectively compared for the complications after EST and serum amylase level before and 24 h after the procedure. RESULTS： Of the 134 patients treated, 79 were assigned to conventional blended cut mode group and 55 to endocut mode group. There was no significant difference in age, sex, and serum amylase level before EST between the two groups. Complications were found in 5 patients of the endocut mode group （9%）： hyperamylasemia （5 times higher than normal） in 4 and moderate pancreatitis in 1. Complications were found in 13 patients of the conventional blended cut mode group （16%）： hyperamylasemia in 12 and moderate pancreatitis in 1. Serum amylase levels were elevated in both groups 24 h after EST （P〈0.02）. The average serum amylase level 24 h after EST in the conventional blended cut mode group was significantly higher than that in the endocut mode group （P〈 0.05）. CONCLUSION： Endocut mode offers a safety advantage over conventional blended cut mode for pancreatitis after EST by reducing hyperamylasemia.

Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders

Inflammation and immune activation in the gut are usually accompanied by alteration of gastrointestinal(GI) motility.In infection,changes in motor function have been linked to host defense by enhancing the expulsion of the infectious agents.In this review,we describe the evidence for inflammation and immune activation in GI infection,inflammatory bowel disease,ileus,achalasia,eosinophilic esophagitis,microscopic colitis,celiac disease,pseudo-obstruction and functional GI disorders. We also describe the possible mechanisms by which inflammation and immune activation in the gut affect GI motility.GI motility disorder is a broad spectrum disturbance of GI physiology.Although several systems including central nerves,enteric nerves,interstitial cells of Cajal and smooth muscles contribute to a coordinated regulation of GI motility,smooth muscle probably plays the most important role.Thus,we focus on the relationship between activation of cytokines induced by adaptive immune response and alteration of GI smooth muscle contractility.Accumulated evidence has shownthat Th1 and Th2 cytokines cause hypocontractility and hypercontractility of inflamed intestinal smooth muscle. Th1 cytokines downregulate CPI-17 and L-type Ca 2+ channels and upregulate regulators of G protein signaling 4,which contributes to hypocontractility of inflamed intestinal smooth muscle.Conversely,Th2 cytokines cause hypercontractilty via signal transducer and activator of transcription 6 or mitogen-activated protein kinase signaling pathways.Th1 and Th2 cytokines have opposing effects on intestinal smooth muscle contraction via 5-hydroxytryptamine signaling.Understanding the immunological basis of altered GI motor function could lead to new therapeutic strategies for GI functional and inflammatory disorders.

Mucosal-incision assisted biopsy for suspected gastric gastrointestinal stromal tumors

To evaluate the diagnostic yield of the procedure, mucosal-incision assisted biopsy (MIAB), for the histological diagnosis of gastric gastrointestinal stromal tumor (GIST), we performed a retrospective review of the 27 patients with suspected gastric GIST who underwent MIAB in our hospitals. Tissue samples obtained by MIAB were sufficient to make a histological diagnosis (diagnostic MIAB) in 23 out of the 27 patients, where the lesions had intraluminal growth patterns. Alternatively, the samples were insufficient (non-diagnosticMIAB) in remaining 4 patients, three of whom had gastric submucosal tumor with extraluminal growth patterns. Although endoscopic ultrasound and fine needle aspiration is the gold standard for obtaining tissue specimens for histological and cytological analysis of suspected gastric GISTs, MIAB can be used as an alternative method for obtaining biopsy specimens of lesions with an intraluminal growth pattern.

Improved techniques for double-balloon-enteroscopy-assisted endoscopic retrograde cholangiopancreatography

AIM: To investigate the clinical outcome of double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (DB-ERCP) in patients with altered gastrointestinal anatomy. METHODS: Between September 2006 and April 2011, 47 procedures of DB-ERCP were performed in 28 patients with a Roux-en-Y total gastrectomy (n = 11), Billroth Ⅱ gastrectomy (n = 15), or Roux-en-Y anastomosis with hepaticojejunostomy (n = 2). DB-ERCP was performed using a short-type DBE combined with several technical innovations such as using an endoscope attachment, marking by submucosal tattooing,selectively applying contrast medium, and CO2 insufflations. RESULTS: The papilla of Vater or hepaticojejunostomy site was reached in its entirety with a 96% success rate (45/47 procedures). There were no significant differences in the success rate of reaching the blind end with a DBE among Roux-en-Y total gastrectomy (96%), Billroth Ⅱ reconstruction (94%), or pancreatoduodenectomy (100%), respectively (P = 0.91). The total successful rate of cannulation and contrast enhancement of the target bile duct in patients whom the blind end was reached with a DBE was 40/45 procedures (89%). Again, there were no significant differences in the success rate of cannulation and contrast enhancement of the target bile duct with a DBE among Roux-en-Y total gastrectomy (88 %), Billroth Ⅱ reconstruction (89%), or pancreatoduodenectomy (100%), respectively (P = 0.67). Treatment was achieved in all 40 procedures (100%) in patients whom the contrast enhancement of the bile duct was successful. Common endoscopic treatments were endoscopic biliary drainage (24 procedures) and extraction of stones (14 procedures). Biliary drainage was done by placement of plastic stents. Stones extraction was done by lithotomy with the mechanical lithotripter followed by extraction with a basket or by the balloon pull-through method. Endoscopic sphincterotomy was performed in 14 procedures with a needle precutting knife using a guidewire. The mean total duration of the procedure was 93.6 ± 6.8 min and the mean time required to reach the papilla was 30.5 ± 3.7 min. The mean time required to reach the papilla tended to be shorter in Billroth Ⅱ reconstruction (20.9 ± 5.8 min) than that in Roux-en-Y total gastrectomy (37.1 ± 4.9 min) but there was no significant difference (P = 0.09). A major complication occurred in one patient (3.5%); perforation of the long limb in a patient with Billroth Ⅱ anastomosis.CONCLUSION: Short-type DBE combined with several technical innovations enabled us to perform ERCP in most patients with altered gastrointestinal anatomy.

Clutch Cutter knife efficacy in endoscopic submucosal dissection for early gastric neoplasms

AIM To compare the outcomes of endoscopic submucosal dissection(ESD) for gastric neoplasms using Clutch Cutter(ESD-C) or other knives(ESD-O).METHODS This was a single-center retrospective study. Gastric neoplasms treated by ESD between April 2016 and October 2017 at Kitakyushu Municipal Medical Center were reviewed. Multivariate analyses and propensity score matching were used to reduce biases. Covariates included factors that might affect outcomes of ESD, including age, sex, underlying disease, anti-thrombotic drugs use, tumor location, tumor position, tumor size, tumor depth, tumor morphology, tumor histology, ulcer(scar), and operator skill. The treatment outcomes were compared among two groups. The primary outcome was ESD procedure time. Secondary outcomes were en bloc, complete, and curative resection rates, and adverse events rates including perforation and delayed bleeding.RESULTS A total of 155 patients were included in this study; 44 pairs were created by propensity score matching. Background characteristics were quite similar among two groups after matching. Procedure time was significantly shorter for ESD-C(median; 49 min) than for ESD-O(median; 88.5 min)(P < 0.01). However, there was no significant difference in treatment outcomes between ESD-C and ESD-O including en bloc resection rate(100% in both groups), complete resection rate(100% in both groups), curative resection rate(86.4% vs 88.6%, P = 0.730), delayed bleeding(2.3% vs 6.8%, P = 0.62) and perforation(0% in both groups).CONCLUSION ESD-C achieved shorter procedure time without an increase in complication risk. Therefore, ESD-C could become an effective ESD option for gastric neoplasms.

Usefulness of percutaneous endoscopic gastrostomy for supportive therapy of advanced aerodigestive cancer

Aerodigestive cancer, like esophageal cancer or head and neck cancer, is well known to have a poor prognosis. It is often diagnosed in the late stages, with dysphagia being the major symptom. Insufficient nutrition and lack of stimulation of the intestinal mucosa may worsen immune compromise due to toxic side effects. A poor nutritional status is a significant prognostic factor for increased mortality. Therefore, it is most important to optimize enteral nutrition in patients with aerodigestive cancer before and during treatment, as well as during palliative treatment. Percutaneous endoscopic gastrostomy(PEG) may be useful for nutritional support. However, PEG tube placement is limited by digestive tract stenosis and is an invasive endoscopic procedure with a risk of complications. There are three PEG techniques. The pull/push and introducer methods have been established as standard techniques for PEG tube placement. The modified introducer method, namely the direct method, allows for direct placement of a larger button-bumper-type catheter device. PEG tube placement using the introducer method or the direct method may be a much safer alternative than the pull/push method. PEG may be recommended in patients with aerodigestive cancer because of the improved complication rate.

Assistant skill in gastric endoscopic submucosal dissection using a clutch cutter

BACKGROUND A clutch cutter is a scissor-type knife used in endoscopic submucosal dissection(ESD)for gastrointestinal tract tumors.The assistant during the ESD using a clutch cutter(ESD-C)needs to rotate the device and grasp the target tissue appropriately;therefore,the assistant’s skill may affect the technical outcomes of ESD-C.AIM To determine how assistant skill level affected the technical outcomes of gastric ESD-C using an ex vivo porcine training model.METHODS In this pilot study,mock lesions of 15-30 mm in diameter were created in the middle or lower third of the porcine stomach.A total of 32 ESD-C procedures were performed by 16 trainees.Each trainee operator performed two ESD-C procedures;one ESD-C was assisted by an expert(ESD-C-E),and the other was assisted by a non-expert(ESD-C-NE).The total procedure time of the ESD was set as the primary outcome,and en bloc resection rate,complete procedure rate,perforation rate,and each procedure time/speed for mucosal incision or submucosal dissection were set as the secondary outcomes.In addition,we investigated factors associated with the difficulty of ESD including incompletion of ESD procedure,a long procedure time(≥20 min)or intraoperative perforation.RESULTS The median total procedure time of the ESD-C-E was significantly shorter than that of the ESD-C-NE(12.9 min vs 21.9 min,P=0.001).The en bloc resection rate was 100%in both groups.Complete resection rates of the ESD-C-E and ESD-C-NE groups were 100%and 93.8%,respectively.No intraoperative perforation was observed in both groups.In the multivariate analysis,assistant skill was significantly associated with the difficulty of ESD,with the highest odds ratio of 16.5.CONCLUSION Assistance by an expert is an important factor when trainees perform ESD-C procedures.

MAPKs represent novel therapeutic targets for gastrointestinal motility disorders

The number of patients suffering from symptoms associated with gastrointestinal(GI) motility disorders is on the rise. GI motility disorders are accompanied by alteration of gastrointestinal smooth muscle functions. Currently available drugs,which can directly affect gastrointestinal smooth muscle and restore altered smooth muscle contractility to normal,are not satisfactory for treating patients with GI motility disorders. We have recently shown that ERK1/2 and p38MAPK signaling pathways play an important role in the contractile response not only of normal intestinal smooth muscle but also of inflamed intestinal smooth muscle. Here we discuss the possibility that ERK1/2 and p38MAPK signaling pathways represent ideal targets for generation of novel therapeutics for patients with GI motility disorders.