Clinical Outcomes of 67 Patients Treated with Chemoradiotherapy for Primary Thyroid Non-Hodgkin’s Lymphoma in Osaka Medical College

Background: The reports of clinical outcomes of patients treated with chemoradiotherapy for primary thyroid non-Hodgkin’s lymphoma are rare. We report our results of chemoradiotherapy for primary thyroid non-Hodgkin’s lymphoma. Materials and Methods: The subjects were 67 patients with thyroid non-Hodgkin’s lymphoma among 269 patients with malignant lymphoma who received radiotherapy in our hospital during a period between May 1990 and June 2005. The patients included 16 men and 51 women, with a mean age of 66.2 ± 10.7 years (30 - 84 years). The disease stage was stage I in 42 patients, stage II in 24, and unclear in 1. The histologic type was B-cell lymphoma in 66 patients, MALT in 9, diffuse type in 52, follicular type in 5, and diffuse and follicular type in 1. CHOP chemotherapy regimen for malignant lymphoma patients was as follows. Intravenous drip infusion of cyclophosphamide 750 mg/m2, (drip) infusion of doxorubicin 50 mg/m2, and intravenous injection of vincristine 1.4 mg/m2 were administered on day 1, followed by 5 consecutive days of oral prednisolone 100 mg/m2. This regimen was repeated every 3 weeks (21 days) in 6 to 8 courses. Modified CHOP chemotherapy regimen was as follows. Intravenous drip infusion of cyclophosphamide 600 mg/m2, intravenous (drip) infusion of doxorubicin 40 mg/m2, intravenous infusion of vindesine 3 mg/m2, and intravenous drip infusion of prednisolone 60 mg/body were administered on day 1, and intravenous prednisolone was changed to oral prednisolone with the dose tapered gradually. After completing one course of this regimen, two courses of radiotherapy (a total of 36 Gy) were performed, followed by 6 courses of the chemotherapy regimen at lower doses (80% of the initial doses) repeated once a month. Results: Results of chemoradiotherapy in all patients were excellent. The 15-year survival rate was over 80%. Although there were no significant differences in the results of chemoradiotherapy among different histologic types of thyroid malignant lymphoma, the survival rate was 100% for MALT type, as compared with poor results for diffuse large type or diffuse mixed type. The analysis of the results of chemoradiotherapy according to the stage of malignant thyroid lymphomas revealed that therapeutic results were significantly better in stage I than in stage II. Conclusion: The CHOP chemoradiotherapy regimen and modified CHOP chemoradiotherapy regimen were excellent for primary thyroid non-Hodgkin’s lymphoma.

Usefulness of a Newly-Developed Device, the Power Tree^(■), for Body Massage: Evidence from a Medical Evaluation

We investigated the effectiveness and usefulness of a novel tool: the Power Tree?, for body massage in 10 healthy female volunteers (age range, 24 - 55 years;mean age, 40.5 years) by evaluating several dermatological and psychological parameters, such as the amount of dermal collagen, the skin temperature, the level of salivary amylase and the scores on the State-Trait Anxiety Index (STAI). After 60-minute Power Tree?-mediated body massage, both the dermal collagen score determined from the DermaLab? images and skin temperature measured by infrared thermography were found to have increased significantly in several body sites compared to those before the treatment (p < 0.01 and p < 0.001, respectively). Although the level of stress estimated by the amount of amylase in the saliva was not significantly different pre- and post-procedure (p = 0.3), the treatment significantly reduced both the state anxiety (SA) and trait anxiety (TA) scores on the STAI (p < 0.001 for the SA, p < 0.01 for the TA). The treatment with this device was smoothly performed without any burden on the therapists during the present study. These data suggest that the newly-developed device is a powerful and useful tool for reflexology when used for full body massage therapy, and massage therapy using this device may produce beneficial, physiological effects as well as psychosocial improvements.

Function-preserving gastrectomy for gastric cancer in Japan

Surgery used to be the only therapy for gastric cancer, and since its ability to cure gastric cancer was the focus of attention, less attention was paid to functionpreserving surgery in gastric cancer, though it was studied for gastroduodenal ulcer. Maki et al developed pylorus-preserving gastrectomy for gastric ulcer in 1967. At the same time, the definition of early gastric cancer(EGC) was being considered, histopathological investigations of EGC were carried out, and the validity of modified surgery was sustained. After the development of H2-blockers, the number of operations for gastroduodenal ulcers decreased, and the number of EGC patients increased simultaneously. As a result, the indications for pylorus-preserving gastrectomy for EGC in the middle third of the stomach extended, and various alterations were added. Since then, many kinds of function-preserving gastrectomies have been performed and studied in other fields of gastric cancer, and proximal gastrectomy, jejunal pouch interposition, segmental gastrectomy, and local resection have been performed. On the other hand, from the overall perspective, it can be said that endoscopic resection, which was launched at almost the same time, is the ultimate function-preserving surgery under the current circumstances. The current function-preserving gastrectomies that are often performed and studied are pylorus-preserving gastrectomy and proximal gastrectomy. The reasons for this are that these procedures that can be performed with systemic lymph node dissection, and they include three important elements:(1) reduction of the extent of gastrectomy;(2) preservation of the pylorus; and(3) preservation of the vagal nerve. In addition, these operations are more likely to be performed with a laparoscopic approach as minimally invasive surgery. Of the above-mentioned three elements, reduction of the extent of gastrectomy is the most important in our view. Therefore, we should try to reduce the extent of gastrectomy if curability of the gastric cancer can still be achieved. However, if we preserve a wider residual stomach in functionpreserving gastrectomy, we should pay attention to the development of metachronous gastric cancer.

Evaluation of the effect of pyrrolidine dithiocarbamate in suppressing inflammation in mice with dextran sodium sulfate-induced colitis

AIM: To evaluate the effect of pyrrolidine dithio- carbamate (PDTC; an NF-κB inhibitor) administered at low (50 mg/kg) and high (100 mg/kg) doses in suppressing colitis in mice with dextran sodium sulfate (DSS)-induced colitis. METHODS: Mice were divided into a DSS-untreated group (normal group), DSS-treated control group, DSS+PDTC-treated groupⅠ(low-dose group), and DSS+PDTC-treated groupⅡ (high-dose group). In each group, the disease activity index score (DAI score), intestinal length, histological score, and the levels of activated NF-κB and inflammatory cytokines (IL-1β and TNF-α) in tissue were measured. RESULTS: The DSS+PDTC-treated groupⅡ exhibited suppression of shortening of intestinal length and reduction of DAI score. Activated NF-κB level and IL-1β and TNF-α levels were significantly lower in DSS+PDTC- treated groupⅡ. CONCLUSION: These findings suggest that PDTC is useful for the treatment of ulcerative colitis.

Effects of acupuncture treatment on natural killer cell activity,pulse rate,and pain reduction for older adults:an uncontrolled,observational study

OBJECTIVE： The aim of this study was to examine the changes in natural killer （NK） cell activity, pulse rate, and pain intensity among older adults before and after acupuncture treatment. METHODS： Fifty-six individuals （16 males and 40 females）, aged 60 to 82 years （mean age 72.4 ＋ 5.0）, who were experiencing pain in the shoulder, low back, or knee, participated in the study. NK cell activity, leukocyte differentiation （granulocytes and lymphocytes）, pulse rate, and blood pressure values were obtained. Pain intensity was evaluated by using the visual analog scale （VAS）. The Wilcoxon test was used to analyze NK cell activity, leukocytes （granulocyte counts and granulocyte-to-lymphocyte ratio）, and the VAS score in accordance with the location of pain complaints before and after acupuncture treatment. RESULTS： NK cell activity decreased after acupuncture treatment for pain in the shoulder-pain and knee-pain groups. Further, the lymphocyte and granulocyte counts increased after acupuncture treatment for the shoulder-pain group. Pulse rate decreased for the shoulder-pain, low-back- pain, and knee-pain groups after acupuncture treatment. The VAS score decreased after acupuncture treatment for the shoulder-pain, low-back-pain, and knee-pain groups. CONCLUSION： This study showed that in older adults, acupuncture treatment decreases pulse rate, relieves pain in the shoulder, low back, and knee, and reduces NK-cell activity.

Primary hepatic benign schwannoma

Schwannoma is predominantly a benign neoplasm of the Schwann cells in the neural sheath of the peripheral nerves.Occurrence of schwannoma in parenchymatous organs,such as liver,is extremely rare.A 64-year-old man without neurofibromatosis was observed to have a space-occupying lesion of 23mm diameter in the liver during follow-up examination for a previously resected gastrointestinal stromal tumor(GIST)in the small intestine.He underwent lateral segmentectomy of the liver under a provisional diagnosis of hepatic metastatic recurrence of the GIST.Histological examination confirmed the diagnosis of a benign schwannoma,confirmed by characteristic pathological findings and positive immunoreactions with the neurogenic marker S-100 protein,but negative for c-kit,or CD34.The tumor was the smallest among the reported cases.When the primary hepatic schwannoma is small in size,preopera- tive clinical diagnosis is difficult.Therefore,this disease should be listed as differential diagnosis for liver tumor with clinically benign characteristics.

Technical tips for endoscopic ultrasound-guided hepaticogastrostomy

Interventional procedures using endoscopic ultrasound(EUS) have recently been developed. For biliary drainage, EUS-guided trans-luminal drainage has been reported. In this procedure, the transduodenal approach for extrahepatic bile ducts is called EUSguided choledochoduodenostomy, and the transgastric approach for intrahepatic bile ducts is called EUSguided hepaticogastrostomy(EUS-HGS). These procedures have several effects, such as internal drainage and avoiding post-endoscopic retrograde cholangiopancreatography(ERCP) pancreatitis, and they are indicated for an inaccessible ampulla of Vater due to duodenal obstruction or surgical anatomy. EUS-HGS has particularly wide indications and clinical impact as an alternative biliary drainage method. In this procedure, it is necessary to dilate the fistula, and several devices and approaches have been reported. Stent selection is also important. In previous reports, the overall technical success rate was 82%(221/270), the clinical success rate was 97%(218/225), and the overall adverse event rate for EUS-HGS was 23%(62/270). Adverse events of EUS-biliary drainage are still high compared with ERCP or PTCD. EUSHGS should continue to be performed by experienced endoscopists who can use various strategies when adverse events occur.

Peritoneovenous shunt for intractable ascites due to hepatic lymphorrhea after hepatectomy

A peritoneovenous shunt has become one of the most effi cient procedures for intractable ascites due to liver cirrhosis.A case of intractable ascites due to hepatic lymphorrhea after hepatectomy for hepatocellular carcinoma that was successfully treated by the placement of a peritoneovenous shunt is presented.A 72-year-old Japanese man underwent partial resection of the liver for hepatocellular carcinoma associated with hepatitis C viral infection.After hepatectomy,a considerable amount of ascites ranging from 800-4600 mL per day persisted despite conservative therapy,including numerous infusions of albumin and plasma protein fraction and administration of diuretics.Since the patient's general condition deteriorated,based on the diagnosis of intractable hepatic lymphorrhea,a subcutaneous peritoneovenous shunt was inserted.The patient's postoperative course was uneventful and the ascites decreased rapidly,with serum total protein and albumin levels and hepatic function improving accordingly.For intractable ascites due to hepatic lymphorrhea after hepatectomy,we recommend the placement of a peritoneovenous shunt as a procedure that can provide immediate effectiveness without increased surgical risk.

Ethanol-induced hepatic autophagy: Friend or foe?

Excessive alcohol intake may induce hepatic apoptosis, steatosis, fibrosis, cirrhosis and even cancer. Ethanolinduced activation of general or selective autophagy as mitophagy or lipophagy in hepatocytes is generally considered a prosurvival mechanism. On the other side of the coin, upregulation of autophagy in nonhepatocytes as stellate cells may stimulate fibrogenesis and subsequently induce detrimental effects on the liver. The autophagic response of other non-hepatocytes as macrophages and endothelial cells is unknown yet and needs to be investigated as these cells play important roles in ethanol-induced hepatic steatosis and damage. Selective pharmacological stimulation of autophagy in hepatocytes may be of therapeutic importance in alcoholic liver disease.

Technical tips of endoscopic ultrasound-guided choledochoduodenostomy

Endoscopic ultrasound(EUS) is clinically useful not only as a diagnostic tool during EUS-guided fine needle aspiration,but also during interventional EUS.EUS-guided biliary drainage has been developed and performed by experienced endoscopists.EUS-guided choledocoduodenostomy(EUS-CDS) is relatively well established as an alternative biliary drainage method for biliary decompression in patients with biliary obstruction.The reported technical success rate of EUS-CDS ranges from 50% to 100%,and the clinical success rate ranges from 92% to 100%.Further,the over-all technicalsuccess rate was 93%,and clinical success rate was 98%.Based on the currently available literature,the overall adverse event rate for EUS-CDS is 16%.The data on the cumulative technical and clinical success rate for EUS-CDS is promising.However,EUS-CDS can still lead to several problems,so techniques or devices that are more feasible and safe need to be established.EUS-CDS has the potential to become a first-line biliary drainage procedure,although standardizing the technique in multicenter clinical trials and comparisons with endoscopic biliary drainage by randomized clinical trials are still needed.

Effects of oral tacrolimus as a rapid induction therapy in ulcerative colitis

AIM:To determine the efficacy and safety of rapid induction therapy with oral tacrolimus without a meal in steroid-refractory ulcerative colitis(UC)patients.METHODS:This was a prospective,multicenter,observational study.Between May 2010 and August 2012,49 steroid-refractory UC patients(55 flare-ups)were consecutively enrolled.All patients were treated with oral tacrolimus without a meal at an initial dose of 0.1mg/kg per day.The dose was adjusted to maintain trough whole-blood levels of 10-15 ng/m L for the first 2 wk.Induction of remission at 2 and 4 wk after tacrolimus treatment initiation was evaluated using Lichtiger’s clinical activity index(CAI).RESULTS:The mean CAI was 12.6±3.6 at onset.Within the first 7 d,93.5%of patients maintained high trough levels(10-15 ng/m L).The CAI significantly decreased beginning 2 d after treatment initiation.At 2wk,73.1%of patients experienced clinical responses.After tacrolimus initiation,31.4%and 75.6%of patients achieved clinical remission at 2 and 4 wk,respectively.Treatment was well tolerated.CONCLUSION:Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation.Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.

Characteristic expression of γ-aminobutyric acid and glutamate decarboxylase in rat jejunum and its relation to differentiation of epithelial cells

AIM: To investigate the expression between γ-aminobutyric acid (GABA) and glutamate decarboxylase and its relation with differentiation and maturation of jejunal epithelial cells in rat jejunum.METHODS: Immunohistochemical expression of GABA and glutamate decarboxylase (GAD, including two isoforms,GAD65 and GAD67) was investigated in rat jejunum.Meanwhile, double staining was performed with GAD65 immunohistochemistry, followed by lectin histochemistry of fluorescent wheat germ agglutinin. Furthermore,evaluation of cell kinetics in jejunum was conducted by ^3Hthymidine autoradiography and immunohistochemistry using a monoclonal antibody to proliferating cell nuclear antigen (PCNA).RESULTS: The cells showing positive immunoreactivity GABA and GAD65 were mainly distributed in the villi in rat jejunum, while jejunal epithelial cells were negative for GAD67. Positive GABA or GAD65 staining was mainly located in the cytoplasm and along the brush border of epithelial cells in the middle and upper portions. In addition, a few GABA and GAD65 strongly positive cells were scattered in the upper two thirds of jejunal villi. Double staining showed that GAD65 immunoreactivity was not found in goblet cells.^3H-thymidine-labeled nuclei were found in the lower and middle portions of jejunal crypts, which was consistent with PCNA staining. Therefore, GABA and GAD65 were expressed in a maturation or functional zone.CONCLUSION: The characteristic expression of GABA and GAD suggests that GABA might be involved in regulation of differentiation and maturation of epithelial cells in rat jejunum.

Usefulness of fecal lactoferrin and hemoglobin in diagnosis of colorectal diseases

AIM:To evaluate prospectively usefulness of fecal lactoferrin(Lf)and fecal hemoglobin(Hb)in the diagnosis of colorectal diseases.METHODS:Fecal Lf and Hb were measured using ELISA in 872 patients before they underwent colorectal endoscopy.RESULTS:Lf was positive in 18(50%)of 36 patients with colorectal cancer,25(15.9%)of 157 with colorectal polyps,29(46.8%)of 62 with ulcerative colitis,and 25(62.5%)of 40(62.5%)with Crohn's disease.The Hb-positive rates were 50%,12.1%,41.9% and 32.5%,respectively.Of the 318 patients free of abnormalities by colorectal endoscopy,Lf was positive in 29(9.1%)and Hb was positive in 15(4.7%).Among patients with Crohn's disease,the Lf-positive rate was significantly higher than the Hb-positive rate.If either high Lf or Hb levels were considered positive,the positive rates rose to 61.1%,51.6%,and 67.5% in the colorectal cancer group,ulcerative colitis group,and Crohn's disease group,respectively.If both high Lf and Hb levels were rated positive,the positive predictive values(PPV)were 21% for colorectal cancer,33% for ulcerative colitis,and 17% for Crohn's disease,and PPV of high Hb level alone was 18%,25% and 13%,respectively.CONCLUSION:Fecal Lf and Hb were found useful in the detection of colorectal diseases,and the combination of the two measurements appears to increase the sensitivity and efficacy of diagnosis.

Diabetic neuropathy research: from mouse models to targets for treatment

Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment.

Increased prevalence of intestinal inflammation in patients with liver cirrhosis

AIM To investigate the pathophysiology of the digestive tract in patients with liver cirrhosis.METHODS In 42 cirrhotic patients and 20control subjects, the following fecal proteinswere measured by enzyme-linkedimmunosorb6nt assay: albumin (Alb ),transferrin (Tf), and al-antitrypsin (a,-AT) as amarker for intestinal protein l0ss, hemoglobin(Hb) for bleeding, PMN-eIastase for intestinalinflammation, and secretory lgA for intestinalimmunity.RESULTS The fecaI concentrations of Hb, Alb,Tf, al-AT, and PMN’eIastase were increased in13 (3l%), 8(19%), l0(24%), 6(14%), and 1l(26%) cases among 42 patients, resPectiveIy.F6cal concentration of secretory IgA wasdecreased in 7 (l7%) of 42 patients. However,these fecal concentrations were not related tothe severity or etiology of liver cirrhosis. Theserum Alb level was significantIy decreased inpatients with intestinal protein Ioss c0mpared tothat in patients without intestinal protein loss.CONCLUSION These findings suggest that: rob6sides the weIl’known pathological conditions,Such as bleeding and protein loss, intestinaIinflammati0n and decreased intestinaI immunityare found in cirrhotic patients, @ intestinalprotein loss contributes to hypoalbuminemia incirrhotic patients, and @ intestinaI inflammationshouId not b6 0verlooked in cirrhotic patients,since it may contribute to or cause intestinalprotein Ioss and oth6r various pathologicalconditions.

Does endoscopic ultrasound-guided biliary drainage really have clinical impact?

The well established, gold standard method for treatment of obstructive jaundice involves biliary drainage under endoscopic retrograde cholangiopancreatography(ERCP) performed by pancreatobiliary endoscopists. Recently, interventions using endoscopic ultrasound(EUS) have been developed not only for obtaining cytological and histological diagnosis, but also for biliary drainage as alternative method. EUS-guided biliary drainage(EUSBD) was first reported by Giovannini et al. EUS-BD broadly includes EUS-guided rendezvous technique, EUS-guided choledochoduodenostomy, and EUS-guided hepaticogastrostomy. More recently, EUS-guided antegrade stenting and EUS-guided gallbladder drainage have also been reported. many case reports, series, and retrospective studies on EUS-BD have been reported. However, because prospective studies and comparisons between the different biliary drainage methods have not been reported, the technical success, functional success, adverse events, and stent patency with long-term follow up of EUS-BD are still unclear. Therefore, prospective, randomized controlled studies addressing these issues are needed. Despite this, EUSBD undoubtedly is clinically useful as an alternative biliary drainage method. EUS-BD has the potential to be a first-line biliary drainage method instead of ERCP if results of clinical trials are favorable and the technique is simplified.

BRIEF ARTICLE New reduced volume preparation regimen in colon capsule endoscopy

AIM:To evaluate the effectiveness of our proposed bowel preparation method for colon capsule endoscopy.METHODS:A pilot,multicenter,randomized controlled trial compared our proposed "reduced volume method"(group A) with the "conventional volume method"(group B) preparation regimens.Group A did not drink polyethylene glycol electrolyte lavage solution(PEGELS) the day before the capsule procedure,while group B drank 2 L.During the procedure day,groups A and B drank 2 L and 1 L of PEG-ELS,respectively,and swallowed the colon capsule(PillCam COLON capsule).Two hours later the first booster of 100 g magnesium citrate mixed with 900 mL water was administered to both groups,and the second booster was administered six hours post capsule ingestion as long as the capsule had not been excreted by that time.Capsule videos were reviewed for grading of cleansing level,RESULTS:Sixty-four subjects were enrolled,with results from 60 analyzed.Groups A and B included 31 and 29 subjects,respectively.Twenty-nine(94%) subjects in group A and 25(86%) subjects in group B had adequate bowel preparation(ns).Twenty-two(71%) of the 31 subjects in group A excreted the capsule within its battery life compared to 16(55%) of the 29 subjects in group B(ns).Of the remaining 22 subjects whose capsules were not excreted within the battery life,all of the capsules reached the left side colon before they stopped functioning.A single adverse event was reported in one subject who had mild symptoms of nausea and vomiting one hour after starting to drink PEG-ELS,due to ingesting the PEG-ELS faster than recommended.CONCLUSION:Our proposed reduced volume bowel preparation method for colon capsule without PEG-ELS during the days before the procedure was as effective as the conventional volume method.

The process of life adjustment in patients at onset of glioma who are receiving continuous oral anticancer drug: A qualitative descriptive study

Objective: Patients with malignant gliomas have to adjust their daily lives because of the threat of impending death and declining abilities.Thus,clarifying the process of life adjustment in such patients would help them lead a normal life.To clarify the process of life adjustment in patients at the onset of glioma,who continuously receive oral anticancer drug.Methods: The study institution consisted of two designated cancer centers.Semi-structured interviews were conducted with 10 patients,and the data were analyzed using the Modified Grounded Theory Approach of Kinoshita (M-GTA).Results: As a core category representing the process of life adjustment in patients at the onset of glioma,"trials and errors for self-fulfillment even in a limited lifespan" was extracted.Patients began "seeking information about the unfamiliar life-threatening disease," and "imaging their uncertain lives after the disease and the resulting disability" while "conducting repeated trials and errors to establish coping methods according to their abilities." When facing difficulties in such trials and errors,they reported "losing self-confidence due to unexpected limitations." However,they regulated their feelings by "resigning themselves to their unchangeable reality." Contrarily,as "functional improvement enhanced their motivation to recover," they attempted to promote functional recovery and organized their daily lives in "fulfilling their desires in their limited lifespan." Conclusion: The process of life adjustment in patients with malignant gliomas involved identifying a way of living despite limited lifespan.To ensure appropriate nursing care for patients at the onset of glioma,it is important to help them establish coping methods in accordance with their abilities.

Disruption of the TWEAK/Fn14 pathway prevents 5-fluorouracil-induced diarrhea in mice

AIM To clarify the roles of TWEAK and its receptor Fn14 in 5-fluorouracil(5-FU)-induced diarrhea.METHODS Diarrhea was induced in wild-type(WT), Fn14 knockout(KO), and IL-13 receptor(IL-13R)α1 KO BALB/c mice using a single injection of 5-FU. Histological analysis, cytokine analysis, and flow cytometry was performed on ileal tissues and cells. Murine colon carcinomabearing mice were co-treated with an anti-TWEAK antibody and 5-FU. Embryonic fibroblast response to cytokines was also analyzed.RESULTS5-FU induced high Fn14 expression in epithelial cells. The severity of 5-FU-induced diarrhea was lower in Fn14 KO mice compared with WT mice. Administration of anti-TWEAK antibody reduced 5-FU-induced diarrhea without affecting the antitumor effects of 5-FU in vivo. 5-FU-induced expression of IL-13, IL-17 A, TNF-α, and IFN-γ in the ileum was Fn14 dependent. The severity of 5-FU-induced diarrhea was lower in IL-13Rα1 KO mice, indicating major role for IL-13 signaling via IL-13Rα1 in pathogenesis. We found that IL-13Rα2, an IL-13 neutralizing/cell protective receptor, was strongly induced by IL-33 in vitro and in vivo. IL-13Rα2 was upregulated in the ileum of 5-FU-treated Fn14 KO mice. Thus, the deletion of Fn14 upregulated IL-13Rα2 expression, which reduced IL-13 expression and activity. CONCLUSION Disruption of the TWEAK/Fn14 pathway affects several interconnected pathways, including those associated with IL-13, IL-33, and IL-13Rα2, to attenuate 5-FUinduced intestinal side effects.

Development and validation of a simple and multifaceted instrument,GERD-TEST,for the clinical evaluation of gastroesophageal reflux and dyspeptic symptoms

AIM To evaluate the psychometric properties of a newly developed questionnaire,known as the gastroesophageal reflux and dyspepsia therapeutic efficacy and satisfaction test(GERD-TEST),in patients with GERD.METHODS Japanese patients with predominant GERD symptoms recruited according to the Montreal definition were treated for 4 wk using a standard dose of proton pump inhibitor(PPI). The GERD-TEST and the Medical Outcome Study Short Form-8 Health Survey(SF-8) were administered at baseline and after 4 wk of treatment. The GERD-TEST contains three domains: the severity of GERD and functional dyspepsia(FD) symptoms(5 items),the level of dissatisfaction with daily life(DS)(4 items),and the therapeutic efficacy as assessed by the patients and medication compliance(4 items).RESULTS A total of 290 patients were eligible at baseline; 198 of these patients completed 4 wk of PPI therapy. The internal consistency reliability as evaluated using the Cronbach's α values for the GERD,FD and DS subscales ranged from 0.75 to 0.82. The scores for the GERD,FD and DS items/subscales were significantly correlated with the physical and mental component summary scores of the SF-8. After 4 wk of PPI treatment,the scores for the GERD items/subscales were greatly reduced,ranging in value from 1.51 to 1.87 and with a large effect size(P < 0.0001,Cohen's d; 1.29-1.63). Statistically significant differences in the changes in the scores for the GERD items/subscales were observed between treatment responders and non-responders(P < 0.0001).CONCLUSION The GERD-TEST has a good reliability,a good convergent and concurrent validity,and is responsive to the effects of treatment. The GERD-TEST is a simple,easy to understand,and multifaceted PRO instrument applicable to both clinical trials and the primary care of GERD patients.