Background
Few studies have investigated measures to prevent small bowel injuries induced by aspirin. Our aim was to evaluate the effect of probiotic treatment on the small bowel injuries induced by ...chronic low-dose aspirin use.
Methods
Thirty-five patients who took low-dose enteric-coated aspirin 100 mg daily (for more than 3 months) plus omeprazole 20 mg daily and were diagnosed as having unexplained iron deficiency anemia participated in this prospective randomized controlled trial. We assigned the patients to receive probiotic treatment with
Lactobacillus casei
for 3 months (
L. casei
group) or not receive the probiotic (control group). Patients underwent capsule endoscopy (CE) before and after treatment.
Results
Twenty-five patients, including 13 in the
L. casei
group and 12 in the control group, underwent the full analysis. Significant decreases in the number of mucosal breaks and the CE score were observed at the 3-month evaluation in the
L. casei
group as compared with the results in the control group (
P
= 0.039). The change from the baseline in the median number of mucosal breaks in the
L. casei
group was −2, as compared with 0.5 in the control group. The change from the baseline in the median CE score in the
L. casei
group was −228 compared with −4 in the control group (
P
= 0.026).
Conclusions
Co-administration of
L. casei
is effective for the treatment of aspirin-associated small bowel injury.
Overexpression of programmed death‐1 (PD‐1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD‐1‐blocking antibody that inhibits the PD‐1 pathway and showed good efficacy ...in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was commenced in March 2015. We report data obtained at a cutoff of 16 March 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow‐up were 7.0 (1.4–10.6) months and 9.8 (6.0–11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval CI: 54.4–96.0%; 13/16 patients), with complete remission and partial remission in 4 and 9 patients, respectively. The overall survival (OS) and progression‐free survival (PFS) rates at 6 months were 100 and 60.0% (95% CI: 31.8–79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin.
We examined the efficacy and safety of nivolumab, a programmed death‐1 (PD‐1)‐blocking antibody, in a phase 1 trial in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. The results indicate that nivolumab is a potentially effective treatment option that achieved relevant decreases in tumor size. Nivolumab was also tolerable in this cohort of patients.
The biguanide metformin is widely used for treating diabetes mellitus. We previously showed the chemopreventive effect of metformin in two rodent models of colorectal carcinogenesis. However, besides ...epidemiologic studies, little is known about the effects of metformin on human colorectal carcinogenesis. The objective of this pilot study was to evaluate the chemopreventive effect of metformin on rectal aberrant crypt foci (ACF), which are an endoscopic surrogate marker of colorectal cancer. We prospectively randomized 26 nondiabetic patients with ACF to treatment with metformin (250 mg/d, n = 12) or no treatment (control, n = 14); 23 patients were evaluable for end point analyses (9 metformin and 14 control); the two groups were similar in ACF number and other baseline clinical characteristics. Magnifying colonoscopy determined the number of rectal ACF in each patient at baseline and after 1 month in a blinded fashion (as were all laboratory end point analyses). We also examined proliferative activity in colonic epithelium (via proliferating cell nuclear antigen labeling index) and apoptotic activity (via terminal deoxynucleotidyl transferase dUTP nick-end labeling). At 1 month, the metformin group had a significant decrease in the mean number of ACF per patient (8.78 +/- 6.45 before treatment versus 5.11 +/- 4.99 at 1 month, P = 0.007), whereas the mean ACF number did not change significantly in the control group (7.23 +/- 6.65 versus 7.56 +/- 6.75, P = 0.609). The proliferating cell nuclear antigen index was significantly decreased and the apoptotic cell index remained unaltered in normal rectal epithelium in metformin patients. This first reported trial of metformin for inhibiting colorectal carcinogenesis in humans provides preliminary evidence that metformin suppresses colonic epithelial proliferation and rectal ACF formation in humans, suggesting its promise for the chemoprevention of colorectal cancer.
The changes in nonalcoholic fatty liver disease (NAFLD) range over a wide spectrum, extending from steatosis to steatohepatitis (NASH). However, it has remained difficult to differentiate between ...NASH and nonprogressive NAFLD by clinical examination. We investigated the interrelationships between serum high-sensitivity C-reactive protein (hs-CRP) and the pathogenesis and progression of NASH.
Hs-CRP was measured in 100 patients with histologically verified NAFLD (29 with steatosis and 71 with NASH), and a real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed to measure the intrahepatic mRNA expressions of CRP and interleukin (IL)-6.
The results of a multiple regression analysis revealed that in comparison with cases of steatosis, hs-CRP was significantly elevated (P = 0.0048) in cases of NASH. Furthermore, among patients with NASH, hs-CRP was significantly elevated in those with advanced fibrosis compared with that in those with mild fibrosis (P = 0.0384), even after adjustment for age, sex, presence of diabetes, body mass index, visceral fat area, subcutaneous fat area, homeostasis model assessment for insulin resistance, high-density lipoprotein cholesterol, triglyceride, and low-density lipoprotein cholesterol. The results of the RT-PCR analysis showed that intrahepatic mRNA expression of CRP, but not IL-6, was increased in patients with NASH compared with those with steatosis (P = 0.0228).
This is the first report to demonstrate consistent and profound elevation of hs-CRP in cases of NASH compared with in cases of simple nonprogressive steatosis. Our results suggest that hs-CRP may be a clinical feature that not only distinguishes NASH from simple nonprogressive steatosis but also indicates the severity of hepatic fibrosis in cases of NASH.
To clarify the roles of microRNAs (miRNAs) in erythropoiesis, the expression of miR-155, miR-221, miR-223, and miR-451 were analyzed during the differentiation of purified normal human erythroid ...progenitors in a liquid culture system. Cells increased almost 500-fold in a number, and differentiated to benzidine-positive mature erythroblasts. Analyses of miRNA expression using the quantitative real-time polymerase chain reaction showed that the expression level of miR-155 decreased about 200-fold, and that the expression of miR-451 increased about 270-fold during 12 days of cultures. A moderate down-regulation of miR-221 and miR-223 was observed. MiR-451 was expressed in red blood cells about 104-fold more than in granulocytes, obtained from normal human peripheral blood. These observations suggest that miR-155 and miR-451 are key molecules for normal erythroid differentiation, and that quantitative assays of the two miRNAs may be a relevant method for analyzing pathological erythropoiesis.
Background The rates of spontaneous remission and relapse of autoimmune pancreatitis (AIP) are not known. Objective To study the clinicopathologic factors predictive of remission and relapse in cases ...of AIP. Design Retrospective study. Patients Of the 20 patients with AIP, complete response to steroid therapy was recognized in 12 patients, and the remaining 8 patients improved without steroid therapy. Seven patients experienced a relapse. Results Patients who were seronegative for immunoglobulin (Ig) G4, had no obstructive jaundice, no diabetes mellitus, no swelling of the duodenal papilla, negative staining of the duodenal papilla for IgG4, and focal pancreatic swelling showed a greater tendency toward spontaneous remission ( P < .05). The results of multivariate analysis revealed that negative staining of the duodenal papilla for IgG4 was the only independent predictor of spontaneous remission of AIP (odds ratio OR 1.395, P = .0304). Seropositivity for IgG4, diffuse swelling of the pancreas, and the presence of stricture in the lower part of the bile duct were significantly associated with a relapse of AIP ( P < .05) according to the results of univariate analysis, whereas the results of multivariate analysis revealed only diffuse pancreatic swelling as an independent predictor of a relapse of AIP (OR 26.197, P = .0331). Conclusions Endoscopic findings are of useful prognostic value, because patients with AIP and with negative staining of the duodenal papilla for IgG4 appeared to have a higher frequency of remission without steroid therapy. Patients with AIP and with diffuse pancreatic swelling were found to be at an increased risk of relapse after the initial steroid administration.
Hemophagocytic lymphohistiocytosis (HLH) is characterized by deregulated engulfment of hematopoietic stem cells (HSCs) by BM macrophages, which are activated presumably by systemic inflammatory ...hypercytokinemia. In the present study, we show that the pathogenesis of HLH involves impairment of the antiphagocytic system operated by an interaction between surface CD47 and signal regulatory protein α (SIRPA). In HLH patients, changes in expression levels and HLH-specific polymorphism of SIRPA were not found. In contrast, the expression of surface CD47 was down-regulated specifically in HSCs in association with exacerbation of HLH, but not in healthy subjects. The number of BM HSCs in HLH patients was reduced to approximately 207 of that of healthy controls and macrophages from normal donors aggressively engulfed HSCs purified from HLH patients, but not those from healthy controls in vitro. Furthermore, in response to inflammatory cytokines, normal HSCs, but not progenitors or mature blood cells, down-regulated CD47 sufficiently to be engulfed by macrophages. The expression of prophagocytic calreticulin was kept suppressed at the HSC stage in both HLH patients and healthy controls, even in the presence of inflammatory cytokines. These data suggest that the CD47-SIRPA antiphagocytic system plays a key role in the maintenance of HSCs and that its disruption by HSC-specific CD47 down-regulation might be critical for HLH development.
Erythropoiesis, a process of erythroid production, is controlled by several factors including oxygen level. In this study, the effect of oxygen tension on erythropoiesis was investigated in K562 ...erythroleukemic cell line and erythroid progenitor cells derived from normal and β-thalassemia/hemoglobin (Hb) E individuals. The enhanced erythroid differentiation specific markers including increased levels of α-, β- and γ-globin gene expressions, numbers of HbF positive cells and the presence of glycophorin A surface marker were observed during cell culture under hypoxic atmosphere. The result also showed that miR-210, one of the hypoxia-induced miRNAs, was up-regulated in K562 and β-thalassemia/HbE progenitor cells cultured under hypoxic condition. Inhibition of miR-210 expression leads to reduction of the globin gene expression and delayed maturation in K562 and erythroid progenitor cells. This indicated that miR-210 contributes to hypoxia-induced erythroid differentiation in both K562 cells and β-thalassemia/HbE erythroid progenitor cells.
B‐cell activating factor (BAFF) promotes the survival and adhesion of multiple myeloma (MM) cells. Tabalumab (LY2127399) is an anti‐BAFF monoclonal antibody. This phase 1, multicenter, open‐label, ...nonrandomized, dose‐escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory MM (RRMM). Sixteen patients received intravenous i.v. tabalumab 100 mg (Cohort 1, n = 4) or i.v. tabalumab 300 mg (Cohort 2, n = 12) in combination with oral dexamethasone 20 mg/day and i.v. or s.c. bortezomib 1.3 mg/m2. All patients had treatment‐emergent adverse events (TEAE) possibly related to study treatment; the most common TEAE were thrombocytopenia (81.3%), lymphopenia (43.8%) and increased alanine aminotransferase (43.8%). Two (20.0%) dose‐limiting toxicities were observed, both in Cohort 2 (tabalumab 300 mg), which was below the predefined cutoff for tolerability (<33%). The pharmacokinetics of tabalumab were similar when bortezomib was coadministered i.v. versus s.c. The overall response rate was 56.3%, suggesting that the combined treatment was effective. In conclusion, combined treatment with these three agents was well tolerated in this population of Japanese patients with RRMM. The study was registered at www.clinicaltrials.gov (NCT01556438).
Tabalumab (LY2127399) is a potent, selective, fully human, immunoglobulin G subclass 4 (IgG4) monoclonal antibody that neutralizes soluble and membrane‐bound BAFF. Tabalumab prevents free BAFF from binding its receptor but does not interfere with bound BAFF and thus does not directly interact with B‐cells. This phase 1, multicenter, open‐label, nonrandomized, dose‐escalation study evaluated the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of tabalumab in combination with bortezomib and dexamethasone in Japanese patients with relapsed or refractory multiple myeloma.
Background The antithrombotic effects of low-dose aspirin (LDA) are well established, and it is used for primary and secondary prevention of cardiovascular events. However, the small intestinal ...toxicity of LDA remains unclear. The aim of this study was to review the characteristics of small bowel injury in long-term LDA users with capsule endoscopy (CE). Methods We retrospectively reviewed all chronic LDA users (>3 months) who underwent CE for suspected small bowel diseases from May 2004 to May 2008 at two medical centers. Results At our institutions, a total of 22 patients (13 males and 9 females, mean age 66.3 years) taking LDA underwent a CE examination. The indications for CE were obscure gastrointestinal bleeding in 21 patients and 1 patient who had abdominal pain. Twenty-one patients (95.5%) had some small bowel mucosal injury. Small bowel erosions were identified in 14 patients (63.6%). This enteropathy was characterized by multiple petechiae, loss of villi, erosions, and ulcers with round, irregular, and punched-out shapes. Two patients had circumferential ulcers with stricture. In most patients, small bowel lesions were multifocal and were evenly distributed in the small bowel. No patients failed to pass the capsule. Conclusions This is the first CE report that has studied the characteristics of small bowel injury in chronic LDA users. CE is useful to diagnose small bowel enteropathy associated with LDA.
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