Tadanobu Nagaya

Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan

Objective A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication. Methods 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD. Results 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a ‘watch and wait’ strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival. Conclusions The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.

Down-regulation of SREBP-1c is associated with the development of burned-out NASH.

BACKGROUND & AIMS It is well-known that hepatic triglycerides (TG) diminish with the progression of non-alcoholic steatohepatitis (NASH), which has been designated as burned-out NASH, but its mechanism remains unclear. We aimed to explore the changes in hepatic fatty acid (FA) and TG metabolism with disease progression. METHODS Hepatic expression of key genes in healthy individuals (n=6) and patients with simple steatosis (SS, n=10), mild NASH (fibrosis stage 1-2, n=20), and advanced NASH (fibrosis stage 3-4, n=20) were assessed by quantitative polymerase chain reaction. RESULTS Hepatic expression of genes related to FA uptake and oxidation and very-low-density lipoprotein synthesis/export did not differ among the groups. However, the mRNA levels of sterol regulatory element-binding protein (SREBP)-1c and its downstream genes FA synthase, acetyl-coenzyme A carboxylase 1, and diacylglycerol acyltransferase 1 were inversely correlated with fibrosis stage. Immunoblot analysis revealed a remarkable reduction in mature SREBP-1c levels in advanced NASH. Furthermore, hepatic expression of tumor necrosis factor-alpha increased in accordance with fibrosis progression, which was possibly related to the decrease in hepatic SREBP-1c expression. CONCLUSIONS Down-regulation of SREBP-1c and lipogenic enzymes may be associated with the development of burned-out NASH.

Serum fragmented cytokeratin 18 levels reflect the histologic activity score of nonalcoholic fatty liver disease more accurately than serum alanine aminotransferase levels.

Background and Goals Reliable noninvasive biomarkers to assess the histologic activity of nonalcoholic fatty liver disease (NAFLD) have not been established. As the frequency of Mallory bodies is known to be closely associated with the disease severity, we hypothesized that serum levels of Mallory body-related proteins were correlated with NAFLD histologic activity and evaluated this possibility. Study Serum levels of total and fragmented cytokeratin (CK) 18, heat shock protein (Hsp) 70, Hsp90α, ubiquitin+1, and p38α at the time of liver biopsy were measured in 118 NAFLD patients and their association with histologic findings and NAFLD histologic activity score (NAS) was investigated. Results Serum levels of both forms of CK18 and Hsp90α were markedly higher in patients having nonalcoholic steatohepatitis (NASH) compared with non-NASH ones. Both forms of CK18 significantly correlated with degree of steatosis, lobular inflammation, and ballooning, and showed stronger positive correlations with NAS than serum aspartate and alanine aminotransferase (AST and ALT). Multiple regression analysis further revealed that fragmented CK18 and AST were effective predictors of NAS, with the former being the more definitive of the two (P<0.001 vs. 0.005). In 20 NAFLD patients who received a follow-up biopsy, changes in fragmented CK18 levels, but not AST or ALT levels, closely paralleled those in NAS. Conclusions These results establish the usefulness of fragmented CK18 measurement for assessing and monitoring the histologic activity of NAFLD.

Near-IR Light-Mediated Cleavage of Antibody–Drug Conjugates Using Cyanine Photocages

Despite significant progress in the clinical application of antibody drug conjugates (ADCs), novel cleavage strategies that provide improved selectivity are still needed. Herein is reported the first approach that uses near-IR light to cleave a small molecule from a biomacromolecule, and its application to the problem of ADC linkage. The preparation of cyanine antibody conjugates, drug cleavage mediated by 690 nm light, and initial in vitro and in vivo evaluation is described. These studies provide the critical chemical underpinning from which to develop this near-IR light cleavable linker strategy.

Chronic gastritis in the setting of autoimmune pancreatitis.

Abstract: Autoimmune pancreatitis (AIP) is a recently recognized disease entity. In some patients, this disease is associated with other inflammatory diseases. In this study, we aimed to elucidate the pathologic characteristics of AIP-associated gastritis (AIP-G). We evaluated and compared the pathologic findings and immunohistochemical expressions of immunoglobulin G (IgG)4 and IgG in gastric biopsy specimens from 13 AIP-G patients with those from patients of 2 control groups. We divided the AIP-G patients who did not receive steroid therapy [AIP-G-ST(−)] into the following 2 groups: without Helicobacter pylori (HP) infection [AIP-G-HP(−)] and with HP infection [AIP-G-HP(+)]. The control groups comprised 19 patients who were diagnosed with chronic active gastritis associated with HP infection and 7 patients with nonsteroidal anti-inflammatory drug-induced gastritis. We classified the findings for the gastric mucosa into those for the upper and the lower lamina propria. The characteristic finding of AIP-G groups was diffusely lymphoplasmacytic infiltration in the lamina propria. The IgG4-positive plasma cell/IgG-positive plasma cell ratios (IgG4/IgG ratios) in both the upper and lower lamina propria in the AIP-G-ST(−) groups were predominantly higher than the corresponding values in the other groups. In the AIP-G-ST(−) groups, the IgG4/IgG ratio in the lower lamina propria was predominantly higher than that in the upper lamina propria, irrespective of the HP status. In conclusion, diffuse lymphoplasmacytic infiltration in the lamina propria and increased IgG4/IgG ratio in the gastric mucosa (notably in the lower lamina propria) may be the characteristic findings of AIP-G.

Near Infrared Photoimmunotherapy in the Treatment of Pleural Disseminated NSCLC: Preclinical Experience

Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet is difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of pleural disseminated non-small cell lung carcinoma (NSCLC). In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180). Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease. In conclusion, NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC in mice. Thus, NIR-PIT is a promising therapy for pleural disseminated tumors.

Glypican-3 Targeted Human Heavy Chain Antibody as a Drug Carrier for Hepatocellular Carcinoma Therapy

Glypican-3 (GPC3) represents an attractive target for hepatocellular carcinoma (HCC) therapy because it is highly expressed in HCC but not in adult normal tissue. Recently, high affinity anti-GPC3 antibodies have been developed; however, full antibodies may not penetrate evenly into tumor parenchyma, reducing their effectiveness. In this study, we compared a whole IgG antibody, anti-GPC3 YP7, with an anti-GPC3 human heavy chain antibody, HN3, with regard to their relative therapeutic effects. Both YP7 and HN3 bound to GPC3-positive A431/G1 cells and were internalized by the cells by in vitro evaluation with (125)I- and (111)In-radiolabeling antibodies. In vivo biodistribution and tumor accumulation was performed with (111)In-labeled antibodies, and intratumoral microdistribution was evaluated using fluorescently labeled antibodies (IR700). HN3 showed similar high tumor accumulation but superior homogeneity within the tumor compared with YP7. Using the same IR700 conjugated antibodies photoimmunotherapy (PIT) was performed in vitro and in a tumor-bearing mouse model in vivo. PIT with IR700-HN3 and IR700-YP7 demonstrated that comparable results could be achieved despite of low reaccumulation 24 h after the first NIR light exposure. These results indicated that a heavy-chain antibody, HN3, showed more favorable characteristics than YP7, a conventional IgG, as a therapeutic antibody platform for designing molecularly targeted agents against HCC.

Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy

CD25-targeted near-infrared photoimmunotherapy depletes Tregs and promotes tumor regression. Photobombing Tregs T regulatory cells, or Tregs for short, are immunosuppressive cells that not only suppress excess inflammation but also interfere with anticancer immunity. Sato et al. developed a way to selectively deplete Tregs in tumors to promote antitumor effects while minimizing the risk of autoimmunity. To achieve this goal, the authors used a method termed near-infrared photoimmunotherapy, where part of an antibody that recognizes Tregs is fused to a light-sensitive dye, and shining near-infrared light on the tumor activates the antibody and triggers killing of the Tregs. Mice subjected to this treatment not only killed the targeted tumor but also could even destroy untreated tumors of the same type located in other parts of the body, suggesting the potential for treatment of metastatic disease. Current immunotherapies for cancer seek to modulate the balance among different immune cell populations, thereby promoting antitumor immune responses. However, because these are systemic therapies, they often cause treatment-limiting autoimmune adverse effects. It would be ideal to manipulate the balance between suppressor and effector cells within the tumor without disturbing homeostasis elsewhere in the body. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are well-known immunosuppressor cells that play a key role in tumor immunoevasion and have been the target of systemic immunotherapies. We used CD25-targeted near-infrared photoimmunotherapy (NIR-PIT) to selectively deplete Tregs, thus activating CD8 T and natural killer cells and restoring local antitumor immunity. This not only resulted in regression of the treated tumor but also induced responses in separate untreated tumors of the same cell line derivation. We conclude that CD25-targeted NIR-PIT causes spatially selective depletion of Tregs, thereby providing an alternative approach to cancer immunotherapy.

Antimicrobial resistance and characteristics of eradication therapy of Helicobacter pylori in Japan: a multi-generational comparison.

Eradication of Helicobacter pylori (H. pylori) at a younger age is considered to be effective in preventing gastric cancer. This study assessed the characteristics of eradication therapy in young patients.

A multicenter, prospective trial of total colonoscopy using a short double-balloon endoscope in patients with previous incomplete colonoscopy

BACKGROUND There is no specific insertion method for patients who previously underwent an incomplete colonoscopy. No multicenter prospective study using a double-balloon endoscope (DBE) for total colonoscopy was previously performed. OBJECTIVE To demonstrate the effectiveness and safety of using short DBEs in patients who previously underwent incomplete colonoscopies. DESIGN A multicenter, prospective trial. SETTING Four tertiary care academic centers and 6 community hospitals. PATIENTS Patients with a history of incomplete colonoscopy, ages 20 to 79 years, were included. Exclusion criteria were colonoscopy performed by endoscopists with experience in fewer than 1000 cases, history of colectomy, poor bowel preparation, inflammatory bowel disease, active bowel obstruction, and active bleeding. INTERVENTION Total colonoscopies using short DBEs were attempted in all patients. MAIN OUTCOME MEASUREMENTS Primary endpoint was the cecal intubation rate. Secondary endpoints were time to cecal intubation, complications, and tolerability. RESULTS A total of 110 patients (62 males, median age 66.5 years) were included. Fifty-four patients had a history of abdominal surgery. The cecal intubation rate was 100% (110/110). Median intubation time was 12 minutes (range 4-47 minutes). Mild mucosal tears without symptoms occurred in 1 patient. For 64.5% of patients, intravenous sedatives and/or analgesics were used during examinations. Based on questionnaires, 50.9% had no pain, 31.8% slight pain, and 17.3% tolerable pain. Moreover, 96.4% of patients answered that their examination was more comfortable than their previous colonoscopy. LIMITATION Uncontrolled trial. CONCLUSION The use of a short DBE is an effective and safe method for total colonoscopy in patients who previously underwent incomplete colonoscopies. ( CLINICAL TRIAL REGISTRATION NUMBER UMIN3464.).