Tadanobu Nagaya

Bio: Tadanobu Nagaya is an academic researcher from Shinshu University. The author has contributed to research in topics: Photoimmunotherapy & Cancer. The author has an hindex of 29, co-authored 90 publications receiving 2563 citations. Previous affiliations of Tadanobu Nagaya include National Institutes of Health.

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

Abstract: 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.

Fluorescence-Guided Surgery.

Abstract: Surgical resection of cancer remains an important treatment modality. Despite advances in preoperative imaging, surgery itself is primarily guided by the surgeon’s ability to locate pathology with conventional white light imaging. Fluorescence guided surgery (FGS) can augment what the surgeon sees by accentuating sites of disease and defining tumor margins during the procedure. Intraoperative visualization of tumors may not only allow more complete resections but also improve safety by avoiding unnecessary damage to normal tissue which can also reduce operative time and decrease the need for second-look surgeries. A number of new FGS imaging probes have recently been developed, complementing a small but useful number of existing probes. In this review, we describe current and new fluorescent probes that may assist FGS.

Immunogenic cancer cell death selectively induced by near infrared photoimmunotherapy initiates host tumor immunity.

Abstract: // Mikako Ogawa 1, 7, * , Yusuke Tomita 2, * , Yuko Nakamura 3 , Min-Jung Lee 2 , Sunmin Lee 2 , Saori Tomita 2 , Tadanobu Nagaya 3 , Kazuhide Sato 3 , Toyohiko Yamauchi 4 , Hidenao Iwai 4 , Abhishek Kumar 5 , Timothy Haystead 6 , Hari Shroff 5 , Peter L. Choyke 3 , Jane B. Trepel 2 , Hisataka Kobayashi 3 1 Medical Photonics Research Center, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan 2 Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA 3 Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA 4 Central Research Laboratory, Hamamatsu Photonics K. K., Hamamatsu 434-8601, Japan 5 Section on High Resolution Optical Imaging, NIBIB/NIH, Bethesda, MD 20892, USA 6 Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA 7 Laboratory for Bioanalysis and Molecular Imaging, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan * Co-first author Correspondence to: Hisataka Kobayashi, email: Kobayash@mail.nih.gov Keywords: near infrared photoimmunotherapy, immunogenic cell death Received: October 12, 2016 Accepted: December 13, 2016 Published: January 02, 2017 ABSTRACT Immunogenic cell death (ICD) is a form of cell death that activates an adaptive immune response against dead-cell-associated antigens. Cancer cells killed via ICD can elicit antitumor immunity. ICD is efficiently induced by near-infrared photo-immunotherapy (NIR-PIT) that selectively kills target-cells on which antibody-photoabsorber conjugates bind and are activated by NIR light exposure. Advanced live cell microscopies showed that NIR-PIT caused rapid and irreversible damage to the cell membrane function leading to swelling and bursting, releasing intracellular components due to the influx of water into the cell. The process also induces relocation of ICD bio markers including calreticulin, Hsp70 and Hsp90 to the cell surface and the rapid release of immunogenic signals including ATP and HMGB1 followed by maturation of immature dendritic cells. Thus, NIR-PIT is a therapy that kills tumor cells by ICD, eliciting a host immune response against tumor.

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

Abstract: 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 (T regs ) 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 T regs , 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 T regs , thereby providing an alternative approach to cancer immunotherapy.

Photoinduced Ligand Release from a Silicon Phthalocyanine Dye Conjugated with Monoclonal Antibodies: A Mechanism of Cancer Cell Cytotoxicity after Near-Infrared Photoimmunotherapy

Abstract: Photochemical reactions can dramatically alter physical characteristics of reacted molecules. In this study, we demonstrate that near-infrared (NIR) light induces an axial ligand-releasing reaction, which dramatically alters hydrophilicity of a silicon phthalocyanine derivative (IR700) dye leading to a change in the shape of the conjugate and its propensity to aggregate in aqueous solution. This photochemical reaction is proposed as a major mechanism of cell death induced by NIR photoimmunotherapy (NIR-PIT), which was recently developed as a molecularly targeted cancer therapy. Once the antibody-IR700 conjugate is bound to its target, activation by NIR light causes physical changes in the shape of antibody antigen complexes that are thought to induce physical stress within the cellular membrane leading to increases in transmembrane water flow that eventually lead to cell bursting and necrotic cell death.

Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report

Abstract: Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

Regulatory T Cells

Abstract: Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

New photosensitizers for photodynamic therapy

Abstract: Photodynamic therapy (PDT) was discovered more than 100 years ago, and has since become a well-studied therapy for cancer and various non-malignant diseases including infections. PDT uses photosensitizers (PSs, non-toxic dyes) that are activated by absorption of visible light to initially form the excited singlet state, followed by transition to the long-lived excited triplet state. This triplet state can undergo photochemical reactions in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy cancer cells, pathogenic microbes and unwanted tissue. The dual-specificity of PDT relies on accumulation of the PS in diseased tissue and also on localized light delivery. Tetrapyrrole structures such as porphyrins, chlorins, bacteriochlorins and phthalocyanines with appropriate functionalization have been widely investigated in PDT, and several compounds have received clinical approval. Other molecular structures including the synthetic dyes classes as phenothiazinium, squaraine and BODIPY (boron-dipyrromethene), transition metal complexes, and natural products such as hypericin, riboflavin and curcumin have been investigated. Targeted PDT uses PSs conjugated to antibodies, peptides, proteins and other ligands with specific cellular receptors. Nanotechnology has made a significant contribution to PDT, giving rise to approaches such as nanoparticle delivery, fullerene-based PSs, titania photocatalysis, and the use of upconverting nanoparticles to increase light penetration into tissue. Future directions include photochemical internalization, genetically encoded protein PSs, theranostics, two-photon absorption PDT, and sonodynamic therapy using ultrasound.

In Vivo Endoscopic Optical Biopsy with Optical Coherence Tomography

Abstract: Current medical imaging technologies allow visualization of tissue anatomy in the human body at resolutions ranging from 100 micrometers to 1 millimeter. These technologies are generally not sensitive enough to detect early-stage tissue abnormalities associated with diseases such as cancer and atherosclerosis, which require micrometer-scale resolution. Here, optical coherence tomography was adapted to allow high-speed visualization of tissue in a living animal with a catheter-endoscope 1 millimeter in diameter. This method, referred to as "optical biopsy," was used to obtain cross-sectional images of the rabbit gastrointestinal and respiratory tracts at 10-micrometer resolution.