Faculty Profiles - IGAWA Takuro

Papers - IGAWA Takuro

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Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome). Reviewed International journal

Chihiro Kageyama, Takuro Igawa, Yuka Gion, Noriko Iwaki, Tetsuya Tabata, Takehiro Tanaka, Eisei Kondo, Hajime Sakai, Koichi Tsuneyama, Kazuhiro Nomoto, Hiroko Noguchi, Tadashi Yoshino, Kenji Yokota, Yasuharu Sato

Pathology international 69 ( 10 ) 572 - 579 2019.10

Authorship：Corresponding author Language：English Publishing type：Research paper (scientific journal)

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

DOI： 10.1111/pin.12856

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Small intestinal intussusception in an adult. International journal

Kenji Takada, Nobukazu Fujimoto, Taichi Ozeki, Jun Nishimura, Yosuke Miyamoto, Michiko Asano, Yasuko Fuchimoto, Sae Wada, Shinji Ozaki, Takuro Igawa, Hiroshi Sonobe, Takumi Kishimoto

Journal of clinical pathology 72 ( 7 ) 510 - 510 2019.7

[Hyper-IL-6 syndrome mimicking IgG4-related disease].

Toshiki Terao, Kazuhiko Yamamoto, Kazuhiro Ikeuchi, Hiroshi Wakabayashi, Takuro Igawa, Dai Inoue, Wakako Oda, Tadashi Oyama, Chihiro Kamoi, Yuichi Sumii, Yutaro Shiraishi, Yoshikazu Yamamoto, Daigo Niiya, Yasuhiro Shiote, Yasuharu Sato, Tadashi Yoshino, Kenji Imajo

[Rinsho ketsueki] The Japanese journal of clinical hematology 60 ( 5 ) 392 - 397 2019

Language：Japanese

Distinguishing between IgG4-related disease (IgG4-RD) and hyper-interleukin (IL) -6 syndrome, such as immune mediated conditions, autoimmune diseases, and idiopathic multicentric Castleman disease (iMCD) is challenging. Here, we report the case of a 69-year-old man with cervical lymphadenopathy who was admitted to our hospital and histologically diagnosed with hyper-IL-6 syndrome mimicking IgG4-RD phenotypically. Laboratory data detected polyclonal hypergammaglobulinemia comprising IgG, including IgG4 (2,350 mg/dl). Computed tomography revealed presence of systemic lymphadenopathy, enlarged bilateral submandibular glands, and infiltrative shadow in the right lower lung. Magnetic resonance imaging revealed diffusely enlarged pancreas the size of a sausage and hypointense rim on T2, suggesting autoimmune pancreatitis as part of IgG4-RD. Biopsy of the cervical lymph node revealed proliferation of IL-6-positive mature plasma cells in the expanded interfollicular area with an elevated IgG4+/IgG+ cell ratio (approximately 70%). These histological findings were consistent with hyper-IL-6 syndrome rather than IgG4-RD; however, the serum IL-6 level was slightly elevated. Bone marrow aspiration detected both IgG4- and IL-6-positive mature plasma cells. Although this case cannot be diagnosed as IgG4-RD because it failed to meet its diagnostic criteria, administration of oral prednisolone (0.5 mg/kg) resulted in rapidly improved lymphadenopathy, enlarged pancreas, and serological findings. This report can be helpful for the diagnostic assessment of polyclonal hypergammaglobulinemia conditions.

DOI： 10.11406/rinketsu.60.392

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J01540&link_issn=&doc_id=20190614340007&doc_link_id=130007659581&url=https%3A%2F%2Fci.nii.ac.jp%2Fnaid%2F130007659581&type=CiNii&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00003_1.gif

The efficacy and safety of anti-interleukin-6 receptor monoclonal blockade in a renal transplant patient with Castleman disease: early post-transplant outcome. Reviewed International journal

Masatoshi Matsunami, Yoshifumi Ubara, Keiichi Sumida, Yoichi Oshima, Masahiko Oguro, Kazuya Kinoshita, Kiho Tanaka, Yuki Nakamura, Keiichi Kinowaki, Kenichi Ohashi, Takeshi Fujii, Takuro Igawa, Yasuharu Sato, Yasuo Ishii

BMC nephrology 19 ( 1 ) 263 - 263 2018.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disease characterized by systemic inflammatory reactions associated with the dysregulated production of interleukin-6 (IL-6). In patients with MCD, renal involvement is uncommon, with only one report published regarding kidney transplantation (KTx) to treat end-stage renal disease (ESRD) secondary to MCD. Recent clinical observations have shown that IL-6 production is implicated in allograft rejection, while IL-6 receptor blockade (with tocilizumab [TCZ]) reduces alloantibody generation and thereby improves graft survival; however, the efficacy and safety of TCZ in MCD patients undergoing KTx is still unknown. CASE PRESENTATION: Herein, we describe the case of a 50-year-old man with MCD who received living-donor KTx for ESRD. Post-operative immunosuppression consisted of a triple-drug regimen (tacrolimus, mycophenolate mofetil and methylprednisolone) with TCZ that was administered intravenously every 2 weeks. At 17 months post-transplantation, the patient remains asymptomatic, and the allograft pathology has shown no evidence of rejection and no development of de novo donor-specific antibody (DSA). CONCLUSIONS: To our knowledge, this is the second reported case of an MCD patient with ESRD who underwent successful KTx. TCZ safely supported the patient during the perioperative period, and this drug may be useful for blocking the generation of donor-specific antibodies and reducing the risk of rejection episodes. KTx in combination with TCZ is thus considered a viable treatment option for ESRD due to MCD.

DOI： 10.1186/s12882-018-1065-4

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TAFRO Syndrome. International journal

Takuro Igawa, Yasuharu Sato

Hematology/oncology clinics of North America 32 ( 1 ) 107 - 118 2018.2

Language：English Publishing type：Research paper (scientific journal)

TAFRO syndrome is a newly recognized variant of idiopathic multicentric Castleman disease (iMCD) that involves a constellation of syndromes: thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Thrombocytopenia and severe anasarca accompanied by relatively low serum immunoglobulin levels are characteristic clinical findings of TAFRO syndrome that are not present in iMCD-not otherwise specified (iMCD-NOS). Lymph node biopsy is recommended to exclude other diseases and to diagnose TAFRO syndrome, which reveals characteristic histopathological findings similar to hyaline vascular-type CD. TAFRO syndrome follows a more aggressive course, compared with iMCD-NOS, and there is no standard treatment.

DOI： 10.1016/j.hoc.2017.09.009

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A possible new morphological variant of mantle cell lymphoma with plasma-cell type Castleman disease-like features. Reviewed International journal

Takuro Igawa, Rika Omote, Hiaki Sato, Kohei Taniguchi, Katsuya Miyatani, Tadashi Yoshino, Yasuharu Sato

Pathology, research and practice 213 ( 11 ) 1378 - 1383 2017.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma characterized by overexpression of cyclin D1 resulting from t(11;14)(q13;q32) translocation. Herein, we report 3 cases of MCL with features of plasma cell-type Castleman disease (CD). The 3 patients were all men, ranging from 51 to 74 years in age, and they all presented with systemic lymphadenopathy with anemia, hypoalbuminemia, elevated serum levels of C-reactive protein, and polyclonal hypergammaglobulinemia. Lymph node biopsy specimens of the 3 cases showed histological features of plasma cell-type CD, including atrophic germinal centers and interfollicular plasmacytosis, with no light chain restriction. However, flow cytometric analysis demonstrated an abnormal B-cell population with CD5 expression, and further analysis using cyclin D1 immunostaining highlighted a neoplastic component that was restricted to the mantle zone. These neoplastic cells were immunohistochemically positive for CD20, CD5, and SOX11, and negative for CD3, CD10, and HHV8. The Ki67 index was low. All patients were finally diagnosed with MCL. This rare type of MCL can be misdiagnosed clinically and histologically as CD. Therefore, it is important to recognize this rare type of MCL, and careful examination is required using both histological and flow cytometric analyses.

DOI： 10.1016/j.prp.2017.09.015

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Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue with plasma cell differentiation: Periodic acid-schiff reaction-positive Dutcher body is a diagnostic clue to distinguish it from plasmacytoma. Reviewed International journal

Atsuko Nasu, Takuro Igawa, Hiaki Sato, Hiroyuki Yanai, Tadashi Yoshino, Yasuharu Sato

Diagnostic cytopathology 45 ( 6 ) 547 - 551 2017.6

Language：English Publishing type：Research paper (scientific journal)

We herein report a case of primary parotid extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) with Dutcher bodies. An 82-year-old man presented with a 4 cm × 2.5 cm mass in the left parotid region. Positron emission tomography/computed tomography (PET/CT) showed localized abnormal fluorodeoxyglucose (FDG) uptake in the left parotid gland and lymph nodes of the left cervical region. Fine needle aspiration (FNA) cytology of the left parotid gland showed lymphoplasmacytoid cells with periodic acid-Schiff (PAS)-positive Dutcher bodies. A subsequent excisional biopsy showed sheets of small- to medium-sized neoplastic B cells with abundant IgM in the cytoplasm as detected by immunohistochemistry. A diagnosis of stage II MALT lymphoma was made, but the patient did not receive therapeutic intervention. As previously reported, Dutcher bodies are mainly observed in B-cell neoplasms with IgM production. Because these characteristic intranuclear inclusions can be easily observed by PAS staining, the presence of PAS reaction-positive Dutcher bodies in FNA cytology can serve as a clue to differentially diagnose MALT lymphoma from plasmacytoma. Diagn. Cytopathol. 2017;45:547-551. © 2017 Wiley Periodicals, Inc.

DOI： 10.1002/dc.23691

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Immunohistochemical analysis of IgA expression differentiates IgG4-related disease from plasma cell-type Castleman disease.

Akihiro Manabe, Takuro Igawa, Mai Takeuchi, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Medical molecular morphology 50 ( 1 ) 34 - 41 2017.3

Language：English Publishing type：Research paper (scientific journal)

Plasma cell-type Castleman disease (PCD) is often encountered when differentiating IgG4-related disease (IgG4-RD). Given that serum IgA is often elevated in Castleman disease, we investigated whether IgA expression levels in histological specimens can be used to differentiate between the two diseases. Lymph node lesions obtained from 12 IgG4-RD and 11 PCD patients were analysed by immunohistochemistry with anti-IgG, -IgG4, and -IgA antibodies. In addition to all 12 cases of IgG4-RD, 8/11 cases (72.7 %) of PCD also met the diagnostic criteria of IgG4-RD (serum IgG4 ≥135 mg/dl and IgG4/IgG-positive cells ≥40 %). IgA-positive cells were sparsely and densely distributed in IgG4-RD and PCD cases, respectively. The median number of IgA-positive cells ± SD in all 12 cases of IgG4-RD was 31 ± 37 cells per three high-powered fields (3HPFs) (range 4-118 cells/3HPFs). In contrast, the median number of IgA-positive cells, which was significantly higher in all 11 cases of PCD, was 303 ± 238 cells/3HPFs (range 74-737 cells/3HPFs) (P < 0.001). In conclusion, our findings indicate that in cases where serum analysis-based data are unavailable, anti-IgA immunostaining can be used for differential diagnosis of IgG4-RD.

DOI： 10.1007/s00795-016-0145-4

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IgG4-producing lymphoma arising in a patient with IgG4-related disease. Reviewed

Takuro Igawa, Toshiaki Hayashi, Kazuya Ishiguro, Yumiko Maruyama, Mai Takeuchi, Katsuyoshi Takata, Tadashi Yoshino, Yasuharu Sato

Medical molecular morphology 49 ( 4 ) 243 - 249 2016.12

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

We herein report a case in which an IgG4-producing lymphoma arose in a patient with a previous diagnosis consistent with an IgG4-related disease. A 43-year-old man presented with enlarged cervical lymph nodes and was treated with steroids and radiation for what was initially assumed to be Kimura's disease, although the lesions were later histologically re-diagnosed as IgG4-related lymphadenopathy. Fourteen years later, when the patient was 58-years-old, he presented with retroperitoneal fibrosis and swollen lymph nodes. The suspicious lesions were not histologically examined as the patient did not give consent. However, the serum IgG4 concentration was high (1400 mg/dL) and he was clinically diagnosed with systemic IgG4-related disease. Although steroid administration reduced the size of the lesions, tapering the dose finally resulted in systemic, prominently enlarged lymph nodes. Analysis of the biopsy specimen revealed that these multiple lymph node lesions were marginal zone B cell lymphomas that themselves expressed IgG4. Complete remission was achieved after a total of six courses of chemotherapy including rituximab. This case suggests that the infiltrating IgG4-expressing cells observed in IgG4-related disease can clonally expand to malignant lymphomas.

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Spontaneous regression of plasmablastic lymphoma in an elderly human immunodeficiency virus (HIV)-negative patient. Reviewed International journal

Takuro Igawa, Yasuharu Sato, Hotaka Kawai, Eisei Kondo, Mai Takeuchi, Tomoko Miyata-Takata, Katsuyoshi Takata, Tadashi Yoshino

Diagnostic pathology 10 183 - 183 2015.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

Plasmablastic lymphoma (PBL) is an aggressive lymphoma commonly associated with human immunodeficiency virus (HIV) infection. Herein we describe a rare case of PBL that spontaneously regressed. An 80-year-old man was referred to our hospital owing to an exophytic gingival tumor in the right maxillary second molar region. He had no significant past medical history, and a screening test for HIV was negative. Imaging showed that the tumor measured 26 × 23 × 16 mm and was confined in the alveolar bone. The tumor was histologically comprised of highly proliferative immunoblastic cells positive for CD138 and Epstein-Barr virus (EBV)-encoded RNA. Monoclonal IgH chain gene rearrangement was detected via polymerase chain reaction. After biopsy and diagnosis of PBL, the tumor began to decrease in size and had apparently disappeared at the time of surgery. There was no histological evidence of a residual lesion in the surgical specimen. In conclusion, a minority of immunosenescence-associated PBLs in the elderly should be recognized as a unique clinicopathological entity distinct from common aggressive PBL.

DOI： 10.1186/s13000-015-0421-y

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Severe liver injury associated with simeprevir plus pegylated interferon/ribavirin therapy in a patient with treatment-naïve genotype 1b hepatitis C virus: a case report.

Takuro Igawa, Soichiro Fushimi, Ryuichi Matsuo, Fusao Ikeda, Kazuhiro Nouso, Tadashi Yoshino, Harushige Nakatsukasa

Clinical journal of gastroenterology 7 ( 5 ) 465 - 70 2014.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

A second-generation direct-acting antiviral agent, simeprevir, now provides a new treatment option for hepatitis C virus (HCV) infection with good safety profile in combination with pegylated interferon and ribavirin. We herein report a rare case of severe liver injury under simeprevir plus pegylated interferon/ribavirin therapy. We initiated this therapy in a 65-year-old male with treatment-naïve genotype 1b HCV. On day 28, the patient's HCV-RNA was successfully eliminated, and his liver function was fully restored. However, on day 49, the serum alanine aminotransferase level was elevated at 700 IU/L. The HCV-RNA titer was still undetectable and the involvement of other possible viruses was negligible. A liver biopsy performed on day 60 showed an acute hepatitis pattern. The discontinuation of therapy alone successfully improved his liver damage on day 84. No other treatments such as steroids were required. According to the diagnostic criteria for drug-induced liver injury in Japan (DDW-J2004), the liver injury observed in this case can be associated with the administration of simeprevir plus pegylated interferon/ribavirin therapy. In conclusion, simeprevir plus pegylated interferon/ribavirin should be used with caution, as these agents may cause unreported serious adverse events including severe liver injury, despite their clinical safety profile.

DOI： 10.1007/s12328-014-0527-x

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De novo CD5-positive diffuse large B-cell lymphomas show high specificity for cyclin D2 expression. International journal

Takuro Igawa, Yasuharu Sato, Katsuyoshi Takata, Noriko Iwaki, Takehiro Tanaka, Naoko Asano, Yoshinobu Maeda, Yorihisa Orita, Naoya Nakamura, Shigeo Nakamura, Tadashi Yoshino

Diagnostic pathology 8 81 - 81 2013.5

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

UNLABELLED: D cyclins positively regulate the cell cycle and mediate the pathogenesis of some lymphomas. Cyclin D1 overexpression is the hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 are reportedly not as specific to certain lymphomas as cyclin D1. In this study, cyclin D2 was found to be overexpressed in 98% of de novo CD5-positive diffuse large B-cell lymphomas (DLBCLs) (50/51) and in 28% of CD5-negative DLBCLs (14/51). A statistically significant difference was observed between these two groups (p<0.0001). In contrast, no statistical difference was found in the cyclin D3 expression between CD5-positive (18/51) and CD5-negative (24/51) DLBCLs (p=0.23). Based on these findings, cyclin D2 is therefore considered to be closely associated with de novo CD5-positive DLBCLs. This insight may be useful for overcoming the inferior survival of this aggressive lymphoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1382856320966453.

DOI： 10.1186/1746-1596-8-81

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Minimally invasive procedure for accurate diagnosis of mucosa-associated lymphoid tissue lymphoma of the head and neck. International journal

Yorihisa Orita, Yasuharu Sato, Eisei Kondo, Hisashi Ishihara, Haruka Hirai, Hiroyuki Hanakawa, Tomoo Onoda, Takuro Igawa, Ryusuke Saito, Kazunori Nishizaki, Tadashi Yoshino

Japanese journal of clinical oncology 42 ( 4 ) 325 - 30 2012.4

Language：English Publishing type：Research paper (scientific journal)

Sonography-guided cutting needle biopsy for the diagnosis of malignant lymphoma has recently come into wide use. However, surgery is sometimes unavoidable for the diagnosis of malignant lymphoma, particularly for low-grade malignant lymphoma such as extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, because cutting needle biopsy offers limited diagnostic accuracy for low-grade malignant lymphoma. Of course, unnecessary invasive procedures like open biopsy should be avoided wherever possible, given the cosmetic problems and burden on the patient. We tried to diagnose malignant lymphoma using the combination of cutting needle biopsy, flow cytometry and polymerase chain reaction to identify monoclonal rearrangement of immunoglobulin heavy chain genes. We have used this method in two cases in whom malignant lymphoma was suspected in the head and neck region, allowing diagnosis of mucosa-associated lymphoid tissue lymphoma in both cases. One case involved a 23-year-old woman with mucosa-associated lymphoid tissue lymphoma in the parotid glands, and the other involved a 77-year-old man with mucosa-associated lymphoid tissue lymphoma in the thyroid. The combination of cutting needle biopsy, flow cytometry and immunoglobulin heavy chain gene rearrangement testing might offer a useful alternative to open biopsy for the diagnosis of mucosa-associated lymphoid tissue lymphoma. We recommend this procedure, particularly for young women or patients with poor performance status in whom malignant lymphoma is suspected.

DOI： 10.1093/jjco/hys011

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Cyclin D2 is overexpressed in proliferation centers of chronic lymphocytic leukemia/small lymphocytic lymphoma. International journal

Takuro Igawa, Yasuharu Sato, Katsuyoshi Takata, Soichiro Fushimi, Maiko Tamura, Naoya Nakamura, Yoshinobu Maeda, Yorihisa Orita, Mitsune Tanimoto, Tadashi Yoshino

Cancer science 102 ( 11 ) 2103 - 7 2011.11

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

The D cyclins are important cell cycle regulatory proteins involved in the pathogenesis of some lymphomas. Cyclin D1 overexpression is a hallmark of mantle cell lymphoma, whereas cyclins D2 and D3 have not been shown to be closely associated with any particular subtype of lymphoma. In the present study, we found that cyclin D2 was specifically overexpressed in the proliferation centers (PC) of all cases of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) examined (19/19). To examine the molecular mechanisms underlying this overexpression, we immunohistochemically examined the expression of nuclear factor (NF)-κB, p15, p16, p18, and p27 in the PC of six patients. Five cases showed upregulation of NF-κB expression, which is known to directly induce cyclin D2 by binding to the promoter region of CCND2. All six PC examined demonstrated downregulation of p27 expression. In contrast, upregulation of p15 expression was detected in five of six PC examined. This discrepancy suggests that unknown cell cycle regulatory mechanisms involving NF-κB-related pathways are also involved, because NF-κB upregulates cyclin D2 not only directly, but also indirectly through c-Myc, which is believed to downregulate both p27 and p15. In conclusion, cyclin D2 is overexpressed in the PC of CLL/SLL and this overexpression is due, in part, to the upregulation of NF-κB-related pathways.

DOI： 10.1111/j.1349-7006.2011.02046.x

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Papers - IGAWA Takuro