Publications by authors named "Masafumi Ito"

217 Publications

Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome.

Leukemia 2021 Feb 15. Epub 2021 Feb 15.

Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.

Myeloid leukemia of Down syndrome (ML-DS) is associated with good response to chemotherapy, resulting in favorable outcomes. However, no universal prognostic factors have been identified to date. To clarify a subgroup with high risk of relapse, the role of minimal residual disease (MRD) was explored in the AML-D11 trial by the Japanese Pediatric Leukemia/Lymphoma Study Group. MRD was prospectively evaluated at after induction therapy and at the end of all chemotherapy, using flow cytometry (FCM-MRD) and GATA1-targeted deep sequencing (GATA1-MRD). A total of 78 patients were eligible and 76 patients were stratified to the standard risk (SR) group by morphology. In SR patients, FCM-MRD and GATA1-MRD after induction were positive in 5/65 and 7/59 patients, respectively. Three-year event-free survival (EFS) and overall survival (OS) rates were 93.3% and 95.0% in the FCM-MRD-negative population, and 60.0% and 80.0% in the positive population. Three-year EFS and OS rates were both 96.2% in the GATA1-MRD-negative population, and 57.1% and 71.4% in the positive population. Adjusted hazard ratios for associations of FCM-MRD or GATA1-MRD with EFS were 10.98 (p = 0.01) and 27.68 (p < 0.01), respectively. Detection of MRD by either FCM or GATA1 after initial induction therapy represents a significant prognostic factor for predicting ML-DS relapse.
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http://dx.doi.org/10.1038/s41375-021-01157-wDOI Listing
February 2021

CREB3L1 overexpression as a potential diagnostic marker of Philadelphia chromosome-negative myeloproliferative neoplasms.

Cancer Sci 2021 Feb 21;112(2):884-892. Epub 2020 Dec 21.

Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Discrimination of Philadelphia-negative myeloproliferative neoplasms (Ph-MPNs) from reactive hypercytosis and myelofibrosis requires a constellation of testing including driver mutation analysis and bone marrow biopsies. We searched for a biomarker that can more easily distinguish Ph-MPNs from reactive hypercytosis and myelofibrosis by using RNA-seq analysis utilizing platelet-rich plasma (PRP)-derived RNAs from patients with essential thrombocythemia (ET) and reactive thrombocytosis, and CREB3L1 was found to have an extremely high impact in discriminating the two disorders. To validate and further explore the result, expression levels of CREB3L1 in PRP were quantified by reverse-transcription quantitative PCR and compared among patients with ET, other Ph-MPNs, chronic myeloid leukemia (CML), and reactive hypercytosis and myelofibrosis. A CREB3L1 expression cutoff value determined based on PRP of 18 healthy volunteers accurately discriminated 150 driver mutation-positive Ph-MPNs from other entities (71 reactive hypercytosis and myelofibrosis, 6 CML, and 18 healthy volunteers) and showed both sensitivity and specificity of 1.0000. Importantly, CREB3L1 expression levels were significantly higher in ET compared with reactive thrombocytosis (P < .0001), and polycythemia vera compared with reactive erythrocytosis (P < .0001). Pathology-affirmed triple-negative ET (TN-ET) patients were divided into a high- and low-CREB3L1-expression group, and some patients in the low-expression group achieved a spontaneous remission during the clinical course. In conclusion, CREB3L1 analysis has the potential to single-handedly discriminate driver mutation-positive Ph-MPNs from reactive hypercytosis and myelofibrosis, and also may identify a subgroup within TN-ET showing distinct clinical features including spontaneous remission.
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http://dx.doi.org/10.1111/cas.14763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893984PMC
February 2021

Multi-Lineage Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features.

Front Oncol 2020 23;10:586567. Epub 2020 Oct 23.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Recently, various blood cell lineages expressing the fusion gene in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have been reported. However, the biological and clinical significance of these lineages has not been established; therefore, we aimed to clarify the impacts of these different -expressing lineages.

Patients: Multi-lineage expression (multi-Ph) was defined as expression outside of the B-lineage compartment, as determined by fluorescence hybridization (FISH) in peripheral blood neutrophils and bone marrow clots, and flow cytometry-sorted polymerase chain reaction (PCR). We analyzed deletion patterns by PCR, examined gene expression profiles using RNA sequencing, and compared treatment outcomes across different -expressing lineages.

Results: Among the 21 multi-Ph patients in our 59-patient cohort (36%), expression was detected at the multipotential progenitor level. However, no deletion patterns or gene expression profiles were identified that were specific for multi-Ph. However, multi-Ph patients were found to have better survival rates than patients with uni-lineage expression [event-free survival (EFS): 74 vs. 33%, = 0.01; overall survival (OS): 79 vs. 44% at 4 years, = 0.01]. In multivariate analyses, multi-Ph was identified as a good prognostic factor for both EFS and OS.

Conclusion: We confirmed that more than one-third of Ph+ALL patients could be classified as mutli-Ph. Although no specific molecular characteristics were identified for multi-Ph, this phenotype was associated with better treatment outcomes.
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http://dx.doi.org/10.3389/fonc.2020.586567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646258PMC
October 2020

Mitochondrial stress and GDF15 in the pathophysiology of sepsis.

Arch Biochem Biophys 2020 12 11;696:108668. Epub 2020 Nov 11.

Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

Mitochondria are multifunctional organelles that regulate diverse cellular processes. Mitochondrial stress, including stress generated by electron transport chain defects and impaired mitochondrial proteostasis, is intimately involved in various diseases and pathological conditions. Sepsis is a life-threatening condition that occurs when an imbalanced host response to infection leads to organ dysfunction. Metabolic disturbances and impaired immune responses are implicated in the pathogenesis and development of sepsis. Given that mitochondria play central roles in cellular metabolism, mitochondrial stress is predicted to be involved in the pathological mechanism of sepsis. Under mitochondrial stress, cells activate stress response systems to maintain homeostasis. This mitochondrial stress response transcriptionally activates genes involved in cell survival and death. Mitochondrial stress also induces the release of distinctive secretory proteins from cells. Recently, we showed that growth differentiation factor 15 (GDF15) is a major secretory protein induced by mitochondrial dysfunction. In this article, we provide a brief overview of mitochondrial stress response and GDF15, and discuss the potential role of GDF15 in the pathophysiology of sepsis.
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http://dx.doi.org/10.1016/j.abb.2020.108668DOI Listing
December 2020

[Marginal zone lymphoma-like primary bone marrow lymphoma with long-term pancytopenia preceding diagnosis].

Rinsho Ketsueki 2020 ;61(10):1469-1475

Department of Hematology, Medical Hospital, Tokyo Medical and Dental University.

A 45-year-old man initially diagnosed with aplastic anemia had been receiving treatment for >4 years when he visited our hospital for a detailed examination. On admission, bone marrow (BM) aspiration showed erythroid dysplasia and chromosomal abnormalities, including trisomy 3 in 1/20 cells. After 3 months of observation, BM aspiration showed the involvement of 5% abnormal lymphocytes, and flow cytometry revealed a monoclonal B-cell phenotype. After a further 5 months of observation, his blood test showed a sudden elevation in white blood cell (WBC) count and the presence of villous lymphocytes. Fluorodeoxyglucose-positron emission tomography (FDG-PET) only revealed strong uptake by systemic BM, and BM aspiration showed the involvement of 76.4% abnormal lymphocytes, which were positive for CD19 and dim CD11c; negative for CD25, CD103, cyclin D1, and BRAF-V600E; and exhibited light chain restriction. The patient was diagnosed with marginal zone lymphoma-like primary bone marrow (BM) lymphoma. Treatment with R-CHOP and R-cladribine failed. He then underwent an allogeneic peripheral blood stem cell transplantation from a human leucocyte antigen (HLA)-identical sibling, and he has since remained in good health and without relapse for 9 years. Further clinical and biological analyses are necessary to establish an optimal treatment strategy for this disease.
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http://dx.doi.org/10.11406/rinketsu.61.1469DOI Listing
January 2021

Serum growth differentiation factor 15 level is associated with muscle strength and lower extremity function in older patients with cardiometabolic disease.

Geriatr Gerontol Int 2020 Oct 4;20(10):980-987. Epub 2020 Sep 4.

Departments of Diabetes, Metabolism, and Endocrinology, Tokyo, Japan.

Aims: Sarcopenia is a serious problem because of its poor prognosis. Growth differentiation factor 15 (GDF15) is associated with mitochondrial dysfunction, inflammation, insulin resistance and oxidative stress, which may play crucial roles for the development of sarcopenia. We aimed to examine whether serum GDF15 level is associated with muscle mass, strength and lower extremity function in older patients with cardiometabolic disease.

Methods: Serum GDF15 levels were measured in 257 patients with cardiometabolic diseases (including 133 patients with diabetes) who had visited the frailty clinic, using a latex turbidimetric immunoassay. Appendicular skeletal muscle index, handgrip strength, timed-up-and-go test and gait speed were evaluated. Power, speed, balance and total scores based on the sit-to-stand test were calculated to assess lower extremity function.

Results: The highest tertile of serum GDF15 was independently associated with low handgrip strength, low gait speed, long timed-up-and-go time and scores of lower extremity function but not an appendicular skeletal muscle index in multiple logistic regression analyses after adjustment for covariates. Patients in the highest tertile of GDF15 were at the risk of having three to nine times lower grip strength, three times lower gait speed, five to six times lower mobility and five to 11 times reduction in lower extremity function as compared with those in the lowest GDF15 tertile dependent on the models.

Conclusions: Elevated serum GDF15 level was independently associated with low muscle strength and lower extremity function in older patients with cardiometabolic disease. Serum GDF15 could be one of the biomarkers for muscle weakness and low physical performance. Geriatr Gerontol Int 2020; 20: 980-987.
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http://dx.doi.org/10.1111/ggi.14021DOI Listing
October 2020

Serum Exosomal Gamma-Glutamyltransferase Activity Increased in Patients with Renal Cell Carcinoma with Advanced Clinicopathological Features.

Oncology 2020 29;98(10):734-742. Epub 2020 Jul 29.

Biological Process of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan,

Background: There has been no clinically useful diagnostic or prognostic biomarker for renal cell carcinoma (RCC). Serum γ-glutamyltransferase (GGT) activity has been reported to be a prognostic marker for several types of cancer including RCC. Exosomes or small extracellular vesicles present in body fluids have potential as a biomarker. We have recently demonstrated that GGT activity on exosomes isolated from serum is useful for the differential diagnosis of prostate cancer and benign prostate hyperplasia. In this study, we aimed to examine if serum exosomal GGT activity could be a marker for RCC.

Methods: We examined GGT1 expression and GGT activity in cell lysates and exosomes from culture medium of HK-2 proximal tubule epithelial and RCC cell lines. GGT activity was measured using a fluorescent probe for GGT, γ-glutamyl hydroxymethyl rhodamine green. Serum and serum exosomal GGT activities were measured in patients with RCC. GGT1 expression in RCC tissues was evaluated by immunohistochemical staining.

Results: GGT1 levels in exosomes from KMRC-1, OS-RC-2 and 786-O cells were elevated compared with those from HK-2 cells. In exosomes, GGT1 expression correlated with GGT activity determined using a fluorescent probe for GGT. In RCC patients, serum exosomal GGT activity was elevated in those with advanced stages (III/IV vs. I/II, p = 0.037) and those with microvascular invasion (with vs. without, p = 0.034). Immunohistochemical analysis showed that membranous GGT1 expression was increased in RCC with microvascular invasion. Notably, preoperative serum exosomal GGT activity could predict the likelihood of having microvascular invasion diagnosed by pathological examination of surgically resected specimens.

Conclusions: Our results suggest that serum exosomal GGT activity could be a clinically useful marker for advanced clinicopathological features of RCC patients, and its combined use with conventional diagnostic modalities may improve the diagnosis and treatment of patients.
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http://dx.doi.org/10.1159/000508688DOI Listing
October 2020

Cytotoxic activity of dimeric acridone alkaloids derived from Citrus plants towards human leukaemia HL-60 cells.

J Pharm Pharmacol 2020 Oct 27;72(10):1445-1457. Epub 2020 Jul 27.

Laboratory of Analytical Neurobiology, Faculty of Pharmacy, Meijo University, Nagoya, Japan.

Objectives: Acridone alkaloids from Citrus and their derivatives show various kinds of biological activity. However, the anticancer activities of dimeric acridone alkaloids with unique structures and the molecular mechanism of these effects are poorly understood.

Methods: We investigated the cytotoxicity effects of dimeric acridone alkaloids isolated from Marsh grapefruit on human myeloid leukaemia HL-60 cells.

Key Findings: Of the six dimeric acridone alkaloids tested, citbismine-E, the most potent, dose- and time-dependently decreased HL-60 cell viability by inducing apoptosis. The treatment of HL-60 cells with citbismine-E yielded a significant increase in levels of intracellular reactive oxygen species (ROS). Citbismine-E lowered the mitochondrial membrane potential and increased the activities of caspase-9 and -3. In addition, citbismine-E-induced apoptosis, decrease in mitochondrial membrane potential and caspase activation were significantly alleviated by pretreatment of the cells with antioxidant N-acetylcysteine (NAC). Citbismine-E induced intrinsic caspase-dependent apoptosis through ROS-mediated c-Jun N-terminal kinase activation. Citbismine-E-induced production of oxidative stress biomarkers, malondialdehyde and 8-hydroxy-2'-deoxyguanosine was also attenuated by pretreatment with NAC.

Conclusions: Citbismine-E is a powerful cytotoxic agent against HL-60 cells that acts by inducing mitochondrial dysfunction-mediated apoptosis through ROS-dependent JNK activation. Citbismine-E also induced oxidative stress damage via ROS-mediated lipid peroxidation and DNA damage in HL-60 cells.
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http://dx.doi.org/10.1111/jphp.13327DOI Listing
October 2020

CD44v8-10 mRNA contained in serum exosomes as a diagnostic marker for docetaxel resistance in prostate cancer patients.

Heliyon 2020 Jul 2;6(7):e04138. Epub 2020 Jul 2.

Research Team for Functional Biogerontology, Tokyo Metropolitan Institute of Gerontology, Tokyo 173-0015, Japan.

Background: Docetaxel is first-line chemotherapy for castration-resistant prostate cancer (CRPC), but most patients acquire docetaxel resistance. CD44 has been shown to be involved in drug resistance of cancers including prostate cancer. We hypothesized that CD44 in serum exosomes could be a diagnostic marker for docetaxel resistance in CRPC patients. In this study, we examined CD44 protein and mRNA expression in cell lysates and exosomes isolated from prostate cancer cells, evaluated the effect of CD44v8-10 knockdown on docetaxel sensitivity and measured CD44 mRNA copy numbers contained in serum exosomes in prostate cancer patients.

Materials And Methods: Docetaxel-sensitive PC-3 prostate cancer cells and docetaxel-resistant PC-3R cells established previously from parental PC-3 cells were used. CD44v8-10 knockdown was performed by siRNA transfection. Blood was collected from 50 docetaxel-naïve and 10 docetaxel-resistant patients and 15 control males. CD44 protein expression was evaluated by Western blotting. CD44 mRNA expression was measured by RT-digital PCR.

Results: The levels of CD44v8-10 protein and mRNA in cell lysates and exosomes were higher in PC-3R cells than in PC-3 cells. CD44v8-10 knockdown significantly increased docetaxel sensitivity of PC-3R cells. The CD44v8-10 mRNA copy numbers in serum exosomes were higher in docetaxel-resistant patients than in docetaxel-naïve patients and control males (median 46, 12 and 17 copies/mL serum, respectively, = 0.032). In contrast, the serum exosomal mRNA copy numbers of CD44 standard isoform (CD44s) were not different among 3 groups (median 25, 14 and 13 copies/mL serum, respectively, = 0.150).

Conclusions: CD44v8-10 may be involved in docetaxel resistance in prostate cancer and serum exosomal CD44v8-10 mRNA could be a diagnostic marker for docetaxel-resistant CRPC.
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http://dx.doi.org/10.1016/j.heliyon.2020.e04138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334415PMC
July 2020

IgG4 plasma cell myeloma: Clinicopathological characteristics and diagnosis.

Pathol Int 2020 Aug 9;70(8):551-556. Epub 2020 Jun 9.

Department of Pathology, Japanese Red Cross Nagoya First Hospital, Aichi, Japan.

Plasma cell myeloma (PCM) is usually associated with the presence of M-protein in the serum and urine of patients, and about half of the PCM cases exhibit the IgG M-protein and increased gamma-globulin fraction on membrane electrophoresis. The IgG4 subclass is located in the beta-2 fraction on membrane electrophoresis. The aim of this study was to develop a method to evaluate IgG4-producing PCM (IgG4-PCM) and its clinicopathological characteristics. We found three cases of IgG4-PCM among 80 cases of IgG-producing PCM by membrane electrophoresis, which were confirmed by IgG4 immunostaining. None of the cases had a clinical history of IgG4-related disease, although they exhibited high levels of serum IgG4. A bone marrow aspiration specimen had an increased number of plasma cells with a relatively mature morphology. No cases exhibited lymphoplasmacytic inflammation, obliterative phlebitis or fibrosis. Immunohistochemistry revealed that tumor cells expressed CD138 and IgG4 and showed monoclonal expression of kappa. We revealed that IgG4-PCM might not be associated with IgG4-related disease and that the detection of M-protein with beta-globulin fraction by electrophoresis may be useful for screening IgG4-PCM.
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http://dx.doi.org/10.1111/pin.12968DOI Listing
August 2020

[Leukemic pulmonary infiltration diagnosed by sputum Giemsa-staining].

Rinsho Ketsueki 2020 ;61(3):257-261

Department of Hematology, Japanese Red Cross Nagoya First Hospital.

A 54-year-old man with acute myeloid leukemia (AML) underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched unrelated donor in nonremission status. Bone marrow aspiration performed on day 14 showed that the patient had achieved complete remission; however, he relapsed on day 28. The patient developed a wet cough, and chest computed tomography performed on day 27 revealed pneumonia. Because pneumonia developed along with the leukemic relapse, we suspected that it was due to pulmonary leukemic infiltration (PLI). Giemsa-stained sputum showed some blast cells and fluorescence in situ hybridization indicated that the patient had monosomy 7, which was also detected in bone marrow blasts. Though we prescribed hydroxycarbamide and decreased tacrolimus rapidly, AML progressed and led to the patient's death on day 45. Histopathological findings of the autopsy performed the next day showed diffuse alveolar damage in both lungs. The blast cells were packed in blood vessels of alveolar septa and were also seen in alveoli. PLI was diagnosed pathologically. In conclusion, our case demonstrates that Giemsa stain of sputum is useful in quick diagnosis of PLI without invasive examination.
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http://dx.doi.org/10.11406/rinketsu.61.257DOI Listing
May 2020

Mouse model of metformin-induced diarrhea.

BMJ Open Diabetes Res Care 2020 03;8(1)

Taiko Pharmaceutical Co Ltd, Osaka, Japan.

Objective: Metformin, an oral medication used for type 2 diabetes mellitus, is the most commonly prescribed drug with less economic burden of patients. Although metformin's efficacy and safety have long been recognized, approximately 5% of the patients treated with this drug develop severe diarrhea as an adverse effect and have to abandon treatment. Because there is no animal model to study metformin-induced diarrhea, it is hard to develop methods to maintain quality of life of patients prescribed with metformin.

Research Design And Methods: Using mouse models, we tried to develop an evaluation system for metformin-induced diarrhea to improve diarrheal symptoms in patients with diabetes. Healthy (C57BL/6J) and diabetic obese () mice were subjected to a stepwise dose escalation of metformin (250 mg/kg/day (125 mg/kg twice daily oral dose)-1000 mg/kg/day (500 mg/kg twice daily oral dose)), and fecal moisture contents and their score were monitored. To evaluate anti-diarrheal medications, wood creosote (a traditional medicine) was tested. Several groups of enterobacteria in fresh feces were examined by using PCR.

Results: 1000 mg/kg/day (four times maximal effective dose) of metformin significantly increased fecal moisture content. Although no symptoms of diarrhea were observed in healthy C57BL/6J mice, the same dose of metformin induced severe diarrhea in diabetic obese mice. A reduction in PCR signals for the group was associated with metformin-induced diarrhea. Wood creosote reduced diarrhea (high water-content) without affecting metformin's efficacy or enterobacterial flora levels.

Conclusions: We have created the first animal model of metformin-induced diarrhea using mice, which will provide better quality of life for patients suffering from diarrhea caused by metformin.
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http://dx.doi.org/10.1136/bmjdrc-2019-000898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170402PMC
March 2020

Mass-forming extramedullary hematopoiesis of the spleen in a patient with CALR-mutated myeloproliferative neoplasm.

Pathol Int 2020 04 26;70(4):237-239. Epub 2020 Feb 26.

Department of Pathology, Tokai University School of Medicine, Kanagawa, Japan.

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http://dx.doi.org/10.1111/pin.12912DOI Listing
April 2020

Oxygen radical based on non-thermal atmospheric pressure plasma alleviates lignin-derived phenolic toxicity in yeast.

Biotechnol Biofuels 2020 28;13:18. Epub 2020 Jan 28.

1Faculty of Agriculture, Meijo University, Nagoya, Aichi 468-8502 Japan.

Background: Vanillin is the main byproduct of alkaline-pretreated lignocellulosic biomass during the process of fermentable-sugar production and a potent inhibitor of ethanol production by yeast. Yeast cells are usually exposed to vanillin during the industrial production of bioethanol from lignocellulosic biomass. Therefore, vanillin toxicity represents a major barrier to reducing the cost of bioethanol production.

Results: In this study, we analysed the effects of oxygen-radical treatment on vanillin molecules. Our results showed that vanillin was converted to vanillic acid, protocatechuic aldehyde, protocatechuic acid, methoxyhydroquinone, 3,4-dihydroxy-5-methoxybenzaldehyde, trihydroxy-5-methoxybenzene, and their respective ring-cleaved products, which displayed decreased toxicity relative to vanillin and resulted in reduced vanillin-specific toxicity to yeast during ethanol fermentation. Additionally, after a 16-h incubation, the ethanol concentration in oxygen-radical-treated vanillin solution was 7.0-fold greater than that from non-treated solution, with similar results observed using alkaline-pretreated rice straw slurry with oxygen-radical treatment.

Conclusions: This study analysed the effects of oxygen-radical treatment on vanillin molecules in the alkaline-pretreated rice straw slurry, thereby finding that this treatment converted vanillin to its derivatives, resulting in reduced vanillin toxicity to yeast during ethanol fermentation. These findings suggest that a combination of chemical and oxygen-radical treatment improved ethanol production using yeast cells, and that oxygen-radical treatment of plant biomass offers great promise for further improvements in bioethanol-production processes.
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http://dx.doi.org/10.1186/s13068-020-1655-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988259PMC
January 2020

Macrophage-mediated complications after stem cell transplantation.

Pathol Int 2019 Dec 16;69(12):679-687. Epub 2019 Oct 16.

Department of Pathology, Japanese Red Cross, Nagoya First Hospital, Aichi, Japan.

Complications after hematopoietic stem cell transplantation (HSCT) especially graft versus host disease (GVHD) are serious events and the keys to success of HSCT. Pathological diagnosis of complications is critical but sometimes not definite in GVHD diagnosis. In this review, we focus on the role of macrophages in HSCT complications. In the early period after HSCT, residual recipient macrophages have important roles for engraftment and rejection. Hemophagocytosis is the main feature of activated recipient macrophages. Skin lesions after HSCT are usually skin GVHD but mimicking histology of interface dermatitis is hardly differentiated. Macrophages and lymphocytes of these lesions were studied and increased numbers of macrophages were significantly associated with overall survival of HSCT. It could be suggested macrophages were good predictive markers for skin GVHD-like lesions. Intestinal type transplantation-associated microangiopathy (i-TAM) is an independent pathogenesis from GVHD with serious prognosis. Activated macrophages in these lesions are important and key to the pathogenesis of i-TAM. These activated macrophages are predominantly residual recipient tissue-resident macrophages. Cryptogenic organizing pneumonitis is a lung complication around day 100 after HSCT caused by activated alveolar macrophages. They are donor-derived tissue-resident macrophages. Residual recipient and donor-derived macrophages work in different ways in HSCT complications.
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http://dx.doi.org/10.1111/pin.12865DOI Listing
December 2019

Essential thrombocytosis attributed to JAK2-T875N germline mutation.

Int J Hematol 2019 Nov 19;110(5):584-590. Epub 2019 Aug 19.

Department of Hematology and Rheumatology, Kagoshima University Hospital, Kagoshima, Japan.

The aim of this study was to elucidate the role of a non-canonical JAK2 mutation JAK2-T875N, which was identified by exome sequencing in a patient with essential thrombocytosis (ET) who had a family history of suspecting ET. Whole exome sequencing was performed on peripheral blood mononuclear cells and buccal swab-derived genomic DNA. Sanger sequencing was performed to confirm the variant. We evaluated the function of the mutation on JAK2 activity and downstream signaling (Erk, STATs) using JAK2-T875N-transfected or transduced cell lines. 293T cells transfected with JAK2 cDNA carrying V617F or T875N mutations showed increased levels of phosphorylated JAK2 and Erk. Enhanced STAT3 and STAT5 activity was confirmed by promoter assay. JAK2-T875N-transduced Ba/F3 cells showed increased cellular growth without IL-3 stimulation. To our knowledge, this is the first case of ET caused by JAK2-T875N mutation with a family history of thrombocytosis and cerebral infarction.
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http://dx.doi.org/10.1007/s12185-019-02725-8DOI Listing
November 2019

Mesenchymal-epithelial transition gene amplification and protein overexpression in stage IV pulmonary adenocarcinoma.

Jpn J Clin Oncol 2019 Aug;49(8):755-761

Department of Pathology, Japanese Red Cross Nagoya First Hospital, 3-35, Nagoya 4538511, Japan.

Background: In non-small cell lung cancer (NSCLC), MET gene copy number gain, including gene amplification and chromosome 7 polysomy, is reportedly associated with patient prognosis. Although relationship between MET copy number gain and poor prognosis has been suggested in surgically resected non-small cell lung cancer, the clinical significance of MET copy number gain and protein overexpression in patients with advanced unresectable tumor is unclear.

Methods: We assessed MET copy number gain and protein expression using fluorescence in situ hybridization and immunohistochemistry in 88 patients with clinical stage IV pulmonary adenocarcinoma receiving chemotherapy, immunotherapy or palliative care.

Results: We found MET amplification, polysomy 7 and high MET protein expression in 10.2, 18.2 and 62.5% of 88 cases, respectively. Gene amplification and high protein expression were not significantly associated. A univariate analysis showed that MET amplification-positive patients had increased overall survival (HR 0.335, 95% CI: 0.119-0.945; P = 0.0388). Although it was not statistically significant in the multivariate analysis of the whole cohort, with the removal of patients who did not receive any treatment other than palliative care, MET amplification independently improved the overall survival (HR 0.178, 95% CI: 0.041-0.770; P = 0.0209). Chromosome 7 polysomy and high MET protein expression did not affect the overall survival.

Conclusions: Although MET amplification-positive tumor is considered aggressive, our results suggest that it has a more favorable prognosis than amplification-negative cases in stage IV pulmonary adenocarcinoma with medical treatment.
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http://dx.doi.org/10.1093/jjco/hyz060DOI Listing
August 2019

Exosomes Expressing Thyrotropin Receptor Attenuate Autoantibody-Mediated Stimulation of Cyclic Adenosine Monophosphate Production.

Thyroid 2019 07 6;29(7):1012-1017. Epub 2019 Jun 6.

2Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.

Exosomes or small extracellular vesicles secreted from cells are nanovesicles with a diameter of 40-150 nm, which play a number of roles in both physiologic and pathologic processes. In Graves' disease (GD), autoantibodies bind to the thyrotropin receptor (TSHR) on the surface of thyroid follicular epithelial cells and stimulate thyroid growth and thyroid hormone synthesis and secretion via cyclic adenosine monophosphate (cAMP) production. The present study aimed to confirm the existence of TSHR in exosomes secreted from thyroid cells and to define the role of TSHR exosomes in GD. Exosomes were isolated by differential centrifugation from the culture medium of the human thyroid follicular epithelial cell line (NTHY-ori 3-1) and thyroid carcinoma cell lines (8305C, 8505C, and FTC-133). TSHR expression in cell lysates and exosomes was evaluated by Western blot analysis. In order to study the function of TSHR exosomes, human embryonic kidney (HEK) 293 cells stably expressing TSHR (HEK/TSHR) were established. Using exosomes isolated from both HEK and HEK/TSHR cells, the binding capacity of the M22 human monoclonal autoantibody to TSHR exosomes and their effect on M22-mediated stimulation of cAMP production in HEK/TSHR cells were evaluated. As a positive control for the functional assay, human recombinant TSHR chimera protein capable of binding to TSH was used. TSHR was detected in exosomes from cancer cells as well as normal epithelial cells. An binding assay showed that alkaline phosphatase-labeled M22 bound to TSHR exosomes in a dose-dependent manner. M22 dose-dependently stimulated intracellular cAMP production in HEK/TSHR cells. The addition of exosomes from HEK/TSHR cells but not those from parental HEK cells significantly ameliorated cAMP production stimulated by treatment with M22 in HEK/TSHR cells. A decoy effect similar to TSHR exosomes was observed for human recombinant TSHR chimera. The results suggest that exosomes expressing TSHR may be secreted from normal and cancerous thyroid cells. In the thyroid gland of patients with GD, TSHR exosomes may exert a decoy effect by sequestering autoantibody, thereby ameliorating autoantibody-mediated activation of thyroid function.
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http://dx.doi.org/10.1089/thy.2018.0772DOI Listing
July 2019

Clinical and molecular features of patients with prefibrotic primary myelofibrosis previously diagnosed as having essential thrombocythemia in Japan.

Eur J Haematol 2019 Jun 25;102(6):516-520. Epub 2019 Apr 25.

Department of Hematology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Objective: Prefibrotic/early primary myelofibrosis (pre-PMF) and essential thrombocythemia (ET) exhibited different features of bone marrow; however, this is not always easy to judge objectively, making pathologists' distinction often suboptimal. In the WHO 2008 criteria, pre-PMF was not defined as a subgroup of PMF; therefore, affected patients were at a higher risk of misdiagnosis with ET. In this study, we examined the prevalence of pre-PMF patients among those previously diagnosed with ET in Japan.

Method: We reviewed bone marrow specimens and clinical and molecular parameters of patients who were previously diagnosed with ET by the WHO 2008 criteria.

Results: Among 107 ET patients, 13 patients were redefined as having pre-PMF. Pre-PMF patients exhibited a higher frequency of MPL mutation and increased platelet counts compared to true ET patients. Molecular analysis revealed the frequencies of high-risk molecular mutations, such as ASXL1, EZH2, and SRSF2, were significantly increased in pre-PMF patients than those in true ET patients.

Conclusion: These results demonstrated the value of reexamining clinical records for patients diagnosed with ET by the WHO 2008 criteria and emphasized that adequate examinations of patients' bone marrow are crucial for an accurate diagnosis of pre-PMF and ET.
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http://dx.doi.org/10.1111/ejh.13236DOI Listing
June 2019

Urinary exosome as a potential biomarker for urinary tract infection.

Cell Microbiol 2019 07 7;21(7):e13020. Epub 2019 Mar 7.

Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan.

Unlike urinary tract infection (UTI), asymptomatic bacteriuria (ABU) should not be treated, with some exceptions such as pregnant women and patients who will undergo traumatic urologic interventions. However, there has been no clinically available marker for their differential diagnosis. Exosomes or small extracellular vesicles carry proteins contained in cells from which they are derived, thus having the potential as a biomarker of several diseases. On the basis of the hypothesis that the molecular signature of exosomes in urine may differ between UTI and ABU patients, we examined if urinary exosomes could serve as a marker for their differential diagnosis. Exosomes were isolated by ultracentrifugation or affinity-based method from cell culture medium of monocytic THP-1 and uroepithelial SV-HUC-1 cells and human urine. Protein expression was examined by Western blot analysis, ELISA, and CLEIA. The results showed that the levels of intracellular signalling molecules Akt and ERK and transcription factor NF-κB increased in exosomes isolated from THP-1 and SV-HUC-1 cells cocultured with Escherichia coli and/or treated with lipopolysaccharide. In urinary exosomes of UTI patients, Akt significantly diminished, and an exosomal marker CD9 showed a trend to decrease after treatment with antimicrobial agents. More importantly, Akt and CD9 levels in urinary exosomes were higher in UTI patients than in ABU patients, which was also observed after correction by urine creatinine. Collectively, these results suggest that Akt and CD9 in urinary exosomes could be useful markers for differential diagnosis of UTI and ABU.
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http://dx.doi.org/10.1111/cmi.13020DOI Listing
July 2019

Divergence and heterogeneity of neoplastic PD-L1 expression: Two autopsy case reports of intravascular large B-cell lymphoma.

Pathol Int 2019 Mar 28;69(3):148-154. Epub 2019 Jan 28.

Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.

Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease, but the neoplastic PD-L1 expression on tumor cells may vary among cases. We evaluated 10 IVLBCL autopsy cases for neoplastic PD-L1 expression, and had positive results in two cases. In one case, neoplastic PD-L1 expression (SP142, 28-8, and E1J2J clones) was dependent on the organ and anatomical site (capillaries vs. vessels) of the tumor tissue. Neoplastic PD-L1 expression was found in tumor cells located in capillaries in the central nervous system, pituitary gland, kidneys, lung, and gastrointestinal tract; sinuses/sinusoids of the spleen, liver, bone marrow, and lymph nodes; and an extravascular location. However, this expression was not detected in tumor cells located in the adrenal gland, thyroid gland, pancreas, ovaries, uterus, pleura, and small or larger-sized vessels of the lung. The other case showed constant neoplastic PD-L1 expression on the tumor cells, and in addition to the affected organs, capillaries, and vessels with two anti-PD-L1 antibodies (28-8 and E1J2J, but not SP142). The divergence and heterogeneity of neoplastic PD-L1 expression were clearly demonstrated in our cases. To the best of our knowledge, this is the first description of divergent neoplastic PD-L1 expression among the affected organs and anatomical sites in IVLBCL.
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http://dx.doi.org/10.1111/pin.12757DOI Listing
March 2019

Serum PD-1 levels measured by ELISA using Nivolumab increased in advanced RCC patients: novel approach to develop companion diagnostics for antibody therapy.

J Cancer Res Clin Oncol 2019 06 5;145(6):1661-1663. Epub 2018 Dec 5.

Research Team for Mechanism of Aging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan.

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http://dx.doi.org/10.1007/s00432-018-2806-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527537PMC
June 2019

Origin of cancer-associated fibroblasts and tumor-associated macrophages in humans after sex-mismatched bone marrow transplantation.

Commun Biol 2018 3;1:131. Epub 2018 Sep 3.

Department of Pathology, Graduate School of Medicine, Osaka University, Yamada-Oka, Suita, Osaka, 565-0871, Japan.

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in tumor stroma play a key role in disease progression. Recent studies using mice models suggest that CAFs are partly derived from bone marrow and TAMs primarily originate from bone marrow-derived inflammatory monocytes. However, the origin of these cells in humans remains unclear. Hence, we investigated their human origin, using specimens from human secondary tumors that developed after sex-mismatched bone marrow transplantation, by modified immunofluorescent in situ hybridization analysis and triple immunostaining. We observed that most of the α-smooth muscle actin (αSMA)-positive CAFs in the mammary gland, liver, and oral mucosa specimens obtained 3-19 years after bone marrow transplantation are recipient-derived cells. In contrast, the majority of the peritumoral αSMA-negative fibroblast-like cells are actually bone marrow-derived HLA-DR-positive myeloid cells, such as macrophages and dendritic cells. Furthermore, almost all CD163-positive TAMs and macrophages present in the non-tumor areas are derived from bone marrow.
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http://dx.doi.org/10.1038/s42003-018-0137-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123637PMC
September 2018

Differences in the bone marrow histology between childhood myelodysplastic syndrome with multilineage dysplasia and refractory cytopenia of childhood without multilineage dysplasia.

Histopathology 2019 Jan 29;74(2):239-247. Epub 2018 Oct 29.

Department of Pathology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan.

Aims: Refractory cytopenia of childhood (RCC) is subdivided into myelodysplastic syndrome with multilineage dysplasia (MDS-MLD) and RCC without (w/o) multilineage dysplasia (RCC without MLD). Although RCC is a histomorphological distinct entity, the bone marrow (BM) histology of RCC is not yet characterised in relation to multilineage dysplasia. We investigated the BM histological features of RCC to clarify the characteristics of BM histology of MDS-MLD in childhood compared to RCC without MLD.

Methods And Results: The BM histology and cytology in 60 RCC patients from the nationwide registry of Japanese Childhood AA-MDS Study Group were reviewed retrospectively. Although a thorough genetic assessment, including GATA2 and/or SAMD9, was not performed, inherited BM failure disorders were excluded by a cytogenetic test, a chromosome fragility test and a telomere length measurement along with careful clinical assessments. Among the 60 patients, 20 (33%) of MDS-MLD and 40 (67%) of RCC w/o MLD were classified according to their BM cytology. We then investigated the BM histological features and compared them between the two groups. The BM cellularity, distribution pattern of haematopoiesis, frequency of left-shifted granulopoiesis, numbers of micromegakaryocytes and p53 immunostaining-positive cells were significantly different between the groups. The BM histology of MDS-MLD in childhood showed higher cellularity, the more common occurrence of diffuse distribution pattern, more frequently left-shifted granulopoiesis and more micromegakaryocytes and p53 immunostaining-positive cells than RCC without MLD.

Conclusions: Our results showed that MDS-MLD in childhood had a characteristic BM histology compared to RCC without MLD. The clinical relevance of MDS-MLD in childhood needs to be evaluated.
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http://dx.doi.org/10.1111/his.13721DOI Listing
January 2019

Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia.

Int J Hematol 2018 Oct 9;108(4):411-415. Epub 2018 Jul 9.

Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki, 889-1692, Japan.

A new entity, namely early/prefibrotic primary myelofibrosis (PMF), was introduced as a subtype of PMF in the 2016 revised World Health Organization (WHO) criteria for myeloproliferative neoplasms (MPN). It was diagnosed based on histopathological features of bone marrow (BM) biopsy specimens together with clinical parameters [leukocytosis, anemia, elevated lactate dehydrogenase (LDH) values, and splenomegaly]. The aim of this study was to evaluate the prevalence of early/prefibrotic PMF in patients who were previously diagnosed with ET, and to compare clinical features at diagnosis and outcomes between early/prefibrotic PMF and essential thrombocythemia (ET) patients. BM biopsy samples obtained at the time of ET diagnosis were available in 42 patients. Sample reevaluation according to the 2016 revised WHO criteria revealed that early/prefibrotic PMF accounted for 14% of patients who were previously diagnosed with ET, which was comparable to the rates in previous reports. Compared to patients with ET, patients with early/prefibrotic PMF had higher LDH values and higher frequencies of splenomegaly. Overall, myelofibrosis-free and acute myeloid leukemia-free survivals were comparable between the 2 groups. Accurate diagnosis is required to clarify the clinical features of Japanese ET patients.
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http://dx.doi.org/10.1007/s12185-018-2495-2DOI Listing
October 2018

Successful treatment of primary bone marrow Hodgkin lymphoma with brentuximab vedotin: a case report and review of the literature.

J Med Case Rep 2018 May 30;12(1):151. Epub 2018 May 30.

Department of Hematology and Oncology, Suzuka General Hospital, Mie, Japan.

Background: Hodgkin lymphoma usually presents with sequential enlargement of peripheral lymph nodes, and bone marrow invasion rarely occurs (approximately 3-5%). However, several cases have been reported as "primary" bone marrow Hodgkin lymphoma, especially among patients with human immunodeficiency virus and the elderly. This type of Hodgkin lymphoma is characterized by no peripheral lymphadenopathies and has been reported to have poorer prognosis.

Case Presentation: A 38-year-old Japanese man was admitted to our hospital because of fever of unknown origin and pancytopenia without lymphadenopathies. Bone marrow examination revealed Hodgkin cells mimicking abnormal cells. These were positive for CD30, EBER-1, CD15, PAX-5, and Bob-1 and negative for Oct-2, CD3, CD20, surface immunoglobulin, CD56. On the basis of systemic evaluation and bone marrow examination, he was diagnosed with primary bone marrow Hodgkin lymphoma. We initiated therapy with DeVIC (dexamethasone, etoposide, ifosfamide, and carboplatin) therapy, but remission was not achieved. Then, the patient was treated with brentuximab vedotin combined with systemic chemotherapy (Adriamycin, vinblastine and dacarbazine), which was effective.

Conclusions: There is no established treatment strategy for Hodgkin lymphoma, and therapeutic outcomes using ABVD (Adriamycin, bleomycin, vinblastine and dacarbazine)-like or CHOP (cyclophosphamide, Adriamycin, vincristine, and prednisone)-like regimens are reportedly poor. Only a few patients have been reported to achieve long-term remission. Through this case report, we suggest an alternative therapeutic option for primary bone marrow Hodgkin lymphoma.
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http://dx.doi.org/10.1186/s13256-018-1693-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975584PMC
May 2018

Paraneoplastic autoimmune encephalitis associated with pleomorphic lung carcinoma: An autopsy case report.

Neuropathology 2018 May 20. Epub 2018 May 20.

Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.

A 64-year-old man was admitted with acute onset disturbed consciousness. Cerebrospinal fluid analysis revealed pleocytosis and elevated protein, with negative cultures and PCR. Serum antibodies for autoimmune encephalitis were also negative. Brain magnetic resonance imaging (MRI) was unremarkable, but whole-body CT scan showed a tumor in the left lower lung lobe. Bronchial brush cytology demonstrated clusters of malignant cells, and F-fluorodeoxyglucose positron emission tomography showed multiple lesions and increased uptake in the lung tumor. Clinically the patient had a stage IV lung carcinoma, graded as T3N3M1b (OSS). Steroid therapy had limited efficacy, but chemotherapy dramatically improved his neurological symptoms. Therefore, he was diagnosed with paraneoplastic autoimmune encephalitis based on the diagnostic criteria for paraneoplastic neurological syndromes. He died due to disease progression 14 months later. Subsequent postmortem examination revealed white ill-defined nodules in the left lung, with similar nodules in other organs. The brain weighed 1500 g before fixation, and a nodule was observed in the right precentral gyrus. Microscopically, the lung tumor was a pleomorphic carcinoma with an adenocarcinoma component. Multiple areas of micro-softening (≤500 μm) were identified in the cerebral cortex, gray-white matter junction and basal ganglia, and were distributed diffusely in both the limbic and non-limbic systems. Mild lymphocytic infiltrates were observed involving few intraparenchymal vessels. Few tumor metastases were observed in the right precentral gyrus. The multiple micro-softenings may reflect a chronic neuropathologic change of paraneoplastic autoimmune encephalitis. They were too small to be detected by brain MRI. However, these lesions may have the potential to cause the neurological symptoms in the acute phase because they were observed in many anatomical regions. We should pay attention to subtle findings such as micro-softenings when estimating the neuropathology of autoimmune encephalitis. Further investigations are needed to understand the characteristic neuropathology of this condition.
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http://dx.doi.org/10.1111/neup.12477DOI Listing
May 2018