Publications by authors named "Naoto Takahashi"

315 Publications

VEGF-VEGFR2 inhibitor-associated hyaline occlusive glomerular microangiopathy: a Japanese single-center experience.

Clin Exp Nephrol 2021 Jun 11. Epub 2021 Jun 11.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.

Background: Inhibitors of vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling, such as bevacizumab (Bmab), are used for the treatment of various advanced cancers. However, these inhibitors induce renal thrombotic microangiopathy (TMA). Recently, two European cohort studies showed a distinctive histopathological pseudothrombotic pattern different from TMA in Bmab-treated patients.

Methods: We analyzed 9 renal biopsies from proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors in our Japanese cohort. Clinical and laboratory features were also assessed in these patients.

Results: All 9 patients had moderate to heavy proteinuria with normal or slightly elevated serum creatinine levels. On light microscopy, a patchy pattern of hemispherical/spherical lesions along glomerular capillary walls was a characteristic finding. On immunofluorescence microscopy, staining for immunoglobulins (IgM dominant) at varying intensities was observed mainly along glomerular capillary walls. Especially, hemispherical/spherical positive staining for immunoglobulins was a characteristic pattern. Immunohistochemical studies showed positive staining for immunoglobulins and negative staining for CD61-positive platelets in capillary hemispherical/spherical lesions and positive VEGF staining in podocytes. On electron microscopy, variably electron-dense material in dilated glomerular capillaries and partial effacement of podocyte foot processes were observed. After the withdrawal of VEGF-VEGFR2 inhibitors, proteinuria improved without any specific treatment in 8 patients.

Conclusions: Histopathological findings in our patients treated with VEGF-VEGFR2 inhibitors were consistent with those observed in the recently described new form of Bmab-associated hyaline occlusive glomerular microangiopathy. This form should be considered in proteinuric cancer patients treated with VEGF-VEGFR2 inhibitors. Discontinuing VEGF-VEGFR2 inhibitors may lead to improvement of glomerular microangiopathy induced by these drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10157-021-02090-zDOI Listing
June 2021

[Primary breast diffuse large B-cell lymphoma in an elderly man maintaining long-term complete response].

Rinsho Ketsueki 2021 ;62(5):341-345

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine.

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare non-Hodgkin's lymphoma that mostly affects women. Here, we report a case of primary breast DLBCL that affected an older man without any autoimmune disease or drug-related female hormones. The patient was a 65-year-old man whose chief complaints were gradually-increasing lump in the right chest and swelling of the right axillary lymph nodes. He was diagnosed with malignant lymphoma through a needle biopsy on suspicion of right breast cancer with right axillary lymph node metastasis. Since the histological type could not be confirmed, right breast mass resection was performed. The patient was referred to our department for treatment because of the diagnoses of primary breast DLBCL, germinal center B-cell type (Hans classification), and clinical stage IIA. In addition to the six courses of R-CHOP therapy, intrathecal injections were used in combination to prevent CNS infiltration. He has been in complete remission for 5 years. Although rare, breast lymphoma can also occur in men; therefore, early histological diagnosis and response to CNS recurrence prevention are important.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.11406/rinketsu.62.341DOI Listing
June 2021

The Combination of Interferon-Alpha and Ponatinib Enables Faster and Deeper Molecular Responses in Patient with De Novo Blast Crisis of CML: Interferon-Alpha May Return as a CML Treatment.

Case Rep Hematol 2021 3;2021:5518727. Epub 2021 May 3.

Department of Hematology Nephrology and Rheumatology, Akita University, 1-1 Hondo 1-Chome, Akita 010-8543, Japan.

In the era of tyrosine kinase inhibitor (TKI) treatment, its effectiveness in treating chronic myelogenous leukemia (CML) has been improved, ensuring the same prognosis as that of healthy people of the same age. However, there are some patients with de novo blast crisis that undergoes acute conversion from the time of diagnosis and does not respond to TKI treatment, especially in the older patients. Here, we present a case of an older patient with de novo lymphoid crisis who was first treated with a combination of TKI and chemotherapy, but it was difficult to maintain a durable deep molecular response (DMR). After he achieved major molecular response (MMR) or less, it was possible to suppress IS% to DMR by performing a combined treatment with interferon- (IFN-) and ponatinib. It is considered that DMR can be maintained by the combination of the two-way action of IFN-, that is, the transfer of dormant CML stem cells to the cellcycle and the activation of a specific immune response to CML cells. This clinical result suggests the possibility of the re-emergence of IFN-, which has been used a therapeutic drug in the past.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2021/5518727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112961PMC
May 2021

Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia.

Nat Commun 2021 05 14;12(1):2833. Epub 2021 May 14.

Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23097-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121838PMC
May 2021

Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update.

Leukemia 2021 Jun 12;35(6):1631-1642. Epub 2021 May 12.

Cancer Center of Bordeaux, Institut Bergonié, INSERM U1218, University of Bordeaux, Bordeaux, France.

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR, 98.3% regained MMR, 94.9% regained MR, and 93.2% regained MR. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-021-01260-yDOI Listing
June 2021

Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1-Related Microglial Activation in Neonatal Hypoxic-Ischemic Encephalopathy: Morphologic Consideration.

Am J Pathol 2021 May 6. Epub 2021 May 6.

Department of Mental Retardation and Birth Defect Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. Electronic address:

Neonatal hypoxic-ischemic encephalopathy (nHIE) is a major neonatal brain injury. Despite therapeutic hypothermia, mortality and sequelae remain severe. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was associated with the pathophysiology of nHIE. In this study, morphologic change and microglial activation under the nHIE condition and LOX-1 treatment were investigated. The authors assessed microglial activity and proliferation with a novel morphologic method, immunostaining, and quantitative PCR in the rat brains of both nHIE model and anti-LOX-1 treatment. Circumference ratio, the long diameter ratio, the cell area ratio, and the roundness of microglia were calculated. The correlation of the morphologic metrics and microglial activation in nHIE model and anti-LOX-1 treated brains was evaluated. LOX-1 was expressed in activated ameboid and round microglia in the nHIE model rat brain. In the evaluation of microglial activation, the novel morphologic metrics correlated with all scales of the nHIE-damaged and treated brains. The circumference and long diameter ratios had a positive correlation. By contrast, the cell area ratio and roundness had a negative correlation. Anti-LOX-1 treatment attenuated morphologic microglial activation and proliferation, and suppressed the subsequent production of inflammatory mediators by microglia. In human nHIE, round microglia and endothelial cells expressed LOX-1. The results indicate that LOX-1 regulates microglial activation in nHIE and anti-LOX-1 treatment attenuates brain injury by suppressing microglial activation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajpath.2021.04.009DOI Listing
May 2021

A term infant with fetal giant meconium hydrocele caused by meconium peritonitis.

Pediatr Neonatol 2021 Mar 18. Epub 2021 Mar 18.

Department of Pediatrics, The University of Tokyo Hospital, Tokyo, 113-8655, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pedneo.2021.03.006DOI Listing
March 2021

Efficacy and safety of ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case series from a single institute.

Int J Hematol 2021 Apr 27. Epub 2021 Apr 27.

Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) is an aggressive leukemia that occurs in 20-40% of adult patients. Ph + ALL is caused by the Philadelphia chromosome (Ph), which consists of a t(9;22)(q34;q11) reciprocal translocation leading to the formation of a BCR-ABL1 fusion gene. The disease is treated with targeted therapy comprising ABL1 tyrosine kinase inhibitors (TKIs). Ponatinib is a third generation TKI that demonstrates higher binding affinity for ABL1 than first/second generation TKIs. Although intensive combined immunotherapy with ponatinib greatly improves the prognosis of Ph + ALL, the safety and efficacy profiles of ponatinib in Japanese patients are unclear. This retrospective study investigated five cases of Ph + ALL at a single institute to evaluate safety and efficacy profiles. Three patients achieved a deep molecular response (DMR) following combined intensive treatment with ponatinib as induction chemotherapy. Four patients received consolidative allogenic stem cell transplantation (allo-SCT) during their first complete response. Three of the four experienced early relapse within 100 days; they subsequently received ponatinib, and one of the three achieved a DMR. No patient experienced severe cardiovascular events. This case series suggests that ponatinib at a concentration of least 30 mg exhibits anti-leukemia effects in Japanese patients with Ph + ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03156-0DOI Listing
April 2021

Aggressive Laparoscopic Cholecystectomy in Accordance with the Tokyo Guideline 2018.

JSLS 2021 Jan-Mar;25(1)

Department of Surgery, Iwate Medical University, Iwate Prefecture, Japan.

Objectives: The Tokyo Guidelines 2018 have been widely adopted since their publication. However, the few reports on clinical outcomes following laparoscopic cholecystectomy have not taken into account the severity of the acute cholecystitis and the patient's general condition, as estimated by the Charlson comorbidity index. This study aimed to assess the relationships between severity, Charlson comorbidity index, and clinical outcomes subsequent to laparoscopic cholecystectomy.

Methods: We extracted the retrospective data for 370 Japanese patients who underwent emergency or scheduled early laparoscopic cholecystectomy within 72 hours from onset between February 2015 and August 2018. We compared postoperative factors in relationship to severity (grade I versus grade II/III). Then, we made a similar comparison between those with low (< 4) and high Charlson comorbidity index (≥ 4).

Results: According to the Tokyo guideline 2018 levels of severity, there were 282 (76.2%), 61 (16.5%), and 27 (7.3%) patients in grades I, II, and III, respectively. With regards to surgical outcomes, the mean operating time was 62.3 minutes and the mean blood loss was 24.4 mL. The mean hospital stay was 3.6 days, with no mortalities. Blood loss was the only factor affected by severity (20.9 mL versus 60.1 mL, = 0.0164), and operating time was the only factor affected by high Charlson comorbidity index (53.4 versus 67.8 minutes, = 0.0153).

Conclusion: Our aggressive strategy is acceptable, and severity and Charlson comorbidity index are not critical factors suggesting the disqualification of early laparoscopic cholecystectomy in patients with any grade acute cholecystitis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4293/JSLS.2020.00116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035821PMC
April 2021

Predictive scoring system for advanced liver fibrosis in Japanese patients with severe obesity.

Surg Today 2021 Apr 7. Epub 2021 Apr 7.

Division of Hepatology, Department of Internal Medicine, Iwate Medical University, 2-1-1 Idaidori, Yahaba, 028-3695, Japan.

Purpose: The aim of this study was to examine the predictive scoring system of advanced liver fibrosis in severely obese Japanese patients.

Methods: Seventy-two patients underwent laparoscopic sleeve gastrectomy and intraoperative liver biopsies. We classified these patients into two groups: Brunt stage ≥ 2 (advanced fibrosis) and 0/1 (none/mild fibrosis). A logistic regression analysis was performed to identify the predictors of advanced fibrosis.

Results: Sixteen patients had advanced fibrosis, while 56 had no/mild fibrosis. The prevalence of type 2 diabetes mellitus (T2DM) in advanced fibrosis group was significantly higher than in none/mild fibrosis. An univariate analysis of the factors predicting advanced fibrosis showed significant differences in AST/ALT ratio, serum insulin levels, HOMA-IR, and type IV collagen 7S in the T2DM group. According to a multivariate analysis, type IV collagen 7S was an independent predictor and the cutoff value was 5.6 ng/mL. We created a flow chart; high risk (T2DM and type IV collagen 7S ≥ 5.6 ng/mL), moderate risk (T2DM and type IV collagen 7S < 5.6 ng/mL), and low risk (non-DM). For those at high risk, the sensitivity, specificity, positive predictive value, and negative predictive value were 56.2%, 94.4%, 75.0%, and 87.9%, respectively.

Conclusion: This classification system has the potential to accurately categorize the risk of liver fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00595-021-02266-wDOI Listing
April 2021

Successful Pregnancies in a Patient with Childhood-onset Steroid-dependent Nephrotic Syndrome during Rituximab Maintenance Therapy.

Intern Med 2021 Mar 29. Epub 2021 Mar 29.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Japan.

There are an increasing number of reports on the safe use of rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, in pregnant women with hematological malignancies or refractory autoimmune diseases. In 2014, the use of RTX for patients with complicated steroid-dependent nephrotic syndrome (SDNS) was approved in Japan. We herein report a woman with childhood-onset complicated SDNS due to focal and segmental glomerulosclerosis, who had two successful pregnancies while receiving RTX maintenance therapy. No adverse complications were observed during the pregnancies, and she delivered healthy newborns. This case suggested that RTX may be used safely in pregnant women complicated with SDNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.6633-20DOI Listing
March 2021

Effects of SLC22A2 808G>T polymorphism and bosutinib concentrations on serum creatinine in patients with chronic myeloid leukemia receiving bosutinib therapy.

Sci Rep 2021 Mar 18;11(1):6362. Epub 2021 Mar 18.

Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, 010-8543, Japan.

The purpose of this study was to investigate the effects of SLC22A2 808G>T polymorphism and trough concentrations (C) of bosutinib on serum creatinine in 28 patients taking bosutinib. At 1, 3, 6, 12, 24, and 36 months after administration, analysis of bosutinib C and creatinine was performed at the same time of day. Significant correlations were observed between bosutinib C and the change rate of serum creatinine or the estimated glomerular filtration rate (eGFR; r = 0.328, P < 0.001 and r = - 0.315, P < 0.001, respectively). These correlations were particularly high in patients having the SLC22A2 808G/G genotype (r = 0.345 and r = - 0.329, respectively); however, in patients having the 808T allele, there were no significant differences. In multivariate analyses, the SLC22A2 808G/G genotype, patient age, bosutinib C and second-line or later bosutinib were independent factors influencing the change rate of creatinine. Bosutinib elevated serum creatinine through organic cation transporter 2 (OCT2). We observed a 20% increase in serum creatinine with a median bosutinib C of 63.4-73.2 ng/mL. Periodic measurement of serum creatinine after bosutinib therapy is necessary to avoid progression to severe renal dysfunction from simple elevation of creatinine mediated by OCT2 following bosutinib treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-85757-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7973796PMC
March 2021

Identification of epigenetic memory candidates associated with gestational age at birth through analysis of methylome and transcriptional data.

Sci Rep 2021 Feb 9;11(1):3381. Epub 2021 Feb 9.

Department of Pediatrics, The University of Tokyo Hospital, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23-41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-021-83016-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873311PMC
February 2021

Methotrexate-induced transient encephalopathy in an adolescent and young adult patient with acute lymphoblastic leukemia.

Intern Med 2021 Feb 1. Epub 2021 Feb 1.

Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Japan.

A 17-year-old girl was diagnosed with acute lymphoblastic leukemia (ALL). After the administration of high-dose methotrexate (MTX) or intrathecal MTX, the patient experienced transient hemiparesis and motor aphasia. Diffusion-weighted magnetic resonance imaging showed a high-intensity lesion in the bilateral centrum semiovale, and a vasospasm was detected in the proximal segment of bilateral A1 on magnetic resonance angiography. Edaravone was administered, and leucovorin rescue treatment was continued; eventually, the patient's neurological symptoms completely resolved. This finding suggested that vasospasm might be a mechanism underlying MTX-induced transient encephalopathy in adolescent and young adult patients with ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.5937-20DOI Listing
February 2021

Prognostic effect of comorbidities in patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor.

Cancer Sci 2020 Oct 12;111(10):3714-3725. Epub 2020 Aug 12.

Department of Hematology and Rheumatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan.

Comorbidities at diagnosis among patients with chronic myeloid leukemia in chronic phase (CML-CP) may affect their overall survival (OS) rate even in the tyrosine kinase inhibitor (TKI) era. However, the prognostic impact of comorbidities in patients with CML-CP treated with a second-generation TKI (2GTKI) has not been elucidated. We evaluated the effect of comorbidities on survival using the Charlson Comorbidity Index (CCI) in patients with CML-CP treated with imatinib or a 2GTKI (nilotinib and dasatinib). From April 2010 to March 2013, 506 patients with CML-CP were registered for the population-based cohort study, and 452 with a median age of 56 y were assessable. Treatment groups included 139 patients receiving imatinib, 169 receiving nilotinib, and 144 receiving dasatinib. Comorbidities were diagnosed in 99 patients. CCI scores were stratified as follows: 2, 353 patients; 3, 72 patients; and ≥4, 27 patients. Treatment response did not vary relative to CCI scores. However, across the entire cohort, the OS rate was significantly lower among patients with higher CCI scores than in those with a CCI score of 2 (94.4% in score 2, 89.0% in score 3, and 72.8% in score ≥4; P < .001). Multivariate analysis identified a CCI score of ≥4 as a strong adverse prognostic factor for OS rather than the disease-specific risk factor, older age, performance status, or selection of TKI (Wald test, P < .01). Our results demonstrated that comorbidities at diagnosis were the most important predictive factor for successful treatment, regardless of the TKI type used in CML-CP. This trial was registered at UMIN-CTR as 00003581.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541002PMC
October 2020

Correlation between increased immune checkpoint molecule expression and refractoriness to blinatumomab evaluated by longitudinal T cell analysis.

Int J Hematol 2021 Apr 2;113(4):600-605. Epub 2021 Jan 2.

Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, 010-8543, Japan.

Blinatumomab enhances survival in patients with B-cell precursor acute lymphoblastic leukemia (B-ALL) by inducing T cell activation. However, approximately 50% of patients with relapsed or refractory B-ALL do not respond to blinatumomab, and the correlation between T cell phenotype and blinatumomab response remains unclear. To assess this correlation, we longitudinally compared immune checkpoint molecules in T cells before and during blinatumomab treatment between a responder and non-responder. In the responder, the expression level of granzyme B increased following infusion of blinatumomab and complete remission was achieved. On the other hand, the non-responder consistently expressed higher levels of programmed death-1 (PD-1), T cell immunoglobulin and mucin domain 3 (Tim-3), and T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) in CD8 + T cells than the responder during blinatumomab treatment and showed no response despite the addition of two donor lymphocyte infusions. Furthermore, the residual tumors in bone marrow after blinatumomab treatment showed increased expression of immune checkpoint ligands: PD-L1 (PD-1 ligand), Galectin-9 (Tim-3 ligand), PD-L2 (PD-1 ligand) and CD155 (TIGIT ligand). In conclusion, immune checkpoint molecule levels could correlate with response to blinatumomab.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-03047-wDOI Listing
April 2021

Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib-induced hypercholesterolaemia in patients with chronic myeloid leukaemia.

J Clin Pharm Ther 2021 Apr 27;46(2):382-387. Epub 2020 Oct 27.

Department of Pharmacy, Akita University Hospital, Akita, Japan.

What Is Known And Objective: The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C ), low-density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia.

Methods: Plasma concentrations of nilotinib and PCSK9 were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively.

Results And Discussion: LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P = .019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut-off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P = .043); however, there were no differences in mean nilotinib C .

What Is New And Conclusion: Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib-induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcpt.13294DOI Listing
April 2021

The BCRP inhibitor febuxostat enhances the effect of nilotinib by regulation of intracellular concentration.

Int J Hematol 2021 Jan 6;113(1):100-105. Epub 2020 Oct 6.

Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, Akita, 010-8543, Japan.

Nilotinib is a substrate of the breast cancer resistance protein (BCRP), which is a drug efflux transporter encoded by ABCG2 and regulates the pharmacokinetics of its substrates. We investigated the interaction between nilotinib and BCRP in chronic myeloid leukemia (CML) cells. An imatinib-resistant K562 cell line (K562/IM-R) treated with nilotinib was analyzed for BCRP expression, proliferation, apoptosis, and intracellular nilotinib concentration. K562/IM-R cells cultured with tyrosine kinase inhibitors (TKIs) showed an increased cell count and retained viability, whereas the growth of parental K562 cells was severely inhibited, suggesting that BCRP is involved in developing resistance to TKIs. Nilotinib-treated K562/IM-R cells showed a reduction in apoptosis; however, febuxostat pretreatment resulted in increased apoptosis. The intracellular concentration of nilotinib in K562/IM-R cells was significantly reduced compared to that in parental K562 cells, and febuxostat-pretreated K562/IM-R cells showed an increased intracellular nilotinib level compared to cells without pretreatment. The reduction in nilotinib levels caused by BCRP in CML cells might play a crucial role in resistance to TKIs. Moreover, febuxostat, as a BCRP inhibitor, could enhance nilotinib sensitivity, and combination therapy with nilotinib and febuxostat may represent a promising strategy for treatment of CML.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-03000-xDOI Listing
January 2021

A multicenter non-randomized phase III study of sentinel node navigation surgery for early gastric cancer.

Jpn J Clin Oncol 2021 Feb;51(2):305-309

Department of Surgery, Keio University School of Medicine, Tokyo, Japan.

This prospective multicenter non-randomized phase III study aims to evaluate the long-term outcome of sentinel node navigation surgery for early gastric cancer compared with conventional distal or total gastrectomy. Clinically diagnosed primary T1N0M0 gastric cancer patients with a single lesion (≤40 mm) and without previous endoscopic treatment will be enrolled in this study. Sentinel nodes are identified by dye and radioisotope tracers and are subjected to intraoperative rapid pathology. For patients with negative sentinel node metastasis, individualized surgery consisting of limited stomach resection and sentinel node basin dissection is performed, while standard gastrectomy with D2 lymph node dissection is employed for the positive sentinel node patients. A total of 225 patients will be accrued from 13 hospitals that have experience in sentinel node mapping. The primary endpoint is 5-year relapse-free survival. The secondary endpoints are overall survival, sentinel node detection rate, diagnostic accuracy for sentinel node, distribution of sentinel nodes and metastatic sentinel node/non-sentinel node, and postoperative quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jjco/hyaa179DOI Listing
February 2021

Evaluation of the plasma concentration of ponatinib in a chronic myeloid leukaemia patient with ponatinib intolerance.

J Clin Pharm Ther 2021 Feb 28;46(1):219-222. Epub 2020 Sep 28.

Department of Pharmacy, Akita University Hospital, Akita, Japan.

What Is Known And Objective: Some patients with chronic myeloid leukaemia (CML) cannot continue tyrosine kinase inhibitor (TKI) treatment due to intolerance associated with higher plasma concentration.

Case Summary: A 76-year-old woman with chronic-phase CML who showed resistance/intolerance to pre-TKIs has been treated with ponatinib. A high ponatinib bioavailability was noted; therefore, we administered ponatinib 15 mg/3 d to avoid adverse events due to high exposure. Eventually, the patient achieved a major molecular response.

What Is New And Conclusion: Monitoring of the ponatinib plasma concentration led to safe and effective CML management in a patient with higher drug bioavailability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jcpt.13257DOI Listing
February 2021

Coinfection with Human Norovirus and Escherichia coli O25:H4 Harboring Two Chromosomal blaCTX-M-14 Genes in a Foodborne Norovirus Outbreak in Shizuoka Prefecture, Japan.

J Food Prot 2020 Sep;83(9):1584-1591

Department of Microbiology, Shizuoka Institute of Environment and Hygiene, 4-27-2 Kitaando, Aoi-ku, Shizuoka, Shizuoka 420-8637, Japan.

Abstract: Hospital-acquired infections caused by extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are a global problem. Healthy people can carry ESBL-producing E. coli in the intestines; thus, E. coli from healthy people can potentially cause hospital-acquired infections. Therefore, the transmission routes of ESBL-producing E. coli from healthy persons should be determined. A foodborne outbreak of human norovirus (HuNoV) GII occurred at a restaurant in Shizuoka, Japan, in 2018. E. coli O25:H4 was isolated from some of the HuNoV-infected customers. Pulsed-field gel electrophoresis showed that these E. coli O25:H4 strains originated from one clone. Because the only epidemiological link among the customers was eating food from this restaurant, the customers were concurrently infected with E. coli O25:H4 and HuNoV GII via the restaurant food. Whole genome analysis revealed that the E. coli O25:H4 strains possessed genes for regulating intracellular iron and expressing the flagellum and flagella. Extraintestinal pathogenic E. coli often express these genes on the chromosome. Additionally, the E. coli O25:H4 strains had plasmids harboring nine antimicrobial resistance genes. These strains harbored ESBL-encoding blaCTX-M-14 genes on two loci of the chromosome and had higher ESBL activity. Multilocus sequence typing and fimH subtyping revealed that the E. coli O25:H4 strains from the outbreak belonged to the subclonal group, ST131-fimH30R, which has been driving ESBL epidemics in Japan. Because the E. coli O25:H4 strains isolated in the outbreak belonged to a subclonal group spreading in Japan, foods contaminated with ESBL-producing E. coli might contribute to spreading these strains among healthy persons. The isolated E. coli O25:H4 strains produced ESBL and contained plasmids with multiple antimicrobial resistance genes, which may make it difficult to select antimicrobials for treating extraintestinal infections caused by these strains.

Highlights:
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4315/JFP-20-042DOI Listing
September 2020

Hypoxia-inducible hexokinase-2 enhances anti-apoptotic function via activating autophagy in multiple myeloma.

Cancer Sci 2020 Nov 8;111(11):4088-4101. Epub 2020 Sep 8.

Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.

Multiple myeloma (MM) is an incurable hematopoietic neoplasm derived from plasma cells, and existing in the bone marrow. Recent developments in the field of myeloma onco-biology have enabled the use of proteasome inhibitors (PIs) as key drugs for MM. PIs can increase cell sensitivity to endoplasmic reticulum stress, leading to apoptosis of myeloma cells. PI cannot kill all myeloma cells, however; one reason of this might be activation of autophagy via hypoxic stress in the bone marrow microenvironment. Hypoxia-inducible gene(s) that regulate autophagy may be novel therapeutic target(s) for PI-resistant myeloma cells. Here, a hypoxia-inducible glycolytic enzyme hexokinase-2 (HK2) was demonstrated to contribute by autophagy activation to the acquisition of an anti-apoptotic phenotype in myeloma cells. We found that hypoxic stress led to autophagy activation accompanied by HK2 upregulation in myeloma cells. Under hypoxic conditions, HK2 knockdown inhibited glycolysis and impaired autophagy, inducing apoptosis. The cooperative effects of a PI (bortezomib) against immunodeficient mice inoculated with HK2-knocked down myeloma cells were examined and significant tumor reduction was observed. An HK2 inhibitor, 3-bromopyruvate (3-BrPA), also induced apoptosis under hypoxic rather than normoxic conditions. Further examination of the cooperative effects between 3-BrPA and bortezomib on myeloma cells revealed a significant increase in apoptotic myeloma cells. These results strongly suggested that HK2 regulates the activation of autophagy in hypoxic myeloma cells. Cooperative treatment using PI against a dominant fraction, and HK2 inhibitor against a minor fraction, adapted to the bone marrow microenvironment, may lead to deeper remission for refractory MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cas.14614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648043PMC
November 2020

Hypereosinophilic syndrome with abundant Charcot-Leyden crystals in spleen and lymph nodes.

Asia Pac Allergy 2020 Jul 8;10(3):e24. Epub 2020 Jul 8.

Department of General Internal Medicine and Clinical Laboratory Medicine, Akita University Graduate School of Medicine, Akita, Japan.

Hypereosinophilic syndrome, which is characterized by eosinophilia in the peripheral blood, often causes various organ disorders. Charcot-Leyden crystals are recognized features of various diseases, such as parasite infection and asthma, and are known to be classic hallmarks of eosinophilic inflammation. Our recent study revealed the mechanism of Charcot-Leyden crystal formation (i.e., galectin-10 crystallization), namely the involvement of eosinophil extracellular trap cell death, a nonapoptotic cell death. Here we report an autopsy case of a 57-year-old man who had died of hypereosinophilic syndrome. We found numerous eosinophil extracellular trap cell death-associated Charcot-Leyden crystals in the spleen and lymph nodes. Observation of abdominal lymph nodes by electron microscopy revealed eosinophil extracellular traps and free extracellular granules, which are characteristic of typical eosinophil extracellular trap cell death. In this case, we observed various sizes of Charcot-Leyden crystals that were stained with anti-galectin-10 immunofluorescent staining. Further studies are required to understand the pathophysiological roles of Charcot-Leyden crystals and these may lead to the development of novel therapeutic modalities for severe eosinophilic inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5415/apallergy.2020.10.e24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402945PMC
July 2020

JSH Practical Guidelines for Hematological Malignancies, 2018: I. Leukemia-4. Chronic myeloid leukemia (CML)/myeloproliferative neoplasms (MPN).

Int J Hematol 2020 Sep 11;112(3):268-291. Epub 2020 Aug 11.

Department of Hematology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-020-02964-0DOI Listing
September 2020

Cdc42 regulates cell polarization and contractile actomyosin rings during terminal differentiation of human erythroblasts.

Sci Rep 2020 07 16;10(1):11806. Epub 2020 Jul 16.

Department of Hematology, Nephrology, and Rheumatology, Graduate School of Medicine, Akita University, Akita, Japan.

The molecular mechanisms involved in the terminal differentiation of erythroblasts have been elucidated by comparing enucleation and cell division. Although various similarities and differences between erythroblast enucleation and cytokinesis have been reported, the mechanisms that control enucleation remain unclear. We previously reported that dynein and microtubule-organizing centers mediated the polarization of nuclei in human erythroblasts. Moreover, the accumulation of F-actin was noted during the enucleation of erythroblasts. Therefore, during enucleation, upstream effectors in the signal transduction pathway regulating dynein or actin, such as cell division control protein 42 homolog (Cdc42), may be crucial. We herein investigated the effects of the Cdc42 inhibitor, CASIN, on cytokinesis and enucleation in colony-forming units-erythroid (CFU-Es) and mature erythroblasts (day 10). CASIN blocked the proliferation of CFU-Es and their enucleation in a dose-dependent manner. Dynein adopted an island-like distribution in the cytoplasm of non-treated CFU-Es, but was concentrated near the nucleus as a dot and co-localized with γ-tubulin in CASIN-treated cells. CASIN blocked the accumulation of F-actin in CFU-Es and day 10 cells. These results demonstrated that Cdc42 plays an important role in cytokinesis, nuclear polarization and nuclear extrusion through a relationship with dynein and actin filament organization during the terminal differentiation of erythroblasts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-68799-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366696PMC
July 2020

Differences in pharmacological property between combined therapy of the vasopressin V2-receptor antagonist tolvaptan plus furosemide and monotherapy of furosemide in patients with hospitalized heart failure.

J Cardiol 2020 11 19;76(5):499-505. Epub 2020 Jul 19.

Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan.

Background: Tolvaptan has been shown to improve congestion in heart failure patients. The purpose of this study was to evaluate the pharmacology and clinical efficacy of combined tolvaptan and furosemide therapy.

Methods: This study included 40 patients with systemic volume overload who were hospitalized for heart failure. Patients who showed no improvement in the condition after receiving 20 mg intravenous furosemide were included and were randomly selected to receive tolvaptan as an add-on to furosemide or to receive an increased dose of furosemide. We evaluated the bioelectrical impedance analyzer parameters, the parameters of the inferior vena cava using echocardiography, vital signs, body weight, urine output, and laboratory data for 5 days.

Results: In the changes from baseline between intracellular water volume (ICW) and extracellular water volume (ECW) after additional use of tolvaptan or furosemide from Day 1 to Day 5, there were no significant differences observed between ICW and ECW over 5 days in the tolvaptan + furosemide group, although differences were found in the furosemide group from Day 2 onward. Changes in the respiratory collapse of inferior vena cava increased significantly, and systolic blood pressure decreased significantly only in the furosemide group.

Conclusions: The present study clearly demonstrates that combined therapy with tolvaptan and furosemide removed excess ICW and ECW to an equal extent, while furosemide alone primarily removed ECW, including intravascular water.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jjcc.2020.05.012DOI Listing
November 2020

Outcome of colorectal cancer in Diamond-Blackfan syndrome with a ribosomal protein S19 mutation.

Clin J Gastroenterol 2020 Dec 8;13(6):1173-1177. Epub 2020 Jul 8.

Department of Clinical Oncology, Graduate School of Medicine, Akita University, Hirosaki University Graduate School of Medicine, Akita, Japan.

Diamond-Blackfan anemia is an autosomal dominant syndrome, characterized by anemia and a predisposition for malignancies. Ribosomal proteins are responsible for this syndrome, and the incidence of colorectal cancer in patients with this syndrome is higher than the general population. This patient's Diamond-Blackfan anemia was caused by a novel ribosomal protein S19 gene mutation, and he received chemotherapy for colorectal cancer caused by it. In his cancer, ribosomal proteins S19 and TP53 were overexpressed. He received 5FU and cetuximab; however, his anemia made chemotherapy difficult, and he did not survive long. Patients with Diamond-Blackfan anemia should be screened earlier and more often for colorectal cancer than usual.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12328-020-01176-7DOI Listing
December 2020

The Impact of Hemodialysis and Liver Cirrhosis on the Plasma Concentrations of Tyrosine Kinase Inhibitors in a Patient with Chronic Myeloid Leukemia.

Intern Med 2020 Nov 7;59(21):2745-2749. Epub 2020 Jul 7.

Departments of Hematology and Rheumatology, Faculty of Medicine, Kindai University Hospital, Japan.

We recently treated a chronic myeloid leukemia (CML) patient with liver and renal dysfunction, who was undergoing hemodialysis (HD). He was treated with 50 mg dasatinib (DAS) once daily just before HD. The maximum plasma concentration of DAS was 227 ng/mL on a non-HD day and 46.9 ng/mL on a HD day. He was subsequently treated with 200 mg bosutinib (BOS) once daily. The plasma concentration of BOS changed from 74.5 ng/mL before HD to 58.8 ng/mL after HD. Our results indicate that close monitoring of the plasma tyrosine kinase inhibitor concentrations should be considered in CML patients with organ impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2169/internalmedicine.4871-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691019PMC
November 2020

Impact of truncal vagotomy on complicated peptic ulcer after distal gastrectomy with reconstruction by jejunal pouch interposition.

Surg Case Rep 2020 Jun 1;6(1):123. Epub 2020 Jun 1.

Department of Surgery, The Jikei University School of Medicine, 3-19-18 Nishi-shinbashi, Minato-ku, Tokyo, 105-8471, Japan.

Background: We encountered a case of marginal ulcer in the jejunum after distal gastrectomy with jejunal pouch interposition. However, it has not been reported and not confirmed the treatment. We chose truncal vagotomy, considering reduced morbidity and postoperative complications.

Case Presentation: A case was a 69-year-old woman who was admitted to our hospital with melena. She had received curative distal gastrectomy with a 15-cm jejunal pouch reconstruction for early gastric cancer. Marginal ulcer in the jejunal pouch was detected by upper gastrointestinal endoscopy. She was given medication; however, she repeated hospitalization for melena and abdominal pain. Therefore, we decided to perform surgery, and truncal vagotomy was performed. The patient's postoperative course was uneventful and was discharged on the 22nd postoperative day. Symptoms such as abdominal pain and melena were improved after truncal vagotomy.

Conclusion: We presented a case with a complicated peptic ulcer after distal gastrectomy with reconstruction by jejunal pouch interposition, which was successfully treated by truncal vagotomy, a surgical acid-reducing procedure which does not require resection of remnant stomach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40792-020-00879-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266894PMC
June 2020