Publications by authors named "Yuichi Ishikawa"

427 Publications

Dasatinib-based Two-step Induction for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Blood Adv 2021 Sep 13. Epub 2021 Sep 13.

Kanazawa University, Kanazawa, Japan.

The standard treatment for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, approximately 40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities and relapse before HSCT, and older age. We evaluated dasatinib-based two-step induction with the primary endpoint of 3-year event-free survival (EFS) in this study. The first induction (IND1) was dasatinib plus prednisolone to achieve CR and the second (IND2) was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD)-negativity. Patients who achieved CR and had an appropriate donor were recommended to undergo HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate. Prophylactic dasatinib after HSCT was assigned to patients with positive pre-transplant MRD. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD-negativity after IND2. Non-relapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight (74.4%) patients underwent HSCT in CR1 and 44 (75.9%) were negative with pre-transplant MRD. At a median follow-up of 4.0 years, the 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based two-step induction was demonstrated to improve the 3-year EFS. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173.
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http://dx.doi.org/10.1182/bloodadvances.2021004607DOI Listing
September 2021

Hemodynamic Characteristics After Fontan Procedure in Patients with Down's Syndrome.

Pediatr Cardiol 2021 Sep 8. Epub 2021 Sep 8.

Department of Pediatric Cardiology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha Higashi-ku, Fukuoka, 813-0017, Japan.

Patients with Down's syndrome (DS) are generally regarded as not being good candidates for the Fontan procedure. However, detailed hemodynamic changes over time are not fully clarified. A retrospective chart review of all patients with DS who underwent the Fontan procedure and 5 times that number of Fontan patients without DS performed in Fukuoka Children's Hospital and Kyushu University Hospital. Seven Fontan patients with DS were identified, and 35 Fontan patients without DS were recruited. During the mean observational periods of 14.7 years and 15.0 years (DS and non-DS, respectively) after the Fontan procedure, only one DS patient died. Central venous pressure (CVP) and transpulmonary pressure gradient significantly increased, and arterial oxygen saturation significantly decreased over time in DS patients after the Fontan procedure compared with those without DS. CVP in DS patients after the Fontan procedure increased over time compared with non-DS patients. Better management including the efficacy of Pulmonary arterial hypertension-specific therapy should be clarified in further studies.
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http://dx.doi.org/10.1007/s00246-021-02727-6DOI Listing
September 2021

Distinct Clinicopathologic Features and Possible Pathogenesis of Localized ALK-positive Histiocytosis of the Breast.

Am J Surg Pathol 2021 Sep 6. Epub 2021 Sep 6.

Division of Pathology Pathology Project for Molecular Targets, Cancer Institute Department of Pathology Breast Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research Department of Pathology, Mita Hospital, International University of Health and Welfare, Tokyo Departments of Pathology Breast Surgery, Saku Central Hospital Advanced Care Center Department of Pathology, Saku Central Hospital, Saku, Nagano Prefecture, Japan.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis is a rare emerging entity characterized by systemic or localized proliferation of histiocytes harboring ALK rearrangements. Breasts are reportedly affected by ALK-positive histiocytosis. Here, we evaluated 2 localized cases of breast ALK-positive histiocytosis through a comprehensive clinicopathologic, molecular, and genomic analysis to further delineate this entity and better understand its pathogenesis. The cases involved 2 undiagnosed ALK-positive spindle-cell breast lesions. Both cases were Asian women aged 30s to 40s who underwent excisions for asymptomatic breast masses. Macroscopically, both lesions were well-circumscribed, solid masses. Microscopically, both lesions were predominantly composed of fascicles with uniform, bland spindle cells, admixed with epithelioid histiocyte-like cells and lymphoid aggregates. Immunohistochemically, the spindle and epithelioid cells coexpressed ALK and histiocytic markers (eg, CD68, CD163). Genetically, both lesions harbored KIF5B-ALK, confirmed by fluorescence in situ hybridization and polymerase chain reaction-direct sequencing analyses. Combining these results, both cases were successfully diagnosed as ALK-positive histiocytosis. Furthermore, no common or previously annotated somatic alterations were identified by whole-exome sequencing. One case harbored clonal immunoglobulin gene rearrangements according to the polymerase chain reaction-based BIOMED-2 protocol. Therefore, ALK-positive histiocytosis can be accurately diagnosed through a combination of morphologic, immunohistochemical, and molecular analyses. In this entity, breast cases may have distinct clinicopathologic features: Asian women aged 30s to 40s, asymptomatic masses, and predominant spindled morphology. For pathogenesis, ALK rearrangements could be the driver alteration, and a subset of ALK-positive histiocytosis may harbor a lymphoid lineage. These findings can be utilized to improve the diagnosis of ALK-positive histiocytosis and better understand its pathogenesis.
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http://dx.doi.org/10.1097/PAS.0000000000001794DOI Listing
September 2021

Elastin in pulmonary pathology: relevance in tumors with lepidic or papillary appearance. A comprehensive understanding from a morphological viewpoint.

Histopathology 2021 Aug 6. Epub 2021 Aug 6.

Department of Pathology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.

Elastin and collagen are the main components of the lung connective tissue network and together provide the lung with elasticity and tensile strength. In pulmonary pathology elastin stain is used to a variable extent in different countries. These uses include evaluation of the pleura in staging and distinction of invasion from collapse of alveoli after surgery (iatrogenic collapse). In the latter, elastin is used to highlight distorted but pre-existing alveolar architecture from true invasion. In addition to variable use and experience, the interpretation of elastin in some adenocarcinomas leads to interpretative differences between collapsed lepidic patterns and true papillary patterns. This review aims to summarize the existing data on the use of elastin in pulmonary pathology, based on literature data and morphological characteristics. The effect of iatrogenic collapse and interpretation of elastin in pulmonary adenocarcinomas is discussed in detail, especially for the distinction between lepidic patterns and papillary carcinoma.
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http://dx.doi.org/10.1111/his.14537DOI Listing
August 2021

[Recent advances in molecular targeted therapy for acute myeloid leukemia].

Authors:
Yuichi Ishikawa

Rinsho Ketsueki 2021 ;62(6):562-571

Department of Hematology, Nagoya University Hospital.

Acute myeloid leukemia (AML) is a heterogeneous disease, and recent advances in sequencing technology have revealed that the accumulation of various genetic abnormalities is deeply involved in the pathogenesis of AML and its clonal evolutions during disease progression. Prognostic classifications and therapeutic strategies based on the cytogenetic and genetic abnormalities have been proposed, and several new therapeutic agents targeting the molecular abnormalities have been energetically investigated to eliminate AML cells. In the last few years, several new agents, including FLT3, IDH, BCL-2, and Hedgehog inhibitors, have been approved for the treatment of newly diagnosed AML, and their clinical applications have begun in the United States. Although there has been a delay of several years, the clinical development of these new agents is also underway in Japan, and it is expected that a new era of AML treatment will begin in the near future. It is necessary to establish novel risk-adopted treatment strategies incorporating these agents in monotherapies and/or effectively designed combination therapies.
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http://dx.doi.org/10.11406/rinketsu.62.562DOI Listing
July 2021

The Impact of the Pulmonary Artery Index and Aortopulmonary Collateral Artery Coil Embolization on Intractable Pleural Effusions After a Fontan Surgery.

Int Heart J 2021 May 15;62(3):559-565. Epub 2021 May 15.

Department of Pediatric Cardiovascular Surgery, Fukuoka Children's Hospital.

An intractable pleural effusion is a common comorbidity of a Fontan operation, occasionally leading to undesirable outcomes. The preventive effect of aortopulmonary collateral (APC) coil embolization against a pleural effusion before a Fontan operation is still controversial.This is a retrospective single-center study; among 227 Fontan cases, 57 cases with complete MRI data were analyzed at first. Factors associated with the duration of pleural drainage (median: 6 (2-41) days) and that of postoperative hospital stay (median: 25 (14-91) days) were analyzed using a multiple regression analysis. The pulmonary artery index (PAI; Nakata index) was associated with both the pleural drainage duration (P < 0.05, r = 0.17) and postoperative hospital stay (P < 0.05, r = 0.10).Thereafter, all the 227 patients were classified into the following three groups: Group A (12 patients in whom the embolization was performed within 30 days before the Fontan surgery), Group B (131 patients in whom the embolization was performed more than 30 days before the Fontan surgery), and Group C (84 patients in whom the embolization was not performed). Patients in Group A were found to be associated with the shortest length of both periods (P < 0.05).Lower PAI values were related to a prolonged pleural drainage duration and postoperative hospital stay. APC coil embolizations may reduce the risk if they are performed shortly (less than 30 days) before the operation.
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http://dx.doi.org/10.1536/ihj.20-498DOI Listing
May 2021

Novel Histologic Classification of Small Tumor Cell Nests for Lung Adenocarcinoma With Prognostic and Etiological Significance: Small Solid Nests and Pure Micropapillary Nests.

Am J Surg Pathol 2021 05;45(5):604-615

Division of Pathology, The Cancer Institute, The Cancer Institute Hospital, Japanese Foundation for Cancer Research.

Small tumor cell nests such as micropapillary nests are histologic poor prognostic markers for adenocarcinomas of various organs, including the lung. However, for the lung, the association of micropapillary patterns with smoking is controversial, which may be because of a vague definition of micropapillary patterns. This study clarifies the implications of small tumor cell nests by introducing a new dichotomic classification based on the glandular polarity of tumor cells: pure micropapillary nests (pMPs), preserving glandular polarity, and small solid nests (SSNs), lacking polarity. We examined the clinicopathologic factors in 436 resected adenocarcinomas, and analyzed the overall survival between groups classified by either the presence or absence of pMPs and SSNs. pMP was positively associated with nonsmoking-related features such as epidermal growth factor receptor mutations and thyroid transcription factor 1 expression. By contrast, SSN was positively associated with smoking-related features such as KRAS mutations and hepatocyte nuclear factor-4a expressions. Besides, pMP and SSN were significant and independent indicators of poor prognosis in all stages. SSN was an indicator in stage I too, whereas pMP was not. Furthermore, prognoses of the group with SSN were significantly worse than those of pMP-only group. In conclusion, the present study has revealed 2 completely different patterns of small tumor cell nests in lung adenocarcinoma, the nonsmoking-related pMPs, and the smoking-related SSNs, by considering glandular polarity. MPP should include only pMPs, and SSNs should be in a solid pattern. This novel classification might boast clinical significance as a potent poor prognostic marker as well as a factor reflecting etiological and genetic characters.
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http://dx.doi.org/10.1097/PAS.0000000000001696DOI Listing
May 2021

R702C is associated with erythroid abnormality with splenomegaly in mice.

Nagoya J Med Sci 2021 Feb;83(1):75-86

Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan.

disorders are characterized by giant platelets, thrombocytopenia, and Döhle body-like cytoplasmic inclusion bodies in granulocytes. However, whether these disorders cause any changes in erythroid cells has yet to be determined. This study analyzed the influence of R702C, as one of the most commonly detected disorders, on erythroid cells in a mouse model. Knock-in mice expressing R702C mutation either systemically or specific to hematological cells (R702C and R702C vav1 mice, respectively) were used in this study. Both displayed lower hemoglobin and higher erythropoietin levels than wild-type (WT) mice, along with significant splenomegaly. Flow cytometric analysis revealed erythroblasts present at a higher rate than WT mice in the spleen. However, no obvious abnormalities were seen in erythroid differentiation from megakaryocyte/erythroid progenitor to erythrocyte. Cell culture assay by fetal liver and colony assay also showed normal progression of erythroid differentiation from erythroid burst-forming unit to red blood cell. In conclusion, R702C and R702C vav1 mice displayed erythroid abnormality with splenomegaly. However, erythroid differentiation showed no obvious abnormality. Further research is required to elucidate the underlying mechanisms.
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http://dx.doi.org/10.18999/nagjms.83.1.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938085PMC
February 2021

Follicular T-cell lymphoma mimicking lymphocyte-rich classic Hodgkin lymphoma: a case report of a diagnostic pitfall.

J Clin Exp Hematop 2021 Jun 15;61(2):97-101. Epub 2021 Mar 15.

Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.

Follicular T-cell lymphoma (FTCL), one of the nodal T-cell lymphomas with T follicular helper (T) phenotype, is an uncommon disease. The diagnosis of FTCL is challenging on the distinction from the morphological mimics mostly exemplified by follicular lymphoma. Here, we described a case of FTCL that mimicked lymphocyte-rich classic Hodgkin lymphoma (LRCHL). A 47-year-old male presented with cervical lymphadenopathy. The biopsy specimen demonstrated nodular lymphoid proliferation, which included scattered CD30+ CD15- CD20- PAX5 weakly+ Hodgkin and Reed-Sternberg (HRS)-like cells and a rich distribution of CD3+ CD4+ PD1+ T-cells. Epstein Barr virus was not detected in HRS-like cells, but it was detected in a small proportion of the scattered lymphocytes. The large cells were also negative for programmed cell death ligand 1, which appeared to be coincidental as described in our previous report of LRCHL. However, flow cytometry showed a CD3- CD4+ T-cell population that constituted 37.4% of all gated lymphocytes. A PCR analysis showed a clonal T-cell receptor-gamma gene rearrangement, but not a clonal immunoglobulin heavy chain gene rearrangement, and showed RHOA G17V mutation. The constellation of these findings led us to revise the diagnosis to FTCL. This result indicated that our case belonged to a relatively indolent subgroup of nodal peripheral T-cell lymphoma of T phenotype, which affects patients ≤60 years old, recently proposed by our group. This case report expands our understanding of the morphologic spectrum of FTCL and its clinicopathologic significance.
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http://dx.doi.org/10.3960/jslrt.20052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265489PMC
June 2021

Estimation of treatment and prognostic factors of pneumocystis pneumonia in patients with connective tissue diseases.

RMD Open 2021 03;7(1)

The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan

Objectives: To investigate short-term prognosis and prognostic factors for connective tissue disease-associated pneumocystis pneumonia (CTD-PCP) using the Japanese nationwide diagnosis procedure combination (DPC) inpatient database.

Methods: The present retrospective cohort study from April 2014 to March 2016 included data of patients with CTD-PCP extracted from the DPC database using the 10 revision of International Classification of Diseases and Injuries codes.

Results: In 15 901 766 cases registered from 1329 hospitals, 333 of 67 890 patients who were admitted with PCP were diagnosed with CTD-PCP and included in the study. The median age was 71.0 years, and 214 (64.3%), 80 (24.0%), and 29 (8.7%) patients received sulfamethoxazole/trimethoprim (ST) monotherapy and pentamidine-containing and atovaquone-containing therapy, respectively. There were 114 (34.2%) in-hospital deaths, and the 30-day and 60-day in-hospital survival rates after PCP treatment initiation were 66.0% and 53.7%, respectively. Older age (HR 1.06, 95% CI 1.03 to 1.08) and concomitant interstitial lung disease (ILD) (HR 1.65, 95% CI 1.12 to 2.42) were poor prognostic factors. Patients who completed PCP treatment with ST monotherapy had a significantly higher survival rate than those treated with those not treated with ST monotherapy (p=0.015; log-rank test). Pentamidine versus atovaquone as second-line therapy was significantly higher with atovaquone (p=0.012; log-rank test).

Conclusion: Older age and concomitant ILD were poor prognostic factors for CTD-PCP. ST was a reasonable first-line therapy in patients with CTD-PCP, and patients with inadequate response to ST treated with atovaquone tended to have a better prognosis than those treated with pentamidine.
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http://dx.doi.org/10.1136/rmdopen-2020-001508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944977PMC
March 2021

Monitoring epidermal growth factor receptor C797S mutation in Japanese non-small cell lung cancer patients with serial cell-free DNA evaluation using digital droplet PCR.

Cancer Sci 2021 Jun 2;112(6):2371-2380. Epub 2021 May 2.

Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is effective in treating both naïve and T790M-mutated EGFR-TKI-resistant non-small cell lung cancer patients. The EGFR C797S mutation is the major osimertinib resistance mechanism. The present study monitored the EGFR C797S mutation during osimertinib treatment in Japanese patients using droplet digital PCR (ddPCR). In our first cohort, C797S detection was validated with tumor specimens and/or plasma samples from 26 patients using ddPCR with custom-designed probes detecting and discriminating T790M and C797S in cis and trans positions. In our second cohort, 18 patients with EGFR-T790M who were going to start osimertinib were analyzed using ddPCR by collecting the plasma samples every month from the beginning of the course of osimertinib. In the first cohort, C797S was detected in 15.4% of patients. C797S and T790M in cis and trans positions were distinguished using ddPCR. In the second cohort, serial cfDNA evaluation revealed that the rate of EGFR mutation changes with disease state. Increases of EGFR mutation were detected, including C797S several months before the diagnosis of disease progression. As with the first cohort, C797S and T790M in cis and trans position were distinguished by ddPCR at disease progression. Coincidentally, in the first cohort, next generation sequencing detected NRAS Q61K mutation and the resistance with NRAS Q61K mutation was overcome by trametinib. In the second cohort, serial cfDNA analysis was useful for evaluating bone oligo-progression and local radiation therapy.
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http://dx.doi.org/10.1111/cas.14879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8177776PMC
June 2021

Unusual presentation of recurrent follicular lymphoma as diffuse granular shadow.

Respirol Case Rep 2021 Mar 22;9(3):e00710. Epub 2021 Feb 22.

Department of Respiratory Medicine Nagoya University Graduate School of Medicine Nagoya Japan.

A 75-year-old man was diagnosed with advanced follicular lymphoma because of enlarged cervical lymph nodes. He received chemotherapy and was in complete remission for four years. However, after four years, he developed diffuse lymphadenopathy in the abdominal and iliac area suspected to be recurrent follicular lymphoma. At the time, he was asymptomatic and did not have any accompanying lung lesions. Due to his asymptomatic state, careful monitoring was chosen. Later, he developed diffuse granular shadow in the lung fields. A definite diagnosis was difficult to achieve without histological findings. Therefore, transbronchial lung biopsy of the lesions was performed. The pathology and immunohistochemistry of the lesions revealed recurrent follicular lymphoma. Although the frequency of recurrent follicular lymphoma presenting with diffuse granular shadow is uncommon, recurrent malignant lymphoma should be considered as a differential diagnosis in case with a history of malignant lymphoma.
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http://dx.doi.org/10.1002/rcr2.710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898273PMC
March 2021

Machine learning-aided risk stratification in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Biomark Res 2021 Feb 18;9(1):13. Epub 2021 Feb 18.

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

We used the eXtreme Gradient Boosting algorithm, an optimized gradient boosting machine learning library, and established a model to predict events in Philadelphia chromosome-positive acute lymphoblastic leukemia using a machine learning-aided method. A model was constructed using a training set (80%) and prediction was tested using a test set (20%). According to the feature importance score, BCR-ABL lineage, polymerase chain reaction value, age, and white blood cell count were identified as important features. These features were also confirmed by the permutation feature importance for the prediction using the test set. Both event-free survival and overall survival were clearly stratified according to risk groups categorized using these features: 80 and 100% in low risk (two or less factors), 42 and 47% in intermediate risk (three factors), and 0 and 10% in high risk (four factors) at 4 years. Machine learning-aided analysis was able to identify clinically useful prognostic factors using data from a relatively small number of patients.
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http://dx.doi.org/10.1186/s40364-021-00268-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890949PMC
February 2021

A Recurrent Case of Adult-onset Still's Disease with Concurrent Acalculous Cholecystitis and Macrophage Activation Syndrome/Hemophagocytic Lymphohistiocytosis Successfully Treated with Combination Immunosuppressive Therapy.

Intern Med 2021 Jun 1;60(12):1955-1961. Epub 2021 Feb 1.

Department of Rheumatology, Yokohama Rosai Hospital, Japan.

We herein report the case of 21-year-old female diagnosed with adult-onset Still's disease (AOSD) three years earlier who presented with fever and right upper abdominal pain. She was diagnosed with acute acalculous cholecystitis (AAC) based on hepatic dysfunction, elevated C-reactive protein, and gallbladder wall thickening on abdominal ultrasound. Based on the presence of pancytopenia, hyperferritinemia, and hemophagocytosis by a bone marrow examination, she was diagnosed with macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH) which was refractory to glucocorticoid pulse therapy. The combination of intravenous cyclosporine A with glucocorticoids was able to successfully control the disease activity of AOSD-related AAC and MAS/HLH.
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http://dx.doi.org/10.2169/internalmedicine.5781-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263191PMC
June 2021

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation.

Stem Cells Transl Med 2021 Apr 14;10(4):542-553. Epub 2020 Dec 14.

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

Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft-vs-host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as number 000024291.
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http://dx.doi.org/10.1002/sctm.20-0381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980216PMC
April 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

[Clinical significance of MRD in AML].

Authors:
Yuichi Ishikawa

Rinsho Ketsueki 2020 ;61(9):1150-1159

Department of Hematology, Nagoya University Hospital.

Some studies have reported the clinical significance of minimal/measurable residual disease (MRD) in considering the prognostic stratification and therapeutic intervention after complete remission in acute myeloid leukemia (AML). In the clinical setting, multicolor flow cytometry (MFC), a quantitative PCR method targeting the expression of fusion genes generated by chromosomal translocation, such as PML-RARA, RUNX1-RUNXT1, and CBFB-MYH11, as well as WT1 mRNA, was used to detect MRD in AML. In recent years, quantitative PCR, next-generation sequence, and digital-droplet PCR methods targeting genetic alterations often detected in AML have been developed to assess its clinical significance. However, besides analysis methods, many common problems persist in MRD evaluation, such as sample collection points, type of samples, and threshold setting. Although several gene mutations involved in clonal hematopoiesis have been detected in CR patients, their presence did not correlate with the prognosis, and some leukemia-specific mutations did not always persist during the clonal evolution of AML. Therefore, it is essential to combine multiple methods, such as target gene mutation, quantitative PCR, and MFC to enhance the sensitivity of measurement. Furthermore, the establishment of novel treatment strategies incorporating MRD and molecular abnormalities is warranted for better clinical outcomes of AML.
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http://dx.doi.org/10.11406/rinketsu.61.1150DOI Listing
January 2021

Primary Tumor Histology Affects Oncological Outcomes Independently of the Anatomical Extent of Disease in Colorectal Liver Metastasis.

JMA J 2020 Jul 7;3(3):240-250. Epub 2020 Jul 7.

Department of Surgery, National Defense Medical College, Saitama, Japan.

Introduction: Growing evidence indicates the prognostic importance of the crosstalk between cancer cells and stroma through the induction of epithelial-mesenchymal transition (EMT). This study aimed to clarify the prognostic value of evaluating primary tumor histology with the anatomical extent of disease in patients with colorectal liver metastasis (CRLM).

Methods: Prognostic analyses were performed in 411 CRLM patients who underwent hepatectomy at two institutions. Tumors were graded into one of three histological categories based on integrated assessment of EMT-associated histology (Histology) in primary tumors, i.e., poorly differentiated clusters (PDCs) and desmoplastic reaction (DR).

Results: A prognostic grouping system for the anatomical extent of disease (N stage, liver metastasis number and size, and extrahepatic disease; Grade) stratified patients into three groups with different five-year relapse-free survival (RFS) rates after hepatectomy: A, 31% (191 patients); B, 15% (124 patients); and C, 6% (96 patients; < 0.0001). Histology (A, G1 PDC and mature-type DR; C, G3 PDC and immature-type DR; and B, others) identified 49, 120, and 242 patients with 46%, 5%, and 22% five-year RFS, respectively ( < 0.0001). Among prognostic factors, the Akaike information criterion was most favorable in Grade, followed by Histology. Multivariate analysis demonstrated that these two factors independently impacted RFS; two-year RFS after hepatectomy in different patient groups had a wide range (10%-76%).

Conclusions: Histological assessment of dedifferentiation and the stromal environment of primary tumors contributed to effective risk stratification of early relapse after hepatectomy, which could be useful to determine clinical management for CRLM patients.
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http://dx.doi.org/10.31662/jmaj.2018-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590386PMC
July 2020

Successful treatment of refractory acute lupus haemophagocytic syndrome using rituximab: a case report.

Mod Rheumatol Case Rep 2020 07 6;4(2):222-228. Epub 2020 Jan 6.

Department of Rheumatology, Yokohama Rosai Hospital, Yokohama, Japan.

Systemic lupus erythematosus (SLE)-associated haemophagocytic lymphohistiocytosis (HLH) is called acute lupus haemophagocytic syndrome (ALHS), which is relatively rare but life-threatening. We present the case of a 43-year-old woman diagnosed with SLE with panniculitis, pleuritis, and autoimmune hepatitis. She was treated with high-dose glucocorticoids. Although disease activity temporarily improved, she developed fever, elevation of liver enzymes, hyperferritinemia, severe inflammatory response, and thrombocytopenia a month after starting glucocorticoids. Bone marrow biopsy was performed and haemophagocytosis was observed. She was diagnosed with ALHS on day 49. Since she developed ALHS during administration of glucocorticoids, her ALHS was determined to be refractory to glucocorticoid monotherapy; therefore, additional immunosuppressive agents were needed. She was treated with methylprednisolone pulse, plasma exchange and cyclosporine A (CyA). However, CyA was discontinued on day 54 because CyA-induced hypertensive encephalopathy was suspected. Subsequently, rituximab (RTX) was introduced to treat refractory ALHS on day 56; the disease activity subsequently reduced. After four courses of RTX, her ferritin levels and platelet counts were within the normal range and the glucocorticoid dose could be tapered to betamethasone 2.0 mg/day on day 132. No subsequent recurrence of SLE and ALHS was observed until day 132. RTX might therefore be an effective therapeutic option for refractory ALHS.
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http://dx.doi.org/10.1080/24725625.2019.1705529DOI Listing
July 2020

Impact of DNA integrity on the success rate of tissue-based next-generation sequencing: Lessons from nationwide cancer genome screening project SCRUM-Japan GI-SCREEN.

Pathol Int 2020 Dec 8;70(12):932-942. Epub 2020 Oct 8.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.

In the nationwide cancer genome screening project SCRUM-Japan GI-SCREEN, 2590 archival formalin-fixed paraffin-embedded (FFPE) tumor tissues from 19 institutions were analyzed with two tissue-based next-generation sequencing (NGS) panels at the Clinical Laboratory Improvement Amendments (CLIA)-certified College of American Pathologists (CAP)-accredited central laboratory. The Oncomine Cancer Research Panel (OCP; 143 genes) succeeded in producing validated results for only 68.3% of the samples (%OCP-success). CE-IVD (25 genes) succeeded in 45.9% of the OCP-failed samples, leading to an overall NGS success (%combined-success) rate as high as 82.9%. Among 2573 samples, the DNA-integrity (ΔC )-high (ΔC  < 4.4, n = 1253) samples showed significantly higher %OCP- and %combined-success rates (90.2% and 97.4%, respectively) than the DNA-integrity-intermediate (4.4 < ΔC  < 6.3, n = 911; 68.9% and 88.7%) and DNA-integrity-low ones (ΔC  > 6.3 or polymerase chain reaction-failed, n = 409; 5.6% and 24.7%). Other factors associated with NGS success included the FFPE-sample storage period (<4 years), the specimen type (surgical) and the primary tumor site (colorectal). Multivariable analysis revealed DNA integrity as the factor with the strongest independent association with NGS success, although it was suggested that other institution-specific factors contribute to the discordance of inter-institutional NGS success rates. Our results emphasize the importance of DNA quality in FFPE samples for NGS tests and the impact of DNA integrity on quality monitoring of pathology specimens for achieving successful NGS.
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http://dx.doi.org/10.1111/pin.13029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820973PMC
December 2020

Characteristics of surgically resected non-small cell lung cancer patients with post-recurrence cure.

Thorac Cancer 2020 11 22;11(11):3280-3288. Epub 2020 Sep 22.

Department of Thoracic Surgical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.

Background: The prognosis of postoperative recurrence in patients with non-small cell lung cancer (NSCLC) is poor. However, depending on the recurrence patterns and treatment options, some patients can achieve long-term survival following recurrence. In this study, we investigated the clinicopathological characteristics of NSCLC patients with curable disease who developed postoperative recurrence.

Methods: This retrospective study enrolled 535 patients who had developed recurrence from among 1760 consecutive patients with NSCLC who underwent curative resection from 1990 to 2008. Post-recurrence cure was defined as being cancer-free for at least five years after treatment for recurrence in patients who had undergone radical local treatment or chemotherapy. The clinicopathological characteristics associated with post-recurrence cure were analyzed.

Results: Among 535 patients who developed recurrence, 24 (4.5%) achieved post-recurrence cure. The median post-recurrence follow-up duration was 151 (85-275) months for those who achieved post-recurrence cure. The solitary recurrent lesions and local treatment for the initial recurrence site were significantly more for patients who could be cured after they developed recurrence. All patients with post-recurrence cure received only radical local treatment for the recurrent lesions.

Conclusions: Some patients with solitary recurrent NSCLC lesions can be cured with only radical local treatment.

Key Points: Significant findings of the study The post-recurrence cure patients maintained a cancer-free status for five years after treatment for recurrence without a second recurrence. All patients with post-recurrence cure received only radical local treatment for recurrence and had significantly higher number of solitary recurrent lesions. What this study adds Some patients with solitary recurrent NSCLC lesions after resection can be cured with only radical local treatment.
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http://dx.doi.org/10.1111/1759-7714.13669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605994PMC
November 2020

Tofacitinib for recurrence of antimelanoma differentiation-associated gene 5 antibody-positive clinically amyopathic dermatomyositis after remission: A case report.

Medicine (Baltimore) 2020 Sep;99(37):e21943

Department of Rheumatology, Yokohama Rosai Hospital, Kohoku-ku, Yokohama, Kanagawa, Japan.

Rationale: Antimelanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive clinically amyopathic dermatomyositis (cADM) is frequently complicated with interstitial lung disease (ILD) and has a poor prognosis. Although the short-term prognosis of anti-MDA5 Ab-positive cADM is poor, it has been suggested that the recurrence rate is not higher than that of anti-MDA5 Ab-negative dermatomyositis. Combination therapy with corticosteroids, calcineurin inhibitors, and cyclophosphamide is the gold standard for the remission induction therapy at the onset. Recently, it has been reported that tofacitinib (TOF) could be effective for refractory anti-MDA5 Ab-positive cADM with ILD. Although initial remission induction therapy has been established, therapeutic strategies for relapse cases have not yet been established.

Patient Concerns: A 57-year-old woman who was diagnosed with anti-MDA5 Ab-positive cADM complicated with ILD. In October 2016, she was treated with prednisolone (PSL), tacrolimus (TAC), and cyclophosphamide (CY). These treatments were successful, and PSL could be tapered. However, she developed strong nausea and general fatigue as adverse events of CY. In April 2018, PSL was discontinued, and maintenance therapy was given with TAC. In July 2018, Gottron's sign and ILD recurred. Skin lesions on the finger were partially ulcerated and ILD was also worsening. We proposed a remission reinduction therapy including CY. However, she was rejected CY from experience with past adverse event of CY.

Diagnosis: Based on skin lesions and chest computed tomography (CT) findings, the diagnosis was a recurrence of anti-MDA5 Ab-positive cADM with ILD.

Interventions: Treatment by TOF 10 mg and PSL 22.5 mg (0.5 mg/kg equivalent) was introduced in November 2018.

Outcomes: After introducing TOF and PSL, her skin lesions and chest CT findings of ILD gradually improved. Six months after the induction of TOF, the skin ulcer was epithelialized. One year after the introduction of TOF, PSL was decreased to 9 mg, and the disease activity did not re-exacerbate.

Lessons: This case report is the first report suggesting the effectiveness of TOF for recurrent case of anti-MDA5 Ab-positive cADM with ILD. TOF might be an effective therapeutic option for treating recurrent case of anti-MDA5 Ab-positive cADM.
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http://dx.doi.org/10.1097/MD.0000000000021943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489601PMC
September 2020

Systemic-to-Pulmonary Collateral Flow Correlates with Clinical Condition Late After the Fontan Procedure.

Pediatr Cardiol 2020 Dec 11;41(8):1800-1806. Epub 2020 Sep 11.

Department of Pediatric Cardiology, Fukuoka Children's Hospital, 5-1-1 Kashiiteriha, Fukuoka, Japan.

In the Fontan circulation, there is a substantial degree of systemic-to-pulmonary collateral flow (SPCF), which can be measured by cardiac magnetic resonance (CMR). However, the correlation between the degree of SPCF and long-term outcomes is not fully understood. We retrospectively studied 321 patients who underwent the Fontan procedure and CMR at a single center. Using CMR, we calculated SPCF as pulmonary blood flow - systemic blood flow. %SPCF was defined as SPCF ÷ pulmonary blood flow. The mean age of patients at CMR was 14.3 ± 7.5 years. The average %SPCF was 13.0% ± 11.0%. With a multivariate analysis, %SPCF was significantly correlated with time (i.e., the longer the time period since the Fontan procedure, the lower the %SPCF) (p = 0.006), previous total anomalous pulmonary vein drainage (p = 0.007), a low pulmonary artery index (Nakata index) before the Fontan procedure (p = 0.04), and older age at the time of the Fontan procedure (p = 0.002). Regarding the findings after the Fontan procedure, %SPCF was significantly correlated with ventricular end-diastolic volume (p < 0.001), ventricular end-systolic volume (p < 0.001), central venous pressure (p < 0.001), plasma brain natriuretic peptide concentration (p < 0.001), hemoptysis (p = 0.009), and poor New York Heart Association functional class (p = 0.007). SPCF was correlated with clinical condition after the Fontan procedure. The importance of sufficient growth of the pulmonary vascular bed should be emphasized because the development of SPCF is believed to result from the poor condition of the pulmonary circulation.
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http://dx.doi.org/10.1007/s00246-020-02450-8DOI Listing
December 2020

Frequent expression of conventional endothelial markers in pleural mesothelioma: usefulness of claudin-5 as well as combined traditional markers to distinguish mesothelioma from angiosarcoma.

Lung Cancer 2020 10 30;148:20-27. Epub 2020 Jul 30.

Division of Pathology, The Cancer Institute, Departments of Pathology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan; Department of Pathology, School of Medicine, International University of Health and Welfare, Tokyo 108-8329, Japan. Electronic address:

Objectives: Distinguishing pleural sarcomatoid mesotheliomas from true sarcomas is challenging because the former does not always express the mesothelial markers, and diagnosis is often made on the basis of keratin expression. Consequently, sarcomas such as angiosarcomas that express keratin complicate the differential diagnosis. Furthermore, some mesotheliomas have been reported to express endothelial markers. The aim of this study is to identify useful markers for distinguishing pleural sarcomatoid mesothelioma from angiosarcoma.

Materials And Methods: This study enrolled 147 patients with pleural mesothelioma-93 with epithelioid, 25 with biphasic, and 29 with sarcomatoid subtypes-and 41 patients with angiosarcomas in various organs. The expression levels of cytokeratin, mesothelial, and endothelial markers were assayed in both groups to identify the markers that could assist in distinguishing mesothelioma from angiosarcoma. Cytokeratin (AE1/AE3, CAM 5.2), endothelial (CD31, CD34, ERG, factor VIII, and claudin-5), and mesothelial (calretinin, WT-1, podoplanin (D2-40), EMA, and CK5/6) markers were immunohistochemically assayed using tissue blocks.

Results: More than 90% of the mesotheliomas and less than 20% of the angiosarcomas expressed cytokeratin. Calretinin was expressed in 82% of all types of mesotheliomas but in only 48% of sarcomatoid mesotheliomas. Endothelial markers were expressed in mesothelioma tissues-CD31 in 10.3%, CD34 in 3.5%, ERG in 29%, and factor VIII in 3.4%-and the positivity was higher in sarcomatoid than in epithelioid and biphasic mesotheliomas. Claudin-5 was expressed in all the angiosarcomas, but not in any of the mesotheliomas.

Conclusion: We found overlapping immunophenotypes in pleural mesotheliomas and angiosarcomas, but the sensitivity and specificity of claudin-5 expression were sufficient to distinguish between them. The differential diagnosis of mesothelioma should therefore include claudin-5 in a panel of immunohistochemical markers to distinguish mesothelioma from angiosarcoma.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.029DOI Listing
October 2020

An extremely rare case of rapidly growing mediastinal well-differentiated liposarcoma with a sclerosing variant: a case report.

Surg Case Rep 2020 Jul 3;6(1):158. Epub 2020 Jul 3.

Department of Thoracic Surgical Oncology, the Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.

Background: Liposarcoma arising from the mediastinum is rare, accounting for less than 1% of mediastinal tumors. Furthermore, a rapidly growing well-differentiated liposarcoma is extremely rare. A well-differentiated liposarcoma is usually considered a low-grade malignancy. However, we present an extremely rare case of a sclerosing variant of well-differentiated liposarcoma that grew rapidly within a year.

Case Presentation: A 77-year-old man with a giant mass in the left thoracic cavity was referred to our hospital. This mass measured about 10 cm and occupied the left-sided mediastinum on a chest radiography; however, there was no abnormal finding on the previous year's chest radiography. Chest-enhanced computed tomography revealed a well-circumscribed 11-cm mass in the left-sided anterior mediastinum. Positron emission tomography showed accumulation of fluorodeoxyglucose uptake in this tumor (maximum standard uptake value = 3.3). The radiological findings of computed tomography and positron emission tomography indicated that this tumor was a benign or low-grade malignancy; therefore, the chest radiographic findings were difficult to explain. To explain this discrepancy and establish the diagnosis, tumor resection was performed via left posterolateral thoracotomy. Intraoperatively, the left phrenic nerve and pericardium were adhered tightly to the tumor, so we resected them. The tumor was well-circumscribed and fibrous; therefore, the initial diagnosis was solitary fibrous tumor. However, based on its histopathological and immunohistochemical patterns, the tumor was diagnosed as a sclerosing variant of well-differentiated liposarcoma. Five years postoperatively, the patient remains alive with no evidence of disease recurrence.

Conclusions: A well-differentiated liposarcoma is usually considered a low-grade malignancy. Nevertheless, the giant tumor in the present case appeared within 1 year. Thus, this was an extremely rare case of a sclerosing variant of well-differentiated liposarcoma with rapid growth.
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http://dx.doi.org/10.1186/s40792-020-00928-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334334PMC
July 2020

Clinical utility of target capture-based panel sequencing in hematological malignancies: A multicenter feasibility study.

Cancer Sci 2020 Sep 17;111(9):3367-3378. Epub 2020 Jul 17.

Department of Hematology, Atomic Bomb Disease and Hibakusha Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.

Although next-generation sequencing-based panel testing is well practiced in the field of cancer medicine for the identification of target molecules in solid tumors, the clinical utility and clinical issues surrounding panel testing in hematological malignancies have yet to be fully evaluated. We conducted a multicenter prospective clinical sequencing study to verify the feasibility of a panel test for hematological tumors, including acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and diffuse large B-cell lymphoma. Out of 96 eligible patients, 79 patients (82%) showed potentially actionable findings, based on the clinical sequencing assays. We identified that genetic alterations with a strong clinical significance were found at a higher frequency in terms of diagnosis (n = 60; 63%) and prognosis (n = 61; 64%) than in terms of therapy (n = 8; 8%). Three patients who harbored a germline mutation in either DDX41 (n = 2) or BRCA2 (n = 1) were provided with genetic counseling. At 6 mo after sequencing, clinical actions based on the diagnostic (n = 5) or prognostic (n = 3) findings were reported, but no patients were enrolled in a clinical trial or received targeted therapies based on the sequencing results. These results suggest that panel testing for hematological malignancies would be feasible given the availability of useful diagnostic and prognostic information. This study is registered with the UMIN Clinical Trial Registry (UMIN000029879, multiple myeloma; UMIN000031343, adult acute myeloid leukemia; UMIN000033144, diffuse large B-cell lymphoma; and UMIN000034243, childhood leukemia).
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http://dx.doi.org/10.1111/cas.14552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469806PMC
September 2020

Favorable efficacy of rituximab in ANCA-associated vasculitis patients with excessive B cell differentiation.

Arthritis Res Ther 2020 06 15;22(1):141. Epub 2020 Jun 15.

School of Medicine, University of Occupational & Environmental Health, 1-1 Iseigaoka, Yahata-nishi, Kitakyushu, Fukuoka, 807-8555, Japan.

Objectives: B cell depletion by rituximab (RTX) is an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, peripheral B cell phenotypes and the selection criteria for RTX therapy in AAV remain unclear.

Methods: Phenotypic characterization of circulating B cells was performed by 8-color flow cytometric analysis in 54 newly diagnosed AAV patients (20 granulomatosis with polyangiitis and 34 microscopic polyangiitis). Patients were considered eligible to receive intravenous cyclophosphamide pulse (IV-CY) or RTX. All patients also received high-dose glucocorticoids (GC). We assessed circulating B cell phenotypes and evaluated the efficacy after 6 months of treatment.

Results: There were no significant differences in the rate of clinical improvement, relapses, or serious adverse events between patients receiving RTX and IV-CY. The rate of Birmingham Vasculitis Activity Score (BVAS) improvement at 6 months tended to be higher in the RTX group than in the IV-CY group. The proportion of effector or class-switched memory B cells increased in 24 out of 54 patients (44%). The proportions of peripheral T and B cell phenotypes did not correlate with BVAS at baseline. However, among peripheral B cells, the proportion of class-switched memory B cells negatively correlated with the rate of improvement in BVAS at 6 months after treatment initiation (r = - 0.28, p = 0.04). Patients with excessive B cell differentiation were defined as those in whom the proportion of class-switched memory B cells or IgDCD27 B cells among all B cells was > 2 SDs higher than the mean in the HCs. The rate of BVAS remission in patients with excessive B cell differentiation was significantly lower than that in patients without. In patients with excessive B cell differentiation, the survival rate, the rate of BVAS-remission, and dose reduction of GC were significantly improved in the RTX group compared to those in the IV-CY group after 6 months of treatment.

Conclusions: The presence of excessive B cell differentiation was associated with treatment resistance. However, in patients with circulating B cell abnormality, RTX was effective and increased survival compared to IV-CY. The results suggest that multi-color flow cytometry may be useful to determine the selection criteria for RTX therapy in AAV patients.
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http://dx.doi.org/10.1186/s13075-020-02215-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294638PMC
June 2020

Allogeneic hematopoietic stem cell transplantation at the first remission for younger adults with FLT3-internal tandem duplication AML: The JALSG AML209-FLT3-SCT study.

Cancer Sci 2020 Jul 29;111(7):2472-2481. Epub 2020 May 29.

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

In this phase II multicenter study (JALSG AML209-FLT3-SCT), we aimed to prospectively elucidate the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) at first complete remission (CR1) for FLT3-internal tandem duplication (ITD)-positive AML. Newly diagnosed de novo AML patients with FLT3-ITD were enrolled at the achievement of CR1 and received allo-HSCT as soon as possible after the first consolidation therapy. Mutations of 57 genes in AML cells at diagnosis were also analyzed. Among 48 eligible patients with a median age of 38.5 (17-49) years, 36 (75%) received allo-HSCT at a median of 108 days after CR1. The median follow-up was 1726 days. The primary end-point, 3-year disease-free survival (DFS) based on an intent to treat analysis, was 43.8% (95% confidence interval [CI], 30%-57%), suggesting the efficacy of this treatment because the lower limit of the 95% CI exceeded the threshold response rate of 20%. The 3-year overall survival, post-transplant DFS, and non-relapse mortality rates were 54.2% (95% CI, 39%-67%), 58.3% (95% CI, 41%-72%), and 25.0% (95% CI, 12%-40%), respectively. The median ITD allelic ratio (AR) was 0.344 (0.006-4.099). Neither FLT3-ITD AR nor cooccurring genetic alterations was associated with a poor DFS. This prospective study indicated the efficacy and safety of allo-HSCT for FLT3-ITD AML patients in CR1. This study was registered at: www.umin.ac.jp/ctr/ as #UMIN000003433.
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http://dx.doi.org/10.1111/cas.14448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484840PMC
July 2020
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