Publications by authors named "Hiromi Iwasaki"

135 Publications

A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Kyushu University Hospital, Japan.

Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell malignancy with varying prognosis after the gold standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Several prognostic models have been established by focusing primarily on characteristics of lymphoma cells themselves, including cell-of-origin, genomic alterations, and gene/protein expressions. However, the prognostic impact of the lymphoma microenvironment and its association with characteristics of lymphoma cells are not fully understood. Using the nCounter-based gene expression profiling of untreated DLBCL tissues, we here assess the clinical impact of lymphoma microenvironment on the clinical outcomes and pathophysiological, molecular signatures in DLBCL. The presence of normal germinal center (GC)-microenvironmental cells, including follicular T cells, macrophage/dendritic cells, and stromal cells, in lymphoma tissue indicates a positive therapeutic response. Our prognostic model, based on quantitation of transcripts from distinct GC-microenvironmental cell markers, clearly identified patients with graded prognosis independently of existing prognostic models. We observed increased incidences of genomic alterations and aberrant gene expression associated with poor prognosis in DLBCL tissues lacking GC-microenvironmental cells relative to those containing these cells. These data suggest that the loss of GC-associated microenvironmental signature dictates clinical outcomes of DLBCL patients reflecting the accumulation of "unfavorable" molecular signatures.
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http://dx.doi.org/10.1182/bloodadvances.2021004618DOI Listing
October 2021

Programmed cell death-ligand 1 (PD-L1) tumour cells and low-reacting programmed cell death 1 (PD1) tumour-infiltrating lymphocytes predict poor prognosis in Epstein-Barr virus diffuse large B-cell lymphoma.

Clin Exp Med 2021 Sep 13. Epub 2021 Sep 13.

Graduate School of Medical Sciences, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan.

Epstein-Barr virus (EBV) diffuse large B-cell lymphoma (DLBCL) has specific tumour cell characteristics, and these patients have worse outcomes than EBV-negative DLBCL patients. We compared 38 EBV DLBCL patients with 43 methotrexate-associated EBV B-cell lymphoproliferative disorders (MTX/EBV BLPDs) and 30 non-germinal centre (GC) subtype DLBCL. Lymphoma cells of the EBV DLBCL group were positive for BCL2 in 17 patients (44.7%), CMYC in 23 patients (60.5%), and p53 in 33 patients (86.8%), which was significantly higher than in the MTX/EBV BLPD group (P < 0.05), and were positive for CD30 in 29 patients (76.3%), compared with two in non-GC subtype DLBCL (6.7%) (P < 0.0001). Significantly more EBV DLBCL patients (n = 16, 42.1%) had programmed cell death-ligand 1 (PD-L1) tumour cells than patients with non-GC subtype DLBCL (n = 5, 16.7%; P = 0.024), and PD-L1 tumour cells were more common in advanced stages than in early stages (P = 0.048). Twenty-five EBV DLBCL patients (69.4%) had few reactive PD1 tumour-infiltrating lymphocytes (TILs), compared with 12 patients with MTX/EBV BLPDs (37.5%) (P = 0.008). In the EBV DLBCL group, CD30, BCL2, CMYC, and p53 expression was not related to patient prognosis. Poor outcomes were associated with PD-L1 tumour cells (P = 0.001) and low-reacting PD1 TILs (P = 0.02), while their combination conferred a worse outcome (P < 0.0001). Immune evasion by PD-L1 tumour cells and exhaustion of PD1 TILs may occur in EBV DLBCL patients, and PD-L1/PD1 interactions may influence tumour progression and poor prognosis.
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http://dx.doi.org/10.1007/s10238-021-00754-4DOI Listing
September 2021

Clinical significance of TP53 mutations in adult T-cell leukemia/lymphoma.

Br J Haematol 2021 Aug 17. Epub 2021 Aug 17.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Adult T-cell leukaemia/lymphoma (ATL) patients have a poor prognosis. Here, we investigated the impact of TP53 gene mutations on prognosis of ATL treated in different ways. Among 177 patients, we identified 47 single nucleotide variants or insertion-deletions (SNVs/indels) of the TP53 gene in 37 individuals. TP53 copy number variations (CNVs) were observed in 38 patients. Altogether, 67 of 177 patients harboured TP53 SNVs/indels or TP53 CNVs, and were categorized as having TP53 mutations. In the entire cohort, median survival of patients with and without TP53 mutations was 1·0 and 6·7 years respectively (P < 0·001). After allogeneic haematopoietic stem cell transplantation (HSCT), median survival of patients with (n = 16) and without (n = 29) TP53 mutations was 0·4 years and not reached respectively (P = 0·001). For patients receiving mogamulizumab without allogeneic HSCT, the median survival from the first dose of antibody in patients with TP53 mutations (n = 27) was only 0·9 years, but 5·1 years in those without (n = 42; P < 0·001). Thus, TP53 mutations are associated with unfavourable prognosis of ATL, regardless of treatment strategy. The establishment of alternative modalities to overcome the adverse impact of TP53 mutations in patients with ATL is required.
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http://dx.doi.org/10.1111/bjh.17749DOI Listing
August 2021

Clinical impact of comprehensive geriatric assessment in patients aged 80 years and older with diffuse large B-cell lymphoma receiving rituximab-mini-CHOP: a single-institute retrospective study.

Eur Geriatr Med 2021 Jul 12. Epub 2021 Jul 12.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.

Purpose: Comprehensive geriatric assessment (CGA) has been used to help identify elderly patients with diffuse large B-cell lymphoma (DLBCL) who were suitable for rituximab combined with CHOP therapy (cyclophosphamide, Adriamycin, vincristine, and prednisolone), but there are few reports of CGA for elderly patients with DLBCL who received R-mini-CHOP.

Methods: We retrospectively analyzed the risk factors for outcomes among 142 patients aged 80 years and older (≤ 85 years, n = 102; > 85 years, n = 40) with DLBCL who received R-mini-CHOP at 4-week intervals at our institute between 2008 and 2019. We performed a comparison between CGA and treatment outcomes.

Results: There were significant differences in progression-free survival between patients with international prognostic index (IPI) scores of > 3 and ≤ 3 at diagnosis and in overall survival between patients with instrumental activities of daily living (IADL) scores of ≥ 5 and IADL < 5 before the initial treatment and patients aged ≤ 85 years and > 85 years.

Conclusion: Strategies that carefully select elderly patients aged 80 years and older with DLBCL using CGA may help to identify individuals suitable for novel therapies.
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http://dx.doi.org/10.1007/s41999-021-00539-8DOI Listing
July 2021

Azacitidine for the treatment of patients with relapsed acute myeloid leukemia after allogeneic stem cell transplantation.

Leuk Lymphoma 2021 Jun 23:1-10. Epub 2021 Jun 23.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

We retrospectively analyzed 38 patients with AML who received azacitidine (AZA) to treat disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with objective response (OR) ( = 20) after AZA had significantly higher 2-year overall survival (OS) (45.0% vs 5.6%;  = 0.004) than progressive disease. The 2-year OS was significantly higher in the retransplant group ( = 23) than in the nonretransplant group ( = 15) (34.8% vs 13.3%;  = 0.034). We analyzed 167 patients who underwent the second allo-HSCT to clarify the impact of pretransplant AZA after the second allo-HSCT. Patients in the AZA group ( = 21) had significantly higher 2-year disease-free survival (DFS) (32.7% vs 14.5%;  = 0.012) and OS (38.1% vs 17.5%;  = 0.044) than those in the SOC group ( = 146). Our data demonstrate that AZA is an effective and well-tolerated bridging therapy to the second allo-HSCT.
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http://dx.doi.org/10.1080/10428194.2021.1941937DOI Listing
June 2021

Platelet decrease and efficacy of platelet-rich plasma return following peripheral blood stem cell apheresis.

J Clin Apher 2021 Oct 16;36(5):687-696. Epub 2021 Jun 16.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medicine, Fukuoka, Japan.

Background: Peripheral blood stem cell (PBSC) transplantation is a key treatment option for hematological diseases and is widely performed in clinical practice. Platelet loss is one of the major complications of PBSC apheresis, and platelet-rich plasma (PRP) return is considered in case of platelet decrease following apheresis; however, little is known about the frequency and severity of platelet loss and the efficacy of PRP return postapheresis.

Methods: We assessed changes in platelet counts following PBSC-related apheresis in 270 allogeneic (allo)- and 105 autologous (auto)-PBSC settings. We also evaluated the efficacy of PRP transfusion on platelet recovery postapheresis.

Results: In both allo- and auto-PBSC settings, the preapheresis platelet count (range, 84-385 and 33-558 × 10 /L, respectively) decreased postapheresis (range, 57-292 and 20-429 × 10 /L, respectively), whereas severe platelet decrease (<50 × 10 /L) was only observed in auto-PBSC patients (n = 9). We confirmed that platelet count before apheresis was a risk factor for severe platelet decrease (<50 × 10 /L) following auto-PBSC apheresis (odds ratio 0.749, P < .049). PRP return postapheresis facilitated platelet recovery in more than 80% of cases in both allo and auto settings.

Conclusion: Lower platelet count preapheresis is a useful predictor of severe platelet decrease following auto-PBSC apheresis and PRP return is an effective process to facilitate platelet recovery postapheresis.
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http://dx.doi.org/10.1002/jca.21917DOI Listing
October 2021

Clinicopathological findings of systemic Epstein-Barr virus-positive T-lymphoproliferative diseases in younger and older adults.

Diagn Pathol 2021 Jun 4;16(1):48. Epub 2021 Jun 4.

Graduate School of Medical Sciences, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 8140180, Japan.

Background: Systemic Epstein-Barr virus T-cell lymphoma (sEBV TCL) occurs in childhood and young adults, and is exceptionally rare in older adults.

Methods: We investigated clinicopathological features in 16 patients of various ages with systemic EBV CD8 T-lymphoproliferative diseases.

Results: Eight younger patients and four of eight older adults had sEBV CD8 TCL, with invasion by medium-sized to/or large atypical lymphocytes primarily in bone marrow and lymph nodes, hemophagocytic lymphohistiocytosis (HLH), and progressive clinicopathological course. A further two patients demonstrated EBV node-based CD8 large TCL without HLH, while the remaining two had the systemic form of chronic active EBV infection (sCAEBV) with CD8 small lymphocytes. Past history of sCAEBV-like lesions was observed in one sEBV TCL patient (8.3%). Immunohistologically, in 12 sEBV TCL patients, atypical lymphocytes were positive for phosphate signal transducer and activator of transcription 3 (66.7%), CMYC (83.3%), and p53 (75%). Strong reactions of programmed cell death-ligand (PD-L)1 tumor or non-neoplastic cells were detected in nine sEBV TCL patients (75%). Clonal peaks of the T-cell receptor (TCR) γ gene were detected in eight sEBV TCL patients by polymerase chain reaction. Four younger patients in sEBV TCL (33.3%) are in remission with chemotherapies including etoposide, and three of the four underwent allogeneic stem cell transplantation (SCT).

Conclusion: sEBV CD8 TCL was observed in younger and older adults with less history of sCAEBV. HLH, tumor cell atypia, immunohistological findings, and progressive clinical course were characteristic of sEBV CD8 TCL. Prompt chemotherapy and SCT induced tumor regression in sEBV CD8 TCL patients.
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http://dx.doi.org/10.1186/s13000-021-01107-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176609PMC
June 2021

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Br J Haematol 2021 Jul 6;194(1):101-110. Epub 2021 Apr 6.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.
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http://dx.doi.org/10.1111/bjh.17456DOI Listing
July 2021

Clinical features and chromosomal/genetic aberration in adult acute lymphoblastic leukemia in Japan: results of Fukuoka Blood & Marrow Transplant Group Studies ALL MRD 2002 and 2008.

Int J Hematol 2021 Jun 16;113(6):815-822. Epub 2021 Mar 16.

Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, 830-0011, Japan.

Acute lymphoblastic leukemia (ALL) is a common neoplasm in children, but less frequent in adults. Since information on clinical features and genetics of adult ALL in Japan is limited, we analyzed 215 subjects aged 16-65 years with untreated ALL enrolled in the Fukuoka Blood & Marrow Transplant Group studies ALL MRD 2002 and 2008. The prevalence of ALL was bimodal, with the larger group aged 56-65 years. Immunophenotypic characterization showed B-lineage is more frequent than T-lineage ALL (78.6 vs 13.0%), with age-related differences. The proportion with BCR-ABL1 rearrangement increased progressively with age, up to 55.7% among subjects aged over 56-65 years. Rearrangements involving the KMT2A gene, ETV6-RUNX1, and TCF3-PBX1 were rare in this study cohort. The overall incidence of hyperdiploidy was only 1.7%, and there were no cases with hypodiploidy. Overall survival varied by age and cytogenetics. Older subjects and those with BCR-ABL1 tended to have inferior outcomes. In this epidemiological study of Japanese adult ALL, the majority of subjects had B-lineage ALL, the T-cell phenotype was most frequent in those aged 16-25, and BCR-ABL1 rearrangement was very common, with prevalence increasing with age. These types of adult ALL are potentially manageable with targeted therapies.
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http://dx.doi.org/10.1007/s12185-021-03116-8DOI Listing
June 2021

Clinical impact of bendamustine exposure on lymphopenia risk after bendamustine and rituximab combination therapy for follicular lymphoma: a single-institute retrospective study.

Ann Hematol 2021 Jan 3. Epub 2021 Jan 3.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.

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http://dx.doi.org/10.1007/s00277-020-04388-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779080PMC
January 2021

Clinical significance of CD28 gene-related activating alterations in adult T-cell leukaemia/lymphoma.

Br J Haematol 2021 01 18;192(2):281-291. Epub 2020 Nov 18.

Department of Pathology and Molecular Diagnostics, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Japan.

Multiple oncogenic events are involved in the development of adult T-cell leukaemia/lymphoma (ATL). Because CD28 plays a pivotal role in T-cell activation, we focused on alterations of the CD28 gene in ATL. We found multiple genetic abnormalities related to CD28 among the 144 patients enrolled in the present study. These involved gene fusions with the cytotoxic T-lymphocyte-associated antigen 4 or the inducible T-cell co-stimulator in 14 patients (10%), CD28-activating mutations in 3 (2%), and CD28 copy number variations in 34 (24%). Patients with such CD28 gene alterations were significantly younger than those without. In patients not receiving allogeneic haematopoietic stem cell transplantation, those with CD28 gene alterations tended to have a worse prognosis than those without. Finally, patients with chronic or smouldering ATL subtypes with CD28 gene alterations had a significantly worse prognosis than those without. These findings indicate that ATL, especially chronic or smouldering subtypes, have a more aggressive clinical course and are more refractory to conventional chemotherapies or mogamulizumab if they harbour CD28 gene alterations, likely because of continuous, prolonged, and enhanced CD28 activatory signalling. Novel treatment strategies to overcome the effects of these CD28 gene alterations are warranted.
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http://dx.doi.org/10.1111/bjh.17211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894310PMC
January 2021

Comparison of prognostic scores in transplant-ineligible patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective study from the national hospital organization in Japan.

Leuk Lymphoma 2021 04 9;62(4):819-827. Epub 2020 Nov 9.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS,  = 100) and angioimmunoblastic T-cell lymphoma (AITL,  = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.
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http://dx.doi.org/10.1080/10428194.2020.1845336DOI Listing
April 2021

Endoscopic and clinicopathological characteristics of colorectal T/NK cell lymphoma.

Diagn Pathol 2020 Oct 21;15(1):128. Epub 2020 Oct 21.

Department of Pathology, Fukuoka University, 7-45-1 Nanakuma, Johnan-ku, Fukuoka, Fukuoka, 814-0180, Japan.

Background: Colorectal T/natural killer (NK)-cell lymphomas (TNKCL) are very rare. Endoscopic and clinicopathological characteristics of colorectal TNKCL have not been clearly demonstrated. In this study, we demonstrated the clinical characteristics of colorectal TNKCL.

Methods: Endoscopic and clinicopathological characteristics were investigated in 27 patients with colorectal monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), adult T-cell leukemia/lymphoma (ATLL), and other types of TNKCL.

Results: Nine TNKCL patients (33%) were classified as MEITL, 11 (41%) as ATLL, and seven (26%) as other. Four patients with Epstein-Barr Virus-positive (EBV+) TNKCL, two indolent T-cell lymphoproliferative disorder and one anaplastic large cell lymphoma were included in the other group. Endoscopically, six MEITL (67%) and five ATLL (46%) showed diffuse-infiltrating type, in which the main endoscopic lesion was edematous mucosa in MEITL, while aphthoid erosion and edematous mucosa were typical in ATLL. Ulcerative type was identified in four other group patients (57%), including two EBV+ TNKCL. An increase in atypical T-intraepithelial lymphocytes (T-IELs) was noted in seven MEITL (88%) and six ATLL (60%) patients, but not in the other group (0%) patients. Five MEITL patients (56%) showed features of lymphocytic proctocolitis with increased CD8+ T-IELs.

Conclusions: MEITL and ATLL occasionally invaded the colorectum, and primary involving MEITL was observed. Diffuse infiltrating type was the characteristic endoscopic finding in colorectal MEITL and ATLL, while ulcerative type was observed in the other group. Features of lymphocytic proctocolitis may be prodromal findings of MEITL.
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http://dx.doi.org/10.1186/s13000-020-01044-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576840PMC
October 2020

Pembrolizumab plus lenalidomide and dexamethasone in treatment-naive multiple myeloma (KEYNOTE-185): subgroup analysis in Japanese patients.

Int J Hematol 2020 Nov 19;112(5):640-649. Epub 2020 Sep 19.

Japanese Red Cross Medical Center, Tokyo, Japan.

The global, randomized, open-label KEYNOTE-185 study closed early after an interim analysis showed an unfavorable benefit-risk profile with pembrolizumab plus lenalidomide and low-dose dexamethasone (Rd) versus Rd alone in treatment-naive, transplant-ineligible multiple myeloma. This subgroup analysis reported outcomes in the Japanese population. Patients were randomly assigned (1:1) to pembrolizumab plus Rd or Rd alone, stratified by age and International Staging System. The primary end point was progression-free survival (PFS). Fifty-two Japanese patients were randomly assigned to pembrolizumab plus Rd (n = 27) or Rd (n = 25). The median follow-up was 7.2 months (range, 0.4-13.8). The median PFS was not reached (NR); 6-month PFS was 91.2% versus 86.2% with pembrolizumab plus Rd versus Rd [hazard ratio (HR), 0.31; 95% CI, 0.06-1.63]. The median overall survival (OS) was NR; 6-month OS was 96.2% versus 95.7% with pembrolizumab plus Rd versus Rd (HR, 0.33; 95% CI, 0.03-3.72). With pembrolizumab plus Rd versus Rd, grade 3-5 adverse events occurred in 70.4% versus 69.6% of patients; serious adverse events occurred in 40.7% versus 52.5%. Although in the Japanese subgroup of KEYNOTE-185 adding pembrolizumab to Rd did not show an unfavorable risk-benefit, the analysis is limited by short follow-up and small sample size, affecting generalizability of the results.
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http://dx.doi.org/10.1007/s12185-020-02953-3DOI Listing
November 2020

Evaluation of prognosis following early disease progression in peripheral T-cell lymphoma.

Int J Hematol 2020 Dec 4;112(6):817-824. Epub 2020 Sep 4.

Department of Hematology, National Hospital Organization Nagoya Medical Center, 4-1-1, Sannomaru, Naka-ku, Nagoya, 460-0001, Japan.

Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.
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http://dx.doi.org/10.1007/s12185-020-02987-7DOI Listing
December 2020

Correction to: Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep;112(3):431-432

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

In the original publication of the article, the "CNS involvement" in the last row under the column "Total N=50" has been published incorrectly. The correct Table 1 is given in this correction.
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http://dx.doi.org/10.1007/s12185-020-02932-8DOI Listing
September 2020

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation.

Bone Marrow Transplant 2021 01 5;56(1):129-136. Epub 2020 Jul 5.

Department of Hematology, Hokkaido University Hospital, Sapporo, Japan.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.
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http://dx.doi.org/10.1038/s41409-020-0985-3DOI Listing
January 2021

Clinical and cytopathological characteristics of HTLV-1 hodgkin lymphoma.

Cancer Med 2020 08 28;9(16):5788-5797. Epub 2020 Jun 28.

Division of Diagnostic Pathology, Faculty of Medicine, Fukuoka University Hospital, Fukuoka, Japan.

Background: Human T-lymphotropic virus-1 (HTLV-1) Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like ATLL).

Methods: Cytological and immunohistological features, HTLV-1 proviral DNA integration, and rearrangements of the T-cell receptor (TCR) Cβ1 gene were examined in 11 HTLV-1 patients with HL-like disease.

Results: Six patients were classified as HTLV-1 HL and five as HL-like ATLL in accordance with genetic findings of HTLV-1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV-1 HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL-like ATLL specimens, small- and medium-sized atypical lymphocytes with indented and irregular-shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30 and CD15 Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein-Barr virus infection. The 50% overall survival period was significantly longer for the HTLV-1 HL group (180 months) than for the HL-like ATLL group (7.8 months; P = .004).

Conclusions: HTLV-1 HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25 and CCR4 lymphocytes. In HTLV-1 endemic areas, distinguishing HTLV-1 HL from HL-like ATLL is important because of their differing treatment strategies and prognoses.
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http://dx.doi.org/10.1002/cam4.3139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433818PMC
August 2020

Measurable residual disease after the first consolidation predicts the outcomes of patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy.

Int J Hematol 2020 Sep 10;112(3):349-360. Epub 2020 Jun 10.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

We stratified patients with newly diagnosed acute promyelocytic leukemia (APL) according to a white blood cell (WBC) count of ≥ 3 × 10/L (high risk) or < 3 × 10/L (low risk) before administering risk-adapted chemotherapy in combination with all-trans retinoic acid (ATRA). In total, 27 low-risk and 23 high-risk patients were assigned to receive induction and three courses of consolidation with ATRA and anthracycline, followed by 2-year maintenance regimen. High-risk group additionally received cytarabine during 1st consolidation and another one-shot idarubicin treatment during 3rd consolidation. We prospectively monitored measurable residual disease (MRD) after induction and each consolidation. In the low-risk and high-risk groups, 5-year disease-free survival (DFS) rates were 86.5% and 81.2% (p = 0.862), and 5-year overall survival rates were 100% and 84.8% (p = 0.062), respectively. In the MRD-negative and MRD-positive groups, 5-year DFS rates were 91.7% and 78.4% (p = 0.402) and 84.7% and 60.0% (p = 0.102) after induction and 1st consolidation, respectively. Relapse rates were 8.3% and 13.3% (p = 0.570) and 9.0% and 40.0% (p = 0.076) after induction and 1st consolidation, respectively. Achieving MRD-negativity after 1st consolidation, rather than after induction, was a potential predictor of relapse and DFS in patients with APL treated with ATRA + chemotherapy.
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http://dx.doi.org/10.1007/s12185-020-02911-zDOI Listing
September 2020

Outcome of stem cell transplantation for Waldenström's macroglobulinemia: analysis of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) Lymphoma Working Group.

Ann Hematol 2020 Jul 18;99(7):1635-1642. Epub 2020 May 18.

Department of Oncology and Hematology, Shimane University Hospital, Izumo, Shimane, Japan.

The role of stem cell transplantation (SCT) for patients with Waldenström's macroglobulinemia (WM) remains undetermined. Therefore, we retrospectively evaluated the outcome of autologous and allogeneic SCT for patients with WM using the registry database of the Japan Society for Hematopoietic Cell Transplantation. Forty-six patients receiving autologous and 31 receiving allogeneic SCT were analyzed. The allogeneic SCT group included more patients with advanced disease status at transplant and received more lines of chemotherapy. The cumulative incidences of non-relapse mortality (NRM) at 1 year were 30.0% (95% CI, 14.7-46.9%) in the allogeneic SCT and 0% in the autologous SCT group. The estimated 3-year overall (OS) and progression-free (PFS) survival rates were 84.5% (95% CI, 66.0-93.4%) and 70.8% (95% CI, 53.0-82.9%) in the autologous SCT group, and 52.2% (95% CI, 32.5-68.6%) and 45.0% (95% CI, 26.3-62.0%) in the allogeneic SCT group. No patients died after the first 2 years following allogeneic SCT. In univariate analyses, disease status at SCT was significantly associated with PFS in autologous SCT, and with OS and PFS in allogeneic SCT. These results suggest that both autologous and allogeneic SCT have each potential role in WM. Allogeneic SCT is more curative for WM, but is associated with high NRM.
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http://dx.doi.org/10.1007/s00277-020-04078-3DOI Listing
July 2020

Tyrosine kinase inhibitors induce alternative spliced BCR-ABL variant via inhibition of RNA polymerase II on genomic BCR-ABL.

Cancer Sci 2020 Jul 14;111(7):2361-2373. Epub 2020 Jun 14.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, Fukuoka, Japan.

To elucidate dynamic changes in native BCR-ABL and alternatively spliced tyrosine kinase inhibitor (TKI)-resistant but function-dead BCR-ABL variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR-ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR-ABL , accounting for 0.8% of the total IS BCR-ABL, corresponding to actual BCR-ABL value of 1.1539% IS. TKI rapidly decreased native BCR-ABL but not BCR-ABL , leading to the initial increase in the proportion of BCR-ABL . Thereafter, both native BCR-ABL and BCR-ABL gradually decreased in the course of TKI treatment, whereas small populations positive for TKI-resistant BCR-ABL continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR-ABL clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function-dead BCR-ABL , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis-splicing BCR-ABL , occurring at the particular pseudo-splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR-ABL extracting BCR-ABL would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.
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http://dx.doi.org/10.1111/cas.14424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385367PMC
July 2020

Effects of stem cell transplantation in patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma.

Int J Hematol 2020 Jul 15;112(1):74-83. Epub 2020 Apr 15.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.

The effects of stem cell transplantation (SCT) in patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) remain controversial. We analyzed the feasibility of SCT and risk factors associated with outcomes of PTCL-NOS and AITL patients to identify the potential clinical efficacy of SCT. We retrospectively analyzed the data of PTCL-NOS (n = 83) and AITL (n = 112) patients who received autologous (n = 10 and 16, respectively) or allogeneic (n = 12 and 4, respectively) SCT, or no SCT (n = 61 and 92, respectively) between 2008 and 2018. All PTCL-NOS and AITL diagnoses were reconfirmed by an experienced hematopathologist. Median age at PTCL-NOS and AITL diagnoses in the SCT group was younger than that in the no SCT group. Significant risk factors for lower overall survival were intermediate-high and high-risk international prognostic indexes in PTCL-NOS patients (P = 0.0052), and a > 2 modified prognostic index for T-cell lymphoma (P = 0.0079) and no SCT (P = 0.028) in AITL patients. Autologous or allogeneic SCT compared with no SCT in AITL patients resulted in 3-year overall survival of 68.6% and 100% vs. 57.2% (P = 0.018). Strategies should be developed to improve selection of PTCL-NOS and AITL patients suitable for SCT and/or additional novel therapies.
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http://dx.doi.org/10.1007/s12185-020-02879-wDOI Listing
July 2020

Phase I/II study of bortezomib, lenalidomide, and dexamethasone treatment for relapsed and refractory multiple myeloma.

Int J Hematol 2020 May 24;111(5):673-680. Epub 2020 Jan 24.

Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Science, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Use of novel agents, including proteasome inhibitors and immunomodulatory drugs, has markedly improved outcomes in multiple myeloma (MM) patients. However, most MM patients eventually relapse and require salvage treatments. We report herein the result of a phase I/II study, performed from 2014 to 2017 to assess the feasibility and efficacy of a maximum tolerated dose (MTD) of lenalidomide (Len) combined with a fixed dose of once weekly subcutaneous (sc) 1.3 mg/m of bortezomib plus 20 mg of dexamethasone (scVRd regimen) in relapsed/refractory MM patients in the Japanese population. In the phase I part, dose-limiting toxicities were observed in three of six patients treated with 20 mg of Len; the MTD was accordingly defined as 15 mg in our cohort. In the phase II part, the recommended dose of the scVRD regimen showed a 71.4% best overall response rate, with a median overall survival of 14.8 months and a median progression-free survival of 8 months. Severe adverse events (≥ grade 3) were observed in ~ 15% of the patients, indicating the tolerability and efficacy of the regimen. Less prior treatment was associated with higher probability of durable response. This scVRd regimen may thus be a better fit for MM patients in early-stage relapse.
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http://dx.doi.org/10.1007/s12185-020-02833-wDOI Listing
May 2020

High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura.

Int J Hematol 2020 Mar 2;111(3):388-395. Epub 2020 Jan 2.

Department of Hematology, National Hospital Organization Hiroshimanishi Medical Center, Otake, Japan.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18-80 years with platelet counts of < 20 × 10/l, or < 50 × 10/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7-77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.
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http://dx.doi.org/10.1007/s12185-019-02808-6DOI Listing
March 2020

Rituximab-Mediated Complement-Dependent Cytotoxicity Enhanced by Gemcitabine in Older Patients with Previously Rituximab-Treated Diffuse Large B-Cell Lymphoma: Study Protocol.

Kurume Med J 2020 Jul 29;66(1):37-42. Epub 2019 Nov 29.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center.

High-dose chemotherapy and autologous stem cell transplantation is too toxic for elderly patients with relapsed or refractory (DLBCL). Therefore, tolerable and efficient salvage regimens for elderly patients are greatly needed. In this study, therapy with rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) will be performed every 4 weeks, and an interim evaluation will be performed after the completion of the 3 course. If a complete response (CR) is achieved at the time of interim evaluation, 1 course of R-GDP therapy and 2 courses of monotherapy with rituximab will be additionally performed. If a partial response (PR) is achieved, 3 courses of R-GDP therapy will be additionally conducted. In patients without a PR or CR by the time of the interim evaluation, treatment will be discontinued. Treatment will also be discontinued at any point if disease progression is observed during protocol treatment. After the completion of the final course of R-GDP therapy, final effects of the regimen will be evaluated. A primary endpoint is the efficacy of R-GDP therapy (CR and response rates). This is the first multicenter phase II clinical study of R-GDP therapy to examine post-treatment activities of daily living in addition to the safety and efficacy of treatment in elderly patients with relapsed or refractory transplantineligible DLBCL.
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http://dx.doi.org/10.2739/kurumemedj.MS661001DOI Listing
July 2020

Phase II Trial Using Romidepsin after Gemcitabine, Dexamethasone, and Cisplatin Therapy in Elderly Transplant-Ineligible Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma: Study Protocol.

Acta Med Okayama 2019 Oct;73(5):469-474

Department of Hematology and Clinical Research Institute, NHO Kyushu Medical Center, Fukuoka 810-0863, Japan.

Romidepsin is an important therapeutic option for patients with peripheral T-cell lymphoma (PTCL). However, the timing of romidepsin administration remains controversial. Romidepsin was launched in Japan as a consolidation therapy agent after conventional salvage chemotherapy with gemcitabine, dexamethasone, and cisplatin (GDP). GDP therapy will be administered every 3 weeks. If complete response, partial response, or stable disease is confirmed after 2-4 GDP cycles, romidepsin will be administered every 4 weeks. The primary endpoint is a 2-year progression-free survival rate. Patients participating in this study and undergoing treatment can expect results similar to or better than those of conventional therapies.
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http://dx.doi.org/10.18926/AMO/57379DOI Listing
October 2019

Comparison of calcineurin inhibitors in combination with conventional methotrexate, reduced methotrexate, or mycophenolate mofetil for prophylaxis of graft-versus-host disease after umbilical cord blood transplantation.

Ann Hematol 2019 Nov 18;98(11):2579-2591. Epub 2019 Oct 18.

Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Umbilical cord blood transplantation (UCBT) is a curative treatment for hematological malignancies. However, appropriate prophylaxis against graft-versus-host disease (GVHD), aimed at obtaining rapid and stable engraftment and avoiding toxicity, remains controversial in UCBT. We retrospectively compared outcomes in 409 patients who received calcineurin inhibitors (CIs) plus conventional-dose methotrexate (conv-MTX/CIs, n = 77; methotrexate, 10 mg/m on day 1, 7 mg/m on days 3 and 6) with those who received CIs plus reduced-dose methotrexate (reduced-MTX/CIs, n = 209; methotrexate, 5 mg/m or 5 mg/body on days 1, 3, and 6) or CIs with mycophenolate mofetil (MMF/CIs, n = 123) for GVHD prophylaxis after UCBT. The cumulative incidence of neutrophil engraftment was significantly higher in the reduced-MTX/CI (82.3%) and MMF/CI (86.6%) groups than the conv-MTX/CI (71.4%) group (p = 0.014), although there were no differences in platelet recovery or infectious complications among the three groups. The incidence and severity of GVHD were comparable among the three groups, and there were no significant differences in transplantation-related mortality among the three groups. In conclusion, GVHD prophylaxis with reduced-dose methotrexate and MMF was closely associated with high incidence of neutrophil engraftment without an effect on the incidence and severity of GVHD, which was compared to GVHD prophylaxis with conventional-dose methotrexate.
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http://dx.doi.org/10.1007/s00277-019-03801-zDOI Listing
November 2019

Acquired Hemophilia A Associated with Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus: A Single-Center Case Series in Japan.

Diabetes Ther 2019 Jun 29;10(3):1139-1143. Epub 2019 Mar 29.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.

Herein we describe four patients with acquired hemophilia A (AHA) caused by factor VIII (FVIII) inhibitor and histories of dipeptidyl peptidase-4 inhibitor (DPP4-I) treatment for diabetes mellitus (DM). Drug exposure can cause a breakdown of immune tolerance to FVIII associated with CD4 T cells, resulting in the induction of autoantibodies against FVIII. In patient 1 in the present series, FVIII inhibitor disappeared after DPP4-I treatment. The DPP4-I treatment was stopped faster in patient 1 than it was in patient 2, whose FVIII inhibitor titer was higher than patient 1's. Two patients died: patient 3 due to brain infarction after recurrence associated with the development of sigmoid colon rupture, and patient 4 due to multiple organ failure associated with Clostridium difficile colitis. DPP4-I treatment may create an ideal environment for the induction of new antibodies and AHA onset associated with tumor necrosis factor-α reduction. These are the first reported cases of the potential development and/or prolonging of AHA after DDP4-I treatment for DM, and they suggest possible disease associations.
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http://dx.doi.org/10.1007/s13300-019-0609-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531581PMC
June 2019

Methotrexate (MTX)-associated malignant lymphoma of the bilateral breast: imaging features in comparison to other nipple-areolar tumors.

Clin Imaging 2019 Jan - Feb;53:120-125. Epub 2018 Oct 6.

Department of Pathology, National Hospital Organization Kyushu Medical Center, Japan.

Tumors originating from the nipple-areolar complex of the breast are rare. We herein report the case of a patient with metachronous bilateral areolar methotrexate (MTX)-associated lymphoma. The patient was a 67-year-old woman who presented with a rapidly enlarging tumor in the areolar region of her left breast. She had a long history of rheumatoid arthritis and had taken MTX for many years. On ultrasonography, the tumor showed well-demarcated margins and hyper-vascularity. On magnetic resonance imaging, the tumor showed a homogeneous low-to-moderate signal intensity that was similar to that of the nipple on both T1- and T2-weighted imaging; the diffusion was significantly reduced on diffusion-weighted images. The tumor showed a medium-plateau pattern on dynamic contrast-enhanced imaging. No necrotic change was observed. Based on the imaging findings, we considered the tumor to have originated from the areola. According to the internal homogeneity, the rapid growth and hyper-cellularity, the potential diagnoses included a small round cell tumor (including malignant lymphoma) and a mesenchymal neoplasm (especially leiomyoma or leiomyosarcoma, which frequently originate from the areolar region). An excisional biopsy of the tumor was performed. The pathological diagnosis was diffuse large, non GC B-cell lymphoma that we suspected was associated with MTX. The tumor shrank rapidly after the withdrawal of MTX. After three months, we detected a B-cell lymphoma of the same type originating in the contralateral areola. We compared the characteristics of the imaging findings of the MTX-associated lymphoma with the nipple-areolar or periareolar tumors and primary breast lymphoma.
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http://dx.doi.org/10.1016/j.clinimag.2018.10.004DOI Listing
March 2019

Risk of secondary primary malignancies in multiple myeloma patients with or without autologous stem cell transplantation.

Int J Hematol 2019 Jan 24;109(1):98-106. Epub 2018 Sep 24.

Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.

Outcomes for patients with multiple myeloma (MM) have improved through use of novel treatments, especially lenalidomide combined with autologous stem cell transplantation. However, because of their increased life expectancy, an increased risk of secondary primary malignancies (SPMs) has been observed in MM patients, particularly after lenalidomide maintenance in both transplant-eligible (TE) and transplant-ineligible (TI) patients. To evaluate the incidence and risk factors of developing SPMs, we identified 17 TE-MM and 12 TI-MM patients with SPMs among 211 TE-MM and 280 TI-MM patients, including seven TE-MM and four TI-MM patients with hematological malignancies and ten TE-MM and eight TI-MM patients with non-hematological cancers, respectively. The median follow-up time from diagnosis was > 4 years. Multivariate analysis identified a history of high-dose cyclophosphamide use for peripheral blood stem cell harvest in TE-MM patients and > 65 years of age at diagnosis, or a history of adriamycin, lenalidomide, or thalidomide use in TI-MM patients as independent risk factors for SPMs (P < 0.001). Patients with a history of lenalidomide use had a lower risk of death among both TE-MM (P = 0.0326) and TI-MM (P < 0.001) patients. The survival benefit of receiving lenalidomide outweighed the increased risk of SPMs in both TE-and TI-MM patients.
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http://dx.doi.org/10.1007/s12185-018-2538-8DOI Listing
January 2019
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