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1.
Cancer Sci ; 115(6): 2002-2011, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38498976

RESUMEN

Triplet regimen comprising proteasome inhibitors, immunomodulatory drugs, and dexamethasone (DEX) is a recommended induction/consolidation therapy for multiple myeloma (MM) patients eligible for transplant. In this Japanese phase II study conducted from 2017 to 2019, newly diagnosed MM patients aged 20-65 received four induction cycles with bortezomib (Bor), lenalidomide (Len), and DEX (VRD), followed by Bor and high-dose melphalan with autologous stem cell rescue. Subsequently, they underwent four consolidation cycles with carfilzomib, Len, and DEX (KRD), followed by Len maintenance until disease progression. A total of 141 patients were analyzed. In an intent-to-treat population, the complete or better response post induction was 19.9%, rising to 39.7%, 58.9%, and 62.4% after transplant, consolidation, and 1-year maintenance, respectively. With a median follow-up of 38 months, the 3-year progression-free survival (PFS) rate was 83.5% and the 3-year overall survival rate was 92.5%. Severe adverse events (≥grade 3) occurred in ~30% of patients; however, there was no treatment-related mortality. These findings clearly showed the tolerability and effectiveness of this protocol. Nevertheless, patients with high-risk cytogenetics showed a trend toward lower 3-year PFS than those without (77.8% vs. 89.4%, p = 0.051), and ultra-high-risk cytogenetics (≥2 high-risk cytogenetics) had an even worse prognosis, with 61.2% 3-year PFS. To overcome this situation, a more potent treatment strategy incorporating novel agents such as the CD38-antibody should be assessed in future studies.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Trasplante de Células Madre Hematopoyéticas , Lenalidomida , Mieloma Múltiple , Trasplante Autólogo , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/terapia , Lenalidomida/administración & dosificación , Lenalidomida/uso terapéutico , Persona de Mediana Edad , Femenino , Masculino , Anciano , Adulto , Trasplante de Células Madre Hematopoyéticas/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dexametasona/administración & dosificación , Dexametasona/uso terapéutico , Bortezomib/administración & dosificación , Bortezomib/uso terapéutico , Quimioterapia de Consolidación/métodos , Melfalán/administración & dosificación , Melfalán/uso terapéutico , Oligopéptidos/uso terapéutico , Oligopéptidos/administración & dosificación , Quimioterapia de Inducción/métodos , Supervivencia sin Progresión , Adulto Joven , Quimioterapia de Mantención/métodos
2.
Biochem Biophys Res Commun ; 619: 117-123, 2022 09 03.
Artículo en Inglés | MEDLINE | ID: mdl-35753219

RESUMEN

Radiation therapy is one of the major treatment modalities for patients with cancers. However, ionizing radiation (IR) damages not only cancer cells but also the surrounding vascular endothelial cells (ECs). Hippo pathway effector genes Yap1 and Taz are the two transcriptional coactivators that have crucial roles in tissue homeostasis and vascular integrity in various organs. However, their function in adult ECs at the steady state and after IR is poorly understood. Here, we report sex- and context-dependent roles of endothelial YAP1/TAZ in maintaining vascular integrity and organismal survival. EC-specific Yap1/Taz deletion compromised systemic vascular integrity, resulting in lethal circulation failure preferentially in male mice. Furthermore, EC-specific Yap1/Taz deletion induced acute lethality upon sublethal IR that was closely associated with exacerbated systemic vascular dysfunction and circulation failure. Consistent with these findings, RNA-seq analysis revealed downregulation of tight junction genes in Yap1/Taz-deleted ECs. Collectively, our findings highlight the importance of endothelial YAP1/TAZ for maintaining adult vascular function, which may provide clinical implications for preventing organ injury after radiation therapy.


Asunto(s)
Neoplasias , Transactivadores , Animales , Células Endoteliales/metabolismo , Masculino , Ratones , Neoplasias/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Proteínas Señalizadoras YAP
3.
Hematol Oncol ; 40(4): 667-677, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35142384

RESUMEN

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.


Asunto(s)
Linfoma Extranodal de Células NK-T , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Asparaginasa , Carboplatino , Sistema Nervioso Central/patología , Dexametasona , Etopósido , Humanos , Ifosfamida , Células Asesinas Naturales/patología , Linfoma Extranodal de Células NK-T/diagnóstico , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Metotrexato , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos
4.
Rinsho Ketsueki ; 63(7): 759-763, 2022.
Artículo en Japonés | MEDLINE | ID: mdl-35922944

RESUMEN

A 68-year-old male patient with lung adenocarcinoma, who was treated with chemotherapy and immune checkpoint inhibitors (ICIs), developed lymphadenopathy during treatment. His para-aortic lymph nodes increased to 2.0 cm in diameter. Both inguinal lymph nodes were 1.5 cm in diameter, and multiple hepatic masses appeared. After the ICI readministration, both inguinal lymph nodes increased to 2.0 cm in diameter, but the para-aortic lymph nodes and hepatic masses remained. Angioimmunoblastic T-cell lymphoma (AITL) diagnosis was established after the right inguinal lymph node biopsy, which was accompanied by an infiltration of Epstein-Barr virus (EBV)-encoded small ribonucleic acid-positive B-cells. After the ICI discontinuation, the inguinal lymph nodes decreased to 1.5 cm in diameter, but the para-aortic lymph nodes remained, and hepatic masses increased. Hepatic lesions were possibly lung cancer metastasis. The ICI administration and EBV reactivation were potentially associated with AITL development in the present case. The natural shrinkage of lymphoma after the ICI cessation implied the immunological mechanism like that of the methotrexate-related lymphoproliferative disease.


Asunto(s)
Infecciones por Virus de Epstein-Barr , Linfadenopatía Inmunoblástica , Neoplasias Pulmonares , Linfoma de Células T , Anciano , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4 , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/complicaciones , Ganglios Linfáticos/patología , Linfoma de Células T/tratamiento farmacológico , Masculino
5.
Cancer Sci ; 112(7): 2845-2854, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33942442

RESUMEN

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m2 , rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/farmacocinética , Esquema de Medicación , Resistencia a Antineoplásicos , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/farmacocinética , Japón , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Supervivencia sin Progresión , Rituximab/administración & dosificación , Rituximab/farmacocinética
6.
Hematol Oncol ; 39(1): 51-59, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32978820

RESUMEN

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with 90 Yttrium-ibritumomab tiuxetan (90 Y-IT) after re-induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re-induction therapy with BR was administered every 4 weeks up to 4-6 cycles. If patients achieved at least partial response, 90 Y-IT was administered as consolidation therapy. The primary endpoint was 2-year progression-free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with 90 Y-IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2-year PFS rate after the consolidation among the 22 patients receiving 90 Y-IT was 59% (95% confidence interval [CI], 38%-77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2-year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2-year overall survival after the consolidation was 95% (95% CI, 74%-99%). In conclusion, in a subset of patients with previously treated FL, 90 Y-IT consolidation after BR re-induction conferred a durable remission, indicating that consolidation therapy using 90 Y-IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia de Consolidación , Linfoma Folicular/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Femenino , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Recurrencia , Rituximab/administración & dosificación , Rituximab/efectos adversos
7.
Jpn J Clin Oncol ; 51(3): 408-415, 2021 Mar 03.
Artículo en Inglés | MEDLINE | ID: mdl-33244584

RESUMEN

OBJECTIVE: Fludarabine, cyclophosphamide and rituximab (FCR) is the standard regimen for fit patients with untreated CD20-positive chronic lymphocytic leukemia (CLL). However, this combination is unavailable in Japan because rituximab is not approved for CLL. We investigated the efficacy and safety of FCR in this single-arm, multicenter study designed as a bridging study to the CLL8 study by the German CLL Study Group. METHODS: The study enrolled previously untreated patients with CLL of Binet stage B or C with active disease. Patients with a Cumulative Illness Rating Scale score of ≤6 and creatinine clearance of ≥70 ml/min were eligible. Patients received 6 cycles of FCR every 28 days and were followed for up to 1 year. RESULTS: Seven patients were enrolled. The best overall response rate according to the 1996 NCI-WG Guidelines, the primary endpoint of the study, was 71.4% (95% confidence interval, 29.0-96.3%), with one patient achieving complete response. No deaths or progression occurred during follow-up. The main adverse event was hematotoxicity. CD4-positive T-cell count decreased in all patients; most patients showed no reduction in serum immunoglobulin G. CONCLUSION: Although the number of patients was limited, FCR appears to be effective with manageable toxicity for treatment-naïve fit Japanese patients with CD20-positive CLL. CLINICAL TRIAL NUMBER: JapicCTI-132285.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Rituximab/uso terapéutico , Vidarabina/análogos & derivados , Anciano , Anticuerpos Antineoplásicos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Ciclofosfamida/efectos adversos , Ciclofosfamida/farmacocinética , Progresión de la Enfermedad , Determinación de Punto Final , Femenino , Humanos , Terapia de Inmunosupresión , Japón , Leucemia Linfocítica Crónica de Células B/sangre , Leucemia Linfocítica Crónica de Células B/inmunología , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab/efectos adversos , Rituximab/sangre , Rituximab/farmacocinética , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/farmacocinética , Vidarabina/uso terapéutico
8.
Lancet Oncol ; 21(4): 593-602, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32171071

RESUMEN

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.


Asunto(s)
Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Metotrexato/administración & dosificación , Neoplasias Vasculares/tratamiento farmacológico , Adulto , Anciano , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Estudios Prospectivos , Rituximab/administración & dosificación , Vincristina/administración & dosificación , Adulto Joven
9.
Cancer Sci ; 111(7): 2608-2619, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32342603

RESUMEN

The interaction between CD47 and signal-regulatory protein-α (SIRPα) inhibits phagocytosis, thus affecting the clinical outcomes of neoplastic diseases. Although CD47 upregulation is associated with poor prognosis in several malignancies, the effect of SIRPα expression and its coexpression with CD47 remains unclear. This study aimed to investigate the clinicopathologic effect of CD47 and SIRPα expression in diffuse large B-cell lymphoma (DLBCL). Immunostaining of 120 biopsy samples showed that CD47 is primarily expressed in tumor cells, whereas SIRPα is expressed in nonneoplastic stromal cells, mostly macrophages. CD47high cases showed higher MYC protein expression and lower MYC translocation. The SIRPαhigh cases presented significantly shorter overall survival (OS) and progression-free survival (PFS) than SIRPαlow cases in the activated B-cell (ABC) subtype of DLBCL (P = .04 and P = .02, respectively). Both CD47high and SIRPαhigh presented significantly shorter OS and PFS than other cases among all DLBCL patients (P = .01 and P = .004, respectively), and the ABC type (P = .04 and P = .008, respectively) but not the germinal center B-cell type. Both CD47high and SIRPαhigh yielded a constant independent prognostic value for OS and PFS in multivariate analysis (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.20-7.43; P = .02; and HR, 2.87; 95% CI, 1.42-5.85; P = .003, respectively). To the best of our knowledge, this is the first study to report that combinatorial CD47 and SIRPα expression is a potential independent prognostic factor for DLBCL. Evaluation of CD47 and SIRPα expression could be useful before CD47 blockade therapy.


Asunto(s)
Antígenos de Diferenciación/metabolismo , Antígeno CD47/metabolismo , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/mortalidad , Receptores Inmunológicos/metabolismo , Transducción de Señal , Adulto , Anciano , Anciano de 80 o más Años , Antígenos de Diferenciación/genética , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores , Antígeno CD47/genética , Ciclofosfamida , Doxorrubicina , Femenino , Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Persona de Mediana Edad , Prednisona , Pronóstico , Receptores Inmunológicos/genética , Rituximab , Resultado del Tratamiento , Vincristina
10.
Pathol Int ; 70(5): 280-286, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32052529

RESUMEN

Primary splenic low-grade B-cell lymphoma of the red pulp comprises hairy cell leukemia (HCL) and splenic B-cell lymphoma/leukemia, unclassifiable (SPLL-U). SPLL-U is a rare disease that includes subtypes of a hairy cell leukemia-variant (HCL-v), splenic diffuse red pulp small B-cell lymphoma (SDRPL) and other types that are known as narrow sense SPLL-U (SPLL-U-NS). Notably, limited information is available regarding the BRAF mutation (V600E) and cyclin D3 expression in subtypes of SPLL-U. Therefore, we performed a pathological analysis of the BRAF mutation (V600E) and characterized pathological features of SPLL-U. We reviewed the pathological findings of 12 SPLL-U cases. The 12 cases considered included two cases of HCL-v, six cases of SPLL-U-NS and four undetermined cases. The BRAF mutation (V600E) was detected in three cases, which were all SPLL-U-NS. Cases with the BRAF mutation (V600E) have increased levels of CD103 expression and decreased cyclin D3 and cyclin D1 expression compared with cases that lacked the BRAF mutation. These findings suggest that the BRAF mutation might play a significant role in SPLL-U. Therefore, the significance of the BRAF mutation should be evaluated via genomic or transcriptional analyses of a large cohort of SPLL-U patients.


Asunto(s)
Linfoma de Células B/genética , Linfoma de Células B/patología , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias del Bazo/genética , Neoplasias del Bazo/patología , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación
11.
Ann Hematol ; 98(7): 1647-1655, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31001658

RESUMEN

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma Extranodal de Células NK-T , Neoplasias Cutáneas , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Asparaginasa/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Japón/epidemiología , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Linfoma Extranodal de Células NK-T/mortalidad , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/mortalidad , Esteroides/administración & dosificación
12.
Mod Pathol ; 31(2): 313-326, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28984304

RESUMEN

Most high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements are aggressive B-cell lymphomas. Occasional double-hit follicular lymphomas have been described but the clinicopathological features of these tumors are not well known. To clarify the characteristics of double-hit follicular lymphomas, we analyzed 10 cases of double-hit follicular lymphomas and 15 cases of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements for clinicopathological and genome-wide copy-number alterations and copy-neutral loss-of-heterozygosity profiles. For double-hit follicular lymphomas, the median age was 67.5 years (range: 48-82 years). The female/male ratio was 2.3. Eight patients presented with advanced clinical stage. The median follow-up time was 20 months (range: 1-132 months). At the end of the follow-up, 8 patients were alive, 2 patients were dead including 1 patient with diffuse large B-cell lymphoma transformation. Rearrangements of MYC/BCL2, MYC/BCL6, and MYC/BCL2/BCL6 were seen in 8, 1, and 1 cases, respectively. The partner of MYC was IGH in 6 cases. There were no cases of histological grade 1, 4 cases of grade 2, 5 cases of grade 3a, and 1 case of grade 3b. Two cases of grade 3a exhibited immunoblast-like morphology. Immunohistochemistry demonstrated 9 cases with ≥50% MYC-positive cells. There was significant difference in MYC intensity (P=0.00004) and MIB-1 positivity (P=0.001) between double-hit follicular lymphomas and high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements. The genome profile of double-hit follicular lymphomas was comparable with conventional follicular lymphomas (GSE67385, n=198) with characteristic gains of 2p25.3-p11.1, 7p22.3-q36.3, 12q11-q24.33, and loss of 18q21.32-q23 (P<0.05). In comparison with high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements, double-hit follicular lymphomas had fewer copy-number alterations and minimal common region of gain at 2p16.1 (70%), locus also significant against conventional follicular lymphomas (P=0.0001). In summary, double-hit follicular lymphomas tended to be high-grade histology, high MYC protein expression, high MYC/IGH fusion, and minimal common region of gain at 2p16.1. Double-hit follicular lymphomas seemed to be a different disease from high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements and have an indolent clinical behavior similar to follicular lymphomas without MYC rearrangement.


Asunto(s)
Reordenamiento Génico , Linfoma de Células B/patología , Linfoma Folicular/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-myc/genética , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Linfoma de Células B/genética , Linfoma Folicular/genética , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Fenotipo
13.
Haematologica ; 103(6): 1018-1028, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29242302

RESUMEN

The characteristics of adult patients with chronic active Epstein-Barr virus infection are poorly recognized, hindering early diagnosis and an improved prognosis. We studied 54 patients with adult-onset chronic active Epstein-Barr virus infection diagnosed between 2005 and 2015. Adult onset was defined as an estimated age of onset of 15 years or older. To characterize the clinical features of these adults, we compared them to those of 75 pediatric cases (estimated age of onset <15 years). We compared the prognosis of adult-onset chronic active Epstein-Barr virus infection with that of patients with nasal-type (n=37) and non-nasal-type (n=45) extranodal NK/T-cell lymphoma. The median estimated age of onset of these lymphomas was 39 years (range, 16-86 years). Compared to patients with pediatric-onset disease, those in whom the chronic active Epstein-Barr virus infection developed in adulthood had a significantly decreased incidence of fever (P=0.005), but greater frequency of skin lesions (P<0.001). Moreover, hypersensitivity to mosquito bites and the occurrence of hydroa vacciniforme were less frequent in patients with adult-onset disease (P<0.001 and P=0.0238, respectively). Thrombocytopenia, high Epstein-Barr virus nuclear antigen antibody titer, and the presence of hemophagocytic syndrome were associated with a poor prognosis (P=0.0087, P=0.0236, and P=0.0149, respectively). Allogeneic hematopoietic stem cell transplantation may improve survival (P=0.0289). Compared to pediatric-onset chronic active Epstein-Barr virus infection and extranodal NK/T-cell lymphoma, adult-onset chronic active Epstein-Barr virus infection had a poorer prognosis (P<0.001 and P=0.0484, respectively). Chronic active Epstein-Barr virus infection can develop in a wide age range, with clinical differences between adult-onset and pediatric-onset disease. Adult-onset chronic active Epstein-Barr virus infection is a disease with a poor prognosis. Further research will be needed.


Asunto(s)
Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/fisiología , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/virología , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Biomarcadores , Biopsia , Femenino , Humanos , Trastornos Linfoproliferativos/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Evaluación de Síntomas , Carga Viral , Adulto Joven
14.
Hematol Oncol ; 36(3): 591-599, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29602174

RESUMEN

Myeloid sarcoma (MS) is a rare condition and is an extramedullary tumour of immature myeloid cells. It is now known that the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway suppresses the host antitumor responses and that these products are expressed on both tumour cells and tumour-infiltrating cells in various malignancies. However, little is known about the significance of PD-1/PD-L1 expression on tumour cells and tumour microenvironmental cells in MS. To investigate the clinicopathological significance of PD-1/PD-L1 expression in MS, we analyzed 98 patients by immunohistochemistry. Of these, 10.2% of cases had neoplastic tumour cells positive for PD-L1 (nPD-L1+ ). However, the rate of nPD-L1+ was <5% (range: 0.27 to 2.97%). On the other hand, PD-L1 expression on 1 or more of stromal cells in the tumour microenvironment (miPD-L1+ ) was observed in 37.8% of cases. Because all nPD-L1+ cases expressed PD-1 on less than 5% of tumour cells, we compared the miPD-L1+ and miPD-L1- groups. There was a correlation between miPD-L1+ status and the number of PD-1-expressing tumour -infiltrating lymphocytes (PD-1+ TILs; P = .0229). miPD-L1+ was found to be associated with poorer overall survival and progression-free survival (P = .00392, P = .00261, respectively). Multivariate analysis also confirmed miPD-L1+ to be an independent poor prognostic factor. In conclusion, our study indicated that the immunotherapy blocking the PD-1/PD-L1 pathway may improve the clinical outcome of MS.


Asunto(s)
Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Sarcoma Mieloide/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Persona de Mediana Edad , Pronóstico , Sarcoma Mieloide/inmunología , Sarcoma Mieloide/metabolismo , Tasa de Supervivencia , Microambiente Tumoral/inmunología , Adulto Joven
15.
Hematol Oncol ; 36(1): 166-173, 2018 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-29052238

RESUMEN

Extranodal NK/T-cell lymphoma, nasal type (ENKTL) is a subtype of non-Hodgkin lymphoma with a poor prognosis. Although first-line treatments for patients with localized ENKTL have been established, there is no gold standard treatment for patients with advanced ENKTL and refractory and/or relapsed disease. Anti-CD30 antibody-based therapy, including brentuximab vedotin (BV), has been shown to target malignant lymphomas with CD30 expression. In particular, this therapeutic agent has recently been suggested to be effective for Hodgkin lymphoma and mature T-cell lymphoma. However, the efficacy of BV toward ENKTL has not yet been established. Therefore, we investigated the expression of CD30 in a large cohort to evaluate BV as a potential treatment for ENKTL. In this study, 97 Japanese patients with newly diagnosed ENKTL between January 2007 and December 2015 were enrolled. Flow cytometry and immunohistochemistry were performed for the evaluation of CD30 expression. If the cut-off value of CD30 expression is 1% or more, there were 55 positive cases (56.5%). According to the localization of lesion, the frequency of CD30 expression was significantly higher in the non-nasal type than in the nasal type (P = .0394). No differences were observed in almost all clinical characteristics between CD30-positive cases and CD30-negative cases. In addition, the expression of CD30 was not a prognostic factor for either overall survival or progression-free survival. In conclusion, frequent expression of CD30 in ENKTL suggests anti-CD30 antibody-based therapy may be an effective treatment.


Asunto(s)
Antígeno Ki-1/metabolismo , Linfoma de Células T Periférico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Linfoma de Células T Periférico/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto Joven
16.
Oncologist ; 22(5): 554-560, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28408622

RESUMEN

BACKGROUND: Decision-making models for elderly patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) are in great demand. PATIENTS AND METHODS: The Society of Lymphoma Treatment in Japan (SoLT-J), in collaboration with the West-Japan Hematology and Oncology Group (West-JHOG), collected and retrospectively analyzed the clinical records of ≥65-year-old patients with DLBCL treated with R-CHOP from 19 sites across Japan to build an algorithm that can stratify adherence to R-CHOP. RESULTS: A total of 836 patients with a median age of 74 years (range, 65-96 years) were analyzed. In the SoLT-J cohort (n = 555), age >75 years, serum albumin level <3.7 g/dL, and Charlson Comorbidity Index score ≥3 were independent adverse risk factors and were defined as the Age, Comorbidities, and Albumin (ACA) index. Based on their ACA index score, patients were categorized into "excellent" (0 points), "good" (1 point), "moderate" (2 points), and "poor" (3 points) groups. This grouping effectively discriminated the 3-year overall survival rates, mean relative total doses (or relative dose intensity) of anthracycline and cyclophosphamide, unanticipated R-CHOP discontinuance rates, febrile neutropenia rates, and treatment-related death rates. Additionally, the ACA index showed comparable results for these clinical parameters when it was applied to the West-JHOG cohort (n = 281). CONCLUSION: The ACA index has the ability to stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of elderly patients with DLBCL treated with R-CHOP. The Oncologist 2017;22:554-560 IMPLICATIONS FOR PRACTICE: Currently, little is known regarding how to identify elderly patients with diffuse large B-cell lymphoma who may tolerate a full dose of chemotherapy or to what extent cytotoxic drugs should be reduced in some specific conditions. The Society of Lymphoma Treatment in Japan developed a host-dependent prognostic model consisting of higher age (>75 years), hypoalbuminemia (<3.7 g/dL), and higher Charlson Comorbidity Index score (≥3) for such elderly patients. This model can stratify the prognosis, tolerability to cytotoxic drugs, and adherence to treatment of these patients and thus help clinicians in formulating personalized treatment strategies for this growing patient population.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Evaluación Geriátrica , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Pronóstico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Comorbilidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Hipoalbuminemia/inducido químicamente , Hipoalbuminemia/patología , Japón , Linfoma de Células B Grandes Difuso/patología , Masculino , Medicina de Precisión , Prednisona/administración & dosificación , Prednisona/efectos adversos , Factores de Riesgo , Rituximab , Vincristina/administración & dosificación , Vincristina/efectos adversos
17.
Eur J Haematol ; 98(5): 459-466, 2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28129454

RESUMEN

OBJECTIVES: T-cell prolymphocytic leukemia (T-PLL) is a very rare, aggressive T-cell neoplasm. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is also a highly aggressive lymphoma. These two diseases can often be confused with each other; therefore, we aimed to determine the clinical and pathological differences between T-PLL and PTCL-NOS. METHODS: We analyzed 15 T-PLL and 91 PTCL-NOS patients and also compared clinical features between T-PLL and PTCL-NOS with leukemic presentation. Peripheral blood images and biopsy specimens were analyzed, and treatment responses were determined via imaging modalities. The clinicopathological characteristics were statistically compared. RESULTS: T-PLL cells were smaller in size than those of PTCL-NOS with leukemic presentation (P=.0068); moreover, PTCL-NOS cells with leukemic presentation were smaller than those of PTCL-NOS without leukemic presentation (P=.0017). Immunophenotypic patterns in T-PLL and PTCL-NOS were similar. Five-year overall survival rates of T-PLL and all PTCL-NOS patients were 57.5% and 36.8%, respectively. No significant differences were found in clinical manifestations or prognoses; T-PLL and PTCL-NOS with leukemic presentation had essentially equivalent characteristics. CONCLUSION: T-PLL and PTCL-NOS may share common biological and clinical characteristics in Japanese patients.


Asunto(s)
Leucemia Prolinfocítica de Células T/diagnóstico , Linfoma de Células T Periférico/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Biopsia , Niño , Diagnóstico Diferencial , Femenino , Reordenamiento Génico , Humanos , Inmunofenotipificación , Leucemia Prolinfocítica de Células T/genética , Leucemia Prolinfocítica de Células T/mortalidad , Leucemia Prolinfocítica de Células T/terapia , Recuento de Leucocitos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/mortalidad , Linfoma de Células T Periférico/terapia , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptores de Antígenos de Linfocitos T/genética , Resultado del Tratamiento , Adulto Joven
18.
Rinsho Ketsueki ; 58(5): 471-479, 2017.
Artículo en Japonés | MEDLINE | ID: mdl-28592762

RESUMEN

Chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in western countries, but it is rare in Japan. Several mutations have been identified in patients with CLL using next-generation sequencing, but disease-specific mutations were not found. Some mutations, such as those in TP53, NOTCH1, SF3B, and BIRC3 are useful for risk stratification and prognosis prediction in patients with CLL. Strategies for treating CLL are rapidly evolving, with targeted agents such as the B-cell receptor signaling pathway inhibitors (ibrutinib, idelalisib), novel anti-CD20 monoclonal antibody (obinutuzumab), and Bcl-2 inhibitor (venetoclax) being approved by the US Food and Drug Administration. Although key drugs such as chlorambucil and rituximab cannot be used in Japan, others such as ibrutinib and bendamustine were recently approved for CLL treatment in Japan.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/terapia , Humanos , Inmunoterapia , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Terapia Molecular Dirigida , Pronóstico
19.
Rinsho Ketsueki ; 58(1): 32-36, 2017.
Artículo en Japonés | MEDLINE | ID: mdl-28190863

RESUMEN

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre de Sangre del Cordón Umbilical , Leucemia-Linfoma de Células T del Adulto/terapia , Humanos , Leucemia-Linfoma de Células T del Adulto/inmunología , Masculino , Persona de Mediana Edad , Receptores CCR4/inmunología , Inducción de Remisión , Trasplante Homólogo
20.
Rinsho Ketsueki ; 58(12): 2402-2405, 2017.
Artículo en Japonés | MEDLINE | ID: mdl-29332874

RESUMEN

A 75-year-old woman suffered a cat bite 10 months after myelodysplastic syndrome (MDS) diagnosis. She visited our hospital because the internal bleeding of the wound did not improve. Although the wound was treated, the bleeding did not stop. She was hospitalized for emergency medical treatment because the bleeding volume exceeded 200 ml. Although her platelet count was normal, the platelet function test showed a decrease in collagen and arachidonic acid aggregation. After platelet transfusion, her bleeding stopped. Patients with MDS may potentially have platelet dysfunction. In the case of bleeding without thrombocytopenia, a platelet function test should be performed and treatment intervention, such as platelet transfusion, should be considered.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas/etiología , Hemorragia/terapia , Síndromes Mielodisplásicos/complicaciones , Anciano , Transfusión Sanguínea , Femenino , Hemorragia/etiología , Humanos , Agregación Plaquetaria , Resultado del Tratamiento
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