RESUMO
Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. Identification of factors associated with CNS progression is essential to improve the prognosis of patients with PVRL. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital to identify factors associated with CNS progression and prognosis. All patients were treated with intravitreal methotrexate (MTX) injections in the affected eyes until lesion resolution. Twenty-four patients were treated with systemic administration of high-dose MTX (systemic HD-MTX) every other week for a total of five cycles following intravitreal MTX injection. Of 24 patients, 20 completed five cycles of systemic HD-MTX. The 5-year cumulative incidence of CNS progression and overall survival (OS) rate were 78.0% and 69.0% respectively. By univariate and multivariate analyses, bilateral disease and the detection of B-cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic HD-MTX completion reduced the risk of CNS progression and was identified as a factor affecting OS. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.
Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma , Neoplasias da Retina , Humanos , Neoplasias da Retina/tratamento farmacológico , Neoplasias da Retina/patologia , Estudos Retrospectivos , Corpo Vítreo/patologia , Linfoma/tratamento farmacológico , Sistema Nervoso Central/patologia , MetotrexatoRESUMO
Primary vitreoretinal lymphoma (PVRL) is a rare malignant lymphoma subtype with an unfavorable prognosis due to frequent central nervous system (CNS) progression. Thus, identifying factors associated with CNS progression is essential for improving the prognosis of PVRL patients. Accordingly, we conducted a comprehensive genetic analysis using archived vitreous humor samples of 36 PVRL patients diagnosed and treated at our institution and retrospectively examined the relationship between genetic alterations and CNS progression. Whole-exome sequencing (n = 2) and amplicon sequencing using a custom panel of 107 lymphomagenesis-related genes (n = 34) were performed to assess mutations and copy number alterations. The median number of pathogenic genetic alterations per case was 12 (range: 0- 22). Pathogenic genetic alterations of CDKN2A, MYD88, CDKN2B, PRDM1, PIM1, ETV6, CD79B, and IGLL5, as well as aberrant somatic hypermutations, were frequently detected. The frequency of ETV6 loss and PRDM1 alteration (mutation and loss) was 23% and 49%, respectively. Multivariate analysis revealed ETV6 loss (hazard ratio [HR]: 3.26, 95% confidence interval [CI]: 1.08-9.85) and PRDM1 alteration (HR: 2.52, 95% CI: 1.03-6.16) as candidate risk factors associated with CNS progression of PVRL. Moreover, these two genetic factors defined slow-, intermediate-, and rapid-progression groups (0, 1, and 2 factors, respectively), and the median period to CNS progression differed significantly among them (52 vs. 33 vs. 20 months, respectively). Our findings suggest that genetic factors predict the CNS progression of PVRL effectively, and the genetics-based CNS progression model might lead to stratification of treatment.
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Our patient was diagnosed with chronic myeloid leukemia (CML) in chronic phase (CP) when he was 40 years old. Although dasatinib (DAS) was prescribed during his clinical course, he was poorly compliant with the treatment. In November 20XX, at 65 years of age, he visited our hospital with leukocytosis. He was diagnosed with CML in CP and recommenced DAS at 50 mg/day, achieving a complete hematological response after 2 months. However, DAS was increased to 100 mg/day because only minimum cytogenetic response was evident even after 9 months, but CML progressed to the accelerated phase after 18 months. The ABL kinase domain mutations T315I and F317L were detected. Ponatinib (PON) was not yet approved, and he declined allogeneic stem cell transplantation therapy. He commenced interferon-α (IFN-α) in addition to DAS, and the F317L mutation (only) disappeared after 7 months; the patient achieved a major cytogenetic response. In January 20XXï¼4, he commenced PON monotherapy (the drug was approved by this time) and achieved a major molecular response after 8 months. The T315I mutation disappeared during PON therapy. Although IFN-α is rarely used in the treatment of CML, this case suggests that IFN-α should be re-considered in patients with CML who exhibit tyrosine kinase inhibitor resistance.
Assuntos
Imidazóis/uso terapêutico , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas Oncogênicas v-abl/genética , Piridazinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Humanos , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
We report the establishment of a novel activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL) cell line, designated as TMD12, from a patient with highly refractory DLBCL. ABC-DLBCL is a subtype with a relatively unfavorable prognosis that was originally categorized using gene expression profiling according to its cell of origin. TMD12 cells were isolated from the pleural effusion of the patient at relapse and passaged continuously in vitro for >4 years. The cells displayed cluster of differentiation (CD)19, CD20, CD22, CD38, human leukocyte antigen-DR isotype, and κ positivity and CD5, CD10, CD23, and λ negativity, as detected using flow cytometric analysis. The chromosomal karyotypic analysis, including the spectral karyotyping method, confirmed t(1;19)(q21:q13.1), del(6q23), gain of chromosome 18, and other abnormalities. Mutation analyses, including whole-exome sequencing, revealed that TMD12 cells harbored mutations in MYD88 and CD79B, indicating an ABC subtype. TMD12 cells exhibited chronic active B-cell receptor signaling and constitutive activation of the nuclear factor κB pathway, which is typically associated with sensitivity to a specific Bruton tyrosine kinase inhibitor, ibrutinib. Intriguingly, TMD12 cells displayed moderate resistance to ibrutinib and lacked activation of Janus kinase/signal transducers and activators of transcription 3 signaling, another hallmark of this DLBCL subtype. Treatment with an inhibitor against tumor progression locus 2 (TPL2), a multifunctional intracellular kinase that is activated particularly downstream of Toll-like receptors or MYD88 and IκB kinase α/ß (IKKα/ß), suppressed the proliferation of TMD12 cells, implying the possible involvement of the TPL2-p105 pathway in the tumorigenesis of ABC-DLBCL. Because only a limited number of ABC-DLBCL cell lines are currently available, TMD12 cells might provide a useful tool in the search for novel druggable targets for this intractable lymphoma.
Assuntos
Linfoma Difuso de Grandes Células B , Fator 88 de Diferenciação Mieloide , Humanos , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Recidiva Local de Neoplasia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfócitos B/metabolismo , Linhagem Celular , Linhagem Celular TumoralRESUMO
We report a case of fever of unknown origin in a patient with MDS associated with IgM-MGUS. The patient was positive for MYD88 mutation, and chemotherapy for LPL/WM improved the fever. Analysis of MYD88 and the effect of chemotherapy on LPL/WM finally revealed the latent LPL/WM in this case.
RESUMO
Objective Patients with hematological malignancies, particularly those with multiple myeloma, often suffer from pathological vertebral compression fractures (VCFs). Consequent and significant spinal pain and paralysis impair the activities of daily living and quality of life and delay subsequent chemotherapy. Balloon kyphoplasty (BKP), which is less invasive than conventional therapies, is a type of percutaneous vertebroplasty in which cement is injected into the broken vertebrae to stabilize the spinal column. The present study assessed the effect of BKP on hematological tumors. Methods We retrospectively analyzed five myeloma patients and one lymphoma patient who underwent BKP for pathological VCFs in our institution. Results The median age was 74 years old. The spinal operation level ranged from T2 to L4. BKP was performed at the diagnosis in two cases, after first-line chemotherapy in one case, and after subsequent chemotherapy in three cases. After approximately 1 month, the patients' average Eastern Cooperative Oncology Group performance status score rapidly improved from 3.2 to 1.3. The numeric rating scale score decreased from 8.8 to 2.0, and the Karnofsky Performance Status score increased from 35 to 75. No severe complications were observed. All patients became able to walk unassisted and underwent early subsequent chemotherapy. Conclusion BKP can be a safe and effective treatment option for pathological VCFs in patients with hematological malignancies and allows for rapid induction with subsequent chemotherapy.
Assuntos
Fraturas por Compressão , Neoplasias Hematológicas , Cifoplastia , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Atividades Cotidianas , Idoso , Fraturas por Compressão/etiologia , Fraturas por Compressão/cirurgia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/terapia , Humanos , Cifoplastia/efeitos adversos , Qualidade de Vida , Estudos Retrospectivos , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: Neurotoxicity is one of the dangerous complications of chimeric antigen receptor (CAR) T-cell therapy, while its pathophysiology remains to be fully understood. Motor weakness not associated with central nervous system (CNS) toxicity has rarely been reported after CAR T-cell therapy. CASE REPORT: A 42-year-old female with a refractory diffuse large B-cell lymphoma received tisagenlecleucel (tisa-cel) and developed cytokine release syndrome (CRS) on day 3. She was treated with tocilizumab and methylprednisolone, which resolved CRS promptly. On day 7, motor weakness in lower extremities appeared, and she gradually became unable to walk without showing any other symptoms attributed to CNS disturbances. Whereas dexamethasone and tocilizumab were ineffective, neuropathy improved after high dose chemotherapy followed by autologous stem cell transplantation. Nerve conduction study (NCS) in lower extremities showed a decline in compound muscle action potential amplitude along with worsening of motor weakness, which was restored after improvement of symptoms. Based on symptoms and NCS, her motor weakness was thought to be due to disturbance in peripheral nerves. CONCLUSION: This study reports a patient who developed severe motor weakness due to disturbance in peripheral nerves after tisa-cel therapy. Neurotoxicity of non-CNS origin should also be noted in CAR T-cell therapy.
Assuntos
Imunoterapia Adotiva/efeitos adversos , Debilidade Muscular/induzido quimicamente , Nervos Periféricos , Receptores de Antígenos de Linfócitos T , Adulto , Síndrome da Liberação de Citocina/induzido quimicamente , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/fisiopatologia , Transplante AutólogoRESUMO
A 64-year-old man was diagnosed with limited cutaneous systemic sclerosis 5 years prior to this report. His sclerotic skin symptoms did not respond to oral low-dose prednisone (5-10 mg/day). Five years after the diagnosis, the patient presented with leukocytosis 3.8 × 109/L in a routine blood test, and was finally diagnosed with chronic-phase chronic myelogenous leukemia (CML). The leukemia responded optimally to initial dasatinib, and a complete cytogenetic response was achieved after 6 months of therapy. His skin symptoms dramatically improved in parallel with dasatinib therapy, as indicated by a decrease in the modified Rodnan skin score, from 12 points at diagnosis to 2 after 9 months. It has been reported that imatinib, a first-generation tyrosine kinase inhibitor, improves skin sclerosis in some patients with systemic sclerosis. To the best of our knowledge, this is the first report of simultaneous improvement of CML and limited cutaneous systemic sclerosis in response to dasatinib. Further study of the mechanism of action of dasatinib is crucial.