RESUMO
BACKGROUND: Pathological examination by endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been reported to be useful in diagnosing pancreatic malignant lymphoma (ML), but some ML cases are difficult to be differentiated from pancreatic ductal adenocarcinoma (PDAC). METHODS: This retrospective study included 8 patients diagnosed with ML that had a pancreatic-head lesion at initial diagnosis and 46 patients with resected PDAC in the pancreatic head between April 2006 and October 2021 at our institute. ML and PDAC were compared in terms of patients' clinical features and imaging examinations. RESULTS: The median tumor size was larger in ML than in PDAC (45.8 [24-64] vs. 23.9 [8-44] mm), but the median diameter of the caudal main pancreatic duct (MPD) was larger in PDAC (2.5 [1.0-3.5] vs. 7.1 [2.5-11.8] mm), both showing significant differences between these malignancies (both, P < 0.001). In the analysis of covariance, MLs showed a smaller caudal MPD per tumor size than PDACs, with a statistical difference (P = 0.042). Sensitivity and specificity using sIL-2R ≥ 658 U/mL plus CA19-9 < 37 U/mL for the differentiation of ML from PDAC were 80.0% and 95.6%, respectively. CONCLUSIONS: Diagnosing pancreatic ML using cytohistological examination through EUS-FNA can be difficult in some cases. Thus, ML should be suspected if a patient with a pancreatic tumor has a small MPD diameter per tumor size, high serum sIL-2R level, normal CA19-9 level. If the abovementioned features are present and still cannot be confirmed as PDAC, re-examination should be considered.
Assuntos
Carcinoma Ductal Pancreático , Linfoma , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Antígeno CA-19-9 , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Ductos Pancreáticos/patologia , Neoplasias PancreáticasRESUMO
RATIONALE: Recently, the incidence of polyoncosis has been increasing due to advancements in treatment, such as antitumor therapy, which led to a prolonged survival. However, few patients with metastatic pancreatic ductal adenocarcinoma (PDAC) develop second tumors, which render a poor prognosis. We report a rare case of PDAC, which is metachronous with a fatal malignant lymphoma (ML). PATIENT CONCERNS: A 68-year-old woman who had been monitored due to liver cirrhosis secondary to hepatitis C virus infection presented with a 10-mm pancreatic head cancer with lung metastasis and had started an anticancer therapy with gemcitabine. Approximately 18 months after diagnosis, lymphadenopathies around the pancreas were noted, which eventually spread to the entire body over time. DIAGNOSIS: Diffuse large B-cell lymphoma was diagnosed using biopsies from cervical lymph nodes. INTERVENTIONS AND OUTCOMES: The patient started a gemcitabineâ +â rituximab regimen; however, the patient died from cachexia-associated lymphoma progression, not PDAC. LESSONS: ML should be considered when intra-abdominal lymphadenopathies are detected in patients with pancreatic cancer, and ML should be differentiated from lymph node metastasis of pancreatic cancer.
Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Linfadenopatia , Linfoma Difuso de Grandes Células B , Neoplasias Pancreáticas , Feminino , Humanos , Idoso , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Adenocarcinoma/patologia , Gencitabina , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias PancreáticasRESUMO
Influenza A(H1N1)pdm09 viruses carrying a dual neuraminidase (NA) substitution were isolated from immunocompromised patients after administration of one or more NA inhibitors. These mutant viruses possessed an H275Y/I223R, H275Y/I223K, or H275Y/G147R substitution in their NA and showed enhanced cross-resistance to oseltamivir and peramivir and reduced susceptibility to zanamivir compared to single H275Y mutant viruses. Baloxavir could be a treatment option against the multidrug-resistant viruses because these dual H275Y mutant viruses showed susceptibility to this drug. The G147R substitution appears to stabilize the NA structure, with the fitness of the H275Y/G147R mutant virus being similar or somewhat better than that of the wild-type virus. Since the multidrug-resistant viruses may be able to transmit between humans, surveillance of these viruses must continue to improve clinical management and to protect public health.
RESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Células T Periférico/terapia , Projetos de Pesquisa , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Prognóstico , Estudos Retrospectivos , Transplante de Células-Tronco , Fatores de Tempo , Adulto JovemRESUMO
Acute myeloid leukemia (AML) harboring Fms-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutation is associated with shorter remission and higher relapse risk. Several FLT3 inhibitors have been used in clinical trials, but their efficacy in extramedullary disease remains unclear. In the present case, a 56-year-old man was diagnosed with FLT3-ITD mutated AML. Due to bone marrow relapse during consolidation therapy, he underwent salvage therapy and a myeloablative conditioning regimen, followed by peripheral blood stem cell transplantation (PBSCT) from a HLA-matched related donor. Acute graft-versus-host disease (GVHD) did not develop, and complete donor chimerism was confirmed on days 27 and 96 after PBSCT. On day 180, he experienced extensive chronic GVHD and had several subcutaneous tumors in his body, which were diagnosed as myeloid sarcoma by pathological examination. We considered this to be a case of isolated extramedullary relapse, as his bone marrow had maintained complete donor chimerism. Treatment with etoposide and ranimustine produced no effect, and tumor progression continued. We started administration of gilteritinib, a FLT3/AXL inhibitor, after identifying the FLT3-ITD mutation in the tumor. Subsequently, there has been a remarkable regression of the tumors. Gilteritinib can be effective in isolated extramedullary relapse after allogeneic stem cell transplantation.
Assuntos
Compostos de Anilina/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Recidiva Local de Neoplasia , Pirazinas/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Sequências de Repetição em Tandem/genética , Transplante Homólogo , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidoresRESUMO
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 × 109/l, or < 50 × 109/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.
Assuntos
Dexametasona/administração & dosagem , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Humanos , Masculino , Pulsoterapia , Resultado do TratamentoRESUMO
Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.
Assuntos
Dexametasona/uso terapêutico , Glucocorticoides/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Adulto , Idoso , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Dexametasona/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Glucocorticoides/administração & dosagem , Infecções por Helicobacter/complicações , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/isolamento & purificação , Hepatite B/complicações , Hepatite B/tratamento farmacológico , Antagonistas dos Receptores H2 da Histamina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/uso terapêutico , Adulto JovemRESUMO
Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16-39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40-60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40-60, 61-79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.
Assuntos
Linfoma Difuso de Grandes Células B , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
A 61-year-old woman with rheumatoid arthritis was diagnosed as having acquired hemophilia A with extensive subcutaneous bleeding. The patient was treated with a corticosteroid, and her symptoms improved temporarily. However, these recurred during the tapering of her corticosteroid dose, and neither the re-increase in the dose nor the addition of cyclophosphamide could control her bleeding tendency. After the administration of an anti-IL-6 receptor antibody (tocilizumab), the doses of corticosteroid and cyclophosphamide could be tapered. Tocilizumab combined with another immunosuppression therapy might be effective in the treatment of acquired hemophilia A.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Artrite Reumatoide/etiologia , Hemofilia A/tratamento farmacológico , Hemorragia/etiologia , Corticosteroides/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Ciclofosfamida/administração & dosagem , Combinação de Medicamentos , Feminino , Hemofilia A/complicações , Humanos , Pessoa de Meia-Idade , RecidivaRESUMO
BACKGROUND: Bortezomib offers a novel approach to the treatment of multiple myeloma producing rapid control. The aim of this study was to investigate the outcomes of bortezomib and dexamethasone-treated patients with multiple myeloma. METHODS: We conducted a retrospective study of 44 consecutively-treated multiple myeloma patients with bortezomib (1.3 mg/m(2) on days 1, 4, 8, and 11 of a 21-day cycle or 1.3 mg/m(2) intravenously 1, 8, 15, and 22 of every 35-day cycle) and dexamethasone. RESULTS: The median time to progression, progression free survival time, and overall survival time in the treatment groups was 14.9, 14.9, and 38.3 months, respectively. The present study also suggests the possibility that the prognosis of patients with high levels of AST and LDH might be worse. CONCLUSIONS: Our results indicate that the treatment of multiple myeloma with bortezomib and dexamethasone is feasible.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aspartato Aminotransferases/metabolismo , Ácidos Borônicos/administração & dosagem , Bortezomib , Dexametasona/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactato Desidrogenases/metabolismo , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prognóstico , Pirazinas/administração & dosagem , Estudos Retrospectivos , Resultado do TratamentoRESUMO
When performing R-CHOP(rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)for diffuse large B-cell lymphoma(DLBCL), neurotoxicity of vincristine(VCR)is the serious dose-limiting factor.Pregabalin is one of the first-line treatments for painful diabetic peripheral neuropathy in many countries, and we have administered it to relieve the neurotoxicity associated with adverse effects of VCR in a DLBCL patient treated with the R-CHOP regimen.A 49-year-old man with kidney DLBCL had surgery performed.Afterward, the R-CHOP regimen was introduced.In order to relieve the neurotoxicity of VCR, pregabalin was used from day 8 in the second course.The severity of sensory neurotoxicity after the administration of pregabalin was improved from CTCAE(v4.0)grade 3 to grade 1.Therefore, there is a possibility that VCR-induced neurotoxicity is relieved by pregabalin.Further trials are needed to confirm the value of pregabalin.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Ácido gama-Aminobutírico/análogos & derivados , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Humanos , Rim/patologia , Rim/cirurgia , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Pregabalina , Rituximab , Tomografia Computadorizada por Raios X , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Ácido gama-Aminobutírico/uso terapêuticoAssuntos
Glucose/administração & dosagem , Compostos de Mostarda Nitrogenada/efeitos adversos , Compostos de Mostarda Nitrogenada/uso terapêutico , Dor/induzido quimicamente , Dor/tratamento farmacológico , Adulto , Idoso , Cloridrato de Bendamustina , Feminino , Humanos , Linfoma Folicular/tratamento farmacológico , Masculino , Pessoa de Meia-IdadeRESUMO
We report two cases of spontaneous bladder rupture. Preoperative diagnosis was difficult and the correct diagnosis was made at surgery. Reviewing the initial abdominopelvic CT of our second patient, the bladder wall defect and blood attenuation near the bladder were observed. These findings were consistent with the operative findings, and would have led to correct preoperative diagnosis if we had had sufficient knowledge of spontaneous bladder rupture. Under urinary catheterization, ascites and free intraperitoneal air were identified in both patients. These findings were indistinguishable from those for bowel perforation, which was our preoperative diagnosis. Significant changes in ascites volume between pre and post urinary catheterization can be an indication of spontaneous bladder rupture.
Assuntos
Tomografia Computadorizada por Raios X , Doenças da Bexiga Urinária/diagnóstico por imagem , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ruptura Espontânea/diagnóstico por imagem , Ruptura Espontânea/cirurgia , Doenças da Bexiga Urinária/cirurgia , Cateterismo UrinárioRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an interferon alpha (IFNalpha)-induced, apoptosis-inducing molecule. TRAIL could be one of the reagents for therapeutic use in combination with imatinib in chronic myeloid leukemia (CML). Here we examined serum-soluble TRAIL (sTRAIL) levels in CML patients either before or during therapies with IFNalpha or imatinib. In untreated CML patients, serum sTRAIL was detectable and the levels were substantially comparable with those in healthy donors. sTRAIL levels significantly increased in patients during IFNalpha therapy, but not at all in patients during imatinib therapy. TRAIL mRNA expressions in neutrophils in CML patients undergoing IFNalpha therapy was significantly elevated when compared with those in patients prior to therapy. TRAIL mRNA expressions were also detectable in CD34-positive cells in bone marrow, and the levels increased in patients during IFNalpha therapy. In vitro IFNalpha stimulation of CML neutrophils increased intracellular TRAIL rather than cell-surface TRAIL, and the secretion of sTRAIL in the culture supernatant was observed. This sTRAIL secretion was augmented with lipopolysaccharide (LPS) stimulation only in IFNalpha-primed neutrophils, whereas LPS alone had no effect. Taken together, in vivo IFNalpha treatment provokes the release of sTRAIL when administered systematically in CML patients. The main source of the IFNalpha-induced serum sTRAIL may be neutrophils in CML, and sTRAIL may be one of the mechanisms of the anti-proliferative action of IFNalpha on CML. These findings give another rationale for the use of IFNalpha or recombinant sTRAIL in CML, and also implicate the potential importance of neutrophils in tumor immunosurveillance.
Assuntos
Apoptose/efeitos dos fármacos , Interferon gama/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Neutrófilos/metabolismo , RNA Mensageiro/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Regulação para Cima/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interferon gama/farmacologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Ligante Indutor de Apoptose Relacionado a TNF/genéticaRESUMO
In chronic myeloid leukemia (CML), resistance to imatinib is diverse. In addition to BCR-ABL-dependent mechanisms, BCR-ABL-independent mechanisms have been proposed. Here we established and characterized novel CML cell lines, an imatinib-sensitive cell line, MYL, and an imatinib-resistant subline, MYL-R. Treatment with imatinib inhibited phosphorylation of BCR-ABL and CrkL in both MYL and MYL-R, even though imatinib-induced apoptosis was preferentially observed in MYL than MYL-R, indicating that the resistance is based on a BCR-ABL-independent mechanism. MYL-R showed elevated expressions of Lyn mRNA, Lyn protein, phosphorylated Lyn, and phosphorylated STAT5. Silencing of Lyn by short-interfering RNA (siRNA) in MYL-R, but not in MYL, induced significant growth-inhibition, increased caspase-3 activity, and induced partial recovery from imatinib-resistance. Expression of Bcl-2, previously reported to be associated with Lyn-mediated resistance, was not elevated in MYL-R. Expression of Bim, which plays an important role in imatinib-induced cell-killing, was not suppressed in MYL-R. These results imply that diverse mechanisms of resistance exist among cell types. Treatment of MYL-R cells with various reagents known to have anti-leukemic activity revealed that zoledronic acid and the farnesyl transferase inhibitor (SCH 66336) showed strong synergism with imatinib; interferon alpha, PP2, CGP76030, and FK228 (depsipeptide) showed synergism; whereas soluble TRAIL and As2O3 showed additivity or antagonism, and 17-AAG and radicicol showed antagonism. Treatment with either PP2 or zoledronic acid induced greater growth-reduction in MYL-R than MYL. Taken together, Lyn may play an important role in imatinib-resistance in MYL-R. Some novel reagents, including siRNA targeting Lyn, may have good potential to overcome this resistance.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Piperazinas/farmacologia , Pirimidinas/farmacologia , Quinases da Família src/genética , Adulto , Apoptose , Sequência de Bases , Benzamidas , Linhagem Celular Tumoral , Primers do DNA , Feminino , Genes abl , Humanos , Mesilato de Imatinib , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The association between four BCL10 single nucleotide polymorphisms at codons 5, 8, 162, and intron 1 and the susceptibility or progression for germ cell tumors (GCTs) was investigated in 73 testicular GCT patients and 72 controls. GCT patients with metastatic disease were more likely to have a variant type allele of the polymorphisms at codon 5 (age-adjusted odds ratio (aOR)=6.25; 95% CI=1.09-35.83; P=0.040) and codon 8 (aOR=4.63; 95% CI=1.35-15.93; P=0.015) than those with the localized disease. Therefore, BCL10 polymorphisms at codons 5 and 8 may play a role in the progression to advanced stage GCTs.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos Par 1 , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Adulto , Proteína 10 de Linfoma CCL de Células B , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Desequilíbrio de Ligação , Masculino , Metástase Neoplásica , Neoplasias Embrionárias de Células Germinativas/patologia , Polimorfismo de Nucleotídeo Único , Neoplasias Testiculares/patologiaRESUMO
The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.
Assuntos
Antineoplásicos/uso terapêutico , Crise Blástica/tratamento farmacológico , Hipercalcemia/tratamento farmacológico , Hipercalcemia/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteína Relacionada ao Hormônio Paratireóideo/genética , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Benzamidas , Células da Medula Óssea/patologia , Feminino , Humanos , Hiperplasia , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação , Proteína Relacionada ao Hormônio Paratireóideo/sangue , RNA Mensageiro/sangue , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an interferon (IFN)-induced molecule with apoptotic activity. We examined gene mutations in the death domains of TRAIL receptor 1 (TRAIL-R1) and TRAIL receptor 2 (TRAIL-R2), and in the TRAIL gene promoter in 46 chronic myelogenous leukemia (CML) patients. In 23 of the 46 patients, all the coding regions of TRAIL-R2 were also examined. However, no mutation or loss of heterozygosity was found. Furthermore, no mutation in the death domains of TRAIL-R1 and TRAIL-R2 genes, which causes amino acid change, was found in 18 myelodysplastic syndrome (MDS) patients. Ribonuclease protection assay (RPA) and real-time quantitative polymerase chain reaction using polymorphonuclear neutrophils of five new CML patients showed that the TRAIL mRNA expression was very low before in vitro IFN-alpha stimulation and markedly upregulated after IFN-alpha stimulation. FAS mRNA was also upregulated with IFN-alpha stimulation but the fold induction was far lower than that of TRAIL mRNA. In addition, RPA revealed that the ratio of (TRAIL-R1 plus TRAIL-R2) to TRAIL-R3 was also increased after IFN-alpha stimulation. Taken together, gene mutations of TRAIL-R1, TRAIL-R2 are infrequent in patients with CML and MDS. And so is the TRAIL promoter for CML. These mutations seem unrelated to tumorigenesis, disease progression, and response to IFN-alpha therapy in CML. A markedly high induction of TRAIL mRNA by IFN-alpha may have some relevance to IFN-alpha action in CML patients.
Assuntos
Substituição de Aminoácidos/genética , Regulação Leucêmica da Expressão Gênica/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Perda de Heterozigosidade/genética , Síndromes Mielodisplásicas/genética , Receptores do Fator de Necrose Tumoral/genética , Proteínas Reguladoras de Apoptose , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interferon-alfa/farmacologia , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Glicoproteínas de Membrana/genética , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Fases de Leitura Aberta/genética , Regiões Promotoras Genéticas/genética , Estrutura Terciária de Proteína/genética , RNA Mensageiro/genética , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , Ligante Indutor de Apoptose Relacionado a TNF , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/genéticaRESUMO
To investigate the relationship of chromosomal aberrations at blastic crisis (BC) in chronic myelogenous leukemia (CML), with previous therapies and with atomic bomb (AB) exposure, we studied 114 CML patients who developed BC, including 23 AB survivors in Hiroshima. In total, only 45.6% showed major-route abnormalities, which figure was far lower than those previously reported, implying possibility of geographical difference. Occurrence of major-route abnormality was not associated with either duration of chronic phase or survival time after BC. Patients treated with interferon-alpha (IFNalpha) showed lower frequency of major-route abnormalities and lower number of abnormal chromosomes than did patients treated with busulfan (Bu). The frequency of trisomy 8 was lower and monosomy 7 was higher in IFNalpha-treated than in Bu-treated patients. The frequency of unusual abnormalities at BC in IFNalpha-treated patients was indistinguishable from those in Bu-treated patients and, notably, a more common (40%) feature in IFNalpha-treated patients was no change in the cytogenetic picture. Thus, we conclude that IFNalpha action on chromosome aberration is basically quite neutral and that IFNalpha does not induce any specific aberrations, including unusual ones at BC, with an exception of deletion of chromosome 7. Atomic bomb exposure status did not make any difference in secondary abnormalities at BC.
Assuntos
Antineoplásicos/uso terapêutico , Aberrações Cromossômicas , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bussulfano/uso terapêutico , Feminino , Humanos , Japão , Cariotipagem , Masculino , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/genética , Guerra NuclearRESUMO
In order to investigate the mechanism of interferon-alpha (IFNalpha) action in the treatment of chronic myelogenous leukemia (CML), we examined surface expressions of both type I interferon receptor 1 (IFNAR1) and 2 (IFNAR2) subunits on CD34-positive cells in bone marrow (BM) in a total of 57 CML patients. Initial cell-surface IFNAR2 expression at diagnosis assessed by flow cytometry widely distributed but showed overall significantly higher expression in CML patients when compared with normal controls. In 15 fresh patients who subsequently received IFNalpha therapy, IFNAR2 expression at diagnosis was significantly higher in cytogenetic good responders than in poor responders. Down-regulation of IFNAR2 expression during IFNalpha therapy was observed only in good responders but not in poor responders. In addition to protein level, both initial high IFNAR2c mRNA expression level and its down-regulation during IFNalpha therapy, in purified CD34-positive cells, were also observed only in good responders. In contrast to IFNAR2, cell-surface IFNAR1 expression was generally lower than IFNAR2, and correlation between either the pretreatment level or down-regulation of IFNAR1 and clinical response was not evident. With in vitro IFNalpha stimulation, CD34-positive cells showed down-regulations of cell-surface IFNAR2, and IFNAR1 to a lesser extent, in one good-responder patient, but not in one poor-responder patient. Serum soluble interferon receptor (sIFNR) was higher in untreated CML patients than in normal controls, without any correlation with clinical response to IFNalpha. Thus, the pretreatment protein and mRNA expression levels of IFNAR2 and their down-regulations during IFNalpha therapy correlate well with IFNalpha response in CML patients.