RESUMO
Accurate prediction of postoperative recurrence is important for optimizing the treatment strategies for non-small cell lung cancer (NSCLC). Previous studies identified the PD-L1 expression in NSCLC as a risk factor for postoperative recurrence. This study aimed to examine the contribution of PD-L1 expression to predicting postoperative recurrence using machine learning. The clinical data of 647 patients with NSCLC who underwent surgical resection were collected and stratified into training (80%), validation (10%), and testing (10%) datasets. Machine learning models were trained on the training data using clinical parameters including PD-L1 expression. The top-performing model was assessed on the test data using the SHAP analysis and partial dependence plots to quantify the contribution of the PD-L1 expression. Multivariate Cox proportional hazards model was used to validate the association between PD-L1 expression and postoperative recurrence. The random forest model demonstrated the highest predictive performance with the SHAP analysis, highlighting PD-L1 expression as an important feature, and the multivariate Cox analysis indicated a significant increase in the risk of postoperative recurrence with each increment in PD-L1 expression. These findings suggest that variations in PD-L1 expression may provide valuable information for clinical decision-making regarding lung cancer treatment strategies.
Assuntos
Antígeno B7-H1 , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Recidiva Local de Neoplasia , Humanos , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Neoplasias Pulmonares/cirurgia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Fatores de Risco , Aprendizado de Máquina , Biomarcadores Tumorais/metabolismo , Modelos de Riscos Proporcionais , Período Pós-Operatório , PrognósticoRESUMO
Adult T-cell leukemia/lymphoma (ATL) occurs after human T-cell leukemia virus type-1 (HTLV-1) infection with a long latency period exceeding several decades. This implies the presence of immune evasion mechanisms for HTLV-1-infected T cells. Although ATL cells have a CD4+CD25+ phenotype similar to that of regulatory T cells (Tregs), they do not always possess the immunosuppressive functions of Tregs. Factors that impart effective immunosuppressive functions to HTLV-1-infected cells may exist. A previous study identified a new CD13+ Treg subpopulation with enhanced immunosuppressive activity. We, herein, describe the paired CD13- (designated as MT-50.1) and CD13+ (MT-50.4) HTLV-1-infected T-cell lines with Treg-like phenotype, derived from the peripheral blood of a single patient with lymphoma-type ATL. The cell lines were found to be derived from HTLV-1-infected non-leukemic cells. MT-50.4 cells secreted higher levels of immunosuppressive cytokines, IL-10 and TGF-ß, expressed higher levels of Foxp3, and showed stronger suppression of CD4+CD25- T cell proliferation than MT-50.1 cells. Furthermore, the CD13 inhibitor bestatin significantly attenuated MT-50.4 cell growth, while it did not for MT-50.1 cells. These findings suggest that CD13 expression may be involved in the increased Treg-like activity of MT-50.4 cells. Hence, MT-50.4 cells will be useful for in-depth studies of CD13+Foxp3+ HTLV-1-infected cells.
Assuntos
Antígenos CD13 , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Linfócitos T Reguladores , Humanos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/metabolismo , Leucemia-Linfoma de Células T do Adulto/virologia , Leucemia-Linfoma de Células T do Adulto/patologia , Antígenos CD13/metabolismo , Infecções por HTLV-I/imunologia , Infecções por HTLV-I/virologia , Linhagem CelularAssuntos
Coagulação Intravascular Disseminada , Linfoma de Célula do Manto , Humanos , Masculino , Pessoa de Meia-Idade , Coagulação Intravascular Disseminada/etiologia , Coagulação Intravascular Disseminada/diagnóstico , Linfoma de Célula do Manto/complicações , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologiaAssuntos
Cromossomos Humanos Par 14 , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core , Leucemia Mieloide Aguda , Proteína 1 Parceira de Translocação de RUNX1 , Translocação Genética , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Cromossomos Humanos Par 21/genética , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 14/genética , Proteínas de Fusão Oncogênica/genética , Cromossomos Humanos Par 15/genética , MasculinoRESUMO
This report covers acute myeloid leukemia (AML) results from a multicenter, prospective observational study of AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia in Japan. From August 2011 to January 2016, 3728 AML patients were registered. Among them, 42% were younger than 65, and the male-to-female ratio was 1.57:1. With a median follow-up time of 1807 days (95% confidence interval [CI]: 1732-1844 days), the estimated 5-year overall survival (OS) rate in AML patients (n = 3707) was 31.1% (95% CI: 29.5-32.8%). Trial-enrolled patients had a 1.7-fold higher OS rate than non-enrolled patients (5-year OS, 58.9% [95% CI: 54.5-63.1%] vs 35.5% [33.3-37.8%], p < 0.0001). Women had a higher OS rate than men (5-year OS, 34% [95% CI; 31.4-36.7%] vs 27.7% [25.7-29.7%], p < 0.0001). The OS rate was lower in patients aged 40 and older than those under 40, and even lower in those over 65 (5-year OS for ages < 40, 40-64, 65-74, ≥ 75: 74.5% [95% CI; 69.3-79.0%] vs 47.5% [44.4-50.6%] vs 19.3% [16.8-22.0%] vs 7.3% [5.5-9.4%], respectively). This is the first paper to present large-scale data on survival and clinical characteristics in Japanese AML patients.
Assuntos
Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Japão/epidemiologia , Leucemia Mieloide Aguda/epidemiologia , Leucemia Mieloide Aguda/terapia , Estudos ProspectivosRESUMO
We conducted a multicenter, prospective observational study of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) in Japan. From August 2011 to January 2016, we enrolled 6568 patients. Herein, we report the results for MDS (n = 2747) and CMML (n = 182). The percentage of patients aged 65 years or older was 79.5% for MDS and 79.7% for CMML. The estimated overall survival (OS) rate and cumulative incidence of AML evolution at 5 years were 32.3% (95% confidence interval: 30.2-34.5%) and 25.7% (23.9-27.6%) for MDS, and 15.0% (8.9-22.7%) and 39.4% (31.1-47.6%) for CMML. Both diseases were more common in men. The most common treatment for MDS was azacitidine, which was used in 45.4% of higher-risk and 12.7% of lower-risk MDS patients. The 5-year OS rate after treatment with azacitidine was 12.1% (9.5-15.1%) for of higher-risk MDS patients and 33.9% (25.6-42.4%) for lower-risk patients. The second most common treatment was erythropoiesis-stimulating agents, given to just 20% of lower-risk patients. This is the first paper presenting large-scale, Japanese data on survival and clinical characteristics in patients with MDS and CMML.
Assuntos
Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crônica , Síndromes Mielodisplásicas , Masculino , Humanos , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Leucemia Mielomonocítica Crônica/epidemiologia , Japão/epidemiologia , Antimetabólitos Antineoplásicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/epidemiologia , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is a global concern, primarily as a cause of skin and soft tissue infections, particularly in young people. Here, we describe a case of unilateral multiple lymphadenitis caused by the CA-MRSA sequence type (ST) 834 strain. A previously healthy 15-year-old girl was referred to our hospital with fever and swollen lymph nodes in the right axillary, cubital, and groin regions. Imaging examinations revealed enlargement of the lymph nodes in these areas but no swelling in any other lymph nodes. The patient had self-destructive lymph nodes in her groin. MRSA was detected in all swollen lymph node samples. Antimicrobial susceptibility tests showed that MRSA was susceptible to clindamycin and levofloxacin, leading to the suspicion of CA-MRSA. Genetic analysis revealed that all strains were ST834 and carried the staphylococcal cassette chromosome mec IV and the toxic shock syndrome toxin-1 gene but not the Panton-Valentine leukocidin gene. The patient was treated with linezolid followed by oral clindamycin. This was a rare case of unilateral multiple lymphadenitis caused by ST834 CA-MRSA. Although ST834 strains are rarely reported, lymphadenitis has been frequently reported and is considered more likely to cause lymphadenitis than other CA-MRSA strains.
Assuntos
Antibacterianos , Infecções Comunitárias Adquiridas , Linfadenite , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Feminino , Staphylococcus aureus Resistente à Meticilina/isolamento & purificação , Staphylococcus aureus Resistente à Meticilina/genética , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Adolescente , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/diagnóstico , Linfadenite/microbiologia , Linfadenite/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Infecções Comunitárias Adquiridas/tratamento farmacológico , Antibacterianos/uso terapêutico , Antibacterianos/farmacologia , Clindamicina/uso terapêutico , Testes de Sensibilidade Microbiana , Linezolida/uso terapêuticoRESUMO
An asymptomatic woman in her early 40s with a history of hyperferritinemia (5,412 ng/ml) was referred to our hospital after repeated phlebotomy for hemosiderosis. She had unexplained hyperferritinemia, low-normal transferrin saturation, and high hepcidin levels, in the absence of iron overload-induced organ injury. She was diagnosed with ferroportin disease based on detection of the SLC40A1 variant SLC40A1 c.485_487del (p.Val162del) on genetic analysis. Her ferritin levels remained stable during pregnancy, and postpartum anemia was successfully treated with 2-week oral iron therapy. Ferroportin disease is characterized by impaired iron export and preferential iron trapping in tissue macrophages. To reduce risk of anemia, a non-aggressive phlebotomy regimen is recommended in patients with ferroportin disease, which shows a milder clinical course compared with other classical hemochromatosis subtypes.
Assuntos
Anemia , Hemocromatose , Hiperferritinemia , Sobrecarga de Ferro , Humanos , Feminino , Gravidez , Hemocromatose/terapia , Hemocromatose/diagnóstico , Hemocromatose/genética , Sobrecarga de Ferro/etiologia , Ferro , HepcidinasRESUMO
BACKGROUND: While PD-L1 expression and neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers for lung cancer, few studies have considered their interaction. We hypothesized that the product of PD-L1 expression (tumor proportion score) and the NLR (PD-L1 × NLR) might be a postoperative prognostic marker reflecting the immune microenvironment of lung cancer. METHODS: We analyzed the association between PD-L1 × NLR and postoperative recurrence-free survival in 647 patients with NSCLC using multivariable Cox proportional hazards models. RESULTS: In the analysis of PD-L1 × NLR as a categorical variable, the group with PD-L1 × NLR ≥ 25.8 had a significantly higher hazard ratio (HR) than the group with < 25.8 (adjusted HR 1.78, 95% confidence interval [CI] 1.23-2.60). The adjusted HR for PD-L1 × NLR, considered a continuous variable, was 1.004 (95% CI, 1.002-1.006). The risk of postoperative recurrence increased by 1.004-fold for each unit increase in PD-L1 × NLR, and a more than 2-fold increase in risk was observed for values ≥ 170. CONCLUSIONS: PD-L1 × NLR may be used in real-world clinical practice as a novel factor for predicting the risk of postoperative recurrence after lung cancer surgery.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neutrófilos/patologia , Prognóstico , Antígeno B7-H1 , Estudos Retrospectivos , Linfócitos/patologia , Microambiente TumoralRESUMO
The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.
Assuntos
Leucemia Mieloide Aguda , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Linhagem Celular Tumoral , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Apoptose/genéticaRESUMO
Anthracycline- and cytarabine-based intensive combination chemotherapies are considered the backbone therapy for patients with acute myeloid leukemia (AML). Although chemotherapy leads to long-term remission and cures many patients with AML, it can induce DNA damage/stress due to acute/chronic toxicities, acquired resistance, relapse, and therapy-related malignancies. Introduction of molecularly targeted agents with less systemic toxicities has considerably improved the scope of treatment, particularly in elderly and frail patients. However, outcomes of TP53-mutated myelodysplastic syndrome (MDS) and AML, a distinct group of myeloid disorders, have not improved irrespective of the treatment used (median overall survival, 5-10 months). In this review, we discuss the biological and clinical significance of TP53 mutations in malignancies, while particularly focusing on MDS/AML, and emerging therapies for TP53-mutated MDS/AML. Rationally designed novel treatment strategies are expected to improve the clinical outcomes of TP53-mutated MDS/AML.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Idoso , Relevância Clínica , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/genética , Antineoplásicos/uso terapêutico , Proteína Supressora de Tumor p53/genéticaRESUMO
Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.
RESUMO
Next-generation sequencing of AML has identified specific genetic mutations in AML patients. Hematologic Malignancies (HM)-SCREEN-Japan 01 is a multicenter study to detect actionable mutations using paraffin-embedded bone marrow (BM) clot specimens rather than BM fluid in AML patients for whom standard treatment has not been established. The purpose of this study is to evaluate the presence of potentially therapeutic target gene mutations in patients with newly diagnosed unfit AML and relapsed/refractory AML (R/R-AML) using BM clot specimens. In this study, 188 patients were enrolled and targeted sequencing was undertaken on DNA from 437 genes and RNA from 265 genes. High-quality DNA and RNA were obtained using BM clot specimens, with genetic alterations successfully detected in 177 patients (97.3%), and fusion transcripts in 41 patients (23.2%). The median turnaround time was 13 days. In the detection of fusion genes, not only common fusion products such as RUNX1-RUX1T1 and KMT2A rearrangements, but also NUP98 rearrangements and rare fusion genes were observed. Among 177 patients (72 with unfit AML, 105 with R/R-AML), mutations in KIT and WT1 were independent factors for overall survival (hazard ratio = 12.6 and 8.88, respectively), and patients with high variant allele frequency (≥40%) of TP53 mutations had a poor prognosis. As for the detection of actionable mutations, 38% (n = 69) of patients had useful genetic mutation (FLT3-ITD/TKD, IDH1/2, and DNMT3AR822 ) for treatment selection. Comprehensive genomic profiling using paraffin-embedded BM clot specimens successfully identified leukemic-associated genes that can be used as therapeutic targets.
Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Medula Óssea , Prognóstico , Nucleofosmina , Japão , Inclusão em Parafina , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , RNA , GenômicaRESUMO
Objective Patients with hematological malignancies and solid organ tumors reportedly tend to have a more severe coronavirus disease 2019 (COVID-19) trajectory than do those with other diseases. We studied the clinical features and outcomes of nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the seventh wave of the pandemic. Methods This study retrospectively described the characteristics of COVID-19 clusters involving patients in the hematology/respirology ward of Kochi Medical School Hospital during the seventh wave of the pandemic of SARS-CoV-2. Patients A total of 40 individuals, including 25 patients and 15 healthcare workers, were studied. The diagnosis of SARS-CoV-2 infection was based on reverse transcription polymerase chain reaction performed on nasopharyngeal samples. Results Eleven patients had hematological diseases, and 14 had respiratory diseases. Most patients presented with a fever (n=19) and/or sore throat (n=10). Lower respiratory tract symptoms and pneumonia were rather infrequent, occurring in two patients. All patients received antivirals. The maximal severities were mild in 21 patients and moderate in 2. Two asymptomatic patients with SARS-CoV-2 infection did not develop symptoms of COVID-19. Cycle threshold values in nasopharyngeal samples were significantly lower in patients with COVID-19 than in those who were asymptomatic at the time of the diagnosis with SARS-CoV-2 infection. All SARS-CoV-2-infected inpatients recovered or did not develop symptoms of COVID-19. Conclusion COVID-19 vaccination, early or preemptive treatment with antivirals, and intrinsic changes in SARS-CoV-2 may have contributed to the more favorable outcomes in our series than in previously reported nosocomial clusters.
Assuntos
COVID-19 , Infecção Hospitalar , Hematologia , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Estudos Retrospectivos , Pandemias , Japão/epidemiologia , Vacinas contra COVID-19 , Hospitais Universitários , AntiviraisRESUMO
Chest computed tomography (CT) is effective for assessing the severity of coronavirus disease 2019 (COVID-19). However, the clinical factors reflecting the disease progression of COVID-19 pneumonia on chest CT and predicting a subsequent exacerbation remain controversial. We conducted a retrospective cohort study of 450 COVID-19 patients. We used an automated image processing tool to quantify the COVID-19 pneumonia lesion extent on chest CT at admission. The factors associated with the lesion extent were estimated by a multiple regression analysis. After adjusting for background factors by propensity score matching, we conducted a multivariate Cox proportional hazards analysis to identify factors associated with severe disease after admission. The multiple regression analysis identified, body-mass index (BMI), lactate dehydrogenase (LDH), C-reactive protein (CRP), and albumin as continuous variables associated with the lesion extent on chest CT. The standardized partial regression coefficients for them were 1.76, 2.42, 1.54, and 0.71. The multivariate Cox proportional hazards analysis identified LDH (hazard ratio, 1.003; 95% confidence interval, 1.001-1.005) as a factor independently associated with the development of severe COVID-19 pneumonia. Increased serum LDH at admission may be useful in real-world clinical practice for the simple screening of COVID-19 patients at high risk of developing subsequent severe disease.
Assuntos
COVID-19 , Humanos , COVID-19/diagnóstico por imagem , Estudos Retrospectivos , SARS-CoV-2 , Tomografia Computadorizada por Raios X/métodos , L-Lactato Desidrogenase , Progressão da DoençaRESUMO
Tocilizumab has been used to treat idiopathic multicentric Castleman disease (iMCD). As tocilizumab prevents interleukin-6 from exerting pro-inflammatory effects, there is some concern about a delayed diagnosis of severe infections during tocilizumab treatment. Although serious infections during tocilizumab therapy have been previously described in patients with rheumatoid arthritis, they have not been reported in iMCD. We herein report a case of disseminated Staphylococcus aureus infection after a superficial skin wound followed by psoas and mediastinal abscesses with pyogenic spondylodiscitis in an iMCD patient with diabetes. Physicians should be alert for the occurrence of disseminated S. aureus infection after even minor skin injury during tocilizumab therapy.
Assuntos
Hiperplasia do Linfonodo Gigante , Humanos , Hiperplasia do Linfonodo Gigante/complicações , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Hiperplasia do Linfonodo Gigante/diagnóstico , Abscesso , Staphylococcus aureusRESUMO
We report a case of early asymptomatic acute promyelocytic leukemia (APL) with leukopenia as the only hematologic abnormality. A 55-year-old woman was referred to our hospital with leukopenia (white blood cell [WBC] count of 1,500/µl with 36% neutrophils), which was incidentally determined during an annual medical checkup. Two months before the presentation, her WBC was 3,400/µl with 60% neutrophils. A WBC count was 1,200/µl with 40% neutrophils. Immature myeloid cells were not observed. Her hemoglobin level and platelet count were normal. Moreover, no clinical or laboratory evidence was suggestive of disseminated intravascular coagulation or infection. The peripheral blood WT1 mRNA level was increased to 26,000 copies/µg RNA. The bone marrow aspirate smear revealed 40% myeloperoxidase-positive promyelocytes with occasional Auer rods and faggots; however, circulating leukemia cells were not revealed by cell morphology or flow cytometry analysis. Quantitative reverse-transcription polymerase chain reaction analysis revealed WT1 and PML-RARA fusion transcripts in both the peripheral blood and bone marrow samples. Thus, the determination of peripheral blood WT1 expression may be sufficiently sensitive for detecting a small number of circulating APL cells.
Assuntos
Leucemia Promielocítica Aguda , Humanos , Pessoa de Meia-Idade , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Proteínas WT1/genéticaRESUMO
Primary human herpesvirus 8 (HHV8)-unrelated effusion large B-cell lymphoma (ELBCL) is recognized as a new clinical entity, but its pathogenesis and therapeutic strategies remain largely unknown. We have generated two mouse models with profuse lymphomatous effusions that resemble HHV8-unrelated ELBCL occurring in humans, by grafting the cell lines designated as Pell-1 and Pell-2. Using these in vivo models, we evaluated the potential role of vascular endothelial growth factor (VEGF) in the pathogenesis of HHV8-unrelated ELBCL. Both Pell-1 and Pell-2 cells consistently produced very high levels of VEGF in mice, in contrast to in vitro findings of relatively low VEGF production in culture medium by HHV8-unrelated ELBCL cells, especially Pell-1 cells. Conversely, returning Pell-1 cells grown in mice to culture medium markedly suppressed VEGF production to the original in vitro level. These findings suggest that the tumour microenvironment plays a role in the steady production of VEGF. We also found that the interaction between HHV8-unrelated ELBCL cells and peritoneal mesothelial cells increased the production of VEGF in vitro. Finally, we found that bevacizumab significantly suppressed effusion formation and lymphoma cell growth in both mouse models. These results suggest that bevacizumab is a rational approach to the treatment of HHV8-unrelated ELBCL.
Assuntos
Herpesvirus Humano 8 , Linfoma Difuso de Grandes Células B , Humanos , Camundongos , Animais , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Fatores de Crescimento do Endotélio Vascular , Microambiente TumoralRESUMO
BACKGROUND: Pulmonary pleomorphic carcinoma (PPC) is a rare type of non-small cell lung cancer characterized by high malignancy and a poor prognosis. PPC is associated with a high frequency of postoperative relapse, and shows resistance to chemotherapy. The high malignancy of cancers is associated with genomic instability, which is related to mutations of tumor suppressor genes, such as tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM). In addition, signaling pathways involving the oncogenes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and epidermal growth factor receptor (EGFR) are associated with resistance to chemotherapy. However, the association of PPC with these gene mutations remains unknown. We investigated the impact of TP53, ATM, PIK3CA, and EGFR mutations on the postoperative prognosis of PPC. METHODS: Fifty-five patients with PPC who underwent complete resection were studied. A gene mutation analysis was performed using next-generation sequencing. Postoperative overall survival of patients with gene mutations was evaluated using a multivariable Cox proportional hazards model in which the explanatory variables were the presence of each gene mutation, and the confounding factors were pathological stage and age. The robustness of the results was evaluated by a sensitivity analysis. RESULTS: The frequencies of pathogenic mutations in TP53, ATM, PIK3CA, and EGFR were 47, 0, 7, and 9%, respectively. A multivariable analysis adjusted for pathological stage and age showed a significant difference for only PIK3CA mutations. The hazard ratio (HR) for overall survival in cases with pathogenic mutations of PIK3CA for wild type or non-pathogenic mutations was 4.5 (95% confidence interval [CI] 1.1-18.8). Likewise, sensitivity analyses adjusted for pathological stage and sex (HR, 7.5; 95% CI 1.7-32.4) and for age and sex (HR, 5.4; 95% CI 1.4-21.7) resulted in similar findings. Although three patients with pathogenic mutations of PIK3CA that recurred postoperatively were treated by chemotherapy or immunotherapy, they survived for less than 2 years. CONCLUSIONS: The postoperative prognosis of PPC with PIK3CA pathogenic mutations is particularly poor. Pathogenic mutations of PIK3CA may be a postoperative prognostic marker. Inhibition of signaling pathways associated with PIK3CA mutations may also be a target for chemotherapy after relapse of PPC.