RESUMO
We conducted a phase I/II multicenter trial using 6 cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive (+) B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma (PMBCL), 5 with diffuse large B-cell lymphoma (DLBCL), and 2 with gray zone lymphoma (GZL). There were no treatment-related deaths; 32% of patients had non-hematological grade 3/4 toxicities. The overall response rate was 100% (95% CI: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end of treatment response assessment was permissible and used in 52% of all patients including 59% of patients with PMBCL. With a median follow-up of 30 months, the 2-year progression-free survival (PFS) and overall survival (OS) were 85% (95% CI: 66-94) and 100%, respectively. In the PMBCL cohort, 2-year PFS was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30+ B-cell lymphomas (NCT01994850).
Assuntos
Imunoconjugados , Linfoma Difuso de Grandes Células B , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Brentuximab Vedotin , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Antígeno Ki-1 , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/uso terapêutico , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype-phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.
Assuntos
Genômica/métodos , Linfoma Difuso de Grandes Células B/genética , Neoplasias do Mediastino/genética , Adolescente , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias do Mediastino/patologia , Pessoa de Meia-Idade , Mutação , Integração de Sistemas , Adulto JovemRESUMO
Dimethyl sulfoxide (DMSO) is currently used as an alternative treatment for various inflammatory conditions as well as for cancer. Despite its widespread use, there is a paucity of data regarding its safety and efficacy as well as its mechanism of action in human cells. Herein, we demonstrate that DMSO has ex-vivo anti-inflammatory activity using Escherichia coli- (E. coli) and herpes simplex virus-1 (HSV-1)-stimulated whole human blood. Specifically, we found that between 0.5%-2%, DMSO significantly suppressed the expression of many pro-inflammatory cytokines/chemokines and prostaglandin E2 (PGE2). However, a significant reduction in monocyte viability was also observed at 2% DMSO, suggesting a narrow window of efficacy. Anti-inflammatory concentrations of DMSO suppressed E. coli-induced ERK1/2, p38, JNK and Akt phosphorylation, suggesting DMSO acts on these signaling pathways to suppress inflammatory cytokine/chemokine production. Although DMSO induces the differentiation of B16/F10 melanoma cells in vitro, topical administration of DMSO to mice subcutaneously implanted with B16 melanoma cells was ineffective at reducing tumor growth, DMSO was also found to block mouse macrophages from polarizing to either an M1- or an M2-phenotype, which may contribute to its inability to slow tumor growth. Topical administration of DMSO, however, significantly mitigated K/BxN serum-induced arthritis in mice, and this was associated with reduced levels of pro-inflammatory cytokines in the joints and white blood cell levels in the blood. Thus, while we cannot confirm the efficacy of DMSO as an anti-cancer agent, the use of DMSO in arthritis warrants further investigation to ascertain its therapeutic potential.
Assuntos
Artrite/patologia , Células Sanguíneas/metabolismo , Citocinas/metabolismo , Dimetil Sulfóxido/farmacologia , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Células Sanguíneas/citologia , Células Sanguíneas/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocinas/análise , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/análise , Citocinas/genética , Dimetil Sulfóxido/uso terapêutico , Dinoprostona/metabolismo , Escherichia coli/metabolismo , Feminino , Herpesvirus Humano 1/fisiologia , Humanos , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Melanoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/antagonistas & inibidores , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Androgen signalling through the androgen receptor (AR) plays a critical role in prostate cancer (PCa) initiation and progression. Estrogen in synergy with androgen is essential for cell growth of the normal and malignant prostate. However, the exact role that estrogen and the estrogen receptor play in prostate carcinogenesis remains unclear. We have previously demonstrated the metastasis-promoting effect of an estrogen receptor beta (ERß) agonist (genistein) in a patient-derived PCa xenograft model mimicking localized and metastatic disease. METHODS: To test the hypothesis that the tumor-promoting activity of genistein was due to its estrogenic properties, we treated the xenograft-bearing mice with genistein and an anti-estrogen compound (ICI 182, 780) and compared the differential gene expression using microarrays. RESULTS: Using a second xenograft model which was derived from another patient, we showed that genistein promoted disease progression in vivo and ICI 182, 780 inhibited metastatic spread. The microarray analysis revealed that the metallothionein (MT) gene family was differentially expressed in tumors treated by these compounds. Using qRT-PCR, the differences in expression levels were validated in the metastatic and non-metastatic LTL313 PCa xenograft tumor lines, both of which were originally derived from the same PCa patient. CONCLUSIONS: Together our data provide evidence that genistein stimulates and ICI 182, 780 inhibits metastatic progression, suggesting that these effects may be mediated by ERß signalling.
Assuntos
Antineoplásicos/uso terapêutico , Progressão da Doença , Estradiol/análogos & derivados , Antagonistas de Estrogênios/uso terapêutico , Genisteína/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Modelos Animais de Doenças , Estradiol/farmacologia , Estradiol/uso terapêutico , Antagonistas de Estrogênios/farmacologia , Receptor beta de Estrogênio/efeitos dos fármacos , Fulvestranto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genisteína/farmacologia , Humanos , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Neoplasias da Próstata/patologia , RNA Interferente Pequeno/farmacologia , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Genistein is an isoflavone found in soy, and its chemo-preventive and -therapeutic effects have been well established from in vitro studies. Recently, however, its therapeutic actions in vivo have been questioned due to contradictory reports from animal studies, which rely on rodent models or implantation of cell lines into animals. To clarify in vivo effects of genistein in advanced prostate cancer patients, we developed a patient-derived prostate cancer xenograft model, in which a clinical prostatectomy sample was grafted into immune deficient mice. Our results showed an increased lymph node (LN) and secondary organ metastases in genistein-treated mice compared to untreated controls. Interestingly, invasive malignant cells aggregated to form islands/micrometastasis only in the secondary organs of the genistein-treated groups, not in the untreated control group. To understand the underlying mechanism for metastatic progression, we examined cell proliferation and apoptosis on paraffin-sections. Immunohistological data show that tumors of genistein-treated groups have more proliferating and fewer apoptotic cancer cells than those of the untreated group. Our immunoblotting data suggest that increased proliferation and metastasis are linked to enhanced activities of tyrosine kinases, EGFR and its downstream Src, in genistein-treated groups. Despite the chemopreventive effects proposed by earlier in vitro studies, the cancer promoting effect of genistein observed here suggests the need for careful selection of patients and safer planning of clinical trials.
Assuntos
Receptores ErbB/metabolismo , Genisteína/farmacologia , Neoplasias da Próstata/patologia , Animais , Anticarcinógenos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Progressão da Doença , Humanos , Masculino , Camundongos , Camundongos SCID , Metástase Neoplásica/patologia , Transdução de Sinais/efeitos dos fármacos , Transplante HeterólogoRESUMO
The human neuronal apoptosis inhibitory protein (NAIP) gene is no longer principally considered a member of the Inhibitor of Apoptosis Protein (IAP) family, as its domain structure and functions in innate immunity also warrant inclusion in the Nod-Like Receptor (NLR) superfamily. NAIP is located in a region of copy number variation, with one full length and four partly deleted copies in the reference human genome. We demonstrate that several of the NAIP paralogues are expressed, and that novel transcripts arise from both internal and upstream transcription start sites. Remarkably, two internal start sites initiate within Alu short interspersed element (SINE) retrotransposons, and a third novel transcription start site exists within the final intron of the GUSBP1 gene, upstream of only two NAIP copies. One Alu functions alone as a promoter in transient assays, while the other likely combines with upstream L1 sequences to form a composite promoter. The novel transcripts encode shortened open reading frames and we show that corresponding proteins are translated in a number of cell lines and primary tissues, in some cases above the level of full length NAIP. Interestingly, some NAIP isoforms lack their caspase-sequestering motifs, suggesting that they have novel functions. Moreover, given that human and mouse NAIP have previously been shown to employ endogenous retroviral long terminal repeats as promoters, exaptation of Alu repeats as additional promoters provides a fascinating illustration of regulatory innovations adopted by a single gene.
Assuntos
Proteína Inibidora de Apoptose Neuronal/química , Regiões Promotoras Genéticas , Elementos Nucleotídeos Curtos e Dispersos , Elementos Alu , Animais , Elementos de DNA Transponíveis , Células HeLa , Humanos , Camundongos , Proteína Inibidora de Apoptose Neuronal/metabolismo , Neurônios/metabolismo , Fases de Leitura Aberta , Isoformas de Proteínas , Estrutura Terciária de Proteína , Retroelementos/genética , Retroviridae/genética , Distribuição TecidualRESUMO
There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue-positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.
Assuntos
Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/patologia , Cloreto de Tolônio , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Fatores de Risco , Coloração e Rotulagem/métodosRESUMO
OBJECTIVE: Recent studies have shown that a loss of chromosome regions (loss of heterozygosity [LOH]) containing known or presumptive tumor suppressor genes is predictive of the cancer risk of oral premalignant lesions. This preliminary study investigated whether the dye toluidine blue (TB) preferentially stains oral premalignant lesions with LOH. This stain has been used by clinicians to delineate dysplasia/carcinoma in the oral cavity. STUDY DESIGN: The study included 32 patients with oral lesions who underwent biopsy after the assessment of TB dye retention. A total of 39 biopsy specimens were examined (14 hyperplastic, 25 dysplastic). Fourteen of the biopsy specimens were TB-negative. The specimens were analyzed for LOH at 10 microsatellite loci on 3 chromosome arms (3p, 9p, and 17p), and the LOH results of TB-positive samples were compared with those that were negative for the tissue staining. RESULTS: TB-positive samples had a higher frequency of loss than TB-negative cases for loci on 3p (P = .013) and 17p (P = .049). In addition, more TB-positive cases showed a loss of multiple arms (>2 arms, P = .015), a pattern that has been associated with markedly increased cancer risk. CONCLUSION: The study results suggest that TB staining may help identify oral premalignant lesions with increased LOH and increased cancer risk.