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OBJECTIVES: Conducting clinical trials in rare malignancies is challenging due to the limited number of patients and differences in biologic behavior. We investigated the feasibility and clinical utility of using genomic profiling for rare gynecologic malignancies. METHODS: Rare epithelial gynecologic cancer patients were analyzed for somatic variants through an institutional molecular profiling program using the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel on the MiSeq platform. Clinical trial outcomes by RECIST 1.1, and time on treatment were evaluated. RESULTS: From March 2012 to November 2015, 767 gynecologic patients were enrolled and 194 (27%) were classified as rare epithelial malignancies. At least one somatic mutation was identified in 72% of patients, most commonly in TP53 (39%), KRAS (28%) and PIK3CA (27%). A total of 14% of patients were treated on genotype-matched trials. There were no significant differences in overall response rate between genotype-matched versus unmatched trials, nor in median time on treatment between genotype trials and the immediate prior systemic standard treatment. Among 13 evaluable Low Grade Serous ovarian cancer patients treated on genotype-matched trials with MEK inhibitor-based targeted combinations, there were four partial responses. CONCLUSIONS: Somatic molecular profiling is feasible and enables the identification of patients with rare gynecologic cancers who are candidates for genotype-matched clinical trials. Genotype-matched trials, predominantly MEK-based combinations in KRAS and/or NRAS mutant Low Grade Serous ovarian cancer patients, and genotype-unmatched trials, have shown potential clinical activity. Prospective trials with integrated genotyping are warranted to assess the clinical utility of next generation sequencing tests as a standard clinical application in rare malignancies.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Técnicas de Genotipagem/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Estudos de Viabilidade , Feminino , Neoplasias dos Genitais Femininos/genética , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Mutação , Seleção de Pacientes , Estudos Prospectivos , Doenças Raras/genética , Critérios de Avaliação de Resposta em Tumores Sólidos , Adulto JovemRESUMO
BACKGROUND: The development and approval of both targeted and immune therapies for patients with advanced non-small cell lung cancer (nsclc) has significantly improved patient survival rates and quality of life. Biomarker testing for patients newly diagnosed with nsclc, as well as for patients progressing after treatment with epidermal growth factor receptor (EGFR) inhibitors, is the standard of care in Canada and many parts of the world. METHODS: A group of thoracic oncology experts in the field of thoracic oncology met to describe the standard for biomarker testing for lung cancer in the Canadian context, focusing on evidence-based recommendations for standard-of-care testing for EGFR, anaplastic lymphoma kinase (ALK), ROS1, BRAF V600 and programmed death-ligand (PD-L1) at the time of diagnosis of advanced disease and EGFR T790M upon progression. As well, additional exploratory molecules and targets are likely to impact future patient care, including MET exon 14 skipping mutations and whole gene amplification, RET translocations, HER2 (ERBB2) mutations, NTRK, RAS (KRAS and NRAS), as well as TP53. RESULTS: The standard of care must include the incorporation of testing for novel biomarkers as they become available, as it will be difficult for national guidelines to keep pace with technological advances in this area. CONCLUSIONS: Canadian patients with nsclc should be treated equally; the minimum standard of care is defined in this paper.
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BACKGROUND: Genomic alterations that activate the MAPK signaling pathway frequently occur in Type I Epithelial Ovarian Cancers (EOCs). We evaluated therapeutic response outcomes in patients with type I EOC treated with genotype-matched therapy on clinical trials enrolled in a prospective molecular profiling program. MATERIAL AND METHODS: Formalin fixed paraffin embedded tumor tissues were prospectively screened for genomic alterations using MALDI-ToF mass-spectrometry platform or targeted sequencing using the Illumina MiSeq TruSeq Amplicon Cancer Panel. Treatment outcomes on genotype-matched trials were retrospectively reviewed using RECIST version 1.1 and Gynecological Cancer Intergroup CA125 related-response criteria RESULTS: 55 patients with type I EOC underwent molecular profiling, 41 (75%) low grade serous (LGS), 9 (16%) clear cell (CC), and 5 (9%) mucinous (MC) histologies. Thirty-five patients (64%) were found to have ≥1 somatic mutations: 23 KRAS, 6 NRAS, 5 PIK3CA, 2 PTEN, 1 BRAF, 1 AKT, 1 TP53, and 1 CTNNB1. Fifteen patients were subsequently enrolled in genotype-matched phase I or II trials, including 14 patients with KRAS/NRAS mutations treated with MEK inhibitor targeted combinations. Among 14 RECIST evaluable patients, there were 7 partial responses (PR), 7 stable disease (SD) and 1 disease progression (PD). CA125 responses were observed in 10/10 evaluable KRAS/NRAS mutant patients treated with MEK inhibitor combinations CONCLUSIONS: Genotyping and targeted sequencing of Type I EOCs frequently identifies actionable mutations. Matched treatment with MEK-based combination therapy in KRAS and/or NRAS mutant type I EOC patients is an active therapeutic strategy.
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Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário , Feminino , GTP Fosfo-Hidrolases/genética , Genes ras , Genótipo , Humanos , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Mutação , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genéticaRESUMO
OBJECTIVE: Fine needle aspiration (FNA) is widely used in the diagnosis of metastatic melanoma, both at initial presentation and in the setting of recurrent disease. The purpose of this study was to evaluate the performance of confirmatory immunohistochemistry (IHC) and molecular analysis of the BRAF mutation in cytological preparations of metastatic melanoma. METHODS: A 2-year retrospective review of pathology reports was performed on cytological samples of metastatic melanoma at the University Health Network (Toronto, Canada) and the Santa Casa Medical School (Sao Paulo, Brazil). IHC was performed on cell block sections prepared from formalin-fixed, fresh samples or residuum of CytoLyt/PreservCyt post-fixed in formalin. BRAF V600E/K mutations were assessed by amplification refractory mutation system (ARMS) analysis. RESULTS: A total of 104 samples (94 FNAs and 10 fluids) from 83 patients (20 women, 63 men) were included. IHC was attempted in 43 cases (41.3%) and successful in 41 (95.3%). The panel number of antibodies ranged from 1 to 15 (median 3). The most frequently used melanoma markers included HMB-45, melanoma cocktail and S100 protein, used in 25 (58.1%), 23 (53.5%) and 18 samples (41.9%). Thirty cases (69.8%) used three or fewer markers. The BRAF V600E/K mutation was tested in eight samples, being successful in seven (87.5%) and positive in three (37.5%). CONCLUSIONS: Cytological samples are a reliable and sufficient source for IHC and subsequent molecular analysis, allowing a reduced diagnostic time and rapid, appropriate treatment options in patients with advanced melanoma.
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Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: This clinical practice guideline was developed to determine the level of evidence supporting the clinical utility of commercially available multigene profiling assays and to provide guidance about whether certain breast cancer patient populations in Ontario would benefit from alternative tests in addition to Oncotype dx (Genomic Health, Redwood City, CA, U.S.A.). METHODS: A systematic electronic Ovid search of the medline and embase databases sought out systematic reviews and primary literature. A systematic review and practice guideline was written by a working group and was then reviewed and approved by Cancer Care Ontario's Molecular Oncology Advisory Committee. RESULTS: Twenty-four studies assessing the clinical utility of Oncotype dx, Prosigna (NanoString Technologies, Seattle, WA, U.S.A.), EndoPredict (Myriad Genetics, Salt Lake City, U.S.A.), and MammaPrint (Agendia, Irvine, CA, U.S.A.) were included in the evidence base. CONCLUSIONS: The clinical utility of multigene profiling assays is currently established for an appropriate subset of patients with estrogen receptor-positive, her2-negative, node-negative breast cancer for whom a decision to give chemotherapy is difficult to make. For patients with estrogen receptor-positive tumours who receive tamoxifen alone, Oncotype dx, Prosigna, and EndoPredict validly identify a low-risk population with favourable outcomes, indicating that a low-risk assay result is actionable and the decision to withhold chemotherapy is supported. Clinical evidence indicates that a high Oncotype dx recurrence score can predict for chemotherapy benefit, but a high Prosigna or EndoPredict score, although prognostic, is not, based on clinical trial evidence, directly actionable. Prosigna and EndoPredict are statistically more likely to identify a population at risk for recurrence beyond 5 years, but that information is currently not actionable because of a lack of interventional studies.
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Starting in the early 2000s, non-small-cell lung cancer (nsclc) subtypes have evolved from being histologically described to molecularly defined. Management of lung adenocarcinomas now generally requires multiple molecular tests at baseline to define the optimal treatment strategy. More recently, second biopsies performed at progression in patients treated with tyrosine kinase inhibitors (tkis) have further defined the continued use of molecularly targeted therapy. In the present article, we focus on one molecular subtype: EGFR-mutated nsclc. For that patient population, multiple lines of tki therapy are now available either clinically or in clinical trials. Each line of treatment is guided by the specific mutations (for example, L858R, T790M, C797S) identified in EGFR. We first describe the various mechanisms of acquired resistance to EGFR tki treatment. We then focus on strategies that clinicians and pathologists can both use during tissue acquisition and handling to optimize patient results. We also discuss future directions for the molecular characterization of lung cancers with driver mutations, including liquid biopsies. Finally, we provide an algorithm to guide treating physicians managing patients with EGFR-mutated nsclc. The same framework can also be applied to other molecularly defined nsclc subgroups as resistance patterns are elucidated and additional lines of treatment are developed.
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BACKGROUND: Although molecular testing has become standard in managing advanced nonsquamous non-small-cell lung cancer (nsclc), most patients undergo minimally invasive procedures, and the diagnostic tumour specimens available for testing are usually limited. A knowledge translation initiative to educate diagnostic specialists about sampling techniques and laboratory processes was undertaken to improve the uptake and application of molecular testing in advanced lung cancer. METHODS: A multidisciplinary panel of physician experts including pathologists, respirologists, interventional thoracic radiologists, thoracic surgeons, medical oncologists, and radiation oncologists developed a specialty-specific education program, adapting international clinical guidelines to the local Ontario context. Expert recommendations from the program are reported here. RESULTS: Panel experts agreed that specialists procuring samples for lung cancer diagnosis should choose biopsy techniques that maximize tumour cellularity, and that conservation strategies to maximize tissue for molecular testing should be used in tissue processing. The timeliness of molecular reporting can be improved by pathologist-initiated reflex testing upon confirmation of nonsquamous nsclc and by prompt transportation of specimens to designated molecular diagnostic centres. To coordinate timely molecular testing and optimal treatment, collaboration and communication between all clinicians involved in diagnosing patients with advanced lung cancer are mandatory. CONCLUSIONS: Knowledge transfer to diagnostic lung cancer specialists could potentially improve molecular testing and treatment for advanced lung cancer patients.
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Anaplastic lymphoma kinase (alk) is an oncogenic driver in non-small-cell lung cancer (nsclc). Chromosomal rearrangements involving the ALK gene occur in up to 4% of nonsquamous nsclc patients and lead to constitutive activation of the alk signalling pathway. ALK-positive nsclc is found in relatively young patients, with a median age of 50 years. Patients frequently have brain metastasis. Targeted inhibition of the alk pathway prolongs progression-free survival in patients with ALK-positive advanced nsclc. The results of several recent clinical trials confirm the efficacy and safety benefit of crizotinib and ceritinib in this population. Canadian oncologists support the following consensus statement: All patients with advanced nonsquamous nsclc (excluding pure neuroendocrine carcinoma) should be tested for the presence of an ALK rearrangement. If an ALK rearrangement is present, treatment with a targeted alk inhibitor in the first-line setting is recommended. As patients become resistant to first-generation alk inhibitors, other treatments, including second-generation alk inhibitors can be considered.
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BACKGROUND: Testing for EGFR mutations and ALK rearrangement has become standard in managing advanced nonsmall-cell lung cancer (NSCLC). However, many institutions in Europe, North America and other world regions continue to face a common challenge of facilitating timely molecular testing with rapid result turnaround time. We assessed the prevalence of biomarker testing for advanced NSCLC patients and whether testing affected the timeliness of treatment decisions. METHODS: We conducted a retrospective chart review of a random sample of one-quarter of all patients with advanced NSCLC referred to the Princess Margaret Cancer Centre from 1 April 2010 to 31 March 2013. RESULTS: Of 300 patients reviewed, 175 seen by medical oncology had nonsquamous NSCLC, 72% of whom had biomarker testing carried out. Patients tested for biomarkers were more likely to be female (47% versus 21%, P = 0.002), Asian (27% versus 6%, P = 0.005) and never smokers (42% versus 8%, P < 0.0001). Only 21% of patients with biomarker testing had results available at their initial oncology consultation. This group had a shorter median time from consultation to treatment decision (0 versus 22 days, P = 0.0008) and time to treatment start (16 versus 29, P = 0.004). Thirteen percent underwent repeat biopsy for molecular testing after the initial consultation. Of those with positive EGFR or ALK results, 19% started chemotherapy before biomarker results became available. CONCLUSIONS: Awaiting biomarker testing results can delay treatment decisions and treatment initiation for patients with advanced NSCLC. This may be avoided by incorporating reflex biomarker testing into diagnostic algorithms for NSCLC at the level of the pathologist, and further education of specialists involved in obtaining diagnostic cancer specimens to ensure they are sufficient for molecular testing.
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Adenocarcinoma/genética , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Tomada de Decisões , Receptores ErbB/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Tempo para o Tratamento , Adulto JovemRESUMO
BACKGROUND: The Notch signalling pathway has been implicated in tumour initiation, progression, angiogenesis and development of resistance to vascular endothelial growth factor (VEGF) targeting, providing a rationale for the combination of RO4929097, a γ-secretase inhibitor, and cediranib, a VEGF receptor tyrosine kinase inhibitor. METHODS: Patients received escalating doses of RO4929097 (on a 3 days-on and 4 days-off schedule) in combination with cediranib (once daily). Cycle 1 was 42 days long with RO4929097 given alone for the first 3 weeks followed by the co-administration of both RO4929097 and cediranib starting from day 22. Cycle 2 and onwards were 21 days long. Soluble markers of angiogenesis were measured in plasma samples. Archival tumour specimens were assessed for expression of three different components of Notch signalling pathway and genotyping. RESULTS: In total, 20 patients were treated in three dose levels (DLs). The recommended phase II dose was defined as 20 mg for RO4929097 on 3 days-on and 4 days-off schedule and 30 mg daily for cediranib. The most frequent treatment-related adverse events (AEs) were diarrhoea, hypertension, fatigue and nausea. Eleven patients had a best response of stable disease and one patient achieved partial response. We did not detect any correlation between tested biomarkers of angiogenesis or the Notch pathway and treatment effect. There was no correlation between mutational status and time to treatment failure. CONCLUSION: RO4929097 in combination with cediranib is generally well tolerated at the DLs tested. Preliminary evidence of antitumour efficacy with prolonged disease stabilisation in some patients with progressive malignancies warrants further clinical investigation of this treatment strategy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzazepinas/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Carcinoma Neuroendócrino , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Sarcoma do Estroma Endometrial/tratamento farmacológico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico , Adulto JovemRESUMO
Acute promyelocytic leukaemia (APL) is uniquely associated with chromosomal translocations that disrupt the gene encoding the retinoic acid receptor, RARA. In more than 99% of cases, this disruption results in the formation of a PML-RARA gene fusion. Two rare variants of APL have been described, in which RARA is fused to one of two other genes, PLZF and NPM. Although RARA dysregulation is evidently important in APL, the role of the various fusion partners remains unclear. We have characterized a fourth APL gene fusion, which links exons encoding the retinoic acid and DNA-binding domains of RARA to 5' exons of NuMA, a gene that encodes the nuclear mitotic apparatus protein. The NuMA-RARA fusion protein exists in sheet-like nuclear aggregates with which normal NuMA partly co-localizes. In contrast to t(15;17) APL, the intracellular distribution of PML is normal in these cells. Our results suggest that interference with retinoid signalling, and not disruption of PML organization, is essential to the APL phenotype and implicates for the first time an element of the mitotic apparatus in the molecular pathogenesis of human malignancy.
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Cromossomos Humanos Par 11 , Cromossomos Humanos Par 17 , Leucemia Promielocítica Aguda/genética , Proteínas Nucleares/genética , Receptores do Ácido Retinoico/genética , Translocação Genética , Sequência de Aminoácidos , Antígenos Nucleares , Sequência de Bases , Medula Óssea/metabolismo , Medula Óssea/patologia , Proteínas de Ciclo Celular , Cromossomos Humanos Par 15 , Primers do DNA , Feminino , Variação Genética , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Proteínas Associadas à Matriz Nuclear , Proteínas Nucleares/biossíntese , Proteínas Nucleares/química , Especificidade de Órgãos , Reação em Cadeia da Polimerase , Receptores do Ácido Retinoico/biossíntese , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/química , Receptor alfa de Ácido Retinoico , Fuso AcromáticoRESUMO
The burden of cancer for Canadian citizens and society is large. New technologies have the potential to increase the use of genetic information in clinical decision-making, furthering prevention, surveillance, and safer, more effective drug therapies for cancer patients. Personalized medicine can have different meanings to different people. The context for personalized medicine in the present paper is genetic testing, which offers the promise of refining treatment decisions for those diagnosed with chronic and life-threatening illnesses. Personalized medicine and genetic characterization of tumours can also give direction to the development of novel drugs. Genetic testing will increasingly become an essential part of clinical decision-making. In Canada, provinces are responsible for health care, and most have unique policies and programs in place to address cancer control. The result is inconsistency in access to and delivery of therapies and other interventions, beyond the differences expected because of demographic factors and clinical education. Inconsistencies arising from differences in resources, policy, and application of evidence-informed personalized cancer medicine exacerbate patient access to appropriate testing and quality care. Geographic variations in cancer incidence and mortality rates in Canada-with the Atlantic provinces and Quebec having higher rates, and British Columbia having the lowest rates-are well documented. Our purpose here is to provide an understanding of current and future applications of personalized medicine in oncology, to highlight the benefits of personalized medicine for patients, and to describe issues and opportunities for improvement in the coordination of personalized medicine in Canada. Efficient and more rapid adoption of personalized medicine in oncology in Canada could help overcome those issues and improve cancer prevention and care. That task might benefit from the creation of a National Genetics Advisory Panel that would review research and provide recommendations on tests for funding or reimbursement, guidelines, service delivery models, laboratory quality assurance, education, and communication. More has to be known about the current state of personalized cancer medicine in Canada, and strategies have to be developed to inform and improve understanding and appropriate coordination and delivery. Our hope is that the perspectives emphasized in this paper will stimulate discussion and further research to create a more informed response.
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BACKGROUND: Oral epithelial dysplasia (OED) is a histologically detectable lesion that may progress to carcinoma but there are no accurate markers that predict progression. This study examined the development of carcinoma from oral dysplastic lesions, and the association between abnormal DNA content and progression to carcinoma. METHODS: Epithelial dysplasias from the Oral Pathology Diagnostic Service were matched against the Ontario Cancer Registry database to identify cases that progressed to carcinoma. A case-control study was conducted to compare DNA image cytometry of dysplasias that progressed with those that have not progressed. For a subset of the progressed dysplasias, DNA content of the carcinoma was also analysed. RESULTS: A total of 8% of epithelial dysplasias progressed to carcinoma after 6-131 months. In all, 28 of 99 dysplasias showed abnormal DNA content by image cytometry. In multivariate analysis of time to progression, abnormal DNA content was a significant predictor with hazard ratio of 3.3 (95% confidence interval: 1.5-7.4) corrected for site and grade of dysplasia. Analysis of sequential samples of dysplasia and carcinoma suggested that epithelial cell populations with grossly abnormal DNA content were transient intermediates during oral cancer development. CONCLUSIONS: Abnormal DNA content is a significant biomarker of a subset of OED that progress to carcinoma.
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DNA de Neoplasias/ultraestrutura , Progressão da Doença , Mucosa Bucal/patologia , Neoplasias Bucais/genética , Lesões Pré-Cancerosas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/genética , Feminino , Humanos , Citometria por Imagem , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , RiscoRESUMO
BACKGROUND: Imatinib could reverse marrow angiogenesis and decrease the plasma level of vascular endothelial growth factor (VEGF) in chronic myeloid leukemia (CML) patients. Methods, materials and patients: The current study investigated the impact of four vascular endothelial growth factor type A (VEGFA) and three vascular endothelial growth factor receptor type 2 (VEGFR2) gene polymorphisms on the outcomes of 228 CML patients following imatinib therapy. VEGFA genotypes such as -2578C>A (rs699947), -460T>C (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) loci and VEGFR2 genotypes (rs1531289, rs1870377 and rs2305948) were analyzed using matrix-assisted laser desorption/ionization time-of-flight-based method. RESULTS: In single marker analyses, strong correlations were noted between complete cytogenetic response (CCyR) and VEGFR2 genotypes (rs1531289/rs1870377), between treatment failure and VEGFR2 genotype (rs1870377) and between progression to advanced disease and VEGFA genotypes (rs699947/rs833061). Three haplotypes of VEGFR2 gene were generated as follows: GT (46.1%), AT (27.9%) and GA (25.7%). Haplotype analyses showed good correlations between VEGFR2 haplotype and CCyR and treatment failure to imatinib. Multivariate analyses confirmed strong correlations of VEGFR2 polymorphisms (especially rs1531289, rs1870377 or VEGFR2 haplotype) with CCyR, treatment failure and of VEGFA genotype (rs699947) with progression to advanced disease. CONCLUSION: The VEGFR2 gene polymorphism correlates with cytogenetic response, treatment failure following imatinib therapy for CML, while VEGFA genotype correlates with progression to advanced disease.
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Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Piperazinas/uso terapêutico , Polimorfismo de Nucleotídeo Único , Pirimidinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Benzamidas , Biomarcadores Farmacológicos/metabolismo , Progressão da Doença , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
A system in which immune-deficient mice are repopulated with cells from the human myeloid lineage, and that provides an in vivo stem cell assay for human hematopoietic cells is described. Generation of the chimeric human/immune-deficient (HID) mice was dependent on the use of immune-deficient bg/nu/xid mice. Infusion of these mice with human bone marrow gave rise to increases in human macrophage progenitors during more than 5 weeks of in vivo growth, indicating the seeding, proliferation, and differentiation of human stem cells. The human identity of the progenitors was confirmed by sequence analysis and their dependence on human growth factors. The creation of HID mice lays the foundation for establishing animal models for a wide variety of human hemopathies, from leukemia to infectious disease.
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Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Animais , Transplante de Medula Óssea , Diferenciação Celular , Divisão Celular , Ensaio de Unidades Formadoras de Colônias , Fatores Estimuladores de Colônias/farmacologia , Modelos Animais de Doenças , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Substâncias de Crescimento/farmacologia , Doenças Hematológicas , Células-Tronco Hematopoéticas/patologia , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/patologia , Interleucina-3/farmacologia , Células Matadoras Naturais/imunologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos CBA , Camundongos Mutantes , Camundongos Nus , Transplante HeterólogoRESUMO
A human acute lymphoblastic leukemia (ALL) cell line that was transplanted into immune-deficient SCID mice proliferated in the hematopoietic tissues, invaded various organs, and led to the death of the mice. The distribution of leukemic cells in SCID mice was similar to the course of the disease in children. A-1 cells marked with a retrovirus vector showed clonal evolution after the transplant. SCID mice that were injected with bone marrow from three patients with non-T ALL had leukemic cells in their bone marrow and spleen. This in vivo model of human leukemia is an approach to understanding leukemic growth and progression and is a novel system for testing new treatment strategies.
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Síndromes de Imunodeficiência/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Encéfalo/patologia , Linhagem Celular , Células Clonais , DNA de Neoplasias/isolamento & purificação , Humanos , Rim/patologia , Fígado/patologia , Camundongos , Camundongos Mutantes , Transplante de Neoplasias , Transplante HeterólogoRESUMO
Background: Practices in somatic variant interpretation and classification vary between Canadian clinical molecular diagnostic laboratories, and understanding of current practices and perspectives is limited. To define gaps and future directions, including consensus guideline development, the Somatic Curation and Interpretation Across Laboratories (social) project examined the present state of somatic variant interpretation in Canadian molecular laboratories, including testing volumes and methods, data sources and evidence criteria, and application of published classification guidelines. Methods: Individuals who perform somatic variant interpretation in Canadian centres were invited to participate in an online survey. Invitees included laboratory directors (certified as Fellows of the Canadian College of Medical Geneticists or the American College of Medical Geneticists), md or md and phd molecular pathologists, and other phd experts, including phd specialists in variant annotation or bioinformatics. Current testing methods, volumes, and platforms in next-generation sequencing, use of variant annotation resources and evidence criteria, and preference for variant classification schemes were evaluated. Results: Responses were received from 37 participants in 8 provinces. A somatic variant classification scheme jointly supported by the Association for Molecular Pathology (amp), the American Society of Clinical Oncology (asco), and the College of American Pathologists (cap) was used by 47% of respondents; an alternative guideline or a combination of published guidelines was used by 35% of respondents. The remaining 18% did not use a published scheme. Only 41% of respondents used a published scheme without alteration. Although all respondents indicated that there is a need for Canadian laboratories to adopt a somatic variant classification guideline, only 38% of respondents felt that it should be mandatory to adopt the amp/asco/cap-endorsed guideline. Conclusions: Data from the social project identified high variability in current practice, yet strong support for standardization of solid-tumour somatic variant interpretation across Canadian institutions. Aligning classification methods will reduce variation in cross-institutional classification and reporting practices, aiding in consistent practice nationwide.
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Neoplasias/genética , Canadá , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/classificação , Patologia Molecular , Guias de Prática Clínica como Assunto , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
Cancer is a genetic disease resulting from germline or somatic genetic aberrations. Rapid progress in the field of genomics in recent years is allowing for increased characterization and understanding of the various forms of the disease. The Ontario-wide Cancer Targeted Nucleic Acid Evaluation (octane) clinical trial, open at cancer centres across Ontario, aims to increase access to genomic sequencing of tumours and to facilitate the collection of clinical data related to enrolled patients and their clinical outcomes. The study is designed to assess the clinical utility of next-generation sequencing (ngs) in cancer patient care, including enhancement of treatment options available to patients. A core aim of the study is to encourage collaboration between cancer hospitals within Ontario while also increasing international collaboration in terms of sharing the newly generated data. The single-payer provincial health care system in Ontario provides a unique opportunity to develop a province-wide registry of ngs testing and a repository of genomically characterized, clinically annotated samples. It also provides an important opportunity to use province-wide real-world data to evaluate outcomes and the cost of ngs for patients with advanced cancer. The octane study is attempting to translate knowledge to help deliver precision oncology in a Canadian environment. In this article, we discuss the background to the study and its implementation, current status, and future directions.
Assuntos
Neoplasias/genética , Ensaios Clínicos como Assunto , Tomada de Decisões , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Disseminação de Informação , Cooperação Internacional , Biópsia Líquida , Neoplasias/diagnóstico , Ontário , Medicina de PrecisãoRESUMO
Prevention of GVHD is one of the most desirable goals of BMT in aplastic anemia (AA). We reviewed the medical records of 24 consecutive patients treated with BMT for acquired AA using two different GVHD prevention strategies. Ten patients were given alemtuzumab-based GVHD prophylaxis (50-60 mg in three divided doses on days -8, -7 and -6), and 14 patients were given conventional GVHD prophylaxis with calcineurin inhibitors plus MTX before the introduction of the alemtuzumab-based protocols. The incidence of acute, chronic and 'serious GVHD' was significantly reduced in alemtuzumab-treated patients compared to conventionally treated patients [11 vs 64% (P=0.03), 0 vs 78% (P=0.002) and 0 vs 57% (P=0.007), respectively]. Engraftment time and rates of graft failure appeared similar in the two groups. A significantly higher proportion of alemtuzumab-treated patients developed CMV reactivation compared to control patients (83 vs 12%; P=0.03); none developed CMV disease. The rates of other infectious complications did not appear significantly different. Our data suggest that 50-60 mg of alemtuzumab given according to the current schedule significantly reduces the risk of GVHD without increasing the risk of graft failure or serious infections.
Assuntos
Anemia Aplástica/terapia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Antineoplásicos/administração & dosagem , Transplante de Medula Óssea/efeitos adversos , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/administração & dosagem , Adulto , Alemtuzumab , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticorpos Antineoplásicos/efeitos adversos , Inibidores de Calcineurina , Estudos de Casos e Controles , Infecções por Citomegalovirus/virologia , Esquema de Medicação , Quimioterapia Combinada , Feminino , Sobrevivência de Enxerto , Humanos , Imunossupressores/efeitos adversos , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estudos Retrospectivos , Ativação ViralRESUMO
Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as first-line systemic therapy for patients with non-small-cell lung cancer (nsclc) having mutations in the EGFR gene. Resistance to tkis eventually occurs in all nsclc patients treated with such drugs. In patients with resistance to tkis caused by the EGFR T790M mutation, the third-generation tki osimertinib is now the standard of care. For optimal patient management, accurate EGFR T790M testing is required. A multidisciplinary working group of pathologists, laboratory medicine specialists, medical oncologists, a respirologist, and a thoracic radiologist from across Canada was convened to discuss best practices for EGFR T790M mutation testing in Canada. The group made recommendations in the areas of the testing algorithm and the pre-analytic, analytic, and post-analytic aspects of clinical testing for both tissue testing and liquid biopsy circulating tumour dna testing. The recommendations aim to improve EGFR T790M testing in Canada and to thereby improve patient care.