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1.
N Engl J Med ; 390(9): 819-829, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38416430

RESUMO

BACKGROUND: Retrospective data suggest that the incidence of parametrial infiltration is low in patients with early-stage low-risk cervical cancer, which raises questions regarding the need for radical hysterectomy in these patients. However, data from large, randomized trials comparing outcomes of radical and simple hysterectomy are lacking. METHODS: We conducted a multicenter, randomized, noninferiority trial comparing radical hysterectomy with simple hysterectomy including lymph-node assessment in patients with low-risk cervical cancer (lesions of ≤2 cm with limited stromal invasion). The primary outcome was cancer recurrence in the pelvic area (pelvic recurrence) at 3 years. The prespecified noninferiority margin for the between-group difference in pelvic recurrence at 3 years was 4 percentage points. RESULTS: Among 700 patients who underwent randomization (350 in each group), the majority had tumors that were stage IB1 according to the 2009 International Federation of Gynecology and Obstetrics (FIGO) criteria (91.7%), that had squamous-cell histologic features (61.7%), and that were grade 1 or 2 (59.3%). With a median follow-up time of 4.5 years, the incidence of pelvic recurrence at 3 years was 2.17% in the radical hysterectomy group and 2.52% in the simple hysterectomy group (an absolute difference of 0.35 percentage points; 90% confidence interval, -1.62 to 2.32). Results were similar in a per-protocol analysis. The incidence of urinary incontinence was lower in the simple hysterectomy group than in the radical hysterectomy group within 4 weeks after surgery (2.4% vs. 5.5%; P = 0.048) and beyond 4 weeks (4.7% vs. 11.0%; P = 0.003). The incidence of urinary retention in the simple hysterectomy group was also lower than that in the radical hysterectomy group within 4 weeks after surgery (0.6% vs. 11.0%; P<0.001) and beyond 4 weeks (0.6% vs. 9.9%; P<0.001). CONCLUSIONS: In patients with low-risk cervical cancer, simple hysterectomy was not inferior to radical hysterectomy with respect to the 3-year incidence of pelvic recurrence and was associated with a lower risk of urinary incontinence or retention. (Funded by the Canadian Cancer Society and others; ClinicalTrials.gov number, NCT01658930.).


Assuntos
Carcinoma de Células Escamosas , Histerectomia , Neoplasias do Colo do Útero , Feminino , Humanos , Canadá , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Histerectomia/efeitos adversos , Histerectomia/métodos , Linfonodos/patologia , Recidiva Local de Neoplasia/epidemiologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Incontinência Urinária/etiologia , Retenção Urinária/etiologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/cirurgia
2.
Br J Haematol ; 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39267295

RESUMO

In the LY.17 randomized phase II clinical trial, adults with relapsed and refractory diffuse large B-cell lymphoma treated with ibrutinib-R-GDP (IR-GDP) for up to three cycles had more documented bacterial and fungal infections, without improvement in overall response, compared with R-GDP. CR, complete response; DLBCL, diffuse large B-cell lymphoma; PD, progressive disease; PR, partial response; R/R, relapsed/refractory; SD, stable disease.

3.
Br J Haematol ; 205(3): 881-890, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38802107

RESUMO

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Ciclofosfamida , Etoposídeo , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Rituximab , Terapia de Salvação , Transplante Autólogo , Humanos , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/uso terapêutico , Etoposídeo/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Pessoa de Meia-Idade , Terapia de Salvação/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Masculino , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/métodos , Canadá , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Dexametasona/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Gencitabina , Resultado do Tratamento
4.
Oncologist ; 28(9): 799-803, 2023 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-37226534

RESUMO

BACKGROUND: When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (""contact days'') can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. PATIENTS AND METHODS: We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level "contact days" by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered "home days''. We compared measures of contact days across arms. RESULTS: The study period was longer in the GDP arm (median 50, vs. 47 days, P = .007). Contact days were comparable in both arms (median 18 vs 19, P = 0.79), but home days were higher in the GDP arm (median 33 vs 28, P < .001). The proportion of contact days was lower in the GDP arm (34%, vs. 38%, P = .009). The GDP arm experienced more contact days related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more inpatient contact days (median, 11 vs. 0 days). CONCLUSIONS: Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.


Assuntos
Cisplatino , Neoplasias , Humanos , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Neoplasias/tratamento farmacológico
5.
Support Care Cancer ; 31(5): 256, 2023 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37043087

RESUMO

Early-stage Hodgkin lymphoma has become one of the most curable hematologic malignancies. Depending upon the disease location, possible toxicities, and patient preference, chemotherapy alone with ABVD remains an accepted treatment modality for this disease. There remains a paucity of data regarding the longitudinal trajectory of health-related quality of life (HRQoL) in patients treated for HL. The impact of disease and treatment on HRQoL is increasingly important to understand as the number of long-term survivors increases. We report the longitudinal HRQoL using data prospectively collected from diagnosis up to 10 years post-treatment in the ABVD arm of the HD.6 randomized controlled trial for early-stage HL patients (N=169). We analyzed HRQoL using the EORTC QLQ-C30 collected at baseline, 3 months, 6 months, and 12 months after completion of chemotherapy and yearly up to year 10. Clinically and statistically significant improvements were noted for specific domains including emotional (3 months post-treatment), social (12 months post-treatment) and financial functioning (2 years post-treatment), and the specific symptom of fatigue (6 months post-treatment) during the follow-up period. To our knowledge, this is the first prospective, longitudinal analysis of HRQoL specifically among patients with early-stage HL treated with ABVD therapy alone. Although improvements were noted, sustained clinically and statistically significant improvements were noted only in select symptoms emphasizing the need to better understand and optimize HRQoL among this patient group.


Assuntos
Doença de Hodgkin , Humanos , Doença de Hodgkin/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Qualidade de Vida , Estudos Prospectivos , Bleomicina , Doxorrubicina/efeitos adversos , Dacarbazina/uso terapêutico , Vimblastina/uso terapêutico
6.
JAMA ; 327(20): 1963-1973, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35608580

RESUMO

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.


Assuntos
Antineoplásicos , Neoplasias da Mama , Metformina , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Metformina/uso terapêutico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapêutico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
7.
Pharmacogenet Genomics ; 31(1): 1-9, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32649577

RESUMO

OBJECTIVES: Based on our previous findings that postmenopausal women with estrone (E1) and estradiol (E2) concentrations at or above 1.3 pg/ml and 0.5 pg/ml, respectively, after 6 months of adjuvant anastrozole therapy had a three-fold risk of recurrence, we aimed to identify a single-nucleotide polymorphism (SNP)-based model that would predict elevated E1 and E2 and then validate it in an independent dataset. PATIENTS AND METHODS: The test set consisted of 322 women from the M3 study and the validation set consisted of 152 patients from MA.27. All patients were treated with adjuvant anastrozole, had on-anastrozole E1 and E2 concentrations and genome-wide genotyping. RESULTS: SNPs were identified from the M3 genome-wide association study. The best model to predict the E1-E2 phenotype with high balanced accuracy was a support vector machine model using clinical factors plus 46 SNPs. We did not have an independent cohort that is similar to the M3 study with clinical, E1-E2 phenotypes and genotype data to test our model. Hence, we chose a nested matched case-control cohort (MA.27 study) for testing. Our E1-E2 model was not validated but we found the MA.27 validation cohort was both clinically and genomically different. CONCLUSIONS: We identified a SNP-based model that had excellent performance characteristics for predicting the phenotype of elevated E1 and E2 in women treated with anastrozole. This model was not validated in an independent dataset but that dataset was clinically and genomically substantially different. The model will need validation in a prospective study.


Assuntos
Anastrozol/efeitos adversos , Neoplasias da Mama/genética , Predisposição Genética para Doença , Recidiva Local de Neoplasia/genética , Adulto , Anastrozol/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/sangue , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/patologia , Estradiol/sangue , Estrona/sangue , Feminino , Genoma Humano/genética , Estudo de Associação Genômica Ampla , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Polimorfismo de Nucleotídeo Único/genética
8.
Eur J Haematol ; 107(3): 333-342, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34053112

RESUMO

BACKGROUND: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. METHODS: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). RESULTS: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. CONCLUSIONS: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Efeitos Psicossociais da Doença , Custos e Análise de Custo , Ciclofosfamida/economia , Dexametasona/economia , Mieloma Múltiplo/economia , Oligopeptídeos/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Canadá , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Oligopeptídeos/uso terapêutico , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Recidiva , Análise de Sobrevida , Resultado do Tratamento
9.
J Med Ethics ; 47(9): 599-602, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34172525

RESUMO

Policies promoted and adopted for allocating ventilators during the COVID-19 pandemic have often prioritised healthcare workers or other essential workers. While the need for such policies has so far been largely averted, renewed stress on health systems from continuing surges, as well as the experience of allocating another scarce resource-vaccination-counsel revisiting the justifications for such prioritisation. Prioritising healthcare workers may have intuitive appeal, but the ethical justifications for doing so and the potential harms that could follow require careful analysis. Ethical justifications commonly offered for healthcare worker prioritisation for ventilators rest on two social value criteria: (1) instrumental value, also known as the 'multiplier effect', which may preserve the ability of healthcare workers to help others, and (2) reciprocity, which rewards past usefulness or sacrifice. We argue that these justifications are insufficient to over-ride the common moral commitment to value each person's life equally. Institutional policies prioritising healthcare workers over other patients also violate other ethical norms of the healthcare professions, including the commitment to put patients first. Furthermore, policy decisions to prioritise healthcare workers for ventilators could engender or deepen existing distrust of the clinicians, hospitals and health systems where those policies exist, even if they are never invoked.


Assuntos
COVID-19 , Pandemias , Pessoal de Saúde , Humanos , Políticas , SARS-CoV-2 , Ventiladores Mecânicos
10.
Cancer ; 126(22): 4859-4866, 2020 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-32910476

RESUMO

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.


Assuntos
Antígeno B7-H1/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Lapatinib/uso terapêutico , Trastuzumab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Metástase Neoplásica , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Estudos Retrospectivos
11.
Breast Cancer Res ; 21(1): 47, 2019 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944027

RESUMO

BACKGROUND: Our previous genome-wide association study using the MA.27 aromatase inhibitors adjuvant trial identified SNPs in the long noncoding RNA MIR2052HG associated with breast cancer-free interval. MIR2052HG maintained ERα both by promoting AKT/FOXO3-mediated ESR1 transcription and by limiting ubiquitin-mediated ERα degradation. Our goal was to further elucidate MIR2052HG's mechanism of action. METHODS: RNA-binding protein immunoprecipitation assays were performed to demonstrate that the transcription factor, early growth response protein 1 (EGR1), worked together with MIR2052HG to regulate that lemur tyrosine kinase-3 (LMTK3) transcription in MCF7/AC1 and CAMA-1 cells. The location of EGR1 on the LMTK3 gene locus was mapped using chromatin immunoprecipitation assays. The co-localization of MIR2052HG RNA and the LMTK3 gene locus was determined using RNA-DNA dual fluorescent in situ hybridization. Single-nucleotide polymorphisms (SNP) effects were evaluated using a panel of human lymphoblastoid cell lines. RESULTS: MIR2052HG depletion in breast cancer cells results in a decrease in LMTK3 expression and cell growth. Mechanistically, MIR2052HG interacts with EGR1 and facilitates its recruitment to the LMTK3 promoter. LMTK3 sustains ERα levels by reducing protein kinase C (PKC) activity, resulting in increased ESR1 transcription mediated through AKT/FOXO3 and reduced ERα degradation mediated by the PKC/MEK/ERK/RSK1 pathway. MIR2052HG regulated LMTK3 in a SNP- and aromatase inhibitor-dependent fashion: the variant SNP increased EGR1 binding to LMTK3 promoter in response to androstenedione, relative to wild-type genotype, a pattern that can be reversed by aromatase inhibitor treatment. Finally, LMTK3 overexpression abolished the effect of MIR2052HG on PKC activity and ERα levels. CONCLUSIONS: Our findings support a model in which the MIR2052HG regulates LMTK3 via EGR1, and LMTK3 regulates ERα stability via the PKC/MEK/ERK/RSK1 axis. These results reveal a direct role of MIR2052HG in LMTK3 regulation and raise the possibilities of targeting MIR2052HG or LMTK3 in ERα-positive breast cancer.


Assuntos
Inibidores da Aromatase/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Receptor alfa de Estrogênio/genética , Proteínas de Membrana/genética , Proteínas Serina-Treonina Quinases/genética , RNA Longo não Codificante/genética , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular/genética , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Proteínas de Membrana/metabolismo , Modelos Biológicos , Polimorfismo de Nucleotídeo Único , Proteínas Serina-Treonina Quinases/metabolismo , Estabilidade Proteica , Transdução de Sinais , Transcrição Gênica
12.
Pharmacogenet Genomics ; 29(8): 183-191, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31211741

RESUMO

OBJECTIVE: To identify additional genetic variants beyond those observed in a previous genome-wide association study (GWAS) in women treated on the MA.27 clinical trial in which women were randomized to 5 years of adjuvant therapy with anastrozole or exemestane. PATIENTS AND METHODS: We performed a matched case-control study in 234 women who had a recurrence of breast cancer (cases) and 649 women who had not (controls). The analysis was restricted to White women with an estrogen receptor-positive breast cancer. Multiplex PCR-based targeted deep sequencing was performed of the MIR2052HG region on chromosome 8 between positions 75.4 and 75.7, a span of 300 kb, in an attempt to identify additional functional single nucleotide polymorphisms (SNPs). RESULTS: A total of 4677 unique variants were identified that had not been identified in the previous GWAS. Clinical Annotation of Variants analysis revealed 10 variants, including eight SNPs and two insertion-deletion mutations with moderate or high impact. However, none of the common and variant regions was significant after adjustment for the most significant SNP (rs13260300) identified in our previous GWAS. We performed haplotype analysis that revealed two regions in which the haplotypes lost significance when adjusted for this prior GWAS SNP and one region with two significant haplotypes (P = 0.046 and 0.031) after adjusting for the GWAS SNP. CONCLUSION: We were unable to identify common or rare variant regions that added value to the findings from our previous GWAS. We did find two haplotypes that were significant after adjusting for our top GWAS SNP but these were considered to be of marginal value.


Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação INDEL , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Estudos de Casos e Controles , Quimioterapia Adjuvante , Cromossomos Humanos Par 8/genética , Feminino , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Pessoa de Meia-Idade , Análise de Sequência de DNA
13.
Transfusion ; 59(7): 2308-2315, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059586

RESUMO

BACKGROUND: Transfusion of 2 units of red blood cells (RBCs) for Hb ≤80 g/L is the prevailing liberal practice for patients undergoing intensive treatment for acute leukemia or hematopoietic transplant across North America. There is little evidence regarding optimal transfusion targets in these highly transfusion-dependent patient populations. STUDY DESIGN AND METHODS: This was a retrospective pre-post cohort study of consecutive patients admitted to Kingston Health Sciences Center between April through December 2016 (pre) and April through December 2017 (post) for acute leukemia induction chemotherapy or high dose chemotherapy (HDCT) for autologous stem cell transplantation (ASCT). The pre-cohort was transfused using a liberal threshold (2 units of RBCs for Hb ≤80 g/L) and the post-cohort using a more restrictive threshold (1 unit RBCs for Hb ≤70 g/L), implemented with a computerized physician order entry form. Primary outcome was number of RBC units transfused per inpatient day. Secondary outcomes included inpatient mortality and select morbidity measures. RESULTS: 124 patients underwent 134 treatment courses: 62 courses of induction chemotherapy (pre = 26, post = 36) and 72 courses of HDCT for ASCT (pre = 39, post = 33). There was a significant decrease in median RBC utilization per admission in both patient populations: 10.5 versus 6.7 in the leukemia group (p = 0.01) and 2.0 versus 1.0 in the ASCT group (p = 0.04). This reduction was seen without a difference in inpatient mortality, length of stay, falls, serious bleeds, requirement for ICU, or time to engraftment post ASCT. CONCLUSIONS: A restrictive transfusion strategy in patients receiving intensive chemotherapy for acute leukemia or ASCT decreased inpatient RBC usage without increasing adverse inpatient events.


Assuntos
Transfusão de Eritrócitos , Quimioterapia de Indução , Leucemia/mortalidade , Leucemia/terapia , Transplante de Células-Tronco , Doença Aguda , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida
14.
Bioethics ; 33(1): 4-12, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30474129

RESUMO

This paper evaluates four recent randomized clinical trials in which the informed consent of participants was either not sought at all, or else was conducted with critical information missing from the consent documents. As these studies have been taking place, various proposals to conduct randomized clinical trials without consent have been appearing in the medical literature. Some of the explanations offered for why it is appropriate to bypass consent or disclosure requirements appear to represent a fundamental misunderstanding of applicable government regulations and even the research enterprise. Others are the result of conceptual disagreements about the importance and application of traditional research ethics norms to 'comparative effectiveness research' and modern research environments. Common among these explanations, however, is a failure to appreciate when a research intervention, rather than merely an observation or review of data, is taking place. Review committees and investigators are failing to see, or choosing to ignore, interventions in the lives of research subjects. When these studies have come to light, government agencies with oversight authority have done little or backed down. Prestigious medical journals have published research results knowing that the required consent was not obtained, or they have stood by the published studies even after the inadequacy of consent is discovered. This article critically examines this erosion of consent in theory and practice and calls for restoring the requirement of informed consent to its proper place as a priority in human subjects research.


Assuntos
Pesquisa Biomédica/ética , Teoria Ética , Consentimento Livre e Esclarecido/ética , Projetos de Pesquisa , Valores Sociais , Pesquisa Biomédica/legislação & jurisprudência , Compreensão , Termos de Consentimento , Revelação , Comitês de Ética em Pesquisa , Ética em Pesquisa , Regulamentação Governamental , Humanos , Estudos Observacionais como Assunto , Editoração/ética , Ensaios Clínicos Controlados Aleatórios como Assunto/ética , Pesquisadores , Sujeitos da Pesquisa , Estados Unidos
15.
JAMA ; 322(20): 1966-1976, 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31634905

RESUMO

IMPORTANCE: Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired hypofibrinogenemia (fibrinogen level <1.5-2.0 g/L), for which guidelines recommend fibrinogen replacement with cryoprecipitate or fibrinogen concentrate. The 2 products have important differences, but comparative clinical data are lacking. OBJECTIVE: To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to hypofibrinogenemia after cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018. INTERVENTIONS: Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass. MAIN OUTCOMES AND MEASURES: Primary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, <1.2). RESULTS: Of 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, -∞ to 1.09; P < .001 for noninferiority] [2-sided 95% CI, 0.84 to 1.09; P = .50 for superiority]). Thromboembolic events occurred in 26 patients (7.0%) in the fibrinogen concentrate group and 35 patients (9.6%) in the cryoprecipitate group. CONCLUSIONS AND RELEVANCE: In patients undergoing cardiac surgery who develop clinically significant bleeding and hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired hypofibrinogenemia in cardiac surgery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03037424.

16.
Breast Cancer Res Treat ; 169(3): 537-548, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29455298

RESUMO

PURPOSE: Aromatase inhibitors are the most commonly prescribed adjuvant endocrine therapy for hormone-dependent early breast cancer in postmenopausal women. Among Canadian Cancer Trials Group MA.27 participants, anastrozole and exemestane had comparable 5-year event-free survival. This companion study examined differences in patient-reported treatment-related symptoms (TRS) and health-related quality of life (HRQL) among postmenopausal women randomized to anastrozole or exemestane. METHODS: MA.27 participants (N = 686, of 7576) randomized to 5 years of anastrozole (1 mg/day, n = 371, Arm A) or exemestane (25 mg/day, n = 315, Arm E) completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) questionnaire to assess TRS and HRQL. The FACT-ES was completed at baseline, 3, 6, 12, and 24 months. RESULTS: No significant differences in FACT-ES median scores measuring TRS and HRQL were observed between treatment arms at any time point. Change in TRS from baseline was statistically significant at 3, 6, 12, and 24 months. HRQL was stable over time in both arms. Greater TRS burden was associated with poorer HRQL (coefficient = 0.57, p < 0.001). Twenty percent of patients discontinued AI therapy by month 24 and 32% discontinued AIs at 4 years. In both arms, patients reporting more side effect bother prior to initiating study treatment had a higher risk of discontinuing treatment before completing protocol therapy (hazard ratio [HR] 1.29, 95% CI 1.08-1.55, p = 0.01). CONCLUSIONS: TRS and HRQL were comparable between anastrozole and exemestane. TRS negatively affect HRQL. Women who report being bothered by treatment side effects prior to initiating an AI are at increased risk for early treatment discontinuation.


Assuntos
Neoplasias da Mama/epidemiologia , Adesão à Medicação , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol/administração & dosagem , Anastrozol/efeitos adversos , Anastrozol/uso terapêutico , Androstadienos/administração & dosagem , Androstadienos/efeitos adversos , Androstadienos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Pós-Menopausa , Ensaios Clínicos Controlados Aleatórios como Assunto
17.
J Pharmacol Exp Ther ; 365(3): 700-710, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29592948

RESUMO

T-cell leukemia 1A (TCL1A) single-nucleotide polymorphisms (SNPs) have been associated with aromatase inhibitor-induced musculoskeletal adverse events. We previously demonstrated that TCL1A is inducible by estradiol (E2) and plays a critical role in the regulation of cytokines, chemokines, and Toll-like receptors in a TCL1A SNP genotype and estrogen-dependent fashion. Furthermore, TCLIA SNP-dependent expression phenotypes can be "reversed" by exposure to selective estrogen receptor modulators such as 4-hydroxytamoxifen (4OH-TAM). The present study was designed to comprehensively characterize the role of TCL1A in transcriptional regulation across the genome by performing RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays with lymphoblastoid cell lines. RNA-seq identified 357 genes that were regulated in a TCL1A SNP- and E2-dependent fashion with expression patterns that were 4OH-TAM reversible. ChIP-seq for the same cells identified 57 TCL1A binding sites that could be regulated by E2 in a SNP-dependent fashion. Even more striking, nuclear factor-κB (NF-κB) p65 bound to those same DNA regions. In summary, TCL1A is a novel transcription factor with expression that is regulated in a SNP- and E2-dependent fashion-a pattern of expression that can be reversed by 4OH-TAM. Integrated RNA-seq and ChIP-seq results suggest that TCL1A also acts as a transcriptional coregulator with NF-κB p65, an important immune system transcription factor.


Assuntos
Estrogênios/metabolismo , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Fator de Transcrição RelA/metabolismo , Linhagem Celular , Regulação da Expressão Gênica , Genótipo , Humanos , Elementos de Resposta/genética , Transcrição Gênica
18.
Haematologica ; 103(2): 288-296, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29097500

RESUMO

The objective of this study was to create a bioclinical model, based on clinical and molecular predictors of event-free and overall survival for relapsed/refractory diffuse large B-cell lymphoma patients treated on the Canadian Cancer Trials Group (CCTG) LY12 prospective study. In 91 cases, sufficient histologic material was available to create tissue microarrays and perform immunohistochemistry staining for CD10, BCL6, MUM1/IRF4, FOXP1, LMO2, BCL2, MYC, P53 and phosphoSTAT3 (pySTAT3) expression. Sixty-seven cases had material sufficient for fluorescent in situ hybridization (FISH) for MYC and BCL2 In addition, 97 formalin-fixed, paraffin-embedded tissue samples underwent digital gene expression profiling (GEP) to evaluate BCL2, MYC, P53, and STAT3 expression, and to determine cell-of-origin (COO) using the Lymph2Cx assay. No method of determining COO predicted event-free survival (EFS) or overall survival (OS). Factors independently associated with survival outcomes in multivariate analysis included primary refractory disease, elevated serum lactate dehydrogenase (LDH) at relapse, and MYC or BCL2 protein or gene expression. A bioclinical score using these four factors predicted outcome with 3-year EFS for cases with 0-1 vs 2-4 factors of 55% vs 16% (P<0.0001), respectively, assessing MYC and BCL2 by immunohistochemistry, 46% vs. 5% (P<0.0001) assessing MYC and BCL2 messenger ribonucleic acid (mRNA) by digital gene expression, and 42% vs 21% (P=0.079) assessing MYC and BCL2 by FISH. This proposed bioclinical model should be further studied and validated in other datasets, but may discriminate relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients who could benefit from conventional salvage therapy from others who require novel approaches. The LY12 study; clinicaltrials.gov Identifier: 00078949.


Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Modelos Biológicos , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-myc/análise , Adulto , Idoso , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Terapia de Salvação/métodos , Adulto Jovem
19.
Am J Bioeth ; 23(8): 47-50, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37450521

Assuntos
Médicos , Humanos
20.
Mol Pharmacol ; 92(2): 175-184, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28615284

RESUMO

In a previous genome-wide association study (GWAS) for musculoskeletal adverse events during aromatase inhibitor therapy for breast cancer, we reported that single nucleotide polymorphisms (SNPs) near the TCL1A gene were associated with this adverse drug reaction. Functional genomic studies showed that TCL1A expression was induced by estradiol, but only in cells with the variant sequence for the top GWAS SNP (rs11849538), a SNP that created a functional estrogen response element. In addition, TCL1A genotype influenced the downstream expression of a series of cytokines and chemokines and had a striking effect on nuclear factor κB (NF-κB) transcriptional activity. Furthermore, this SNP-dependent regulation could be reversed by selective ER modulators (SERMs). The present study was designed to pursue mechanisms underlying TCL1A SNP-mediated, estrogen-dependent NF-κB activation. Functional genomic studies were performed using a panel of 300 lymphoblastoid cell lines for which we had generated genome-wide SNP and gene expression data. It is known that toll-like receptors (TLRs) can regulate NF-κB signaling by a process that requires the adaptor protein MYD88. We found that TLR2, TLR7, TLR9, and TLR10 expression, as well as that of MYD88, could be modulated by TCL1A in a SNP and estrogen-dependent fashion and that these effects were reversed in the presence of SERMs. Furthermore, MYD88 inhibition blocked the TCL1A SNP and estrogen-dependent NF-κB activation, as well as protein-protein interaction between TCL1A and MYD88. These observations greatly expand the range of pathways influenced by TCL1A genotype and raise the possibility that this estrogen- and SNP-dependent regulation might be altered pharmacologically by SERMs.


Assuntos
Estrogênios/farmacologia , Mediadores da Inflamação/metabolismo , Glicoproteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas/genética , Receptores de Interleucina-1/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Linhagem Celular Tumoral , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/fisiologia , Inflamação/metabolismo , Polimorfismo de Nucleotídeo Único/genética
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