RESUMO
Mitotic errors can activate cyclic GMP-AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2'3'-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.
Assuntos
Cromatina/fisiologia , Mitose/fisiologia , Nucleotidiltransferases/metabolismo , Linhagem Celular Tumoral , Cromatina/genética , Humanos , Interferon Tipo I/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/genética , Micronúcleo Germinativo/genética , Micronúcleo Germinativo/fisiologia , Mitose/efeitos dos fármacos , Mitose/genética , Neoplasias/metabolismo , Nucleotídeos Cíclicos/metabolismo , Nucleotidiltransferases/genética , Nucleotidiltransferases/fisiologia , Transdução de SinaisRESUMO
BACKGROUND: Unit cohesion may protect service member mental health by mitigating effects of combat exposure; however, questions remain about the origins of potential stress-buffering effects. We examined buffering effects associated with two forms of unit cohesion (peer-oriented horizontal cohesion and subordinate-leader vertical cohesion) defined as either individual-level or aggregated unit-level variables. METHODS: Longitudinal survey data from US Army soldiers who deployed to Afghanistan in 2012 were analyzed using mixed-effects regression. Models evaluated individual- and unit-level interaction effects of combat exposure and cohesion during deployment on symptoms of post-traumatic stress disorder (PTSD), depression, and suicidal ideation reported at 3 months post-deployment (model n's = 6684 to 6826). Given the small effective sample size (k = 89), the significance of unit-level interactions was evaluated at a 90% confidence level. RESULTS: At the individual-level, buffering effects of horizontal cohesion were found for PTSD symptoms [B = -0.11, 95% CI (-0.18 to -0.04), p < 0.01] and depressive symptoms [B = -0.06, 95% CI (-0.10 to -0.01), p < 0.05]; while a buffering effect of vertical cohesion was observed for PTSD symptoms only [B = -0.03, 95% CI (-0.06 to -0.0001), p < 0.05]. At the unit-level, buffering effects of horizontal (but not vertical) cohesion were observed for PTSD symptoms [B = -0.91, 90% CI (-1.70 to -0.11), p = 0.06], depressive symptoms [B = -0.83, 90% CI (-1.24 to -0.41), p < 0.01], and suicidal ideation [B = -0.32, 90% CI (-0.62 to -0.01), p = 0.08]. CONCLUSIONS: Policies and interventions that enhance horizontal cohesion may protect combat-exposed units against post-deployment mental health problems. Efforts to support individual soldiers who report low levels of horizontal or vertical cohesion may also yield mental health benefits.
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Militares , Transtornos de Estresse Pós-Traumáticos , Humanos , Militares/psicologia , Saúde Mental , Campanha Afegã de 2001- , Transtornos de Estresse Pós-Traumáticos/psicologia , Ideação Suicida , Fatores de RiscoRESUMO
BACKGROUND: The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. SUBJECTS, MATERIALS, AND METHODS: Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. RESULTS: E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3-4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. CONCLUSION: At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. IMPLICATIONS FOR PRACTICE: At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.
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Fluoruracila , Neoplasias Retais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/uso terapêutico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/uso terapêutico , Qualidade de Vida , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapiaRESUMO
Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.
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Cloridrato de Bendamustina/uso terapêutico , Dacarbazina/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin , Feminino , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Indução de Remissão , Análise de SobrevidaRESUMO
Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. Perceived wellness associated with practice and competition in National Collegiate Athletic Association Division I football players. J Strength Cond Res 33(1): 112-124, 2019-This study assessed the influence of movement demands resulting from weekly practice sessions and games, on perceived wellness measurements taken postgame (Sunday) and 48 hours pregame (Thursday) throughout the in-season period in National Collegiate Athletic Association (NCAA) Division I football players. Thirty players were monitored using global positioning system receivers (OptimEye S5; Catapult Innovations) during 12 games and 24 in-season practices. Movement variables included low-intensity distance, medium-intensity distance, high-intensity distance, sprint distance, total distance, player load, and acceleration and deceleration distance. Perceived wellness, including fatigue, soreness, sleep quality and quantity, stress, and mood, was examined using a questionnaire on a 1-5 Likert scale. Multilevel mixed linear regressions determined the differential effects of movement metrics on perceived wellness. Post hoc tests were conducted to evaluate the pairwise differentials of movement and significance for wellness ratings. Notable findings included significantly (p ≤ 0.05) less player load, low-intensity distance, medium-intensity distance, high-intensity distance, total distance, and acceleration and deceleration distance at all intensities, in those reporting more favorable (4-5) ratings of perceived fatigue and soreness on Sunday. Conversely, individuals reporting more favorable Sunday-perceived stress ratings demonstrated significantly (p ≤ 0.05) higher player load, low-intensity and medium-intensity distance, total distance, low-intensity and medium-intensity deceleration distance, and acceleration distance at all intensities than individuals reporting less favorable (1-2) perceived stress ratings. Data from this study provide a novel investigation of perceived wellness associated with college football practice and competition. Results support the use of wellness questionnaires for monitoring perceived wellness in NCAA Division I college football players.
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Futebol Americano , Nível de Saúde , Inquéritos e Questionários , Aceleração , Afeto , Desempenho Atlético , Desaceleração , Fadiga , Sistemas de Informação Geográfica , Humanos , Masculino , Modelos Estatísticos , Movimento , Mialgia , Universidades , Adulto JovemRESUMO
Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. A Comparison of preseason and in-season practice and game loads in NCAA Division I football players. J Strength Cond Res 33(4): 1020-1027, 2019-The aim of this study was to quantify the individual practice and game loads throughout the National Collegiate Athletic Association (NCAA) Division I football season to determine whether significant differences exist between the practice loads associated with the preseason training camp and those undertaken during the in-season period. Thirty-one NCAA Division I football players were monitored using the global positioning system and triaxial accelerometer (IA) (MinimaxX S5; Catapult Innovations, Melbourne, Australia) during 22 preseason practices, 36 in-season practices, and 12 competitions. The season was divided into 4 distinct phases for data analysis: preseason week 1 (preseason 1), preseason week 2 (preseason 2), preseason week 3 (preseason 3), and 12 in-season weeks. Individual IA data sets represented players from every offensive and defensive position group Wide Receiver (WR: n = 5), Offensive Line (OL: n = 4), Running Back (RB: n = 4), Quarterback (QB: n = 2), Tight End (TE: n = 3), Defensive Line (DL: n = 4), Linebacker (LB: n = 4), Defensive Back (DB: n = 5). Data were set at the practice level, where an observation for each player's maximum player load (PLMax) or mean player load (PLMean) from each training camp phase was referenced against each player's respective PL from each game, Tuesday, Wednesday, or Thursday practice session. Notable results included significantly (p ≤ 0.05) greater PLMax values attributed to preseason 1 compared with PL resulting from all in-season practices, and significantly (p ≤ 0.05) higher cumulative PL reported for preseason 1, 2, and 3 compared with every in-season week. Data from this study augment our understanding of the practice demands experienced by NCAA Division I college football players, and provide scope for the improvement of preseason practice design and physical conditioning strategies for coaches seeking to optimize performance.
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Futebol Americano/fisiologia , Condicionamento Físico Humano/fisiologia , Esforço Físico , Prática Psicológica , Acelerometria , Adolescente , Sistemas de Informação Geográfica , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Glioblastoma/patologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Sorafenibe/administração & dosagem , Taxa de SobrevidaRESUMO
Microtubule dynamic instability allows search and capture of kinetochores during spindle formation, an important process for accurate chromosome segregation during cell division. Recent work has found that microtubule rotational diffusion about minus-end attachment points contributes to kinetochore capture in fission yeast, but the relative contributions of dynamic instability and rotational diffusion are not well understood. We have developed a biophysical model of kinetochore capture in small fission-yeast nuclei using hybrid Brownian dynamics/kinetic Monte Carlo simulation techniques. With this model, we have studied the importance of dynamic instability and microtubule rotational diffusion for kinetochore capture, both to the lateral surface of a microtubule and at or near its end. Over a range of biologically relevant parameters, microtubule rotational diffusion decreased capture time, but made a relatively small contribution compared to dynamic instability. At most, rotational diffusion reduced capture time by 25%. Our results suggest that while microtubule rotational diffusion can speed up kinetochore capture, it is unlikely to be the dominant physical mechanism for typical conditions in fission yeast. In addition, we found that when microtubules undergo dynamic instability, lateral captures predominate even in the absence of rotational diffusion. Counterintuitively, adding rotational diffusion to a dynamic microtubule increases the probability of end-on capture.
Assuntos
Cinetocoros/metabolismo , Microtúbulos/metabolismo , Modelos Biológicos , Rotação , Difusão , Cinética , Método de Monte Carlo , Schizosaccharomyces/citologiaRESUMO
The aims of this study were to examine the movement demands of preseason practice in National Collegiate Athletic Association Division I college football players using portable global positioning system (GPS) technology and to assess perceived wellness associated with preseason practice to determine whether GPS-derived variables from the preceding day influence perceived wellness the following day. Twenty-nine players were monitored using GPS receivers (Catapult Innovations, Melbourne, Australia) during 20 preseason practices. Individual observations (n = 550) were divided into offensive and defensive position groups. Movement variables including low-, medium-, high-intensity, and sprint distance, player load, and acceleration and deceleration distance were assessed. Perceived wellness ratings (n = 469) were examined using a questionnaire which assessed fatigue, soreness, sleep quality, sleep quantity, stress, and mood. A 1-way analysis of variance for positional movement demands and multilevel regressions for wellness measures were used, followed by post hoc testing to evaluate the relational significance between categorical outcomes of perceived wellness scores and movement variables. Results demonstrated significantly (p ≤ 0.05) greater total, high-intensity, and sprint distance, along with greater acceleration and deceleration distances for the defensive back and wide receiver position groups compared with their respective offensive and defensive counterparts. Significant (p ≤ 0.05) differences in movement variables were demonstrated for individuals who responded more or less favorably on each of the 6 factors of perceived wellness. Data from this study provide novel quantification of the position-specific physical demands and perceived wellness associated with college football preseason practice. Results support the use of position-specific training and individual monitoring of college football players.
Assuntos
Futebol Americano/fisiologia , Futebol Americano/psicologia , Percepção , Corrida/fisiologia , Corrida/psicologia , Aceleração , Adolescente , Afeto , Austrália , Fadiga/epidemiologia , Sistemas de Informação Geográfica , Humanos , Masculino , Sono , Estresse Psicológico/epidemiologia , Universidades , Adulto JovemRESUMO
PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) occurs in as high as 70% of patients receiving certain types of chemotherapy agents. The FDA has yet to approve a therapy for CIPN. The aim of this multicenter, phase III, randomized, double-blind, placebo-controlled trial was to investigate the efficacy of 2% ketamine plus 4% amitriptyline (KA) cream for reducing CIPN. METHODS: Cancer survivors who completed chemotherapy at least 1 month prior and had CIPN (>4 out of 10) were enrolled (N=462). CIPN was assessed using average scores from a 7-day daily diary that asks patients to rate the average "pain, numbness, or tingling in [their] hands and feet over the past 24 h" on an 11-point numeric rating scale at baseline and 6 weeks post intervention. ANCOVA was used to measure differences in 6-week CIPN with effects including baseline CIPN, KA treatment arm, and previous taxane therapy (Y/N). RESULTS: The KA treatment showed no effect on 6-week CIPN scores (adjusted mean difference=-0.17, p=0.363). CONCLUSIONS: This study suggests that KA cream does not decrease CIPN symptoms in cancer survivors.
Assuntos
Amitriptilina/administração & dosagem , Antineoplásicos/efeitos adversos , Ketamina/administração & dosagem , Neoplasias/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Tópica , Adulto , Idoso , Amitriptilina/efeitos adversos , Antineoplásicos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Síndromes Neurotóxicas/etiologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Estados UnidosRESUMO
IMPORTANCE: Uveal melanoma is characterized by mutations in GNAQ and GNA11, resulting in mitogen-activated protein kinase pathway activation. OBJECTIVE: To assess the efficacy of selumetinib, a selective, non-adenosine triphosphate competitive inhibitor of MEK1 and MEK2, in uveal melanoma. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, phase 2 clinical trial comparing selumetinib vs chemotherapy conducted from August 2010 through December 2013 among 120 patients with metastatic uveal melanoma at 15 academic oncology centers in the United States and Canada. INTERVENTIONS: One hundred one patients were randomized in a 1:1 ratio to receive selumetinib, 75 mg orally twice daily on a continual basis (n = 50), or chemotherapy (temozolomide, 150 mg/m2 orally daily for 5 of every 28 days, or dacarbazine, 1000 mg/m2 intravenously every 21 days [investigator choice]; n = 51) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After primary outcome analysis, 19 patients were registered and 18 treated with selumetinib without randomization to complete the planned 120-patient enrollment. Patients in the chemotherapy group could receive selumetinib at the time of radiographic progression. MAIN OUTCOMES AND MEASURES: Progression-free survival, the primary end point, was assessed as of April 22, 2013. Additional end points, including overall survival, response rate, and safety/toxicity, were assessed as of December 31, 2013. RESULTS: Median progression-free survival among patients randomized to chemotherapy was 7 weeks (95% CI, 4.3-8.4 weeks; median treatment duration, 8 weeks; interquartile range [IQR], 4.3-16 weeks) and among those randomized to selumetinib was 15.9 weeks (95% CI, 8.4-21.1 weeks; median treatment duration, 16.1 weeks; IQR, 8.1-25.3 weeks) (hazard ratio, 0.46; 95% CI, 0.30-0.71; P < .001). Median overall survival time was 9.1 months (95% CI, 6.1-11.1 months) with chemotherapy and 11.8 months (95% CI, 9.8-15.7 months) with selumetinib (hazard ratio, 0.66; 95% CI, 0.41-1.06; P = .09). No objective responses were observed with chemotherapy. Forty-nine percent of patients treated with selumetinib achieved tumor regression, with 14% achieving an objective radiographic response to therapy. Treatment-related adverse events were observed in 97% of patients treated with selumetinib, with 37% requiring at least 1 dose reduction. CONCLUSIONS AND RELEVANCE: In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival and response rate; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01143402.
Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Benzimidazóis/uso terapêutico , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Melanoma/tratamento farmacológico , Neoplasias Uveais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/efeitos adversos , Benzimidazóis/efeitos adversos , Dacarbazina/efeitos adversos , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Temozolomida , Resultado do TratamentoRESUMO
Despite the prevalence of research on the consequences of collective turnover (TO), we lack an understanding of how, when, and why changes in the external environment influence collective turnover. The present study extends context emergent turnover and threat-rigidity theories to consider temporal changes in rates of collective turnover brought on by an external disruption. We also conduct variance decomposition to evaluate the relative influence of internal and external factors on collective turnover and examine how changes in the external environment impact relative influences. Finally, we examine the role of collective engagement in explaining patterns of collective turnover over time. Our study is based on a large, geographically dispersed U.S. firm. Findings from a two-phase longitudinal model reveal that rates of collective turnover change over time in ways that are predictable from threat-rigidity theory. Variance decomposition analysis finds that internal store-level factors explain substantially more variance than external factors, but the balance changes in response to an external disruption. We also show that collective engagement can mitigate increases in collective turnover. Results inform theory regarding the relative importance of internal versus external factors in influencing collective turnover and provide a framework for predicting how contextual change in the external environment impacts collective turnover over time. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
RESUMO
PURPOSE: Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. PATIENTS AND METHODS: Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). RESULTS: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. CONCLUSIONS: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.
Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Anastrozol/uso terapêutico , Anastrozol/efeitos adversos , Anastrozol/administração & dosagem , Estudos de Coortes , Pós-Menopausa , Idoso de 80 Anos ou mais , Medidas de Resultados Relatados pelo Paciente , Aromatase/genéticaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.
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Neoplasias da Mama , Taxoides , Humanos , Feminino , Taxoides/uso terapêutico , Seguimentos , Neoplasias da Mama/tratamento farmacológico , Antraciclinas , Hormônios , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) are rational targets for therapy in hepatocellular cancer (HCC). METHODS: Patients with histologically proven HCC and not amenable to curative or liver directed therapy were included in this 2-stage phase 2 trial. Eligibility included an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 and Child's Pugh score of A or B, and 1 prior systemic therapy. Patients received erlotinib 150 mg daily and bevacizumab 10 mg/kg on days 1 and 15 every 28 days. Objective tumor response was the primary end point. RESULTS: Twenty-seven patients with advanced HCC (median age, 60 years) were enrolled in this multi-institutional study. The proportion of patients with Child's A classification was 74%. One patient had a confirmed partial response and 11 (48%) achieved stable disease. Median time to disease progression was 3.0 months (95% confidence interval [CI], 1.8-7.1). Median survival time was 9.5 months (95% CI, 7.1-17.1). Grade 3 toxicities included rash, hypertension, fatigue, and diarrhea. CONCLUSIONS: In this trial, erlotinib combined with bevacizumab had minimal activity in patients with advanced HCC based on objective response and progression-free survival. The role of targeting EGFR and VEGF in HCC needs further evaluation in molecularly selected patients.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Cloridrato de Erlotinib , Feminino , Humanos , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
PURPOSE: Despite the widespread use of antiemetics, nausea continues to be reported by over 70% of patients receiving chemotherapy. METHODS: In this double blind, multicenter trial, we randomly assigned 744 cancer patients to four arms: 1) placebo, 2) 0.5 g ginger, 3) 1.0 g ginger, or 4) 1.5 g ginger. Nausea occurrence and severity were assessed at a baseline cycle and the two following cycles during which patients were taking their assigned study medication. All patients received a 5-HT(3) receptor antagonist antiemetic on Day 1 of all cycles. Patients took three capsules of ginger (250 mg) or placebo twice daily for 6 days starting 3 days before the first day of chemotherapy. Patients reported the severity of nausea on a 7-point rating scale ("1" = "Not at all Nauseated" and "7" = "Extremely Nauseated") for Days 1-4 of each cycle. The primary outcomes were to determine the dose and efficacy of ginger at reducing the severity of chemotherapy-induced nausea on Day 1 of chemotherapy. RESULTS: A total of 576 patients were included in final analysis (91% female, mean age = 53). Mixed model analyses demonstrated that all doses of ginger significantly reduced acute nausea severity compared to placebo on Day 1 of chemotherapy (p = 0.003). The largest reduction in nausea intensity occurred with 0.5 g and 1.0 g of ginger (p = 0.017 and p = 0.036, respectively). Anticipatory nausea was a key factor in acute chemotherapy-induced nausea (p < 0.0001). CONCLUSIONS: Ginger supplementation at a daily dose of 0.5 g-1.0 g significantly aids in reduction of the severity of acute chemotherapy-induced nausea in adult cancer patients.
Assuntos
Antieméticos/uso terapêutico , Náusea/prevenção & controle , Fitoterapia , Vômito/prevenção & controle , Zingiber officinale/química , Antieméticos/administração & dosagem , Antieméticos/isolamento & purificação , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/tratamento farmacológico , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Índice de Gravidade de Doença , Resultado do Tratamento , Vômito/induzido quimicamente , Vômito Precoce/prevenção & controleRESUMO
BACKGROUND: Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. METHODS: This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. FINDINGS: 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35-68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response (r=-0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. INTERPRETATION: Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. FUNDING: National Cancer Institute, supported in part by NCI CA15083 and CM62205.
Assuntos
Antineoplásicos/uso terapêutico , Diferenciação Celular , Radioisótopos do Iodo/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Compostos Radiofarmacêuticos/uso terapêutico , Sulfonamidas/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Indazóis , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Radiografia , Sulfonamidas/efeitos adversos , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/mortalidade , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/secundário , Fatores de Tempo , Falha de Tratamento , Estados Unidos , Adulto JovemRESUMO
Images from social media can reflect diverse viewpoints, heated arguments, and expressions of creativity, adding new complexity to retrieval tasks. Researchers working on Content-Based Image Retrieval (CBIR) have traditionally tuned their algorithms to match filtered results with user search intent. However, we are now bombarded with composite images of unknown origin, authenticity, and even meaning. With such uncertainty, users may not have an initial idea of what the search query results should look like. For instance, hidden people, spliced objects, and subtly altered scenes can be difficult for a user to detect initially in a meme image, but may contribute significantly to its composition. It is pertinent to design systems that retrieve images with these nuanced relationships in addition to providing more traditional results, such as duplicates and near-duplicates - and to do so with enough efficiency at large scale. We propose a new approach for spatial verification that aims at modeling object-level regions using image keypoints retrieved from an image index, which is then used to accurately weight small contributing objects within the results, without the need for costly object detection steps. We call this method the Objects in Scene to Objects in Scene (OS2OS) score, and it is optimized for fast matrix operations, which can run quickly on either CPUs or GPUs. It performs comparably to state-of-the-art methods on classic CBIR problems (Oxford 5K, Paris 6K, and Google-Landmarks), and outperforms them in emerging retrieval tasks such as image composite matching in the NIST MFC2018 dataset and meme-style imagery from Reddit.
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Purpose: GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected ras-mutated pancreas cancer. Methods: Subjects (n = 176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer. Immune responses were measured by interferon-γ (IFNγ) ELISpot assay and by regulatory T cell (Treg) frequencies on treatment. Pretreatment plasma was retrospectively analyzed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry for proteomic signatures predictive of GI-4000 responsiveness. Results: GI-4000 was well tolerated, with comparable safety findings between treatment groups. The GI-4000 group showed a similar pattern of median recurrence-free and overall survival (OS) compared with placebo. For the prospectively defined and stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs. 56%), an improvement in OS (523.5 vs. 443.5 days [hazard ratio (HR) = 1.06 [confidence interval (CI): 0.53-2.13], p = 0.872), and increased frequency of immune responders (40% vs. 8%; p = 0.062) for GI-4000 versus placebo and a 159-day improvement in OS for R1 GI-4000 immune responders versus placebo (p = 0.810). For R0 resection subjects, no increases in IFNγ responses in GI-4000-treated subjects were observed. A higher frequency of R0/R1 subjects with a reduction in Tregs (CD4+/CD45RA+/Foxp3low) was observed in GI-4000-treated subjects versus placebo (p = 0.033). A proteomic signature was identified that predicted response to GI-4000/gemcitabine regardless of resection status. Conclusion: These results justify continued investigation of GI-4000 in studies stratified for likely responders or in combination with immune check-point inhibitors or other immunomodulators, which may provide optimal reactivation of antitumor immunity. ClinicalTrials.gov Number: NCT00300950.
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The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.