RESUMEN
Traumatic brain injury (TBI) in military populations can cause disruptions in brain structure and function, along with cognitive and psychological dysfunction. Diffusion magnetic resonance imaging (dMRI) can detect alterations in white matter (WM) microstructure, but few studies have examined brain asymmetry. Examining asymmetry in large samples may increase sensitivity to detect heterogeneous areas of WM alteration in mild TBI. Through the Enhancing Neuroimaging Genetics Through Meta-Analysis Military-Relevant Brain Injury working group, we conducted a mega-analysis of neuroimaging and clinical data from 16 cohorts of Active Duty Service Members and Veterans (n = 2598). dMRI data were processed together along with harmonized demographic, injury, psychiatric, and cognitive measures. Fractional anisotropy in the cingulum showed greater asymmetry in individuals with deployment-related TBI, driven by greater left lateralization in TBI. Results remained significant after accounting for potentially confounding variables including posttraumatic stress disorder, depression, and handedness, and were driven primarily by individuals whose worst TBI occurred before age 40. Alterations in the cingulum were also associated with slower processing speed and poorer set shifting. The results indicate an enhancement of the natural left laterality of the cingulum, possibly due to vulnerability of the nondominant hemisphere or compensatory mechanisms in the dominant hemisphere. The cingulum is one of the last WM tracts to mature, reaching peak FA around 42 years old. This effect was primarily detected in individuals whose worst injury occurred before age 40, suggesting that the protracted development of the cingulum may lead to increased vulnerability to insults, such as TBI.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Sustancia Blanca , Humanos , Adulto , Sustancia Blanca/patología , Pruebas Neuropsicológicas , Lesiones Encefálicas/patología , Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/diagnóstico por imagen , Lesiones Traumáticas del Encéfalo/patología , EncéfaloRESUMEN
BACKGROUND: Data are limited regarding the use of poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors, such as veliparib, in combination with chemotherapy followed by maintenance as initial treatment in patients with high-grade serous ovarian carcinoma. METHODS: In an international, phase 3, placebo-controlled trial, we assessed the efficacy of veliparib added to first-line induction chemotherapy with carboplatin and paclitaxel and continued as maintenance monotherapy in patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. Patients were randomly assigned in a 1:1:1 ratio to receive chemotherapy plus placebo followed by placebo maintenance (control), chemotherapy plus veliparib followed by placebo maintenance (veliparib combination only), or chemotherapy plus veliparib followed by veliparib maintenance (veliparib throughout). Cytoreductive surgery could be performed before initiation or after 3 cycles of trial treatment. Combination chemotherapy was 6 cycles, and maintenance therapy was 30 additional cycles. The primary end point was investigator-assessed progression-free survival in the veliparib-throughout group as compared with the control group, analyzed sequentially in the BRCA-mutation cohort, the cohort with homologous-recombination deficiency (HRD) (which included the BRCA-mutation cohort), and the intention-to-treat population. RESULTS: A total of 1140 patients underwent randomization. In the BRCA-mutation cohort, the median progression-free survival was 34.7 months in the veliparib-throughout group and 22.0 months in the control group (hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.28 to 0.68; P<0.001); in the HRD cohort, it was 31.9 months and 20.5 months, respectively (hazard ratio, 0.57; 95 CI, 0.43 to 0.76; P<0.001); and in the intention-to-treat population, it was 23.5 months and 17.3 months (hazard ratio, 0.68; 95% CI, 0.56 to 0.83; P<0.001). Veliparib led to a higher incidence of anemia and thrombocytopenia when combined with chemotherapy as well as of nausea and fatigue overall. CONCLUSIONS: Across all trial populations, a regimen of carboplatin, paclitaxel, and veliparib induction therapy followed by veliparib maintenance therapy led to significantly longer progression-free survival than carboplatin plus paclitaxel induction therapy alone. The independent value of adding veliparib during induction therapy without veliparib maintenance was less clear. (Funded by AbbVie; VELIA/GOG-3005 ClinicalTrials.gov number, NCT02470585.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Carboplatino/administración & dosificación , Terapia Combinada , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirugía , Método Doble Ciego , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Análisis de Intención de Tratar , Quimioterapia de Mantención , Persona de Mediana Edad , Mutación , Neoplasias Ováricas/genética , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Calidad de VidaRESUMEN
Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (ß = -0.633), executive functioning (ß = -0.566), and global fractional anisotropy (ß = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.
Asunto(s)
Apolipoproteína E4 , Proteína C-Reactiva , Cognición , Sustancia Blanca , Apolipoproteína E4/genética , Apolipoproteínas E , Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora , Humanos , Pruebas Neuropsicológicas , Veteranos , Sustancia Blanca/diagnóstico por imagenRESUMEN
OBJECTIVE: In the phase 3 VELIA/GOG-3005 trial, veliparib added to carboplatin-paclitaxel and continued as maintenance improved progression-free survival (PFS) compared to carboplatin-paclitaxel alone in patients with newly diagnosed ovarian carcinoma. Primary analysis of PFS was by investigator (INV) assessment, with a supplemental analysis of PFS by blinded independent central review (BICR). METHODS: Patients received veliparib or placebo with carboplatin-paclitaxel (6â¯cycles) and as maintenance (30 additional cycles). The primary analysis compared PFS in the veliparib-throughout arm to the carboplatin-paclitaxel only arm in the BRCA mutation (BRCAm), homologous recombination deficiency (HRD), and intention-to-treat (ITT) populations. Exploratory analyses of PFS in BRCA wildtype (BRCAwt), homologous recombination proficient (HRP), and HRDâ¯+â¯BRCAwt populations were also performed. PFS per BICR and overall concordance rates between INV and BICR assessments were analyzed. RESULTS: Hazard ratios for PFS by INV and BICR were consistent in each of the primary analysis and exploratory populations. In the ITT population, median PFS per INV was 23.5â¯months in the veliparib-throughout arm versus 17.3â¯months in the control arm (hazard ratio [HR] 0.683, 95% confidence interval [CI] 0.562-0.831; Pâ¯<â¯0.001). Median PFS by BICR was 29.3â¯months versus 19.2â¯months (HR 0.687, 95% CI 0.504-0.806). In the ITT population, the overall concordance rates between INV and BICR were 78% and 75% for the veliparib-throughout and control arms, respectively. CONCLUSIONS: Hazard ratios for PFS per BICR and per INV were consistent, with no suggestion of investigator bias. These findings support the reliability of PFS by INV in ovarian cancer trials.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencimidazoles/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Carboplatino/uso terapéutico , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/mortalidad , Interpretación Estadística de Datos , Femenino , Humanos , Clasificación del Tumor , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/mortalidad , Paclitaxel/uso terapéutico , Supervivencia sin Progresión , Reproducibilidad de los Resultados , Proyectos de Investigación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Análisis de SupervivenciaRESUMEN
OBJECTIVES: Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury's long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer's disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. METHODS: To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. RESULTS: As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. CONCLUSIONS: These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.
Asunto(s)
Apolipoproteína E4 , Cognición , Explosiones , Personal Militar , Veteranos , Apolipoproteína E4/genética , Genotipo , Humanos , Pruebas NeuropsicológicasRESUMEN
Hyaluronic acid (HA) intra-articular injections are increasingly used for the treatment of knee osteoarthritis. Described adverse reactions of HA intra-articular injections include injection site pain or swelling. A 71-year-old man and a 65-year-old woman independently presented with photodistributed lesions shortly after receiving a repeat HA injection (hylan G-F 20) intra-articularly. A punch biopsy was performed which was consistent with a photodrug reaction or hypersensitivity reaction. Two cases are presented to describe a novel presentation of a photosensitivity reaction to HA.
Asunto(s)
Dermatitis Fototóxica , Osteoartritis de la Rodilla , Trastornos por Fotosensibilidad , Anciano , Femenino , Humanos , Ácido Hialurónico/efectos adversos , Ácido Hialurónico/análogos & derivados , Inyecciones Intraarticulares/efectos adversos , Masculino , Osteoartritis de la Rodilla/tratamiento farmacológicoRESUMEN
BACKGROUND: Addressing risk factors of delayed melanoma detection minimizes disparities in outcome. OBJECTIVE: To elucidate the significance of marital status in melanoma outcomes across anatomic sites. METHODS: Retrospective cohort study of 73,558 patients from the Surveillance, Epidemiology, and End Results (SEER) program and 2992 patients at Johns Hopkins University. Patients were stratified by marital status, anatomic site, age, and sex. Endpoints were prevalence of advanced melanoma (stages III or IV) and survival. RESULTS: In the SEER cohort, single patients were more likely than married patients to present in stages III or IV among both men (prevalence ratio [PR], 1.45; 95% confidence interval [CI], 1.37-1.53) and women (PR, 1.28; 95% confidence interval, 1.18-1.39). This trend was consistent across all anatomic sites and in all age groups, particularly in those 18 to 68 years old. Overall and cancer-specific survival times were shorter in unmarried patients. Similarly, at Johns Hopkins, single patients had increased prevalence of advanced melanoma (PR, 1.54; 95% CI, 1.21-1.94) and experienced shorter overall survival (hazard ratio, 1.51; 95% CI, 1.15-1.99). LIMITATIONS: The anatomic sites were not very specific, and this was a retrospective study. CONCLUSIONS: Unmarried patients, especially men and those younger than 68 years, are diagnosed at more advanced stages, even in readily visible sites such as the face. They also experience worse survival independent of stage.
Asunto(s)
Estado Civil/estadística & datos numéricos , Melanoma/epidemiología , Melanoma/patología , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Diagnóstico Tardío , Femenino , Humanos , Masculino , Melanoma/diagnóstico , Persona de Mediana Edad , Estadificación de Neoplasias , Prevalencia , Estudios Retrospectivos , Programa de VERF , Factores Sexuales , Neoplasias Cutáneas/diagnóstico , Tasa de Supervivencia , Centros de Atención Terciaria , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: Metastatic colorectal cancer (mCRC) has low survival rates. We assessed if addition of veliparib, concurrent to FOLFIRI, improves survival in patients with previously untreated mCRC. METHODS: This study compared veliparib (200 mg BID for 7 days of each 14-day cycle) to placebo, each with FOLFIRI. Bevacizumab was allowed in both arms. The primary endpoint was progression-free survival (PFS). RESULTS: Patients were randomised to receive veliparib (n = 65) or placebo (n = 65) in combination with FOLFIRI. Median PFS was 12 vs 11 months (veliparib vs placebo) [HR = 0.94 (95% CI: 0.60, 1.48)]. Median OS was 25 vs 27 months [HR = 1.26 (95% CI: 0.74, 2.16)]. Response rate was 57% vs 62%. Median DOR was 11 vs 9 months [HR = 0.73 (95% CI: 0.38, 1.40)]. AEs with significantly higher frequency (p < 0.05) in the veliparib group were anaemia (39% vs 19%, p = 0.019) and neutropenia (66% vs 37%, p = 0.001) for common AEs (≥20%); neutropenia (59% vs 22%, p < 0.001) for common Grade 3/4 AEs (≥5%); none in serious AEs. Haematopoietic cytopenias were more common with veliparib (79% vs 52%, p = 0.003). Fourteen percent of patients on veliparib and 15% on placebo discontinued treatment due to AEs. CONCLUSION: Veliparib added to FOLFIRI ± bevacizumab demonstrated similar efficacy as FOLFIRI ± bevacizumab in frontline mCRC patients. No unexpected safety concerns occurred.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bencimidazoles/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencimidazoles/efectos adversos , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Neoplasias Colorrectales/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Supervivencia sin ProgresiónRESUMEN
The original version of this article contained an error in Figure 1a. The number of patients at risk listed in the Veliparib arm of Figure 1a should have read "65" instead of "35".An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
BACKGROUND: Longevity gene klotho (KL) is associated with age-related phenotypes but has not been evaluated against a direct human biomarker of cellular aging. We examined KL and psychiatric stress, including posttraumatic stress disorder (PTSD), which is thought to potentiate accelerated aging, in association with biomarkers of cellular aging. METHODS: The sample comprised 309 white, non-Hispanic genotyped veterans with measures of epigenetic age (DNA methylation age), telomere length (nâ¯=â¯252), inflammation (C-reactive protein), psychiatric symptoms, metabolic function, and white matter neural integrity (diffusion tensor imaging; nâ¯=â¯185). Genotyping and DNA methylation were obtained on epi/genome-wide beadchips. RESULTS: In gene by environment analyses, two KL variants (rs9315202 and rs9563121) interacted with PTSD severity (peak corrected pâ¯=â¯0.044) and sleep disturbance (peak corrected pâ¯=â¯0.034) to predict advanced epigenetic age. KL variant, rs398655, interacted with self-reported pain in association with slowed epigenetic age (corrected pâ¯=â¯0.048). A well-studied protective variant, rs9527025, was associated with slowed epigenetic age (pâ¯=â¯0.046). The peak PTSD interaction term (with rs9315202) also predicted C-reactive protein (pâ¯=â¯0.049), and white matter microstructural integrity in two tracts (corrected psâ¯=â¯0.005 - 0.035). This SNP evidenced a main effect with an index of metabolic syndrome severity (pâ¯=â¯0.015). Effects were generally accentuated in older subjects. CONCLUSIONS: Rs9315202 predicted multiple biomarkers of cellular aging such that psychiatric stress was more strongly associated with cellular aging in those with the minor allele. KL genotype may contribute to a synchronized pathological aging response to stress and could be a therapeutic target to alter the pace of cellular aging.
Asunto(s)
Senescencia Celular/genética , Glucuronidasa/genética , Estrés Psicológico/metabolismo , Adulto , Envejecimiento/genética , Envejecimiento/metabolismo , Alelos , Encéfalo/metabolismo , Proteína C-Reactiva/análisis , Senescencia Celular/fisiología , Metilación de ADN/genética , Imagen de Difusión Tensora/métodos , Epigénesis Genética/genética , Femenino , Genotipo , Glucuronidasa/metabolismo , Humanos , Proteínas Klotho , Longevidad/genética , Longevidad/fisiología , Masculino , Trastornos por Estrés Postraumático/metabolismo , Estrés Psicológico/genética , Homeostasis del Telómero/genética , Homeostasis del Telómero/fisiología , Veteranos , Sustancia Blanca/metabolismoRESUMEN
OBJECTIVES: Mild traumatic brain injury (mTBI) is a major public health concern that has generated considerable scientific interest as a complex brain disorder that is associated with long-term neural consequences. This article reviews the literature on cerebrovascular dysfunction in chronic mTBI, with a focus on the long-term neural implications of such dysfunction. METHODS AND RESULTS: Evidence is presented from human neuroimaging studies to support cerebrovascular involvement in long-term mTBI pathology. In addition, a pathway between mTBI and neurodegeneration via cerebrovascular dysfunction is explored. CONCLUSIONS: Future work focused on identifying the neurobiological mechanisms underlying the neural consequences of mTBI will be important to guide therapeutic interventions and long-term care for patients with mTBI.
Asunto(s)
Conmoción Encefálica/complicaciones , Trastornos Cerebrovasculares/etiología , Enfermedades Neurodegenerativas/etiología , Enfermedad Crónica , HumanosRESUMEN
BACKGROUND: Although several randomised trials in patients with triple-negative breast cancer have shown that the addition of carboplatin, with or without poly(ADP-ribose) polymerase (PARP) inhibitors, to neoadjuvant chemotherapy increases the likelihood of achieving a pathological complete response, the use of these therapies in this setting has remained controversial. The BrighTNess trial was designed to assess the addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled trial (BrighTNess) across 145 sites in 15 countries. Patients aged 18 years and older with previously untreated histologically or cytologically confirmed clinical stage II-III triple-negative breast cancer, who were candidates for potentially curative surgery and had an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned (2:1:1) by an interactive response technology system via permuted blocks (block size of four) within strata to receive one of three segment 1 regimens: paclitaxel (80 mg/m2 intravenously weekly for 12 doses) plus carboplatin (area under the curve 6 mg/mL per min, intravenously every 3 weeks, for four cycles) plus veliparib (50 mg orally, twice a day); paclitaxel plus carboplatin plus veliparib placebo (twice a day); or paclitaxel plus carboplatin placebo (every 3 weeks for four cycles) plus veliparib placebo. Following segment 1, all patients were assigned to segment 2 in which they received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. Randomisation for segment 1 was stratified by germline BRCA mutation status, nodal stage, and planned schedule of doxorubicin and cyclophosphamide administration. The primary endpoint was pathological complete response in breast and lymph nodes as determined by site pathologists following completion of neoadjuvant therapy. Efficacy analyses were done by intention to treat and safety analyses included all patients who received at least one dose of study treatment. These are the first results of an ongoing clinical trial; the data cutoff for the analyses presented was Dec 8, 2016. This study is registered with ClinicalTrials.gov, number NCT02032277. FINDINGS: Between April 4, 2014, and March 18, 2016, 634 patients were randomly assigned: 316 to paclitaxel plus carboplatin plus veliparib, 160 to paclitaxel plus carboplatin, and 158 to paclitaxel alone. The proportion of patients who achieved a pathological complete response was higher in the paclitaxel, carboplatin, and veliparib group than in patients receiving paclitaxel alone (168 [53%] of 316 patients vs 49 [31%] of 158, p<0·0001), but not compared with patients receiving paclitaxel plus carboplatin (92 [58%] of 160 patients, p=0·36). Grade 3 or 4 toxicities, and serious adverse events were more common in patients receiving carboplatin, whereas veliparib did not substantially increase toxicity. The most common grade 3 or 4 events overall were neutropenia (352 [56%] of 628 patients), anaemia (180 [29%]), and thrombocytopenia (75 [12%]) through complete treatment, and febrile neutropenia (88 [15%] of 601 patients) during segment 2. The most common serious adverse events were febrile neutropenia (80 [13%] of 628 patients) and anaemia (20 [3%]). INTERPRETATION: Although the addition of veliparib and carboplatin to paclitaxel followed by doxorubicin and cyclophosphamide improved the proportion of patients with triple-negative breast cancer who achieved a pathological complete response, the addition of veliparib to carboplatin and paclitaxel did not. Increased toxicities with the addition of carboplatin (with or without veliparib) to paclitaxel were manageable and did not substantially affect treatment delivery of paclitaxel followed by doxorubicin and cyclophosphamide. Given the consistent results with previous studies, the addition of carboplatin appears to have a favourable risk to benefit profile and might be considered as a potential component of neoadjuvant chemotherapy for patients with high-risk, triple-negative breast cancer. FUNDING: AbbVie.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anemia/inducido químicamente , Bencimidazoles/administración & dosificación , Bencimidazoles/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Quimioterapia Adyuvante , Neutropenia Febril Inducida por Quimioterapia/etiología , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Método Doble Ciego , Doxorrubicina/administración & dosificación , Femenino , Genes BRCA1 , Genes BRCA2 , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática , Mastectomía , Persona de Mediana Edad , Mutación , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Tasa de Supervivencia , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/cirugía , Carga Tumoral/efectos de los fármacosRESUMEN
OBJECTIVE: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies. METHODS: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated. RESULTS: Seventy-five patients were enrolled (ovarian cancer, n=54; breast cancer, n=12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs; ≥60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (≥40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250mg with carboplatin AUC 4 plus gemcitabine 800mg/m2. Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310mg BID) for >34cycles. CONCLUSIONS: Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. Trial registration ID: NCT01063816.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Área Bajo la Curva , Teorema de Bayes , Bencimidazoles/administración & dosificación , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carboplatino/administración & dosificación , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Transicionales/tratamiento farmacológico , Colangiocarcinoma/tratamiento farmacológico , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Neoplasias de la Vesícula Biliar/tratamiento farmacológico , Genes BRCA1 , Genes BRCA2 , Mutación de Línea Germinal , Humanos , Quimioterapia de Inducción , Neoplasias Renales/tratamiento farmacológico , Pelvis Renal , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quimioterapia de Mantención , Masculino , Dosis Máxima Tolerada , Mesotelioma/tratamiento farmacológico , Persona de Mediana Edad , Náusea/inducido químicamente , Metástasis de la Neoplasia , Neutropenia/inducido químicamente , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , GemcitabinaRESUMEN
OBJECTIVES: Research on the cognitive sequelae of mild traumatic brain injury (mTBI) suggests that, despite generally rapid recovery, difficulties may persist in the domain of cognitive control. The goal of this study was to examine whether individuals with chronic blast-related mTBI show behavioral or neural alterations associated with cognitive control. METHODS: We collected event-related functional magnetic resonance imaging (fMRI) data during a flanker task in 17 individuals with blast-related mTBI and 16 individuals with blast-exposure without TBI (control). RESULTS: Groups did not significantly differ in behavioral measures of cognitive control. Relative to the control group, the mTBI group showed greater deactivation of regions associated with the default mode network during the processing of errors. Additionally, error processing in the mTBI group was associated with enhanced negative coupling between the default mode network and the dorsal anterior cingulate cortex as well as the dorsolateral prefrontal cortex, regions of the salience and central executive networks that are associated with cognitive control. CONCLUSIONS: These results suggest that deactivation of default mode network regions and associated enhancements of connectivity with cognitive control regions may act as a compensatory mechanism for successful cognitive control task performance in mTBI. (JINS, 2018, 24, 662-672).
Asunto(s)
Traumatismos por Explosión/fisiopatología , Conmoción Encefálica/fisiopatología , Corteza Cerebral/fisiopatología , Disfunción Cognitiva/fisiopatología , Conectoma , Función Ejecutiva/fisiología , Red Nerviosa/fisiopatología , Veteranos , Adulto , Traumatismos por Explosión/complicaciones , Traumatismos por Explosión/diagnóstico por imagen , Conmoción Encefálica/complicaciones , Conmoción Encefálica/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Femenino , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Red Nerviosa/diagnóstico por imagen , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatologíaRESUMEN
BACKGROUND: To examine shared genetic and environmental risk factors across PTSD symptoms and resilience. METHODS: Classical twin study of 2010-2012 survey data conducted among 3,318 male twin pairs in the Vietnam Era Twin Registry. Analyses included: (a) estimates of genetic and environmental influences on PTSD symptom severity (as measured by the PTSD Checklist) and resilience (assessed with the Connor-Davidson Resilience Scale-10); (b) development of a latent model of traumatic stress, spanning both PTSD and resilience; and (c) estimates of genetic and environmental influences on this spectrum. RESULTS: The heritability of PTSD was 49% and of resilience was 25%. PTSD and resilience were correlated at r = -.59, and 59% of this correlation was attributable to a single genetic factor, whereas the remainder was due to a single non-shared environment factor. Resilience was also influenced by common and unique environmental factors not shared with PTSD, but there was no genetic factor specific to resilience. Confirmatory factor analysis supported the Development of a revised phenotype reflecting the broader dimension of traumatic stress, with biometric models suggesting increased heritability (66%) of this spectrum compared to PTSD or resilience individually. CONCLUSIONS: Genetic factors contribute to a single spectrum of traumatic stress reflecting resilience at one end and high symptom severity at the other. This carries implications for phenotype refinement in the search for molecular genetic markers of trauma-related psychopathology. Rather than focusing only on genetic risk for PTSD, molecular genetics research may benefit from evaluation of the broader spectrum of traumatic stress.
Asunto(s)
Susceptibilidad a Enfermedades , Enfermedades en Gemelos , Sistema de Registros , Resiliencia Psicológica , Trastornos por Estrés Postraumático , Anciano , Enfermedades en Gemelos/epidemiología , Enfermedades en Gemelos/etiología , Enfermedades en Gemelos/genética , Enfermedades en Gemelos/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/fisiopatología , Veteranos/estadística & datos numéricosRESUMEN
BACKGROUND & AIMS: Telaprevir plus pegylated interferon/ribavirin (TPV+PegIFN/RBV) remains a therapeutic option for chronic hepatitis C virus (HCV) genotype (GT) 1 infection in many regions. We conducted two open-label, phase IIIb trials comparing safety and efficacy of all-oral ombitasvir/paritaprevir/ritonavir and dasabuvir±ribavirin (OBV/PTV/r+DSV±RBV) and TPV+PegIFN/RBV. METHODS: Treatment-naïve (MALACHITE-I) or PegIFN/RBV-experienced (MALACHITE-II) non-cirrhotic, chronic HCV GT1-infected patients were randomized to OBV/PTV/r+DSV+weight-based RBV, OBV/PTV/r+DSV (treatment-naïve, GT1b-infected patients only), or 12weeks of TPV+PegIFN+weight-based RBV and 12-36 additional weeks of PegIFN/RBV. The primary endpoint was sustained virologic response 12weeks post-treatment (SVR12). Patient-reported outcome questionnaires evaluated mental and physical health during the studies. RESULTS: Three hundred eleven treatment-naïve and 148 treatment-experienced patients were randomized and dosed. Among treatment-naïve patients, SVR12 rates were 97% (67/69) and 82% (28/34), respectively, in OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV-treated GT1a-infected patients; SVR12 rates were 99% (83/84), 98% (81/83), and 78% (32/41) in OBV/PTV/r+DSV+RBV, OBV/PTV/r+DSV, and TPV+PegIFN/RBV-treated GT1b-infected patients. Among treatment-experienced patients, SVR12 rates were 99% (100/101) and 66% (31/47) with OBV/PTV/r+DSV+RBV and TPV+PegIFN/RBV. Mental and physical health were generally better with OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. Rates of discontinuation due to adverse events (0-1% and 8-11%, respectively, p<0.05) and rates of hemoglobin decline to <10g/dl (0-4% and 34-47%, respectively, p<0.05) were lower for OBV/PTV/r+DSV±RBV than TPV+PegIFN/RBV. CONCLUSIONS: Among non-cirrhotic, HCV GT1-infected patients, SVR12 rates were 97-99% with 12week, multi-targeted OBV/PTV/r+DSV±RBV regimens and 66-82% with 24-48 total weeks of TPV+PegIFN/RBV. OBV/PTV/r+DSV±RBV was associated with a generally better mental and physical health, more favorable tolerability, and lower rates of treatment discontinuation due to adverse events.
Asunto(s)
Anilidas/administración & dosificación , Antivirales/administración & dosificación , Carbamatos/administración & dosificación , Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Compuestos Macrocíclicos/administración & dosificación , Sulfonamidas/administración & dosificación , Uracilo/análogos & derivados , 2-Naftilamina , Adulto , Anciano , Anilidas/efectos adversos , Carbamatos/efectos adversos , Ciclopropanos , Quimioterapia Combinada , Femenino , Genotipo , Hepacivirus/clasificación , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Lactamas Macrocíclicas , Compuestos Macrocíclicos/efectos adversos , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , Proteínas Recombinantes/administración & dosificación , Sulfonamidas/efectos adversos , Uracilo/administración & dosificación , Uracilo/efectos adversos , ValinaRESUMEN
Posttraumatic stress disorder (PTSD) is a heterogeneous disorder, and symptom severity varies over time. Neurobiological factors that predict PTSD symptoms and their chronicity remain unclear. This study investigated whether the volume of the hippocampus and its subfields, particularly cornu ammonis (CA) 1, CA3, and dentate gyrus, are associated with current PTSD symptoms and whether they predict PTSD symptom changes over 2 years. We examined clinical and structural magnetic resonance imaging measures from 252 trauma-exposed post-9/11 veterans (159 with Time 1 PTSD diagnosis) during assessments approximately 2 years apart. Automated hippocampal subfield segmentation was performed with FreeSurfer Version 7.1, producing 19 bilateral subfields. PTSD symptoms were measured at each assessment using the Clinician-Administered PTSD Scale-IV (CAPS). All models included total intracranial volume as a covariate. First, similar to previous reports, we showed that smaller overall hippocampal volume was associated with greater PTSD symptom severity at Time 1. Notably, when examining regions of interest (CA1, CA3, dentate gyrus), we found that smaller Time 1 hippocampal volumes in the bilateral CA1-body and CA2/3-body predicted decreased PTSD symptom severity at Time 2. These findings were not accounted for by combat exposure or treatment history. Additionally, both Time 1 CA1-body and CA2/3-body volume showed unique associations with changes in avoidance/numbing, but not with changes in reexperiencing or hyperarousal symptoms. This supports a more complex and nuanced relationship between hippocampal structure and PTSD symptoms, where during the posttrauma years bigger may not always mean better, and suggests that the CA1-body and CA2/3-body are important factors in the maintenance of PTSD symptoms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Hipocampo , Imagen por Resonancia Magnética , Trastornos por Estrés Postraumático , Veteranos , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/patología , Humanos , Masculino , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Adulto , Femenino , Persona de Mediana Edad , Tamaño de los Órganos , Índice de Severidad de la EnfermedadRESUMEN
Perinatal mood disorders, such as postpartum depression (PPD), are costly for society, with potentially serious consequences for mother and child. While multiple genes appear to play a role in PPD susceptibility, the contributions of specific genetic variations remain unclear. Previously implicated as a candidate gene, the estrogen receptor alpha gene (ESR1) is a key player in mediating hormonal differences during pregnancy and the postpartum period. This study addresses genetic factors in perinatal mood disorders, testing nine polymorphisms in ESR1. Two hundred fifty-seven postpartum women were screened for mood disorders, including 52 women with PPD and 32 without any symptoms of mood disorders. We detected a significant association for the upstream TA microsatellite repeat with Edinburgh Postnatal Depression Scale scores (p = 0.007). The same variant was also associated with the occurrence of PPD. Separately, 11 candidate functional polymorphisms in 7 additional genes were genotyped to investigate gene-gene interaction with the ESR1 TA repeat, identifying a potential interaction with the serotonin transporter. Our results support a role for ESR1 in the etiology of PPD, possibly through the modulation of serotonin signaling. Our findings for ESR1 could have broad implications for other disorders and therapies that involve estrogens.
Asunto(s)
Depresión Posparto/genética , Receptor alfa de Estrógeno/genética , Madres/psicología , Polimorfismo de Longitud del Fragmento de Restricción , Adulto , Estudios de Casos y Controles , Depresión Posparto/diagnóstico , Femenino , Variación Genética , Genotipo , Humanos , Entrevista Psicológica , Entrevistas como Asunto , Modelos Logísticos , Proyectos Piloto , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Statins are indicated for prevention of atherosclerotic cardiovascular disease. Metabolism of certain statins involves the cytochrome P450 3A (CYP3A) enzymes, and CYP3A4*22 significantly influences the dose needed for achieving optimal lipid control for atorvastatin, simvastatin, and lovastatin. CYP3A4/5 combined genotype approaches have proved useful in some studies involving CYP3A substrates. We intend to compare a combined genotype analysis to our previously reported single gene CYP3A4 analysis. METHODS: A total of 235 patients receiving stable statin doses were genotyped and grouped by CYP3A4/5 status. RESULTS: The number and demographic composition of the patients categorized into the combined genotype groups were consistent with those reported for other cohorts. Dose requirement was significantly associated with the ordered combined-genotype grouping; median daily doses were nearly 40% greater for CYP3A4/5 intermediate metabolizers compared with poor metabolizers, and median daily doses were nearly double for extensive metabolizers compared with poor metabolizers. The combined-genotype approach, however, did not improve the genotype-dosage correlation p-values when compared with the previously-reported analysis; values changed from 0.129 to 0.166, 0.036 to 0.185, and 0.014 to 0.044 for atorvastatin, simvastatin, and the combined statin analysis, respectively. CONCLUSIONS: The previously-reported single-gene approach was superior for predicting statin dose requirement in this cohort.
Asunto(s)
Citocromo P-450 CYP3A/genética , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Anciano , Atorvastatina , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/metabolismo , Ácidos Heptanoicos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lovastatina/administración & dosificación , Lovastatina/metabolismo , Lovastatina/farmacología , Masculino , Persona de Mediana Edad , Pirroles/administración & dosificación , Pirroles/metabolismo , Pirroles/farmacología , Simvastatina/administración & dosificación , Simvastatina/metabolismo , Simvastatina/farmacologíaRESUMEN
Approximately 10%-30% of individuals with posttraumatic stress disorder (PTSD) exhibit a dissociative subtype of the condition defined by symptoms of depersonalization and derealization. This study examined the psychometric evidence for the dissociative subtype of PTSD in a sample of young, primarily male post-9/11-era Veterans (n = 374 at baseline and n = 163 at follow-up) and evaluated its biological correlates with respect to resting state functional connectivity (default mode network [DMN]; n = 275), brain morphology (hippocampal subfield volume and cortical thickness; n = 280), neurocognitive functioning (n = 337), and genetic variation (n = 193). Multivariate analyses of PTSD and dissociation items suggested a class structure was superior to dimensional and hybrid ones, with 7.5% of the sample comprising the dissociative class; this group showed stability over 1.5 years. Covarying for age, sex, and PTSD severity, linear regression models revealed that derealization/depersonalization severity was associated with: decreased DMN connectivity between bilateral posterior cingulate cortex and right isthmus (p = .015; adjusted-p [padj] = .097); increased bilateral whole hippocampal, hippocampal head, and molecular layer head volume (p = .010-.034; padj = .032-.053); worse self-monitoring (p = .018; padj = .079); and a candidate genetic variant (rs263232) in the adenylyl cyclase 8 gene (p = .026), previously associated with dissociation. Results converged on biological structures and systems implicated in sensory integration, the neural representation of spatial awareness, and stress-related spatial learning and memory, suggesting possible mechanisms underlying the dissociative subtype of PTSD. (PsycInfo Database Record (c) 2023 APA, all rights reserved).