Assuntos
Ceratoacantoma , Melanoma , Neoplasias Cutâneas , Humanos , Ceratoacantoma/induzido quimicamente , Ceratoacantoma/diagnóstico , Nivolumabe/efeitos adversos , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Melanoma/tratamento farmacológico , Ipilimumab , Protocolos de Quimioterapia Combinada Antineoplásica , Melanoma Maligno CutâneoRESUMO
Psychopathology is a risk factor for accelerated biological aging and early mortality. We examined associations between broad underlying dimensions of psychopathology (reflecting internalizing and externalizing psychiatric symptoms), PTSD, and age-adjusted GrimAge ("GrimAge residuals"), a DNA methylation biomarker of mortality risk relative to age. We also examined neurobiological correlates of GrimAge residuals, including neurocognitive functioning, blood-based biomarkers (of inflammation, neuropathology, metabolic disease), and cortical thickness. Data from two independent trauma-exposed military cohorts (n = 647 [62.9% male, Mage = 52], n = 434 [90% male, Mage = 32]) were evaluated using linear regression models to test associations between GrimAge residuals, psychopathology, and health correlates. Externalizing psychopathology significantly predicted GrimAge residuals in both cohorts (ps < 0.028). PTSD predicted GrimAge residuals in the younger (p = 0.001) but not the older cohort. GrimAge residuals were associated with several neurobiological variables available in the younger cohort, including cognitive disinhibition (padj = 0.021), poorer memory recall (padj = 0.023), cardiometabolic pathology (padj < 0.001), oxidative stress (padj = 0.003), astrocyte damage (padj = 0.021), inflammation (C-reactive protein: padj < 0.001; IL-6: padj < 0.001), and immune functioning (padj < 0.001). A subset of inflammatory and neuropathology analytes were available in the older cohort and showed associations with GrimAge residuals (IL-6: padj < 0.001; TNF-α: padj < 0.001). GrimAge residuals were also associated with reduced cortical thickness in right lateral orbitofrontal cortex (padj = 0.018) and left fusiform gyrus (padj = 0.030), which are related to emotion regulation and facial recognition, respectively. Psychopathology may be a common risk factor for elevated mortality risk. GrimAge could help identify those at risk for adverse health outcomes and allow for early disease identification and treatment.
Assuntos
Metilação de DNA , Transtornos Mentais , Adulto , Envelhecimento , Biomarcadores , Proteína C-Reativa , Epigênese Genética , Feminino , Humanos , Inflamação , Interleucina-6 , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfaRESUMO
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Carboplatina/uso terapêutico , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/mortalidade , Interpretação Estatística de Dados , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Paclitaxel/uso terapêutico , Intervalo Livre de Progressão , Reprodutibilidade dos Testes , Projetos de Pesquisa , Critérios de Avaliação de Resposta em Tumores Sólidos , Análise de SobrevidaRESUMO
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.
Assuntos
Dermatite Fototóxica , Osteoartrite do Joelho , Transtornos de Fotossensibilidade , Idoso , Feminino , Humanos , Ácido Hialurônico/efeitos adversos , Ácido Hialurônico/análogos & derivados , Injeções Intra-Articulares/efeitos adversos , Masculino , Osteoartrite do Joelho/tratamento farmacológicoRESUMO
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.
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Estado Civil/estatística & dados numéricos , Melanoma/epidemiologia , Melanoma/patologia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Tardio , Feminino , Humanos , Masculino , Melanoma/diagnóstico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prevalência , Estudos Retrospectivos , Programa de SEER , Fatores Sexuais , Neoplasias Cutâneas/diagnóstico , Taxa de Sobrevida , Centros de Atenção Terciária , Estados Unidos , Adulto JovemRESUMO
Importance: Neoadjuvant systemic therapy (NST) is often administered to enable breast-conserving therapy (BCT) in stages II to III breast cancer. Objectives: To prospectively evaluate the role of NST in conversion from BCT ineligibility to BCT eligibility and to assess the association of response to NST, germline BRCA (gBRCA) status, and region of treatment with surgical choice in women with triple-negative breast cancer (TNBC). Design, Setting, and Participants: This prespecified secondary analysis of a multicentered, phase 3, double-blind, randomized clinical trial (BrighTNess) enrolled 634 eligible women across 145 centers in 15 countries in North America, Europe, and Asia. Women with operable, clinical stages II to III TNBC who underwent gBRCA mutation testing before initiating NST were eligible to participate. Data were collected from April 1, 2014, to December 8, 2016. This preplanned analysis was performed from January 5, 2018, to October 28, 2019. Interventions: Study participants were randomized to receive 12 weeks of weekly paclitaxel alone or with the addition of carboplatin and/or veliparib, followed by 4 cycles of doxorubicin hydrochloride and cyclophosphamide. Main Outcomes and Measures: Surgeons assessed BCT candidacy by clinical and radiographic criteria before and after NST. Surgical choices and whether BCT eligibility was associated with the likelihood of pathologic complete response were then analyzed. Results: Among the 634 randomized patients (median age, 51 [range, 22-78] years), pre- and post-NST assessments were available for 604 patients. Of 141 patients deemed BCT ineligible at baseline, 75 (53.2%) converted to BCT eligible. Overall, 342 (68.1%) of 502 patients deemed BCT eligible after NST underwent BCT, including 42 (56.0%) of the 75 who converted to BCT eligible. Patients treated in Europe and Asia were more likely to undergo BCT (odds ratio, 2.66; 95% CI, 1.84-3.84) compared with those treated in North America. Among patients without gBRCA mutation undergoing mastectomy, those treated in North America were more likely to undergo contralateral prophylactic mastectomy (57 of 81 [70.4%] vs 6 of 30 [20.0%]; P < .001). Rates of pathologic complete response were similar between patients deemed BCT eligible at baseline and those who were BCT ineligible but converted to BCT eligibility after NST (55.3 [235 of 425] vs 49.3% [37 of 75]; P = .38). Conclusions and Relevance: This prospective analysis of NST and BCT eligibility in TNBC demonstrates a conversion from BCT ineligibility to BCT eligibility of 53.2%. Lower BCT rates among eligible patients and higher bilateral mastectomy rates among patients without gBRCA mutation in North America merit investigation. Trial Registration: ClinicalTrials.gov identifier: NCT02032277.
Assuntos
Mastectomia Segmentar , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/cirurgia , Adulto , Idoso , Quimioterapia Adjuvante , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Seleção de Pacientes , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: The ability of breast magnetic resonance imaging (MRI) to predict pathologic complete response (pCR) to neoadjuvant systemic therapy (NST) varies across biological subtypes. We sought to determine how well breast MRI findings following initial treatment on the phase III BrighTNess trial correlated with pCR in patients with triple negative breast cancer (TNBC). METHODS: Baseline and mid-treatment imaging and pathologic response data were available in 519 patients with stage II-III TNBC who underwent NST as per protocol. MRI complete response (mCR) was defined as disappearance of all target lesion(s) and MRI partial response (mPR) as a ≥50% reduction in the largest tumor diameter. RESULTS: Overall, mCR was demonstrated in 116 patients (22%), whereas 166 (32%) had mPR and 237 (46%) had stable/progressive disease (SD/PD). The positive predictive value (PPV), negative predictive value, and overall accuracy of the mid-treatment MRI for pCR were 78%, 56%, and 61%, respectively; accuracy did not differ significantly between gBRCA mutation carriers and non-carriers (52% vs. 63%, pâ¯=â¯0.10). When compared to patients with SD/PD, those with mPR or mCR were 3.35-fold (95% CI 2.07-5.41) more likely to have pCR at surgery. MRI response during NST was significantly associated with eligibility for breast-conserving surgery following completion of treatment (93.1% for mCR vs. 81.6% for SD/PD, pâ¯<â¯0.001). CONCLUSIONS: Complete response on mid-treatment MRI in the BrighTNess trial had a PPV of 78% for demonstration of pCR after completion of NST in TNBC. However, a substantial proportion of patients with mPR or SD/PD also achieved a pCR. CLINICAL TRIAL REGISTRATION: NCT02032277.
Assuntos
Imageamento por Ressonância Magnética/métodos , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Quimioterapia Adjuvante , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Valor Preditivo dos Testes , Estudos Prospectivos , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
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.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carboplatina/administração & dosagem , Terapia Combinada , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/cirurgia , Método Duplo-Cego , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Análise de Intenção de Tratamento , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/cirurgia , Paclitaxel/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Qualidade de VidaRESUMO
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.
RESUMO
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.
Assuntos
Senescência Celular/genética , Glucuronidase/genética , Estresse Psicológico/metabolismo , Adulto , Envelhecimento/genética , Envelhecimento/metabolismo , Alelos , Encéfalo/metabolismo , Proteína C-Reativa/análise , Senescência Celular/fisiologia , Metilação de DNA/genética , Imagem de Tensor de Difusão/métodos , Epigênese Genética/genética , Feminino , Genótipo , Glucuronidase/metabolismo , Humanos , Proteínas Klotho , Longevidade/genética , Longevidade/fisiologia , Masculino , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/genética , Homeostase do Telômero/genética , Homeostase do Telômero/fisiologia , Veteranos , Substância Branca/metabolismoRESUMO
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.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Neoplasias Colorretais/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de ProgressãoRESUMO
The poly(ADP-ribose) polymerase-1/2 inhibitor veliparib is active against tumors deficient in homologous DNA damage repair. The pharmacokinetics and safety of veliparib extended-release (ER) were evaluated in patients with advanced solid tumors. This phase I study assessed veliparib-ER up to 800 mg once daily or 600 mg twice daily. Dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), and maximum tolerated dose (MTD) were assessed in cycle 1 and safety/tolerability during continuous administration (28-day cycles). Seventy-one patients (n = 53 ovarian, n = 17 breast, n = 1 prostate carcinoma) received veliparib; 50 had deleterious breast cancer susceptibility (BRCA) gene mutations. Single-dose veliparib-ER 200 mg (fasting) led to 58% lower peak concentration and similar area under the concentration-time curve compared with veliparib immediate-release (IR). Three patients experienced DLTs (grade 2: asthenia; grade 3: nausea/vomiting, seizure). RP2D and MTD for veliparib-ER were 400 mg BID. The most frequent adverse events (AEs) were nausea (78.9%) and vomiting (50.7%). The most common grade 3/4 treatment-related AEs were as follows: thrombocytopenia (7.0%), nausea, and anemia (4.2% each). Overall, 12 (27.3%) patients with ovarian and 10 (62.5%) patients with breast carcinoma had a partial response. Veliparib-ER, versus veliparib-IR, exhibited an improved pharmacokinetic profile and was well tolerated in patients with ovarian and BRCA-mutated breast cancers.
Assuntos
Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Adulto , Benzimidazóis/farmacocinética , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Anemia/induzido quimicamente , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Quimioterapia Adjuvante , Neutropenia Febril Induzida por Quimioterapia/etiologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Método Duplo-Cego , Doxorrubicina/administração & dosagem , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/cirurgia , Carga Tumoral/efeitos dos fármacosRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Área Sob a Curva , Teorema de Bayes , Benzimidazóis/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carboplatina/administração & dosagem , Carcinoma Basocelular/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células de Transição/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Genes BRCA1 , Genes BRCA2 , Mutação em Linhagem Germinativa , Humanos , Quimioterapia de Indução , Neoplasias Renais/tratamento farmacológico , Pelve Renal , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Quimioterapia de Manutenção , Masculino , Dose Máxima Tolerável , Mesotelioma/tratamento farmacológico , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Metástase Neoplásica , Neutropenia/induzido quimicamente , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , GencitabinaRESUMO
Purpose: Adverse reactions reported in patients treated with antibody-calicheamicin conjugates such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin include thrombocytopenia and sinusoidal obstruction syndrome (SOS). The objective of this experimental work was to investigate the mechanism for thrombocytopenia, characterize the liver injury, and identify potential safety biomarkers.Experimental Design: Cynomolgus monkeys were dosed intravenously at 6 mg/m2/dose once every 3 weeks with a nonbinding antibody-calicheamicin conjugate (PF-0259) containing the same linker-payload as gemtuzumab ozogamicin and inotuzumab ozogamicin. Monkeys were necropsied 48 hours after the first administration (day 3) or 3 weeks after the third administration (day 63).Results: PF-0259 induced acute thrombocytopenia (up to 86% platelet reduction) with nadirs on days 3 to 4. There was no indication of effects on megakaryocytes in bone marrow or activation of platelets in peripheral blood. Microscopic evaluation of liver from animals necropsied on day 3 demonstrated midzonal degeneration and loss of sinusoidal endothelial cells (SECs) associated with marked platelet accumulation in sinusoids. Liver histopathology on day 63 showed variable endothelial recovery and progression to a combination of sinusoidal capillarization and sinusoidal dilation/hepatocellular atrophy, consistent with early SOS. Among biomarkers evaluated, there were early and sustained increases in serum hyaluronic acid (HA) that correlated well with serum aspartate aminotransferase and liver microscopic changes, suggesting that HA may be a sensitive diagnostic marker of the liver microvascular injury.Conclusions: These data support the conclusion that target-independent damage to liver SECs may be responsible for acute thrombocytopenia (through platelet sequestration in liver sinusoids) and development of SOS. Clin Cancer Res; 23(7); 1760-70. ©2016 AACR.
Assuntos
Aminoglicosídeos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Doença Hepática Induzida por Substâncias e Drogas/patologia , Trombocitopenia/patologia , Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/química , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Enedi-Inos/administração & dosagem , Enedi-Inos/química , Gemtuzumab , Humanos , Ácido Hialurônico/sangue , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Inotuzumab Ozogamicina , Fígado/efeitos dos fármacos , Macaca fascicularis , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Trombocitopenia/induzido quimicamenteRESUMO
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.