RESUMEN
The safety and efficacy of sabatolimab, a novel immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), was assessed in combination with hypomethylating agents (HMAs) in patients with HMA-naive revised International Prognostic System Score (IPSS-R) high- or very high-risk myelodysplastic syndromes (HR/vHR-MDS) or chronic myelomonocytic leukemia (CMML). Sabatolimab + HMA had a safety profile similar to that reported for HMA alone and demonstrated durable clinical responses in patients with HR/vHR-MDS. These results support the ongoing evaluation of sabatolimab-based combination therapy in MDS, CMML, and acute myeloid leukemia.
Asunto(s)
Anticuerpos Monoclonales , Leucemia Mieloide Aguda , Leucemia Mielomonocítica Crónica , Síndromes Mielodisplásicos , Humanos , Azacitidina/uso terapéutico , Decitabina/uso terapéutico , Antimetabolitos Antineoplásicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Receptor 2 Celular del Virus de la Hepatitis A/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Anticuerpos/uso terapéutico , Resultado del TratamientoRESUMEN
Aggressive neurosurgical resection to achieve sustained local control is essential for prolonging survival in patients with lower-grade glioma. However, progression in many of these patients is characterized by local regrowth. Most lower-grade gliomas harbor isocitrate dehydrogenase 1 (IDH1) or IDH2 mutations, which sensitize to metabolism-altering agents. To improve local control of IDH mutant gliomas while avoiding systemic toxicity associated with metabolic therapies, we developed a precision intraoperative treatment that couples a rapid multiplexed genotyping tool with a sustained release microparticle (MP) drug delivery system containing an IDH-directed nicotinamide phosphoribosyltransferase (NAMPT) inhibitor (GMX-1778). We validated our genetic diagnostic tool on clinically annotated tumor specimens. GMX-1778 MPs showed mutant IDH genotype-specific toxicity in vitro and in vivo, inducing regression of orthotopic IDH mutant glioma murine models. Our strategy enables immediate intraoperative genotyping and local application of a genotype-specific treatment in surgical scenarios where local tumor control is paramount and systemic toxicity is therapeutically limiting.
Asunto(s)
Neoplasias Encefálicas , Cianuros/farmacología , Genotipo , Glioma , Guanidinas/farmacología , Isocitrato Deshidrogenasa/genética , Terapia Molecular Dirigida/métodos , Mutación , Proteínas de Neoplasias/genética , Animales , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/genética , Sistemas de Liberación de Medicamentos/métodos , Femenino , Glioma/tratamiento farmacológico , Glioma/enzimología , Glioma/genética , Humanos , Masculino , Ratones , Ratones SCID , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Glioblastoma is both the most common and lethal primary malignant brain tumor. Extensive multiplatform genomic characterization has provided a higher-resolution picture of the molecular alterations underlying this disease. These studies provide the emerging view that "glioblastoma" represents several histologically similar yet molecularly heterogeneous diseases, which influences taxonomic classification systems, prognosis, and therapeutic decisions.
Asunto(s)
Neoplasias Encefálicas/clasificación , Neoplasias Encefálicas/genética , Glioblastoma/clasificación , Glioblastoma/genética , Neoplasias Encefálicas/patología , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Genómica , Glioblastoma/patología , Humanos , Neovascularización Patológica/genética , Transcripción GenéticaRESUMEN
Bing-Neel syndrome (BNS) is a rare complication seen in patients with Waldenström macroglobulinaemia (WM), in which lymphoplasmacytic lymphoma cells colonize the central nervous system. In this retrospective multi-centre study, we present the clinicopathological features, imaging findings, therapy, response and outcomes of 34 patients with BNS. The median time from WM diagnosis to BNS diagnosis was 3 years, 15% of patients were diagnosed with BNS at the time of WM diagnosis, and 22% of patients developed BNS when responding to active treatment for WM. Patients with BNS presented with variable clinical features including limb motor deficits, change in mental status and cranial nerve palsies. The diagnosis was made using a combination of cerebrospinal fluid cytology, flow cytometry and detection of the MYD88 L265 mutation, and magnetic resonance imaging. The estimated 3-year overall survival rate was 59%. Of the survivors, 40% have evidence of pathological and/or radiological persistence of disease. Age older than 65 years, platelet count lower than 100 × 10(9) /l, and treatment for WM prior to BNS diagnosis were associated with worse outcome. Exposure to rituximab for treatment of BNS was associated with a better outcome. Multi-institutional collaboration is warranted to improve treatment and outcomes in patients with BNS.
Asunto(s)
Neoplasias del Sistema Nervioso Central/diagnóstico , Macroglobulinemia de Waldenström/diagnóstico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Síndrome , Resultado del Tratamiento , Macroglobulinemia de Waldenström/tratamiento farmacológicoRESUMEN
BACKGROUND: The prognosis for patients with atypical and malignant meningioma is guarded; whether the extent of resection is associated with survival-based outcomes in this population remains poorly defined. This study investigated the association between gross total resection (GTR) and all-cause mortality in patients with atypical and malignant meningioma. METHODS: The Surveillance, Epidemiology, and End Results program was used to identify 575 and 64 patients betweens the ages of 18 and 70 years who were diagnosed with atypical and malignant meningioma, respectively, between 2004 and 2009. Multivariate Cox proportional hazards regression was used to assess the adjusted impact of GTR versus subtotal resection on all-cause mortality. RESULTS: Baseline patient characteristics were similar for patients who did undergo GTR and patients who did not undergo GTR. The 5-year overall survival rates were 91.3% (95% confidence interval [CI], 86.2%-94.5%) and 78.2% (95% CI, 70.0%-84.3%) for patients with atypical meningioma who did and did not undergo GTR, respectively, and 64.5% (95% CI, 45.9%-78.1%) and 41.1% (95% CI, 17.9%-63.1%) for patients with malignant meningioma who did and did not undergo GTR, respectively. After adjustments for available, pertinent confounding variables, GTR was associated with lower all-cause mortality in patients with atypical (hazard ratio, 0.39; 95% CI, 0.23-0.67; P < .001) and malignant meningioma (hazard ratio, 0.35; 95% CI, 0.15-0.81; P = .01). CONCLUSIONS: The extent of resection is a powerful predictor of outcome for patients with atypical and malignant meningioma. These data highlight the hazard associated with the presence of gross tumor bulk after surgery and suggest a value for more extensive resections that should be balanced against the additional potential morbidity.
Asunto(s)
Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Adolescente , Adulto , Factores de Edad , Anciano , Estudios de Cohortes , Procedimientos Quirúrgicos de Citorreducción , Femenino , Humanos , Masculino , Neoplasias Meníngeas/mortalidad , Meningioma/mortalidad , Persona de Mediana Edad , Neoplasia Residual , Procedimientos Neuroquirúrgicos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Programa de VERF , Tasa de Supervivencia , Carga Tumoral , Adulto JovenRESUMEN
Tumor cell infiltration is a major mechanism of treatment escape in glioblastoma. Src is an intracellular tyrosine kinase that mediates tumor cell motility and invasiveness. We evaluated the efficacy and safety of bosutinib, a tyrosine kinase inhibitor that potently inhibits Src and Abl, in patients with recurrent glioblastoma. In this two-arm study, patients with histologically confirmed recurrent glioblastoma and ≤2 relapses, not previously treated with anti-vascular endothelial growth factor (VEGF) therapy, were administered oral bosutinib 400 mg daily. Arm A planned for 6 patients who were candidates for surgical resection to be given bosutinib for 7-9 days prior to resection. Arm B was a two-stage design phase 2 trial targeting 30 patients. The primary endpoint was progression-free survival at 6 months (PFS6) in Arm B. After 9 patients enrolled onto stage 1 of Arm B, 9 (100 %) patients progressed within 6 months. Therefore, the study met the pre-specified criteria for early closure and both Arms were closed. In Arm B, Median PFS was 7.71 weeks and median OS was 50 weeks. Best objective response was stable disease in one patient (11.1 %). Seven patients (77.8 %) had treatment-related AEs of any grade and 2 (22.2 %) were grade ≥3. Arm A was closed after 2 patients enrolled. Src activation was evident in all archival tumor samples. Bosutinib monotherapy does not appear to be effective in recurrent glioblastoma. However, Src remains a potential target based on its upregulation in tumor samples and role in glioma invasion.
Asunto(s)
Compuestos de Anilina/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Nitrilos/uso terapéutico , Quinolinas/uso terapéutico , Familia-src Quinasas/antagonistas & inhibidores , Adulto , Neoplasias Encefálicas/mortalidad , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Familia-src Quinasas/metabolismoRESUMEN
Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/ß, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Glioma/tratamiento farmacológico , Indoles/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Bevacizumab , Estudios de Cohortes , Femenino , Glioma/patología , Humanos , Indoles/efectos adversos , Estimación de Kaplan-Meier , Estado de Ejecución de Karnofsky , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Recurrencia Local de Neoplasia/patología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
INTRODUCTION: Primary and metastatic brain tumors remain a major challenge. The most common primary adult malignant brain tumor, glioblastoma (GBM), confers a dismal prognosis as does the development of CNS metastases for most systemic malignancies. Anti-angiogenic therapy has been a major clinical research focus in neuro-oncology over the past 5 years. AREAS COVERED: Culmination of this work includes US FDA accelerated approval of bevacizumab for recurrent GBM and the completion of two placebo-controlled Phase III studies of bevacizumab for newly diagnosed GBM. A multitude of anti-angiogenics are in evaluation for neuro-oncology patients but none has thus far surpassed the therapeutic benefit of bevacizumab. EXPERT OPINION: These agents demonstrate adequate safety and the majority of GBM patients derive benefit. Furthermore, their anti-permeability effect can substantially decrease tumor-associated edema leading to stable or improved neurologic function and quality of life. In particular, anti-angiogenics significantly prolong progression-free survival - a noteworthy achievement in the context of infiltrative and destructive brain tumors like GBM; however, in a manner analogous to other cancers, their impact on overall survival for GBM patients is modest at best. Despite substantial clinical research efforts, many fundamental questions regarding anti-angiogenic agents in brain tumor patients remain unanswered.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Bevacizumab , Glioblastoma/tratamiento farmacológico , HumanosRESUMEN
Sabatolimab is a novel immunotherapy with immuno-myeloid activity that targets T-cell immunoglobulin domain and mucin domain-3 (TIM-3) on immune cells and leukemic blasts. It is being evaluated for the treatment of myeloid malignancies in the STIMULUS clinical trial program. The objective of this analysis was to support the sabatolimab dose-regimen selection in hematologic malignancies. A population pharmacokinetic (PopPK) model was fit to patients with solid tumors and hematologic malignancies, which included acute myeloid leukemia, myelodysplastic syndrome (including intermediate-, high-, and very high-risk per Revised International Prognostic Scoring System), and chronic myelomonocytic leukemia. The PopPK model, together with a predictive model of sabatolimab distribution to the bone marrow and binding to TIM-3 was used to predict membrane-bound TIM-3 bone marrow occupancy. In addition, the total soluble TIM-3 (sTIM-3) kinetics and the pharmacokinetic (PK) exposure-response relationship in patients with hematologic malignancies were examined. At intravenous doses above 240 mg Q2w and 800 mg Q4w, we observed linear PK, a plateau in the accumulation of total sTIM-3, and a flat exposure-response relationship for both safety and efficacy. In addition, the model predicted membrane-bound TIM-3 occupancy in the bone marrow was above 95% in over 95% of patients. Therefore, these results support the selection of the 400 mg Q2w and 800 mg Q4w dosing regimens for the STIMULUS clinical trial program.
Asunto(s)
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Receptor 2 Celular del Virus de la Hepatitis A , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Síndromes Mielodisplásicos/tratamiento farmacológico , Desarrollo de MedicamentosRESUMEN
PURPOSE: The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial that uses response adaptive randomization and genomic profiling to efficiently identify novel therapies for phase III testing. Three initial experimental arms (abemaciclib [a cyclin-dependent kinase [CDK]4/6 inhibitor], neratinib [an epidermal growth factor receptor [EGFR]/human epidermal growth factor receptor 2 inhibitor], and CC-115 [a deoxyribonucleic acid-dependent protein kinase/mammalian target of rapamycin inhibitor]) were simultaneously evaluated against a common control arm. We report the results for each arm and examine the feasibility and conduct of the adaptive platform design. PATIENTS AND METHODS: Patients with newly diagnosed O6-methylguanine-DNA methyltransferase-unmethylated glioblastoma were eligible if they had tumor genotyping to identify prespecified biomarker subpopulations of dominant glioblastoma signaling pathways (EGFR, phosphatidylinositol 3-kinase, and CDK). Initial random assignment was 1:1:1:1 between control (radiation therapy and temozolomide) and the experimental arms. Subsequent Bayesian adaptive randomization was incorporated on the basis of biomarker-specific progression-free survival (PFS) data. The primary end point was overall survival (OS), and one-sided P values are reported. The trial is registered with ClinicalTrials.gov (identifier: NCT02977780). RESULTS: Two hundred thirty-seven patients were treated (71 control; 73 abemaciclib; 81 neratinib; 12 CC-115) in years 2017-2021. Abemaciclib and neratinib were well tolerated, but CC-115 was associated with ≥ grade 3 treatment-related toxicity in 58% of patients. PFS was significantly longer with abemaciclib (hazard ratio [HR], 0.72; 95% CI, 0.49 to 1.06; one-sided P = .046) and neratinib (HR, 0.72; 95% CI, 0.50 to 1.02; one-sided P = .033) relative to the control arm but there was no PFS benefit with CC-115 (one-sided P = .523). None of the experimental therapies demonstrated a significant OS benefit (P > .05). CONCLUSION: The INSIGhT design enabled efficient simultaneous testing of three experimental agents using a shared control arm and adaptive randomization. Two investigational arms had superior PFS compared with the control arm, but none demonstrated an OS benefit. The INSIGhT design may promote improved and more efficient therapeutic discovery in glioblastoma. New arms have been added to the trial.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Humanos , Glioblastoma/patología , Distribución Aleatoria , Teorema de Bayes , Neoplasias Encefálicas/terapia , Receptores ErbB/genética , BiomarcadoresRESUMEN
As more effective therapies prolong the survival of patients with cancer, therapy-related toxicities, particularly those affecting the central nervous system (CNS) become increasingly important. CNS complications can cause significant morbidity and can limit the dose or duration of otherwise effective treatments. Because effects on the CNS are disabling and often permanent and treatments remain limited, it is important that clinicians recognize the effects of cancer therapy on the CNS. Cytotoxic chemotherapy and radiation are well-known causes of neurotoxicity, but there is increasing recognition that novel therapies are also sources of adverse effects on the CNS. This review highlights the CNS complications that result from radiation, chemotherapy, and novel therapeutics.
Asunto(s)
Antineoplásicos/efectos adversos , Enfermedades del Sistema Nervioso Central/etiología , Radioterapia/efectos adversos , Hemorragia Cerebral/etiología , Cefalea/etiología , Humanos , Leucoencefalopatías/etiología , Convulsiones/etiología , Accidente Cerebrovascular/etiologíaAsunto(s)
Enfermedad de Alzheimer/diagnóstico , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Demencia/etiología , Priones/aislamiento & purificación , Anciano de 80 o más Años , Enfermedad de Alzheimer/etiología , Síndrome de Creutzfeldt-Jakob/complicaciones , Demencia/diagnóstico , Diagnóstico Diferencial , Resultado Fatal , Humanos , MasculinoAsunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/análogos & derivados , Oligodendroglioma/tratamiento farmacológico , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Medicina Basada en la Evidencia , Glioma/tratamiento farmacológico , Glioma/patología , Humanos , Lomustina/administración & dosificación , Clasificación del Tumor , Estadificación de Neoplasias , Oligodendroglioma/mortalidad , Oligodendroglioma/patología , Procarbazina/administración & dosificación , Pronóstico , Radioterapia Adyuvante , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Temozolomida , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: Adequately prioritizing the numerous therapies and biomarkers available in late-stage testing for patients with glioblastoma (GBM) requires an efficient clinical testing platform. We developed and implemented INSIGhT (Individualized Screening Trial of Innovative Glioblastoma Therapy) as a novel adaptive platform trial (APT) to develop precision medicine approaches in GBM. METHODS: INSIGhT compares experimental arms with a common control of standard concurrent temozolomide and radiation therapy followed by adjuvant temozolomide. The primary end point is overall survival. Patients with newly diagnosed unmethylated GBM who are IDH R132H mutation negative and with genomic data available for biomarker grouping are eligible. At the initiation of INSIGhT, three experimental arms (neratinib, abemaciclib, and CC-115), each with a proposed genomic biomarker, are tested simultaneously. Initial randomization is equal across arms. As the trial progresses, randomization probabilities adapt on the basis of accumulating results using Bayesian estimation of the biomarker-specific probability of treatment impact on progression-free survival. Treatment arms may drop because of low probability of treatment impact on overall survival, and new arms may be added. Detailed information on the statistical model and randomization algorithm is provided to stimulate discussion on trial design choices more generally and provide an example for other investigators developing APTs. CONCLUSION: INSIGhT (NCT02977780) is an ongoing novel biomarker-based, Bayesian APT for patients with newly diagnosed unmethylated GBM. Our goal is to dramatically shorten trial execution timelines while increasing scientific power of results and biomarker discovery using adaptive randomization. We anticipate that trial execution efficiency will also be improved by using the APT format, which allows for the collaborative addition of new experimental arms while retaining the overall trial structure.
RESUMEN
PURPOSE: Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS: This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway-activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS: Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION: Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.
Asunto(s)
Aminopiridinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Morfolinas/uso terapéutico , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Fosfatidilinositol 3-Quinasa/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Aminopiridinas/efectos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efectos adversos , Neoplasias Encefálicas/enzimología , Neoplasias Encefálicas/patología , Quimioterapia Adyuvante , Progresión de la Enfermedad , Activación Enzimática , Femenino , Glioblastoma/enzimología , Glioblastoma/patología , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Morfolinas/farmacocinética , Terapia Neoadyuvante/efectos adversos , Inhibidores de las Quinasa Fosfoinosítidos-3/efectos adversos , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Supervivencia sin Progresión , Factores de TiempoRESUMEN
Biomass fuel used for cooking results in widespread exposure to indoor air pollution (IAP), affecting nearly 3 billion people throughout the world. Few studies, however, have tested for an exposure-response relationship between biomass fuel and health outcomes. The aim of this study was to explore the relationship between biomass fuel, infant mortality, and children's respiratory symptoms. Eighty households in a rural community in Ecuador were selected based on their use of biomass fuel and questioned regarding a history of infant mortality and children's respiratory symptoms. Carbon monoxide (CO) and particulate matter (PM) were measured in a subset of these homes to confirm the relationship between biomass fuel use and IAP. Results showed a significant trend for higher infant mortality among households that cooked with a greater proportion of biomass fuel (P=0.008). Similar trends were noted for history of cough (P=0.02) and earache (P<0.001) among children living in these households.
Asunto(s)
Contaminación del Aire Interior/efectos adversos , Biomasa , Protección a la Infancia , Culinaria , Fuentes Generadoras de Energía , Mortalidad Infantil , Humo/efectos adversos , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Análisis MultivarianteRESUMEN
Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.
Asunto(s)
Apoptosis , Sinergismo Farmacológico , Inhibidores Enzimáticos/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Quinasas Quinasa Quinasa PAM , Ratones SCID , Neoplasias Experimentales/terapia , Trasplante Heterólogo , Resultado del TratamientoRESUMEN
Approximately half the world uses biomass fuel for domestic energy, resulting in widespread exposure to indoor air pollution (IAP) from biomass smoke. IAP has been associated with many respiratory diseases, though it is not clear what relationship exists between biomass use and pulmonary function. Four groups containing 20 households each were selected in Santa Ana, Ecuador based on the relative amount of liquid petroleum gas and biomass fuel that they used for cooking. Pulmonary function tests were conducted on each available member of the households 7 years of age. The pulmonary functions of both children (7-15 years) and women (16 years) were then compared between cooking fuel categories using multivariate linear regression, controlling for the effects of age, gender, height, and exposure to tobacco smoke. Among the 80 households, 77 children and 91 women performed acceptable and reproducible spirometry. In multivariate analysis, children living in homes that use biomass fuel and children exposed to environmental tobacco smoke had lower forced vital capacity and lower forced expiratory volume in 1s (P<0.05). However, no significant difference in pulmonary function was observed among women in different cooking categories. Results of this study demonstrate the harmful effects of IAP from biomass smoke on the lung function of children and emphasize the need for public health efforts to decrease exposure to biomass smoke.
Asunto(s)
Contaminación del Aire Interior/efectos adversos , Culinaria , Fuentes Generadoras de Energía , Volumen Espiratorio Forzado/efectos de los fármacos , Capacidad Vital/efectos de los fármacos , Adolescente , Adulto , Biomasa , Niño , Ecuador , Femenino , Humanos , Masculino , Salud Rural/estadística & datos numéricos , Humo/efectos adversos , Espirometría , Contaminación por Humo de Tabaco/efectos adversosRESUMEN
BACKGROUND: The appropriate use of adjuvant therapy in patients with gross totally resected atypical meningioma requires an accurate assessment of recurrence risk. We sought to determine whether cytogenetic/genetic characterization may facilitate better estimation of the probability of recurrence. METHODS: We first analyzed our clinical database, including high-resolution DNA copy number data, to identify 11 common copy number aberrations in a pilot cohort of meningiomas of all grades. We summed these aberrations to devise a cytogenetic abnormality score (CAS) and determined the CAS from archived tissue of a separate cohort of 32 patients with gross totally resected atypical meningioma managed with surgery alone. Propensity score adjusted Cox regression was used to determine whether the CAS was predictive of recurrence. RESULTS: An association between higher CAS and higher grade was noted in our pilot cohort with heterogeneity among atypical tumors. Among the 32 patients who underwent gross total resection of an atypical meningioma, the CAS was not significantly associated with age, gender, performance status, or tumor size/location but was associated with the risk of recurrence on univariable analysis (hazard ratio per aberration = 1.52; 95% CI = 1.08-2.14; P = .02). After adjustment, the impact of the dichotomized number of copy aberrations remained significantly associated with recurrence risk (hazard ratio = 4.47; 95% CI = 1.01-19.87; P = .05). CONCLUSIONS: The number of copy number aberrations is strongly associated with recurrence risk in patients with atypical meningioma following gross total resection and may inform the appropriate use of adjuvant radiation therapy in these patients or be useful for stratification in clinical trials.