Asunto(s)
Factores de Coagulación Sanguínea/uso terapéutico , Inhibidores del Factor Xa/efectos adversos , Factor Xa/uso terapéutico , Hemorragia/tratamiento farmacológico , Proteínas Recombinantes/uso terapéutico , Hemorragia/inducido químicamente , Humanos , Pirazoles/efectos adversos , Piridonas/efectos adversos , Rivaroxabán/efectos adversosRESUMEN
Meningiomas are increasingly appreciated to share similar features with other intra-axial central nervous system neoplasms as well as systemic cancers. Immune checkpoint inhibition has emerged as a promising therapy in a number of cancers, with durable responses of years in a subset of patients. Several lines of evidence support a role for immune-based therapeutic strategies in the management of meningiomas, especially high-grade subtypes. Meningiomas frequently originate juxtaposed to venous sinuses, where an anatomic conduit for lymphatic drainage resides. Multiple populations of immune cells have been observed in meningiomas. PD-1/PD-L1 mediated immunosuppression has been implicated in high-grade meningiomas, with association between PD-L1 expression with negative prognostic outcome. These data point to the promise of future combinatorial therapeutic strategies in meningioma.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/terapia , Neoplasias Hematológicas/terapia , Inmunoterapia/métodos , Meningioma/terapia , Animales , Neoplasias del Sistema Nervioso Central/inmunología , Terapia Combinada , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Neoplasias Hematológicas/inmunología , Humanos , Meningioma/inmunologíaRESUMEN
This Water Environment Research Foundation study considered the relationship between varying nutrient-removal levels at wastewater treatment plants, greenhouse gas emissions, receiving water quality (measured by potential algal production), and costs. The effluent nutrient concentrations required by some U.S. permits are very low, approaching the technology-best-achievable performance. This study evaluated five different treatment levels at a nominal 40 ML/d (10 mgd) flow. Greenhouse gas emissions and costs increase gradually up to the technologies' best-achievable performance, after which they increase exponentially. The gradual increase is attributed to additional biological treatment facilities, increased energy and chemical use, and additional tertiary nitrogen and phosphorus removal processes. Within the limited focus of this study, the evaluation shows that a point of diminishing return is reached as nutrient-removal objectives approach the technology-best-achievable performance, where greenhouse gas emissions and cost of treatment increases rapidly while the potential for algal growth reduce marginally.
Asunto(s)
Dióxido de Carbono/química , Nitrógeno/química , Fósforo/química , Eliminación de Residuos Líquidos/métodos , Purificación del Agua/métodos , Calidad del AguaRESUMEN
Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Subunidad alfa del Receptor de Interleucina-2/antagonistas & inhibidores , Depleción Linfocítica/métodos , Linfopenia/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/terapia , Vacunas contra el Cáncer/uso terapéutico , Células Cultivadas , Terapia Combinada , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Daclizumab , Evaluación Preclínica de Medicamentos , Glioblastoma/inmunología , Glioblastoma/terapia , Humanos , Inmunoglobulina G/farmacología , Inmunoglobulina G/uso terapéutico , Inmunoterapia/métodos , Subunidad alfa del Receptor de Interleucina-2/inmunología , Linfopenia/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Especificidad por Sustrato/efectos de los fármacos , Especificidad por Sustrato/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Temozolomida , Adulto JovenRESUMEN
Cilengitide, a cyclicized arginine-glycine-aspartic acid-containing pentapeptide, potently blocks ανß3 and ανß5 integrin activation. Integrins are upregulated in many malignancies and mediate a wide variety of tumor-stroma interactions. Cilengitide and other integrin-targeting therapeutics have preclinical activity against many cancer subtypes including glioblastoma (GBM), the most common and deadliest CNS tumor. Cilengitide is active against orthotopic GBM xenografts and can augment radiotherapy and chemotherapy in these models. In Phase I and II GBM trials, cilengitide and the combination of cilengitide with standard temozolomide and radiation demonstrate consistent antitumor activity and a favorable safety profile. Cilengitide is currently under evaluation in a pivotal, randomized Phase III study (Cilengitide in Combination With Temozolomide and Radiotherapy in Newly Diagnosed Glioblastoma Phase III Randomized Clinical Trial [CENTRIC]) for newly diagnosed GBM. In addition, randomized controlled Phase II studies with cilengitide are ongoing for non-small-cell lung cancer and squamous cell carcinoma of the head and neck. Cilengitide is the first integrin inhibitor in clinical Phase III development for oncology.
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Antineoplásicos/uso terapéutico , Glioblastoma/tratamiento farmacológico , Integrinas/antagonistas & inhibidores , Oligopéptidos/uso terapéutico , Venenos de Serpiente/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Industria Farmacéutica/tendencias , Humanos , Oligopéptidos/efectos adversos , Oligopéptidos/química , Oligopéptidos/farmacocinética , Venenos de Serpiente/efectos adversos , Venenos de Serpiente/química , Venenos de Serpiente/farmacocinética , Resultado del TratamientoRESUMEN
Primary extradural meningiomas (PEMs) represent about 2% of all meningiomas and are often encountered by non-neurosurgeons. These lesions typically present as enlarging, painless, benign masses that can be surgically cured. Imaging is critical for defining involvement of adjacent structures; however, diagnosis depends on classic histologic patterns. Treatment for benign PEMs (WHO I) consists of resection with wide margins, whereas adjuvant therapy after resection of atypical (WHO II) or malignant (WHO III) PEMs should be considered. By using the collective experience from our comprehensive cancer center, including neuro-oncologists, neuroradiologists, and neurosurgeons, in addition to a complete literature review, the authors have established treatment guidelines not previously reported. This manuscript describes key features of these challenging tumors to aid in diagnosis, presents the largest published review of all reported PEMs (n = 163), and provides salient treatment guidelines to surgeons unfamiliar with these challenging tumors.
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Neoplasias de Cabeza y Cuello/terapia , Meningioma/terapia , Neoplasias Abdominales/diagnóstico , Neoplasias Abdominales/patología , Neoplasias Abdominales/terapia , Algoritmos , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/terapia , Neoplasias de Cabeza y Cuello/diagnóstico , Humanos , Neoplasias Meníngeas , Guías de Práctica Clínica como AsuntoRESUMEN
Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.
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Anticonvulsivantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Citocromo P-450 CYP3A/metabolismo , Dacarbazina/análogos & derivados , Glioblastoma/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anticonvulsivantes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/farmacocinética , Neoplasias Encefálicas/mortalidad , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Dacarbazina/farmacocinética , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/farmacocinética , Recurrencia , Sorafenib , TemozolomidaAsunto(s)
Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Bevacizumab , Humanos , Factor A de Crecimiento Endotelial Vascular/efectos de los fármacos , Yin-YangRESUMEN
Vascular endothelial growth factor (VEGF) targeted therapy, either alone or in combination with chemotherapy, has become the standard of care in several solid tumours, including colorectal cancer, renal-cell carcinoma, breast cancer, non-small-cell lung cancer, and glioblastoma. VEGF is crucial in the process of angiogenesis and wound healing and, thus, its inhibition has the potential to affect wound healing in patients undergoing surgery. In this review, we summarise the data available on the use of VEGF-targeted therapies, and their effect on perioperative wound complications. Surgery in patients receiving VEGF-targeted therapies seems to be safe when an appropriate interval of time is allowed between surgical procedures and treatment. Recommendations regarding this interval are provided in a disease and agent site-specific manner. We also discuss complications arising from the use of VEGF-directed therapies that might require surgical intervention and the considerations important in their management. At this juncture, safety data on the use of VEGF-targeted therapies in the perioperative period are sparse, and investigators are urged to continue to study this issue prospectively in current and future clinical trials to establish firm guidelines.
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Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/cirugía , Complicaciones Posoperatorias/inducido químicamente , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Cicatrización de Heridas/efectos de los fármacos , Inhibidores de la Angiogénesis/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Bencenosulfonatos/administración & dosificación , Bencenosulfonatos/efectos adversos , Bevacizumab , Quimioterapia Adyuvante , Humanos , Indoles/administración & dosificación , Indoles/efectos adversos , Terapia Neoadyuvante , Neoplasias/patología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Complicaciones Posoperatorias/prevención & control , Piridinas/administración & dosificación , Piridinas/efectos adversos , Pirroles/administración & dosificación , Pirroles/efectos adversos , Sorafenib , SunitinibRESUMEN
BACKGROUND: Glioblastoma multiforme (GBM), a highly invasive and vascular cancer, responds poorly to conventional cytotoxic therapy. Integrins, widely expressed in GBM and tumor vasculature, mediate cell survival, migration and angiogenesis. Cilengitide is a potent alphavbeta3 and alphavbeta5 integrin inhibitor. OBJECTIVE: To summarize the preclinical and clinical experience with cilengitide for GBM. METHODS: Preclinical studies and clinical trials evaluating cilengitide for GBM were reviewed. RESULTS/CONCLUSIONS: Cilengitide is active and synergizes with external beam radiotherapy in preclinical GBM models. In clinical trials for recurrent GBM, single-agent cilengitide has antitumor benefits and minimal toxicity. Among newly diagnosed GBM patients, single-arm studies incorporating cilengitide into standard external beam radiotherapy/temozolomide have shown encouraging activity with no increased toxicity and have led to a planned randomized Phase III trial.
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Antineoplásicos/uso terapéutico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Glioblastoma/tratamiento farmacológico , Integrinas/metabolismo , Oligopéptidos/uso terapéutico , Venenos de Serpiente/uso terapéutico , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/química , Neoplasias del Sistema Nervioso Central/diagnóstico , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos , Glioblastoma/diagnóstico , Humanos , Modelos Moleculares , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Oligopéptidos/química , Unión Proteica , Venenos de Serpiente/administración & dosificación , Venenos de Serpiente/efectos adversos , Venenos de Serpiente/química , Resultado del TratamientoAsunto(s)
Amígdala del Cerebelo/patología , Neoplasias Encefálicas/complicaciones , Giro del Cíngulo/patología , Síndrome de Kluver-Bucy/etiología , Imagen por Resonancia Magnética/métodos , Bulbo Raquídeo/patología , Oligodendroglioma/complicaciones , Tálamo/patología , Adulto , Neoplasias Encefálicas/patología , Progresión de la Enfermedad , Humanos , Síndrome de Kluver-Bucy/patología , Masculino , Oligodendroglioma/patología , Trastornos Paranoides/etiologíaRESUMEN
TP-38 is a recombinant chimeric targeted toxin composed of the EGFR binding ligand TGF-alpha and a genetically engineered form of the Pseudomonas exotoxin, PE-38. After in vitro and in vivo animal studies that showed specific activity and defined the maximum tolerated dose (MTD), we investigated this agent in a Phase I trial. The primary objective of this study was to define the MTD and dose limiting toxicity of TP-38 delivered by convection-enhanced delivery in patients with recurrent malignant brain tumors. Twenty patients were enrolled in the study and doses were escalated from 25 ng/mL to 100 with a 40 mL infusion volume delivered by two catheters. One patient developed Grade IV fatigue at the 100 ng/mL dose, but the MTD has not been established. The overall median survival after TP-38 for all patients was 23 weeks whereas for those without radiographic evidence of residual disease at the time of therapy, the median survival was 31.9 weeks. Overall, 3 of 15 patients, with residual disease at the time of therapy, have demonstrated radiographic responses and one patient with a complete response and has survived greater than 83 weeks.