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1.
Br J Clin Pharmacol ; 86(9): 1778-1789, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32543711

RESUMEN

Immune checkpoint inhibitors have emerged as a revolutionary treatment option for patients with various types of malignancy. Although these agents afford a significant improvement in outcomes for melanoma and other previously untreatable malignancies, their novel mechanism of action may predispose patients to immune-related adverse effects (irAEs). In the tumour neoantigen environment, these irAEs are due to the activation of the immune system by the blockade of suppressive checkpoints, leading to increases in T-cell activation and proliferation. IrAEs have been reported in almost any organ and at any point in time, even months to years after discontinuation of therapy. Certain populations with distinct physiological changes, genetic risk factors, and specific antigen exposures may be more highly predisposed to develop irAEs. This review discusses the incidence and mechanisms of irAEs and the relationship between host factors and irAE occurrence.


Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inhibidores de Puntos de Control Inmunológico , Melanoma , Neoplasias , Humanos , Incidencia , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/uso terapéutico
2.
J Oncol Pharm Pract ; 25(3): 706-709, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-29334337

RESUMEN

Autoimmune hemolytic anemia occurs due to an interaction of IgG antibodies with protein antigens expressed on red blood corpuscles. Glucocorticoids are the mainstay of treatment for autoimmune hemolytic anemia. For patients not responding to initial therapy, other agents such as rituximab, immunosuppressive therapy, or splenectomy are considered. When refractory to these treatment options, alemtuzumab is an alternative agent. However, long-term outcomes of patients supporting its use are lacking. We present three patients with refractory autoimmune hemolytic anemia treated with alemtuzumab.


Asunto(s)
Alemtuzumab/uso terapéutico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino
3.
Oncologist ; 23(6): 686-692, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29487220

RESUMEN

BACKGROUND: Pazopanib is an oral tyrosine-kinase inhibitor that is approved by the U.S. Food and Drug Administration for treatment of metastatic renal cell carcinoma (mRCC). Pharmacokinetic data have shown that concomitant administration of pazopanib and esomeprazole, a proton pump inhibitor (PPI), leads to decreased area under the curve and thus decreased exposure of pazopanib by 40%. Despite the pharmacokinetic data published to date, the clinical significance and impact on patient outcomes resulting from decreased pazopanib exposure remains unknown. MATERIALS AND METHODS: In this retrospective, observational, cohort study, 90 patients with mRCC who either received pazopanib in combination with a PPI or histamine 2 receptor antagonist (H2RA; concurrent PPI/H2RA group) or who did not take concurrent pH-elevating medications (no PPI/H2RA group) were compared to determine if there was an impact on progression-free survival (PFS), the primary endpoint, and secondary endpoints, overall survival (OS) and safety. RESULTS: The differences between the PFS of 9.0 months and OS of 28.0 months for the concomitant PPI/H2RA group versus 11.0 months and 30.1 months, respectively, for the no PPI/H2RA group were not statistically significant. Rates of adverse events were similar between the concomitant PPI/H2RA and no PPI/H2RA groups. CONCLUSION: Concomitant PPI or H2RA usage was not shown to be associated with a reduction in PFS or OS for patients receiving pazopanib for mRCC, with a similar toxicity profile in each group. Based on the results of this retrospective cohort study and the palliative nature of the treatment of patients with mRCC, clinicians should consider allowing patients to remain on concomitant pazopanib and acid-reducing therapy. IMPLICATIONS FOR PRACTICE: Pazopanib is a preferred category-one first-line treatment for predominant clear cell metastatic renal cell carcinoma (mRCC). However, because of an aging demographic, coupled with patients with mRCC presenting with multiple comorbidities, including symptomatic dyspepsia or gastroesophageal reflux disease, patients are commonly required to take pazopanib concomitantly with a proton pump inhibitor (PPI) or a histamine 2 receptor antagonist (H2RA). Despite earlier pharmacokinetic reports suggesting that an alkaline pH may result in poorer absorption, this institutional retrospective study found no effect on clinical outcomes. These data suggest that concurrent treatment of mRCC with pazopanib and a PPI or H2RA may be safe in everyday practice.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Estudios de Cohortes , Femenino , Humanos , Indazoles , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Pirimidinas/farmacología , Estudios Retrospectivos , Sulfonamidas/farmacología , Análisis de Supervivencia
4.
Cancers (Basel) ; 14(15)2022 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-35954493

RESUMEN

A lower baseline neutrophil-to-eosinophil ratio (NER) has been associated with improved responses to immune checkpoint inhibitors (ICI)-treated metastatic renal cell carcinoma (mRCC). This study investigated the decrease in NER at week 6 after ipilimumab/nivolumab (ipi/nivo) initiation and treatment responses in mRCC. A retrospective study of ipi/nivo-treated mRCC at two US academic cancer centers was conducted. A landmark analysis at week 6 was performed to assess the association between the change in NER and clinical responses (progression-free survival (PFS)/overall survival (OS)). Week 6 NER was modeled as a continuous variable, after log transformation (Ln NER), and a categorical variable by percent change. There were 150 mRCC patients included: 78% had clear cell histology, and 78% were IMDC intermediate/poor risk. In multivariable regression analysis, every decrease of 1 unit of Ln NER at week 6 was associated with improved PFS (adjusted hazard ratio (AHR): 0.78, p-value:0.005) and OS (AHR: 0.67, p-value: 0.002). When NER was modeled by percent change, decreased NER > 50% was associated with improved PFS (AHR: 0.55, p-value: 0.03) and OS (AHR: 0.37, p-value: 0.02). The decrease in week 6 NER was associated with improved PFS/OS in ipi/nivo-treated mRCC. Prospective studies are warranted to validate NER change as a biomarker to predict ICI responses.

5.
Biomark Res ; 9(1): 80, 2021 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-34732251

RESUMEN

BACKGROUND: The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. METHODS: We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. RESULTS: A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with mNER (OR 2.39, p = 0.04). The median PFS for patients with mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with mNLR group. CONCLUSIONS: A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

6.
Cancers (Basel) ; 13(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33806963

RESUMEN

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05-5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

7.
PLoS One ; 14(12): e0225652, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31834899

RESUMEN

In urban areas green roofs provide important environmental advantages in regard to biodiversity, storm water runoff, pollution mitigation and the reduction of the urban heat island effect. There is a paucity of literature comparing different types of green roof substrates and their contributions to ecosystem services or their negative effects. This study investigated if there was a difference between sedum and wildflower green roof substrate properties (soil organic matter (SOM), potassium (K) and phosphorus (P) concentrations and pH values) of 12 green roofs in the city of Brighton & Hove. One hundred substrate samples were collected (50 from sedum roof substrates and 50 from wildflower roof substrates) and substrate properties were investigated using standard protocols. Comparisons were made between substrate characteristics on both types of roof substrate with a series of multiple linear regressions. Sedum roofs displayed significantly higher values of SOM, P and pH. There were significant positive relationships between SOM and K concentrations, SOM and P concentrations, pH and K concentrations and pH and P concentrations on sedum roofs. This study concluded that sedum roof substrates are more favourable for plant water use efficiency and also contained a significantly higher percentage of SOM than wildflower roofs. However, higher concentrations of P in sedum roof substrates may have implications in regard to leachates.


Asunto(s)
Conservación de los Recursos Naturales/métodos , Industria de la Construcción , Flores/crecimiento & desarrollo , Sedum/crecimiento & desarrollo , Suelo/química , Ciudades , Concentración de Iones de Hidrógeno , Fósforo/análisis , Potasio/análisis
8.
Pharmacotherapy ; 35(7): e122-6, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26147471

RESUMEN

In the setting of acute heparin-induced thrombocytopenia (HIT), argatroban is one of the initial anticoagulants of choice, which is eventually bridged to warfarin over a period of 5 or more days. Argatroban prolongs prothrombin time (PT) and increases international normalized ratio (INR). However, the effects of prolonged argatroban exposure on the PT and INR are not known. We describe an unusual case of prolonged argatroban treatment in a patient with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS) resulting in a minimal elevation of the INR. The patient received a total of 58 days of argatroban and was resistant to warfarin therapy, requiring a 13-day bridge to achieve a therapeutic INR of 2.0 to 3.0. Ultimately, argatroban was successfully transitioned to warfarin therapy when the INR was 2.7 on both agents, producing the confirmatory true INR of 2.4. Argatroban and warfarin cotherapy did not increase the INR beyond 4.0 after prolonged argatroban exposure. Clinicians should consider this unusual response in other cases of prolonged argatroban use, and monitor INR carefully during warfarin and argatroban cotherapy. The use of other methods to monitor anticoagulant therapy, such as chromogenic factor X assay (CFX), may be helpful in this setting.


Asunto(s)
Antitrombinas/administración & dosificación , Ácidos Pipecólicos/administración & dosificación , Tiempo de Protrombina , Anticoagulantes/efectos adversos , Anticoagulantes/uso terapéutico , Arginina/análogos & derivados , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/cirugía , Sustitución de Medicamentos , Femenino , Heparina/efectos adversos , Humanos , Relación Normalizada Internacional , Neoplasias Mandibulares/patología , Neoplasias Mandibulares/cirugía , Persona de Mediana Edad , Mucosa Bucal/patología , Sulfonamidas , Síndrome , Trombocitopenia/inducido químicamente , Trombosis/inducido químicamente , Insuficiencia del Tratamiento , Warfarina/uso terapéutico
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