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Metastatic pancreatic adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of only 11%, necessitating identification of novel treatment paradigms. Tumor tissue specimens from patients with PDAC, breast cancer, and other solid tumor malignancies were collected and tumor cells were enriched using laser microdissection (LMD). Reverse phase protein array (RPPA) analysis was performed on enriched tumor cell lysates to quantify a 32-protein/phosphoprotein biomarker panel comprising known anticancer drug targets and/or cancer-related total and phosphorylated proteins, including HER2Total, HER2Y1248, and HER3Y1289. RPPA analysis revealed significant levels of HER2Total in PDAC patients at abundances comparable to HER2-positive (IHC 3+) and HER2-low (IHC 1+ /2+ , FISH-) breast cancer tissues, for which HER2 screening is routinely performed. These data support a critical unmet need for routine clinical evaluation of HER2 expression in PDAC patients and examination of the utility of HER2-directed antibody-drug conjugates in these patients.
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BACKGROUND: Incidental pulmonary nodules (IPNs) are lung nodules detected on imaging studies performed for an unrelated reason. Approximately 1.6 million IPNs are detected in the United States every year. Unfortunately, close to 1.1 million (69%) of these IPNs are not managed with appropriate follow-up care. The goal of this study was to assess the utility of a noncommercial electronic medical record (EMR)-based IPN keyword recognition program in identifying IPNs and the ability of lung navigators to communicate these findings to patients. METHODS: This is a observational, implementation study aimed identify IPNs using an EMR-based protocol and to relay results of findings to patients. The patient population included patients 16 and older undergoing computed tomography (CT) chest, CT chest/abdomen, CT angiogram chest, CT chest/abdomen/pelvis, and chest radiography through the radiology department within a large community tertiary medical campus between June 2019 and August 2020. EPIC EMR were queried using criteria designed to find IPNs. A lung navigator reviewed these cases and sorted them into categories based on their size and risk status. After identification of risk factors, actions were taken to directly communicate results to patients. RESULTS: Seven hundred and fifty-three patients were found to have true IPNs without a history of active malignancy involving the lung. On the basis of radiographic measurements, 60% of the nodules identified were <6 mm, 17% were between 6 and 8 mm, 22% were >8 mm, and 12% were deemed nodular opacities. Lung navigators were able to contact a total of 637 (87%) individuals with IPNs and results were directly communicated. Of the 637 patients identified to have an IPN, a total of 12 (2%) cancers were diagnosed. CONCLUSION: We have here demonstrated that the development of an EMR-based keyword recognition platform for the identification of IPNs is a useful and successful tool for communication of IPN findings to patients using lung navigators.
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Neoplasias Pulmonares , Nódulos Pulmonares Múltiples , Humanos , Neoplasias Pulmonares/diagnóstico por imagen , Registros Electrónicos de Salud , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Pulmón , Tomografía Computarizada por Rayos X/métodos , Hallazgos IncidentalesRESUMEN
PURPOSE: Programmed death-1 immune checkpoint blockade improves survival of patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but the benefits of addition to (chemo)radiation for newly diagnosed patients with HNSCC remain unknown. METHODS AND MATERIALS: We evaluated the safety of nivolumab concomitant with 70 Gy intensity modulated radiation therapy and weekly cisplatin (arm 1), every 3-week cisplatin (arm 2), cetuximab (arm 3), or alone for platinum-ineligible patients (arm 4) in newly diagnosed intermediate- or high-risk locoregionally advanced HNSCC. Patients received nivolumab from 2 weeks prior to radiation therapy until 3 months post-radiation therapy. The primary endpoint was dose-limiting toxicity (DLT). If ≤2 of the first 8 evaluable patients experienced a DLT, an arm was considered safe. Secondary endpoints included toxicity and feasibility of adjuvant nivolumab to 1 year, defined as all 7 additional doses received by ≥4 of the first 8 evaluable patients across arms. RESULTS: Of 39 patients (10 in arms 1, 3, 4 and 9 in arm 2), 72% had T3-4 tumors, 85% had N2-3 nodal disease, and 67% had >10 pack-years of smoking. There were no DLTs in arms 1 and 2, 1 in arm 3 (mucositis), and 2 in arm 4 (lipase elevation and mucositis in 1 and fatigue in another). The most common grade ≥3 nivolumab-related adverse events were lipase increase, mucositis, diarrhea, lymphopenia, hyponatremia, leukopenia, fatigue, and serum amylase increase. Adjuvant nivolumab was feasible as defined in the protocol. CONCLUSIONS: Concomitant nivolumab with the 4 tested regimens was safe for patients with intermediate- and high-risk HNSCC, and subsequent adjuvant nivolumab was feasible as defined (NCT02764593).
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Mucositis , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Nivolumab/uso terapéutico , Cisplatino/uso terapéutico , Carcinoma de Células Escamosas/patología , Recurrencia Local de Neoplasia/patología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Fatiga/tratamiento farmacológicoRESUMEN
PURPOSE: The COVID-19 pandemic has posed significant challenges in the care of patients with cancer, including how to manage outpatients who are COVID-positive but do not require hospitalization. We explored the use of a remote patient monitoring (RPM) program to care for such outpatients. METHODS: Consecutive patients who were tested for COVID-19 because of symptom onset but were clinically stable were offered enrollment into a pilot RPM program. Patients were provided equipment for vital sign measurements and a computer tablet to enter results three times per day. The results were monitored centrally by clinical staff. The goal was to closely monitor patients and escalate care as warranted. RESULTS: Between March and June of 2020, 29 patients were approached and 26 were enrolled. The mean age was 57 years old (range, 30-88), 14 were women, and patients remained in the program for an average of 16 days (range, 2-63). Twenty-four patients (83%) were on active anticancer therapy. During that time period, only one patient was admitted to the hospital for worsening respiratory symptoms. The percentage of days during which at least one set of data and all three sets of data were entered was 97.2% and 65.7%, respectively. There was no association between the demographic factors of age, sex, or the reason for being monitored with the level of engagement (P > .05). CONCLUSION: In this pilot study, patients with cancer were readily enrolled in a remote home monitoring program. Monitoring was feasible, and there was a high rate of engagement with the program. The role of RPM should be further tested as the COVID pandemic continues.
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COVID-19 , Neoplasias , Femenino , Humanos , Persona de Mediana Edad , Neoplasias/epidemiología , Pandemias , Proyectos Piloto , SARS-CoV-2RESUMEN
Background/Objective: Understanding the influence of genetically determined ancestry may give insight into the disparities of obesity seen in different ethnic groups beginning at a very early age. Aim: To investigate the relationship between children's ancestral genetic proportions and excess weight at 12 months of age. Methods: Eight hundred twenty-one 12-month-old children were included in this cross-sectional study. Their genetic admixture was estimated using the ancestry and kinship tool kit by projecting the samples into the 1000 Genomes principal component database. Weight-for-length percentile (WFLP) at 12 months of age was categorized as <95th percentile or ≥95th percentile. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for the association of admixture proportions, including European (EUR), admixed American (AMR), African (AFR), South Asian (SAS), and East Asian (EAS) populations, with WFLP categories, adjusting for maternal education, birth weight, frequency of breastfeeding, and juice consumption. Results: Eight hundred twenty-one children were included; WFLP <95th percentile = 671 (81.7%) and WFLP ≥95th percentile = 150 (18.3%). Crude ORs showed that the EUR admixture was protective [OR 0.45 (95% CI 0.27-0.74)], whereas AMR [OR 3.85 (95% CI 1.92-7.70)] and AFR [OR 5.70 (95% CI 2.19-14.85)] admixtures were positively associated with excess weight. After adjusting for confounding variables, only the AFR admixture was associated with WFLP ≥95th percentile [OR 7.38 (95% CI 2.31-23.59)]. Conclusions: AFRs remain associated with early excess weight after accounting for confounding variables, suggesting that this ancestral genetic background may contribute to the differences seen in early childhood obesity.
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Peso Corporal/genética , Obesidad Infantil/genética , Grupos Raciales/genética , Estatura/genética , Estudios Transversales , Femenino , Fenómenos Genéticos/genética , Genoma Humano/genética , Humanos , Lactante , Masculino , Factores de RiesgoRESUMEN
Traditional cancer models including cell lines and animal models have limited applications in both basic and clinical cancer research. Genomics-based precision oncology only help 2-20% patients with solid cancer. Functional diagnostics and patient-derived cancer models are needed for precision cancer biology. In this review, we will summarize applications of conditional cell reprogramming (CR) in cancer research and next generation living biobanks (NGLB). Together with organoids, CR has been cited in two NCI (National Cancer Institute, USA) programs (PDMR: patient-derived cancer model repository; HCMI: human cancer model initiatives. HCMI will be distributed through ATCC). Briefly, the CR method is a simple co-culture technology with a Rho kinase inhibitor, Y-27632, in combination with fibroblast feeder cells, which allows us to rapidly expand both normal and malignant epithelial cells from diverse anatomic sites and mammalian species and does not require transfection with exogenous viral or cellular genes. Establishment of CR cells from both normal and tumor tissue is highly efficient. The robust nature of the technique is exemplified by the ability to produce 2 × 106 cells in five days from a core biopsy of tumor tissue. Normal CR cell cultures retain a normal karyotype and differentiation potential and CR cells derived from tumors retain their tumorigenic phenotype. CR also allows us to enrich cancer cells from urine (for bladder cancer), blood (for prostate cancer), and pleural effusion (for non-small cell lung carcinoma). The ability to produce inexhaustible cell populations using CR technology from small biopsies and cryopreserved specimens has the potential to transform biobanking repositories (NGLB: next-generation living biobank) and current pathology practice by enabling genetic, biochemical, metabolomic, proteomic, and biological assays, including chemosensitivity testing as a functional diagnostics tool for precision cancer medicine. We discussed analyses of patient-derived matched normal and tumor models using a case with tongue squamous cell carcinoma as an example. Last, we summarized applications in cancer research, disease modeling, drug discovery, and regenerative medicine of CR-based NGLB.
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Técnicas de Reprogramación Celular/métodos , Reprogramación Celular/fisiología , Amidas , Animales , Bancos de Muestras Biológicas/tendencias , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/patología , Técnicas de Cultivo de Célula/métodos , Diferenciación Celular , Línea Celular , Línea Celular Tumoral , Técnicas de Cocultivo/métodos , Células Epiteliales/patología , Humanos , Neoplasias Pulmonares/patología , Masculino , Modelos Biológicos , Medicina de Precisión/métodos , Neoplasias de la Próstata/patología , Proteómica , Piridinas , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Congenital disorders of autophagy are multisystem disorders with significant neurological involvement. Ectopic p-granules protein 5 (EPG5)-associated Vici syndrome is a prototypical congenital disorder of autophagy and presents with the cardinal features of agenesis of the corpus callosum, cataracts, cardiomyopathy, immunodeficiency, and oculocutaneous hypopigmentation. The majority of EPG5 variants leading to Vici syndrome are null alleles with only a few missense variants published to date. Here we report a 3.5-year-old male with compound heterozygous EPG5 variants [NM_020964.2: c.772G > T/c.5943-9_5943-5del]. His clinical presentation deviates notably from classic Vici syndrome with a lack of hypopigmentation, cataracts, immunodeficiency, cardiomyopathy, or failure to thrive. Neurological manifestations within the known disease spectrum include early-onset global developmental delay, hypotonia, and postnatal microcephaly. Seizures, hearing loss, or optic nerve atrophy are absent, however. Magnetic resonance imaging demonstrates a thin but fully formed corpus callosum. Based on the ameliorated and primarily neurological phenotype, we hypothesized that the functional impact of the EPG5 variants present would be milder with a higher amount of residual EPG5 expression. Analyses of EPG5 messenger ribonucleic acid (mRNA) in the patient and his parents were performed to examine expression level and splicing; mRNA from a healthy control and a patient with classic Vici syndrome was also included. Aberrant splicing due to the intronic mutation was detected, but no loss of expression. In contrast, we observed a 50% reduction in mRNA expression in classic Vici syndrome patient fibroblasts. These results support a model of disease severity, which correlates to the dosage of EPG5 expression.
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Agenesia del Cuerpo Calloso/genética , Proteínas Relacionadas con la Autofagia/genética , Catarata/genética , Cuerpo Calloso/diagnóstico por imagen , Mutación , Fenotipo , Proteínas de Transporte Vesicular/genética , Agenesia del Cuerpo Calloso/diagnóstico por imagen , Catarata/diagnóstico por imagen , Preescolar , Humanos , Imagen por Resonancia Magnética , Masculino , Índice de Severidad de la EnfermedadRESUMEN
The uncharacterized gene KIAA1 109 has recently been associated with a congenital neurological malformation disorder that variably presents with arthrogryposis, craniofacial and/or cardiac abnormalities. We have identified two additional patients with compound heterozygous KIAA1109 variants presenting with the same neurological malformations. The mechanism whereby KIAA1109 loss of function causes this spectrum of disorders was the primary focus of our studies. We hypothesized that KIAA1109 function could be conserved relative to the fly gene tweek and examined endocytosis and endosome recycling in patient fibroblasts. Furthermore, we examined the structure of the cytoskeleton and cilia based on functional overlap with endocytosis and several known etiologies for neuronal migration disorders. Utilizing primary dermal fibroblasts from one patient and a healthy donor, we performed immunofluorescence and endocytosis assays to examine the endosomal, cytoskeletal, and ciliary cellular phenotypes. We found notable abnormalities in endosomal trafficking and endosome recycling pathways. We also observed changes in the actin cytoskeleton and cilia structural dynamics. We conclude that the function of KIAA1109 in humans may indeed overlap with the function of the Drosophila ortholog, resulting in perturbations to endosomal trafficking and the actin cytoskeleton. These alterations have ripple effects, altering many pathways that are critical for proper neuronal migration and embryonic development.
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BACKGROUND: Hispanic children are disproportionately affected by obesity, with this disparity starting at a young age, and there is a paucity of data comparing factors associated with excess weight in the first year of life in Hispanic vs. non-Hispanic populations. METHODS: Excess weight was defined as weight-for-length ≥95th percentile. The associations of potential risk factors were compared by ethnicity stratification. RESULTS: Of the 1009 children, 302 (30.0%) were Hispanic and 707 (70.0%) were non-Hispanic White. The rate of excess weight was 30.1% and 13.6% among Hispanic and non-Hispanic White children, respectively. Factors associated with excess weight for non-Hispanic White children were higher than recommended weight gain during pregnancy (odds ratio (OR) 1.8 (1.2-3.1)), higher paternal body mass index (BMI) (OR 1.1 (1.02-1.15)), higher birth weight (OR 1.001 (1.001-1.002)), and lower breast milk feedings at 6 months (OR 0.98 (0.96-0.98)). Factors associated with excess weight for Hispanic children were lower maternal education (OR 2.37 (1.1-4.5)) and lower breast milk feedings at 6 months (OR 0.98 (0.96-0.99)). CONCLUSION: There are differential risk factors associated with excess weight at 12 months between Hispanic and non-Hispanic White children. Identification of differential factors in different ethnicities may allow for more targeted anticipatory guidance reduce obesity in at-risk populations.
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Peso Corporal , Obesidad Infantil/etnología , Obesidad Infantil/genética , Aumento de Peso , Peso al Nacer , Índice de Masa Corporal , Lactancia Materna , Padre , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Masculino , Madres , Oportunidad Relativa , Embarazo , Factores de Riesgo , Determinantes Sociales de la Salud , Estados Unidos/epidemiología , Población Blanca/estadística & datos numéricosRESUMEN
Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent-offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in previously identified regions with accelerated maternal mutation rates. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G transversions. Finally, we found that maternal clusters were associated with processes involving double-strand-breaks (DSBs), such as meiotic gene conversions and de novo deletion events. This result suggested accumulation of DSB-induced mutations throughout oocyte aging as the mechanism underlying the formation of maternal mutation clusters.
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Senescencia Celular/genética , Roturas del ADN de Doble Cadena , Mutación de Línea Germinal , Oocitos/citología , Oocitos/metabolismo , Adulto , Estudios de Cohortes , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Femenino , Humanos , Recién Nacido , Masculino , Edad Materna , Persona de Mediana Edad , Familia de Multigenes , Edad Paterna , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
PURPOSE: The artemisinin class of anti-malarial drugs has shown significant anti-cancer activity in pre-clinical models. Proposed anti-cancer mechanisms include DNA damage, inhibition of angiogenesis, TRAIL-mediated apoptosis, and inhibition of signaling pathways. We performed a phase I study to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous artesunate (IV AS). METHODS: Patients were enrolled in an accelerated titration dose escalation study with planned dose levels of 8, 12, 18, 25, 34 and 45 mg/kg given on days 1 and 8 of a 21-day cycle. Toxicities were assessed using the NCI CTCAE (ver. 4.0), and response was assessed using RECIST criteria (version 1.1). Pharmacokinetic (PK) studies were performed during cycle 1. RESULTS: A total of 19 pts were enrolled, 18 of whom were evaluable for toxicity and 15 were evaluable for efficacy. DLTs were seen at dosages of 12 (1 of 6 patients), 18 (1 of 6) and 25 mg/kg (2 of 2), and were neutropenic fever (Gr 4), hypersensitivity reaction (Gr 3), liver function test abnormalities (Gr 3/4) along with neutropenic fever, and nausea/vomiting (Gr 3) despite supportive care. The MTD was determined to be 18 mg/kg. No responses were observed, while four patients had stable disease, including three with prolonged stable disease for 8, 10, and 11 cycles, for a disease control rate of 27%. PK parameters of AS and its active metabolite, dihydroartemisinin (DHA), correlated with dose. CONCLUSION: The MTD of intravenous artesunate is 18 mg/kg on this schedule. Treatment was well tolerated. Modest clinical activity was seen in this pre-treated population. CLINICALTRIALS. GOV IDENTIFIER: NCT02353026.
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Artesunato/uso terapéutico , Neoplasias/tratamiento farmacológico , Administración Intravenosa , Adulto , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Área Bajo la Curva , Artesunato/administración & dosificación , Artesunato/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Neoplasias/metabolismo , Neoplasias/patología , Resultado del Tratamiento , Vómitos/inducido químicamenteRESUMEN
PURPOSE: Prevalence of non-AIDS-defining cancers (NADCs) has increased in the era of potent antiretroviral treatments. Incidence rates of NADCs now exceed AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by interactions between antiretrovirals and chemotherapy mostly via inhibition or induction of CYP3A4. Erlotinib is used to treat non-small cell lung and pancreatic cancer and is primarily metabolized by CYP3A4 into multiple products including the active metabolite (OSI-420). Preclinical in vivo assessment was performed to gain a better understanding of CYP3A4-mediated interactions between antiretrovirals and erlotinib. METHODS: Erlotinib (50 mg/kg p.o.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. QDx4), efavirenz (25 mg/kg p.o. QDx4), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). Blood samples were collected to characterize exposure (AUC). RESULTS: Administration of erlotinib with CYP3A4 inducers (dexamethasone) and inhibitors (ketoconazole and ritonavir) resulted in significant alterations in erlotinib exposure. Ketoconazole and ritonavir resulted in a 1.7- and 3.0-fold increase in erlotinib AUC, respectively, while dexamethasone results in a 0.6-fold decrease in erlotinib AUC. The CYP3A4 inducer efavirenz did not have a significant effect on erlotinib exposure. CONCLUSION: CYP3A4 inducers and inhibitors altered the exposure of erlotinib. Until a definitive clinical trial is performed, erlotinib should be used with caution in patients on a ritonavir-containing antiretroviral regimen, while standard doses may be appropriate for patients on an efavirenz-containing antiretroviral regimen.
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Antirretrovirales/farmacología , Antineoplásicos/farmacocinética , Inductores del Citocromo P-450 CYP3A/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Clorhidrato de Erlotinib/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Ritonavir/farmacología , Administración Oral , Alquinos , Animales , Antirretrovirales/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Benzoxazinas/administración & dosificación , Benzoxazinas/farmacología , Disponibilidad Biológica , Biotransformación/efectos de los fármacos , Ciclopropanos , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Dexametasona/administración & dosificación , Dexametasona/farmacología , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Clorhidrato de Erlotinib/administración & dosificación , Clorhidrato de Erlotinib/sangre , Semivida , Cetoconazol/administración & dosificación , Cetoconazol/farmacología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Ratones Endogámicos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/sangre , Quinazolinas/sangre , Ritonavir/administración & dosificaciónRESUMEN
Opinion statement: The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer. Epidermal growth factor receptor (EGFR) inhibitors have been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations. Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry, as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors. However, expanded analyses of first-line metastatic trials reveal that other RAS mutations, such as other KRAS mutations in exons 3 and 4, along with NRAS mutations, are predictive of poor responses to EGFR inhibitors as well. Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor. Further clinical trials are required to determine the predictive impact of each of these individual mutations. To date, they have been analyzed in the aggregate. The addition of targeted therapy, bevacizumab or an EGFR inhibitor, to a chemotherapy backbone should be considered for all appropriate patients. The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition. The largest trial that compared bevacizumab with an EGFR inhibitor in the first line, CALGB/SWOG 80405, did not show a statistically significant difference between the two groups, making the use of bevacizumab, cetuximab, or panitumumab reasonable in the first line.
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Anticuerpos Monoclonales/administración & dosificación , Antineoplásicos/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Mutación/efectos de los fármacos , Proteínas Proto-Oncogénicas p21(ras)/efectos de los fármacos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Receptores ErbB/antagonistas & inhibidores , Exones , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
BACKGROUND: Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors. METHODS: Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies. RESULTS: Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders. CONCLUSIONS: The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Neoplasias del Ano/tratamiento farmacológico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Células Escamosas/tratamiento farmacológico , Cetuximab , Neoplasias Colorrectales/tratamiento farmacológico , Diarrea/inducido químicamente , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Erupciones por Medicamentos/etiología , Receptores ErbB/genética , Femenino , Variación Genética , Genotipo , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Lapatinib , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Farmacogenética , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Receptor ErbB-2/genética , Transducción de Señal/efectos de los fármacos , Resultado del TratamientoRESUMEN
BACKGROUND: The purpose of this study was to report long-term outcomes for a large cohort of patients with head and neck squamous cell carcinoma (HNSCC) who underwent stereotactic body radiotherapy (SBRT) reirradiation. METHODS: From 2002 to 2011, 85 patients with previously irradiated HNSCC were treated with SBRT to 94 lesions. Some underwent surgery (29%), and many were treated with induction, concurrent, and/or adjuvant chemotherapy or biologic therapy (70%). RESULTS: Reirradiation occurred at a median interval from initial radiotherapy (RT) of 32 months. Median follow-up for survivors was 17.3 months. Two-year Kaplan-Meier estimates of overall survival (OS) and locoregional control for patients and lesions treated with curative intent were 24% and 28%, respectively. Interval from initial RT to SBRT of 2 years or more was associated with improved OS (p = .019). Five patients had grade 3 or higher late toxicity (5.9%). CONCLUSION: SBRT reirradiation results in limited toxicity. Further research is needed to refine optimal roles for SBRT and intensity-modulated radiotherapy (IMRT) reirradiation.
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Carcinoma de Células Escamosas/cirugía , Neoplasias de Cabeza y Cuello/cirugía , Radiocirugia/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Terapia Combinada , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Radiocirugia/efectos adversos , Reirradiación , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: The optimal treatment for patients with recurrent human papillomavirus (HPV)-positive head and neck cancer is poorly understood. METHODS: We investigated treatments and outcomes in patients with recurrent head and neck cancer. Treatments included salvage neck surgery, metastasectomy, hypofractionated reirradiation, chemoembolization, and chemotherapy. Treatment outcomes were compared based on HPV status. RESULTS: A total of 37 patients were identified (12 HPV positive and 25 HPV negative). Demographics were similar. Overall, there was a trend toward a higher number of total treatment interventions in patients with HPV-positive disease (4.5 vs 2.6), but this was statistically insignificant (p=.066). After a mean follow-up of 21 months, median survival in HPV-negative patients was 10.6 months, whereas the median survival had not been reached for HPV-positive patients. Of the 12 HPV-positive patients, 7 were still alive (58%) after a mean follow-up period of 33 months. CONCLUSION: Multimodality aggressive therapy may improve overall survival in patients with recurrent HPV-positive disease. Further prospective research is warranted.
Asunto(s)
Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/virología , Infecciones por Papillomavirus/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Quimioradioterapia/métodos , Estudios de Cohortes , Terapia Combinada , Supervivencia sin Enfermedad , Embolización Terapéutica/métodos , Femenino , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/virología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Disección del Cuello/métodos , Recurrencia Local de Neoplasia/terapia , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/terapia , Pronóstico , Estudios Retrospectivos , Terapia Recuperativa , Carcinoma de Células Escamosas de Cabeza y Cuello , Estadísticas no Paramétricas , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. PATIENTS AND METHODS: Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1-5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. RESULTS: The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. CONCLUSIONS: The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted.
Asunto(s)
Epotilonas/uso terapéutico , Neoplasias/tratamiento farmacológico , Moduladores de Tubulina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Epotilonas/farmacocinética , Epotilonas/farmacología , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/farmacologíaRESUMEN
PURPOSE: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug-drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. METHODS: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. ×4d), efavirenz (25 mg/kg p.o. ×4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. RESULTS: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. CONCLUSIONS: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered.
Asunto(s)
Antineoplásicos/farmacocinética , Inhibidores de la Proteasa del VIH/farmacología , Ritonavir/farmacología , Taxoides/farmacocinética , Alquinos , Animales , Antineoplásicos/farmacología , Benzoxazinas/farmacología , Ciclopropanos , Citocromo P-450 CYP3A/biosíntesis , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Dexametasona/farmacología , Docetaxel , Interacciones Farmacológicas , Quimioterapia Combinada , Inducción Enzimática/efectos de los fármacos , Cetoconazol/farmacología , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Inhibidores de la Transcriptasa Inversa/farmacología , Taxoides/farmacologíaRESUMEN
BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non-ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir.