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1.
Ann Oncol ; 27(2): 332-8, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26578727

RESUMEN

BACKGROUND: MicroRNAs (miRNAs) have been identified as key players in posttranscriptional gene regulation and have a significant impact on basal cell carcinoma (BCC) development. The Sonic hedgehog pathway inhibitor vismodegib has been approved for oral therapy of metastatic or advanced BCC. Here, a high-throughput miRNA sequencing analysis was carried out to identify differentially expressed miRNAs and possible novel miRNA candidates in vismodegib-treated BCC tissue. Additionally, we described our surgical experience with neoadjuvant oral vismodegib therapy. PATIENTS AND METHODS: A punch biopsy (4 mm) from a patient with an extensive cranial BCC under oral vismodegib therapy and a corresponding nonlesional epithelial skin biopsy were harvested. Total RNA was isolated, after which a sequencing cDNA library was prepared, and cluster generation was carried out, which was followed by an ultra-high-throughput miRNA sequencing analysis to indicate the read number of miRNA expression based on miRBase 21. In addition to the identification of differentially expressed miRNAs from RNA sequencing data, additional novel miRNA candidates were determined with a tool for identifying new miRNA sequences (miRDeep2). RESULTS: We identified 33 up-regulated miRNAs (fold change ≥2) and 39 potentially new miRNA candidates (miRDeep scores 0-43.6). A manual sequence analysis of the miRNA candidates on the genomic locus of chromosome 1 with provisional IDs of chr1_1913 and chr1_421 was further carried out and rated as promising (chr1_1913) and borderline (chr1_421). Histopathology revealed skip lesions in clinically healthy appearing skin at the tumor margins, which were the cause of seven re-excisions by micrographic controlled surgery to achieve tumor-free margins. CONCLUSION: miRNA sequencing revealed novel miRNA candidates that need to be further confirmed in functional Dicer knockout studies. Clinically, on the basis of our surgical experience described here, neoadjuvant vismodegib therapy in BCC appears to impede histopathologic evaluations with effects on surgical therapy. Thus, larger studies are necessary, but are not preferable at this time if other options are available.


Asunto(s)
Carcinoma Basocelular/genética , Regulación Neoplásica de la Expresión Génica/genética , MicroARNs/genética , Neoplasias Cutáneas/genética , Piel/patología , Anciano , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Secuencia de Bases , Biopsia , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/cirugía , Femenino , Proteínas Hedgehog/antagonistas & inhibidores , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Datos de Secuencia Molecular , Piridinas/uso terapéutico , Análisis de Secuencia de ARN , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía
2.
Eur J Cancer ; 45(4): 551-60, 2009 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-18996690

RESUMEN

BACKGROUND: Few data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer. METHODS: Self-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression. RESULTS: Of 892 women, 55% (n=489) used CAM, 6% (n=53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83-3.58, p<0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00-1.10, p=0.049), greater anxiety (OR 1.92, 95% CI 1.16-3.16, p=0.01), not currently smoking (OR 0.64, 95% CI 0.42-0.97, p=0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72-0.94, p=0.005). CONCLUSIONS: The majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.


Asunto(s)
Neoplasias de la Mama/prevención & control , Terapias Complementarias/estadística & datos numéricos , Síndromes Neoplásicos Hereditarios/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/psicología , Proteínas Reguladoras de la Apoptosis , Actitud Frente a la Salud , Australia , Proteína BRCA2/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/psicología , Terapias Complementarias/psicología , Escolaridad , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Persona de Mediana Edad , Actividad Motora , Mutación , Nueva Zelanda , Ubiquitina-Proteína Ligasas/genética , Adulto Joven
3.
Br J Cancer ; 92(5): 832-7, 2005 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-15756253

RESUMEN

This study determined the efficacy and safety of a modified FOLFOX regimen that improved patient convenience without compromising oxaliplatin dose intensity. A total of 62 patients with previously untreated metastatic colorectal cancer were enrolled to receive, entirely as outpatients, 2-weekly cycles of oxaliplatin 100 mg m(-2) i.v. over 2 h, together with leucovorin 400 mg m(-2) over 2 h, 5-fluorouracil (5-FU) 400 mg m(-2), bolus, followed by a 46-h infusion of 5-FU at 2.4 g m(-2). Treatment was given until progression or unmanageable toxicity. In all, 61 patients received > or =one oxaliplatin dose and a median of 11 treatment cycles (range 1-20 cycles); 22 (36%) reported grade 3/4 neutropenia and 13 patients (21%) experienced grade 3 neurotoxicity; 16 patients (26%) discontinued treatment due to disease progression or death, 15 (25%) due to neurotoxicity and six (10%) due to haematological toxicity. Of the 56 eligible patients, complete or partial responses were observed in 29 or 52% (95% confidence interval 38-65%). Median progression-free survival was 8.2 months (7.1-9.9) and median overall survival was 18.7 months (14.0-23.4). In our experience, a modified schedule of FOLFOX improves convenience without compromising efficacy or toxicity.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Leucovorina/uso terapéutico , Compuestos Organoplatinos/uso terapéutico , Neoplasias del Recto/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Australia , Quimioterapia Adyuvante , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Hospitalización/estadística & datos numéricos , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Neoplasias del Recto/mortalidad , Neoplasias del Recto/patología , Análisis de Supervivencia
4.
Lancet ; 357(9270): 1767-8, 2001 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-11403819

RESUMEN

Cancer cells that have DNA mismatch repair deficiency are resistant to many cytotoxic drugs. Calcium channel blockers may inhibit the pathways that cause such resistance. We report a patient with hereditary non-polyposis coli and metastatic colon cancer who had a complete response after treatment with a high dose of nifedipine, a calcium channel blocker. Our findings suggest that drugs that interfere with signal transduction could have a clinical role and deserve further study in selected patients.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Poliposis Adenomatosa del Colon/tratamiento farmacológico , Bloqueadores de los Canales de Calcio/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/secundario , Reparación del ADN/genética , Nifedipino/uso terapéutico , Neoplasias Gástricas/patología , Adenocarcinoma/patología , Neoplasias del Colon/patología , Reparación del ADN/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Células Tumorales Cultivadas/efectos de los fármacos
5.
Semin Surg Oncol ; 19(1): 11-9, 2000.
Artículo en Inglés | MEDLINE | ID: mdl-10883019

RESUMEN

Epithelial carcinoma of the ovary is the most lethal of gynaecological malignancies and it affects about one in 70 women in developed countries. Over 75% of women with the disease have tumour spread beyond the pelvis at the time of diagnosis, and their treatment requires the appropriate use of surgery and chemotherapy. The strategies used in the treatment of ovarian cancer are constantly evolving. An overview of current treatment regimens and their evolution is provided, with particular emphasis on the interdependence of surgery and chemotherapy in the optimal management of the disease.


Asunto(s)
Carcinoma/tratamiento farmacológico , Carcinoma/cirugía , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Ca-125/sangre , Carcinoma/diagnóstico , Quimioterapia Adyuvante , Femenino , Humanos , Laparotomía , Escisión del Ganglio Linfático , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasias Ováricas/diagnóstico , Compuestos de Platino/uso terapéutico , Reoperación
6.
J Neurosci ; 19(13): 5528-48, 1999 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-10377361

RESUMEN

Nitric oxide (NO) modulates neurotransmitter release, induction of long-term synaptic potentiation and depression, and activity levels of neurons. However, it is not known whether NO contributes to the ability of the CNS to distinguish sensory signals from background noise and/or extract sensory information with greater reliability. We addressed these questions in the visual cortex, in vivo, using electrophysiological recording and analysis of signal detection from individual neurons. This was combined with microiontophoretic application of arginine analogs that either upregulate or downregulate the brain's endogenous NO-generating pathways or compounds that produce exogenous NO. Protocols that enhance NO levels generally increased the number of action potentials per trial evoked by visual stimuli, improved signal detection, and decreased the coefficient of variation of visually evoked responses, whereas NO-reducing protocols predominantly had complementary effects. Control experiments demonstrate that these effects are likely attributable to the specific ability of these arginine compounds to modify NO levels versus other nonspecific effects. Differential effects between neighboring cells and between single-cell receptive subfields suggest that these actions have a significant direct neural component versus exclusively operating indirectly on neurons through the central vascular actions of NO.


Asunto(s)
Arginina/farmacología , Neuronas/fisiología , Corteza Visual/citología , Percepción Visual/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Arginina/análogos & derivados , Gatos , Regulación hacia Abajo/efectos de los fármacos , Electrofisiología , Potenciales Evocados Visuales/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Óxido Nítrico/metabolismo , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Estimulación Luminosa , Flujo Sanguíneo Regional/fisiología , Sinapsis/efectos de los fármacos , Sinapsis/metabolismo , Sinapsis/fisiología , Regulación hacia Arriba/efectos de los fármacos , Corteza Visual/irrigación sanguínea , Corteza Visual/efectos de los fármacos , Corteza Visual/fisiología , Percepción Visual/fisiología
7.
J Clin Oncol ; 16(5): 1948-53, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9586914

RESUMEN

PURPOSE: Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS: Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS: A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION: Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Taxoides , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Progresión de la Enfermedad , Docetaxel , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/análogos & derivados , Tasa de Supervivencia
8.
Shock ; 9(2): 84-8, 1998 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9488251

RESUMEN

RBC deformability (RBCD) is decreased in critically ill patients. This is thought to impede the passage of the RBC through the microcirculation. The cell transit analyzer (CTA) provides an evaluation of RBCD. RBCD was examined in 16 patients admitted to the surgical intensive care unit. CTA analysis was conducted within 24 h of admission to the surgical intensive care unit or as soon as possible thereafter, and then repeated every 72 h. Counts per second (C/s) was the parameter used as an index of RBCD. Patients were classified as Septic/SIRS or nonseptic at the time of each blood collection by standard clinical criteria. There were 34 total specimens, 22 septic/SIRS and 12 nonseptic. The C/s for the SIRS samples (41.7 +/- 3.4 was significantly (p < .05) lower than that of the non-SIRS samples (54.3 +/- 5.3). Seventeen of the Septic/SIRS samples were obtained following blood transfusion. Pearson's test calculated for the C/s and the total number of packed RBC transfusions showed a positive correlation (r = .594) that was statistically significant (p < .02). CTA was also performed on 10 U of banked packed RBC in vitro. Deformability was maintained at a constant level until the very end of the storage period, at which time there was a statistically significant decrease in C/s (p < .0001). These data suggest that packed RBC transfusion is associated with a significant improvement in the abnormally low RBCD seen in critically ill patients. This may be due to replacement of previously rigidified cells by cells with a more normal RBCD.


Asunto(s)
Deformación Eritrocítica , Transfusión de Eritrocitos , Sepsis/terapia , Síndrome de Respuesta Inflamatoria Sistémica/terapia , Adulto , Anciano , Anciano de 80 o más Años , Transfusión de Sangre Autóloga , Tamaño de la Célula , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Sepsis/microbiología
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