RESUMEN
The cause of the high degree of variability in cognition and behavior among individuals with Down syndrome (DS) is unknown. We hypothesized that birth defects requiring surgery in the first years of life (congenital heart defects and gastrointestinal defects) might affect an individual's level of function. We used data from the first 234 individuals, age 6-25 years, enrolled in the Down Syndrome Cognition Project (DSCP) to test this hypothesis. Data were drawn from medical records, parent interviews, and a cognitive and behavior assessment battery. Results did not support our hypothesis. That is, we found no evidence that either birth defect was associated with poorer outcomes, adjusting for gender, race/ethnicity, and socioeconomic status. Implications for study design and measurement are discussed.
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Síntomas Conductuales/epidemiología , Disfunción Cognitiva/epidemiología , Anomalías del Sistema Digestivo/epidemiología , Trisomía del Cromosoma 21/epidemiología , Cardiopatías Congénitas/epidemiología , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
HLA-DRB1*07:01 allele carriage was characterised as a risk biomarker for lapatinib-induced liver injury in a large global study evaluating lapatinib, alone and in combination with trastuzumab and taxanes, as adjuvant therapy for advanced breast cancer (adjuvant lapatinib and/or trastuzumab treatment optimisation). HLA-DRB1*07:01 carriage was associated with serum alanine aminotransferase (ALT) elevations in lapatinib-treated patients (odds ratio 6.5, P=3 × 10-26, n=4482) and the risk and severity of ALT elevation for lapatinib-treated patients was higher in homozygous than heterozygous HLA-DRB1*07:01 genotype carriers. A higher ALT case incidence plus weaker HLA association observed during concurrent administration of lapatinib and taxane suggested a subset of liver injury in this combination group that was HLA-DRB1*07:01 independent. Furthermore, the incidence of ALT elevation demonstrated an expected correlation with geographic HLA-DRB1*07:01 carriage frequency. Robust ALT elevation risk estimates for HLA-DRB1*07:01 may support causality discrimination and safety risk management during the use of lapatinib combination therapy for the treatment of metastatic breast cancer.
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Neoplasias de la Mama/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Cadenas HLA-DRB1/genética , Lapatinib/efectos adversos , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lapatinib/administración & dosificación , Hígado/efectos de los fármacos , Hígado/patología , Estadificación de Neoplasias , Factores de Riesgo , Taxoides/administración & dosificación , Taxoides/efectos adversos , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversosRESUMEN
Background: We performed whole-exome sequencing of pretreatment biopsies and examined whether genome-wide metrics of overall mutational load, clonal heterogeneity or alterations at variant, gene, and pathway levels are associated with treatment response and survival. Patients and Methods: Two hundred and three biopsies from the NeoALTTO trial were analyzed. Mutations were called with MuTect, and Strelka, using pooled normal DNA. Associations between DNA alterations and outcome were evaluated by logistic and Cox-proportional hazards regression. Results: There were no recurrent single gene mutations significantly associated with pathologic complete response (pCR), except PIK3CA [odds ratio (OR) = 0.42, P = 0.0185]. Mutations in 33 of 714 pathways were significantly associated with response, but different genes were affected in different individuals. PIK3CA was present in 23 of these pathways defining a 'trastuzumab resistance-network' of 459 genes. Cases with mutations in this network had low pCR rates to trastuzumab (2/50, 4%) compared with cases with no mutations (9/16, 56%), OR = 0.035; P < 0.001. Mutations in the 'Regulation of RhoA activity' pathway were associated with higher pCR rate to lapatinib (OR = 14.8, adjusted P = 0.001), lapatinib + trastuzumab (OR = 3.0, adjusted P = 0.09), and all arms combined (OR = 3.77, adjusted P = 0.02). Patients (n = 124) with mutations in the trastuzumab resistance network but intact RhoA pathway had 2% (1/41) pCR rate with trastuzumab alone (OR = 0.026, P = 0.001) but adding lapatinib increased pCR rate to 45% (17/38, OR = 1.68, P = 0.3). Patients (n = 46) who had no mutations in either gene set had 6% pCR rate (1/15) with lapatinib, but had the highest pCR rate, 52% (8/15) with trastuzumab alone. Conclusions: Mutations in the RhoA pathway are associated with pCR to lapatinib and mutations in a PIK3CA-related network are associated with resistance to trastuzumab. The combined mutation status of these two pathways could define patients with very low response rate to trastuzumab alone that can be augmented by adding lapatinib or substituting trastuzumab with lapatinib.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/uso terapéutico , Biopsia con Aguja Fina/métodos , Neoplasias de la Mama/enzimología , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , ADN de Neoplasias/genética , Femenino , Humanos , Lapatinib , Terapia Molecular Dirigida , Mutación , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/administración & dosificación , Trastuzumab/administración & dosificación , Secuenciación del Exoma , Proteína de Unión al GTP rhoA/genética , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
As the first approved epidermal growth factor receptor (EGFR)-targeted therapy for nonsmall cell lung cancer (NSCLC), the clinical development of gefitinib was complex. Advances in scientific understanding of the target biology during its clinical development enabled the identification of a biomarker to define patients most likely to derive benefit from gefitinib. Initial phase II trials showed clinically meaningful anti-tumour activity in 12-18% of unselected pretreated patients with advanced NSCLC at the optimum biological dose (250 mg). Subgroup analyses of these and subsequent phase III trials in unselected patients suggested that EGFR mutation and some clinical characteristics associated with a higher incidence of EGFR mutation (Asian ethnicity, adenocarcinoma histology, never-smoking and female sex) were linked with increased response to gefitinib. Consequently, the IRESSA Pan-Asia Study (IPASS) was conducted in never-smokers or former light-smokers in East Asia who had adenocarcinoma of the lung. IPASS showed that EGFR mutation was the strongest predictor of improved progression-free survival (mutation-positive subgroup hazard ratio (HR) 0.48, 95% CI 0.36-0.64 (p<0.001, n = 261); mutation-negative subgroup HR 2.85, 95% CI 2.05-3.98 (p<0.001, n = 176); interaction test p<0.001) with gefitinib versus carboplatin/paclitaxel as first-line therapy for advanced NSCLC. Important lessons for the development of future personalised medicines are discussed.
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Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/uso terapéutico , Gefitinib , Humanos , Medicina de PrecisiónRESUMEN
UNLABELLED: The objectives of this study were to confirm: (i) whether progestin treatment suppressed GnRH agonist-induced estrus in anestrous greyhound bitches; and (ii) the site of progestin action (i.e. pituitary, ovary). All bitches received a deslorelin implant on Day 0 and blood samples were taken from -1 h to +6 h. Five bitches were treated with megestrol acetate (2 mg/kg orally once daily) from -7 d to +6 d (Group 1) and 10 bitches were untreated controls (Group 2). Proestrous or estrous signs were observed in 4 of 5 bitches in Group 1, and 4 of 10 bitches in Group 2 (P = 0.28). The plasma LH responses (area under the curve from 0 to 6h after implantation) were higher (P = 0.008) in Group 2 than in Group 1. Plasma LH responses were similar (P = 0.59) in bitches showing signs of proestrus or estrus (responders) and in non-responders. The plasma estradiol responses (calculated as for LH response) were greater in Group 1 than in Group 2 (P = 0.048), and in responders than in non-responders (P = 0.02). IN CONCLUSION: (i) progestin treatment (a) did not suppress the incidence of bitches showing deslorelin-induced proestrus or estrus, and (b) was associated with a reduced pituitary responsiveness and an increased ovarian responsiveness to deslorelin treatment; (ii) the occurrence of proestrous or estrous signs reflected increased ovarian responsiveness to induced gonadotrophin secretion and not increased pituitary responsiveness to deslorelin.
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Anestro/fisiología , Perros/fisiología , Estradiol/sangre , Hormona Luteinizante/sangre , Progestinas/farmacología , Pamoato de Triptorelina/análogos & derivados , Anestro/efectos de los fármacos , Animales , Perros/sangre , Implantes de Medicamentos , Estro/efectos de los fármacos , Estro/fisiología , Femenino , Acetato de Megestrol/farmacología , Progesterona/sangre , Pamoato de Triptorelina/administración & dosificación , Pamoato de Triptorelina/antagonistas & inhibidores , Pamoato de Triptorelina/farmacologíaAsunto(s)
Eritema/etiología , Neoplasias de la Próstata/complicaciones , Anciano , Humanos , MasculinoRESUMEN
The superwet technique has been shown in previous studies to dramatically reduce blood loss in breast reduction surgery, compared with standard infiltration. A retrospective chart review of 303 consecutive patients undergoing bilateral breast reduction surgery was undertaken to demonstrate additional differences in complication rate, operative time, or sponge use in the operating room. In this series, 132 consecutive patients received standard infiltration along incision lines (25 cc per breast of 1:100,000 epinephrine), and 171 patients received superwet infiltration with 240 cc per breast of 1:1,000,000 epinephrine. The average operative time was significantly reduced in the superwet group, from 78.5 minutes to 70.7 minutes (p < 0.01 level). The average number of sponges used intraoperatively was also decreased significantly (p < 0.01), from 26 to 20 sponges. Complication rates were equally low in both groups, demonstrating the safety of the superwet technique. In addition to limiting blood loss, the superwet infiltration effectively reduces operative time and sponge use without increasing complications in breast reduction surgery.
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Anestesia Local , Epinefrina/administración & dosificación , Hemostasis Quirúrgica , Mamoplastia/métodos , Vasoconstrictores/administración & dosificación , Adulto , Anestésicos Locales/administración & dosificación , Pérdida de Sangre Quirúrgica/prevención & control , Femenino , Humanos , Lidocaína/administración & dosificación , Mamoplastia/efectos adversos , Complicaciones Posoperatorias , Estudios RetrospectivosRESUMEN
Continuous low-dose administration of a GnRH analogue postpones oestrus in bitches and suppresses reproductive function in dogs. A new drug delivery formulation that could enhance the practicality of this approach for the control of reproduction has been developed. The objective of the present study was to determine whether this method of delivery could, by sustained release of the GnRH analogue deslorelin, act as a reversible anti-fertility agent in domestic male and female dogs for periods exceeding 1 year. Several long-term studies were performed, which monitored reproductive function in 30 dogs and 52 bitches. Suppression of reproductive function in male dogs was dose-related. Spermatogenesis was suppressed for more than a year in 14 of 16 dogs that received doses of > 0.25 mg deslorelin kg-1. In females, postponement of oestrus for periods of up to 27 months was observed, but there was no relationship between the stage of the oestrous cycle at the start of treatment and the duration of efficacy. Treatment-induced effects on fertility were reversible in both sexes. In summary, sustained release deslorelin implants were shown to elicit reversible long-term reproductive control in male and female domestic dogs.
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Anticoncepción/veterinaria , Anticonceptivos/administración & dosificación , Perros , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/administración & dosificación , Animales , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Masculinos/administración & dosificación , Relación Dosis-Respuesta a Droga , Implantes de Medicamentos , Estro/efectos de los fármacos , Femenino , Masculino , Espermatogénesis/efectos de los fármacos , Pamoato de Triptorelina/análogos & derivadosRESUMEN
Studies were undertaken in Australia and Belgium to determine whether the initial pro-oestrous-oestrous responses of anoestrous bitches to treatment with deslorelin administered in a s.c. implant were inhibited by progestin treatment. Thirty-nine bitches of mixed breeding were treated daily with 2 mg megestrol acetate kg-1 body weight for 21 (group 1, n = 5) or 14 days (group 2, n = 10), or with 1 mg megestrol acetate kg-1 body weight for 14 days (group 3, n = 10). A deslorelin (6 mg) implant was placed s.c. on day 14 (group 1) or day 7 (groups 2 and 3) of treatment. Bitches not treated with progestin also received a deslorelin implant (group 4, n = 9) or were untreated controls (group 5, n = 9). Signs of pro-oestrus-oestrus were not observed in bitches in groups 1, 2 and 5, but were observed in bitches in groups 3 (4/10) and 4 (9/9). Four bitches in group 4 were mated, two of which became pregnant. The pregnancies failed at about day 40 of gestation and were associated with low plasma progesterone concentrations. Treatment with progestin inhibited the pro-oestrous-oestrous responses of bitches to deslorelin.
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Anticonceptivos/administración & dosificación , Perros , Estro/efectos de los fármacos , Hormona Liberadora de Gonadotropina/análogos & derivados , Hormona Liberadora de Gonadotropina/administración & dosificación , Acetato de Megestrol/administración & dosificación , Animales , Depresión Química , Implantes de Medicamentos , Estradiol/sangre , Femenino , Embarazo , Progesterona/antagonistas & inhibidores , Progesterona/sangre , Factores de Tiempo , Pamoato de Triptorelina/análogos & derivadosAsunto(s)
Neoplasias de la Mama/patología , Carcinoma in Situ/patología , Carcinoma Lobular/patología , Adulto , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Carcinoma in Situ/química , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/cirugía , Carcinoma Lobular/química , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/cirugía , Humanos , Inmunohistoquímica , Queratinas/análisis , Invasividad Neoplásica , Receptor ErbB-2/análisis , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Tamoxifeno/uso terapéuticoRESUMEN
BACKGROUND: Apoptosis, or programmed cell death, can be induced by radiotherapy. The extent of apoptosis in a tumour before treatment may have important implications for response to radiotherapy and long term survival. AIM: To examine the extent of apoptosis in tumour tissue from patients with squamous carcinoma of the cervix before radiotherapy, and to correlate this with response to treatment and prognosis. METHODS: The percentage of apoptotic cells was assessed in 146 carcinomas of the cervix from patients scheduled to receive radiotherapy. The CAS 200 static image analysis system was used to count the number of tumour nuclei per high power field, while the numbers of apoptotic cells in the same field were visualised simultaneously on the image analyser and recorded manually. RESULTS: The median apoptotic level was 0.73%. Patients were divided into two groups around the median. There was no statistically significant difference in outcome between the two groups as determined by long term survival following radiotherapy. CONCLUSIONS: The CAS 200 static image analyser system can be used to assist in the rapid semiautomated assessment of apoptosis in conventionally prepared tissue. The results suggest that the apoptotic state of a tumour before treatment is of no value in predicting response to radiotherapy and subsequent prognosis. Tumour stage, size, and BrdU labelling index, as a measure of proliferation rate, remain the most important prognostic factors in terms of predicting local tumour control.
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Apoptosis/efectos de la radiación , Carcinoma de Células Escamosas/radioterapia , Neoplasias del Cuello Uterino/radioterapia , Análisis de Varianza , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/fisiopatología , Femenino , Humanos , Valor Predictivo de las Pruebas , Tasa de Supervivencia , Neoplasias del Cuello Uterino/mortalidad , Neoplasias del Cuello Uterino/fisiopatologíaRESUMEN
We report three patients in whom standard radiation therapy was given and serious late radiation damage was seen. The first patient suffered recurrent parotiditis and a parotid fistula. He was treated initially with 20 Gy in ten fractions via a 300 kV field. Further irradiation was required 1 year later and 40 Gy was given in 2 Gy fractions by an oblique anterior and posterior wedged photon pair. Ten years later he developed localized temporal bone necrosis. The second patient, with pleomorphic salivary adenoma, developed localized temporal bone necrosis 6 years after 60 Gy had been given using standard fractionation and technique. The third patient received 55 Gy in 25 fractions for a pleomorphic salivary adenoma and after 3 years developed temporal bone necrosis. Sixteen years later the same patient developed cerebellar and brainstem necrosis. All patients developed chronic persistent infection during or shortly after the radiation therapy, which increased local tissue sensitivity to late radiation damage. As a result, severe bone, cerebellar and brainstem necrosis was observed at doses that are normally considered safe. We therefore strongly recommend that any infection in a proposed irradiated area should be treated aggressively, with surgical debridement if necessary, before radiotherapy is administered, or that infection developing during or after irradiation is treated promptly.
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Cerebelo/patología , Enfermedades de las Parótidas/radioterapia , Traumatismos por Radiación/patología , Radioterapia/efectos adversos , Anciano , Anciano de 80 o más Años , Cerebelo/efectos de la radiación , Femenino , Humanos , Infecciones , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Necrosis , Enfermedades de las Parótidas/patología , RecurrenciaRESUMEN
[131I]meta-iodobenzylguanidine ([131I]MIBG) provides a means of selectively delivering radiation to neuroblastoma cells and is a promising addition to the range of agents used to treat neuroblastoma. As MIBG is now being incorporated into multimodal approaches to therapy, important questions arise about the appropriate scheduling and sequencing of the various agents employed. As the ability of neuroblastoma cells to actively accumulate MIBG is crucial to the success of this therapy, the effect of chemotherapeutic agents on this uptake capacity needs to be investigated. We report here our initial findings on the effect of cisplatin pretreatment on the neuroblastoma cell line SK-N-BE (2c). After treating these cells with therapeutically relevant concentrations of cisplatin (2 microM and 20 microM), a stimulation in uptake of [131I]MIBG was observed. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that this effect was due to increased expression of the noradrenaline transporter. These results suggest that appropriate scheduling of cisplatin and [131I]MIBG may lead to an increase in tumour uptake of this radiopharmaceutical with consequent increases in radiation dose to the tumour.
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Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Proteínas Portadoras/metabolismo , Cisplatino/farmacología , Yodobencenos/farmacocinética , Proteínas de Neoplasias/metabolismo , Neuroblastoma/metabolismo , Simportadores , 3-Yodobencilguanidina , Recuento de Células , Humanos , Neuroblastoma/patología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática , Células Tumorales Cultivadas , Ensayo de Tumor de Célula MadreRESUMEN
UNLABELLED: Iodine-131-metaiodobenzylguanidine ([131I]MIBG) is a radiopharmaceutical for imaging as well as targeted radiotherapy of neuroblastoma. It is predicted that the use of no-carrier-added [131I]MIBG, rather than the conventional low specific activity preparation, will result in an enhanced therapeutic ratio because of different transport processes in neuroblastoma compared with most normal tissues. METHODS: The main aims of the study were: (1) to determine whether [131I]MIBG of substantially greater specific activity is transported into tumor cells by the same process as the existing compound; (2) to evaluate the effect of nonradiolabeled MIBG on the cytotoxicity of no-carrier-added [131I]MIBG; and (3) to compare the biodistribution of both preparations of the radiochemical in neuroblastoma xenografts. RESULTS: Active uptake of no-carrier-added [131I]MIBG was temperature-, sodium- and oxygen-dependent; ouabain- and desmethylimipramine-inhibitable; and could be blocked competitively by monoamine inhibitors of the noradrenaline transport mechanism. The rank order of specific uptake capacity in a panel of neuroblastoma cell lines was the same for both low and high specific activity drug. Neuroblastoma spheroid regrowth was 85% inhibited by no-carrier-added [131I]MIBG at 2 MBq.ml-1. Inhibitory potency was reduced in a dose-dependent manner by nonradiolabeled MIBG. The accumulation of no-carrier-added [131I]MIBG was significantly greater in tumor, adrenal, heart and skin of tumor-bearing mice than that of the conventional therapy preparation of [131I]MIBG. CONCLUSION: These data indicate that there may be clinical advantages in the use of no-carrier-added [131I]MIBG rather than conventional [131I]MIBG.
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Radioisótopos de Yodo/uso terapéutico , Yodobencenos/uso terapéutico , 3-Yodobencilguanidina , Animales , Femenino , Humanos , Radioisótopos de Yodo/farmacocinética , Yodobencenos/farmacocinética , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neuroblastoma/metabolismo , Neuroblastoma/radioterapia , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/radioterapia , Células Tumorales CultivadasRESUMEN
Successful imaging or treatment of neuroblastoma with 131I-meta-iodobenzylguanidine (131I-mIBG) depends on the selectivity of active (type 1) uptake of mIBG in neuroblastoma cells relative to passive (type 2) uptake present in most normal tissues. This study investigates the effects of moderately elevated temperature (39-41 degrees C) on the cellular uptake of 131I-mIBG in two neuroblastoma cell lines [SK-N-BE(2c) and IMR-32] and in a non-neuronal (ovarian carcinoma) cell line (A2780). In SK-N-BE(2c), a cell line with high active uptake capacity, the specific (type 1) uptake was reduced by 75% (P < 0.001) at 39 degrees C. Both IMR-32 and A2780 have a low capacity for accumulation of mIBG by active uptake. These cell lines demonstrated a statistically significant increase in accumulation at 39 degrees C, mainly as a result of increased non-specific transport. At 41 degrees C uptake of 131I-mIBG was reduced in all cell lines. Thus, the active component of mIBG uptake is more vulnerable to increased temperature than the passive component. It seems probable that moderately increased temperature will have an unfavourable effect on the therapeutic differential for targeted radiotherapy of neuroblastoma using radiolabelled mIBG.
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Antineoplásicos/farmacocinética , Yodobencenos/farmacocinética , Neuroblastoma/metabolismo , 3-Yodobencilguanidina , Desipramina/farmacología , Femenino , Calor , Humanos , Radioisótopos de Yodo , Cinética , Inhibidores de la Captación de Neurotransmisores/farmacología , Neoplasias Ováricas/metabolismo , Temperatura , Células Tumorales CultivadasRESUMEN
Ectopic 'hamartomatous' thymoma is a rare benign neoplasm. These tumours are found in the neck and are thought to be part of a spectrum of ectopic cervical thymic neoplasia. The clinical and histological features are discussed and the literature is reviewed. An attempt is made to explain in embryological terms why such lesions appear to occur more commonly on the left side.