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BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.
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Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Linfedema/inducido químicamente , Mastectomía , Complicaciones Posoperatorias/inducido químicamente , Taxoides/efectos adversos , Adulto , Anciano , Brazo , Axila , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Estudios de Cohortes , Femenino , Humanos , Escisión del Ganglio Linfático , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).
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Neoplasias de la Mama/complicaciones , Linfedema/etiología , Neoplasias de la Mama/fisiopatología , Neoplasias de la Mama/cirugía , Femenino , Humanos , Pierna , Escisión del Ganglio Linfático/métodos , Vasos Linfáticos/fisiología , Linfedema/fisiopatología , Linfedema/cirugía , Linfocintigrafia/métodos , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Myoblast differentiation is mediated by a cascade of changes in gene expression including transcription factors such as myogenin. Subsequent to myoblast differentiation, there is an increase in expression of the transmembrane protein NADPH oxidase (Nox). Nox is one of the primary factors for the generation of reactive oxygen species (ROS) in myogenic (C2C12) cells. Recently, ROS have been shown to be important regulators of several intracellular signaling pathways, and the full extent of their regulatory roles is yet to be discovered. In the present study, qRT PCR analysis demonstrated that Nox4 isoform is primarily expressed in differentiating C2C12 cells and contributes to the generation of ROS in C2C12 myoblast during differentiation. Over-expression and silencing of Nox4 expression during myoblast differentiation was accompanied by a reduction in intracellular ROS concentrations and an alteration in the expression patterns of Myf5, Pax7, MyoD1, and myogenin. This modulation was found to be associated with ERK1/2 phosphorylation. In both over-expression and reduced expression of Nox4, we found significant reductions in ERK1/2 phosphorylation. This indicates that cellular differentiation may be affected by Nox4-mediated endogenous ROS generation. These data suggest a new opportunity to study the temporal expression of Nox4 in the generation of ROS accompanying changes in myogenic differentiation.
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Biomarcadores/metabolismo , Diferenciación Celular/genética , Expresión Génica/genética , Mioblastos/metabolismo , NADPH Oxidasas/genética , Animales , Línea Celular , Regulación hacia Abajo/genética , Sistema de Señalización de MAP Quinasas/genética , Ratones , Proteína MioD/genética , Proteína MioD/metabolismo , Factor 5 Regulador Miogénico/genética , Factor 5 Regulador Miogénico/metabolismo , Miogenina/genética , Miogenina/metabolismo , NADPH Oxidasa 4 , NADPH Oxidasas/metabolismo , Factor de Transcripción PAX7/genética , Factor de Transcripción PAX7/metabolismo , Fosforilación/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
INTRODUCTION: Ordered subset expectation maximisation with depth-dependent resolution recovery (OSEM-RR) is a processing algorithm reported to improve images with halved tracer activity in myocardial perfusion scintigraphy (MPS) compared to filtered backprojection (FBP) using conventional activities. OSEM-RR has not yet been compared with maximal likelihood expectation maximisation (MLEM). METHODS: 39 patients undergoing MPS and two anthropomorphic phantoms (one with, one without an inferior wall insert) had full-time (FT) and half-time (HT) SPECT datasets acquired simultaneously and processed by FBP, MLEM and OSEM-RR. Two experienced reporters scored images of all clinical studies (n=234) for conspicuity of a perfusion defect, with results being compared using Wilcoxon paired and Kappa tests. A quantitative assessment based on mean segmental pixel counts taken from numbers automatically displayed over the 20 segments of Cedars Sinai Autoquant QPS image were compared using Pearson's correlation and Bland Altman analysis. RESULTS: A small but consistent superior concurrence between FT and HT datasets for OSEM-RR compared to FBP and MLEM was observed for both qualitative and quantitative analyses. OSEM-RR resulted in better definition of the inferior wall defect on the phantom study. CONCLUSION: OSEM-RR appears superior to both FBP and MLEM in terms of handling reduced count statistics.
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Algoritmos , Procesamiento de Imagen Asistido por Computador , Funciones de Verosimilitud , Imagen de Perfusión Miocárdica/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fantasmas de ImagenRESUMEN
BACKGROUND: In adults, dosages of some anaesthetic agents are based on lean body mass (LBM) rather than body weight. Our aim was to derive an equation for estimating LBM in children. METHODS: Patients comprised three groups: prospective kidney transplant donors from two separate centres (centres 1 and 3) and children referred to a further centre (centre 2) for the routine clinical measurement of glomerular filtration rate (GFR). GFR and extracellular fluid volume (ECV) were measured using Cr-51-EDTA. LBM was directly estimated (eLBM) in adults using an equation based on height and weight. ECV in children was estimated (eECV) from another equation based on height and weight, converted to eLBM using the relationship between eLBM and ECV determined in the adults from centre 1 and then compared with adult data from centre 3. RESULTS: In children, the ratio of eECV to ECV was 1.04 (SD 0.18). In centre 1, eLBM (kg) was 3.81 (SD 0.55) times greater than ECV (litres) in men (n=50) and 3.77 (0.77) times greater in women (n=51). eLBM in children was therefore derived by multiplying eECV by 3.8. In children, eLBM showed a close linear correlation with measured ECV (eLBM=3.50ECV+2.0; R(2)=0.857), similar to adults (eLBM=2.82ECV+14.5; R(2)=0.582). In all groups, eLBM/weight correlated inversely with weight. CONCLUSIONS: In terms of the relationships between eLBM, ECV, and weight, children are similar to adults. Therefore, drug dosage in children should also be based on eLBM rather than weight.
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Índice de Masa Corporal , Adolescente , Adulto , Anciano , Envejecimiento/fisiología , Anestésicos/administración & dosificación , Antropometría/métodos , Estatura/fisiología , Peso Corporal/fisiología , Niño , Preescolar , Esquema de Medicación , Líquido Extracelular/fisiología , Tasa de Filtración Glomerular/fisiología , Humanos , Lactante , Persona de Mediana Edad , Valores de Referencia , Caracteres Sexuales , Adulto JovenRESUMEN
Obesity has been suggested as a risk factor for chronic kidney disease. However, it has also been suggested that the association between obesity and impaired glomerular filtration rate (GFR) arises from the invalid use of body surface area (BSA) for scaling. This study assesses the effect of obesity on GFR by comparing the age-dependent decline in obese (body mass index (BMI) >30 kg/m(2); n=149) and non-obese patients (n=589), aged >30 years, referred for measurement of GFR (Cr-51-EDTA and three blood samples). GFR was scaled to a BSA of 1.73 m(2) (GFR/BSA) and extracellular fluid volume of 13 l (GFR/ECV), both corrected for the one-compartment assumption. When non-obese patients were categorized into 10-year age brackets (from 31 to >70), GFR/BSA and GFR/ECV declined from 92 ml per min per 1.73 m(2) and 95 ml per min per 13 l, respectively, at 31-40 years to 58 and 59 at >70. The declines in obese patients were similar with corresponding values of 88 ml per min per 1.73 m(2) and 97 ml per min per 13 l at 31-40 and 57 and 59 at >70 years. Linear regression analysis of non-categorized data from age 40 years showed rates of decline slightly slower in the obese (0.82 vs 0.95 ml per min per 1.73 m(2) per year and 0.87 vs 1.02 ml per min per 13 l per year). No effect of obesity on renal function was shown. Scaling to BSA did not distort the results.
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Envejecimiento/fisiología , Tasa de Filtración Glomerular/fisiología , Enfermedades Renales/fisiopatología , Obesidad/fisiopatología , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Superficie Corporal , Femenino , Humanos , Pruebas de Función Renal/métodos , Masculino , Persona de Mediana Edad , Valores de ReferenciaRESUMEN
BACKGROUND: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor. METHODS: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet. RESULTS: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema. CONCLUSION: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery.
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Neoplasias de la Mama/cirugía , Escisión del Ganglio Linfático/efectos adversos , Linfedema/etiología , Sistema Nervioso Simpático/lesiones , Traumatismos del Sistema Nervioso/etiología , Adulto , Anciano , Anciano de 80 o más Años , Axila , Femenino , Antebrazo/irrigación sanguínea , Humanos , Persona de Mediana Edad , Periodo Posoperatorio , Cuidados Preoperatorios , Resistencia Vascular/fisiologíaRESUMEN
To characterize cell surface molecules involved in control of growth of malignant lymphocytes, monoclonal antibodies were raised against the human B lymphoblast cell line SKW6.4. One monoclonal antibody, anti-APO-1, reacted with a 52-kilodalton antigen (APO-1) on a set of activated human lymphocytes, on malignant human lymphocyte lines, and on some patient-derived leukemic cells. Nanogram quantities of anti-APO-1 completely blocked proliferation of cells bearing APO-1 in vitro in a manner characteristic of a process called programmed cell death or apoptosis. Cell death was preceded by changes in cell morphology and fragmentation of DNA. This process was distinct from antibody- and complement-dependent cell lysis and was mediated by the antibody alone. A single intravenous injection of anti-APO-1 into nu/nu mice carrying a xenotransplant of a human B cell tumor induced regression of this tumor within a few days. Histological thin sections of the regressing tumor showed that anti-APO-1 was able to induce apoptosis in vivo. Thus, induction of apoptosis as a consequence of a signal mediated through cell surface molecules like APO-1 may be a useful therapeutic approach in treatment of malignancy.
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Anticuerpos Monoclonales/inmunología , Leucemia de Células B/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Autorradiografía , Linfocitos B/inmunología , Linfoma de Burkitt/inmunología , Linfoma de Burkitt/terapia , Supervivencia Celular , Células Cultivadas , Electroforesis en Gel de Poliacrilamida , Humanos , Leucemia de Células B/patología , Leucemia de Células B/terapia , Ratones , Ratones Desnudos , Pruebas de Precipitina , Inducción de Remisión , Linfocitos T/inmunología , Células Tumorales CultivadasRESUMEN
We experimentally study the dynamics of water in the Cassie-Baxter state to Wenzel state transition on surfaces decorated with assemblies of micrometer-size square pillars arranged on a square lattice. The transition on the micro-patterned superhydrophobic polymer surfaces is followed with a high-speed camera. Detailed analysis of the movement of the liquid during this transition reveals the wetting front velocity dependence on the geometry and material properties. We show that a decrease in gap size as well as an increase in pillar height and intrinsic material hydrophobicity result in a lower front velocity. Scaling arguments based on balancing surface forces and viscous dissipation allow us to derive a relation with which we can rescale all experimentally measured front velocities, obtained for various pattern geometries and materials, on one single curve.
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BACKGROUND: The accuracy of estimating glomerular filtration rate from plasma creatinine (eGFR) has been questioned but it is unclear how much covert error in several reference methods that have been used has contributed to this perceived inaccuracy. The aim of the study was to evaluate eGFR in comparison with a second 'gold standard' to test the performance of the primary gold standard and to examine the influence of patient demographics (age, body mass index (BMI), extracellular fluid volume (ECV) and gender). DESIGN: Non-fasting multisample GFR and ECV were measured in 80 subjects simultaneously and independently with Cr-51-EDTA (GFR(EDTA)) and iohexol (GFR(iohexol)). Percentage bias and imprecision in the prediction of, and disagreement with, GFR(EDTA) were compared between eGFR and GFR(iohexol). Another simplified method for measuring GFR, the slope-only method ((SO)GFR), was also evaluated against multisample GFR (measured with the opposing indicator). Accuracies were assessed in all subjects and across age, BMI and ECV boundaries of 65 y, 29 kg m(-2) and 14 L. RESULTS: eGFR was less precise than GFR(iohexol) (imprecisions of 22.3% and 12.9%; P < 0.01). The precision of (SO)GFR was intermediate between eGFR and GFR(iohexol). Both GFR(iohexol) and eGFR were less precise in the elderly, the obese and men, but minimally influenced by ECV. (SO)GFR was minimally influenced by subject demographics. CONCLUSION: Although eGFR does not predict GFR (based on a primary gold standard) as accurately as a second gold standard, a significant component of its poor performance is the result of inaccuracy in the primary gold standard. (SO)GFR measured with Cr-51-EDTA is superior to eGFR.
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Índice de Masa Corporal , Radioisótopos de Cromo , Creatinina/sangre , Líquido Extracelular/fisiología , Tasa de Filtración Glomerular/fisiología , Yohexol , Adulto , Factores de Edad , Anciano , Ingestión de Alimentos/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estándares de Referencia , Reproducibilidad de los Resultados , Factores Sexuales , Estadística como AsuntoRESUMEN
OBJECTIVE: The Paediatric Working Group AIDS (PAAD) initiated a prospective cohort study in order to investigate disease progression in HIV- infected children and adolescents and the effect of antiretroviral treatment regimes. PATIENTS AND METHODS: Between 1998 and 2003, paediatric centres documented HIV-infected patients under clinical care using a questionnaire for basic data and annual follow up. Main outcome measures were: use of antiretroviral therapy, adverse events, disease progression and change of therapeutic regimes. RESULTS: 174 HIV- infected paediatric patients were followed up in 12 centres in Germany and Austria between 1998 and 2003. Initially 54 (31%) patients had no antiretroviral therapy, 35 (20%) received a two-drug regimen (ART) and 85 patients (49%) a highly active antiretroviral therapy (HAART>or=3 drugs). After an observation period of 5 years, 8 patients (4%) had no therapy, 17 (10%) were on ART and 134 patients on HAART (77%). The number of patients with salvage therapy (>or=4 drugs) increased from 5 (3%) to 15 patients (9%). 72 of 166 treated patients (43%) had no change of their drug regimes, 68 patients (41%) had one change and 26 patients (16%)>or=2 changes. Main reasons for changes were increased viral load (49%), immunologic deterioration (21%) and adverse events (14%). During the follow up period no patient died. According to the CDC classification, disease progression was seen in 48 of 174 patients (28%), of whom 20 had deteriorations of clinical categories (A, B, C) and 28 of immunologic categories. Using Kaplan-Meier curves, the mean time from study onset until change of clinical categories was 61 months for patients on HAART, 26 months for patients on ART and 14 months for patients without ART. CONCLUSION: In paediatric patients with HIV infection, disease progression has declined substantially by introduction of HAART. Superiority of HAART compared with ART was demonstrated. Non-adherence as well as other reasons for treatment failure have to be studied more carefully.
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Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Adolescente , Adulto , Antirretrovirales/farmacología , Terapia Antirretroviral Altamente Activa , Niño , Preescolar , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Alemania , Infecciones por VIH/patología , Humanos , Lactante , Masculino , Cumplimiento de la Medicación , Estados UnidosRESUMEN
Abnormal processing of immune complexes (IC) may be important in the pathogenesis of systemic lupus erythematosus (SLE). The clearance of large soluble IC (comprising hepatitis B surface antigen (HBsAg)/anti-HBsAg) radiolabeled with 123I was examined in 12 normal subjects and 10 patients with SLE. IC localization was analyzed by static and dynamic gamma-scintigraphy. Initial IC clearance from blood was more rapid in patients (median t1/2 = 2.15 min) than normals (median t1/2 = 5.15 min) due to more rapid uptake in the liver. However, in the SLE group, up to 12% of complexes were released from the liver after 30-50 min. Splenic uptake of immune complexes was reduced in the patients and there was reduced ability to retain IC in this organ. Plasma complement levels and erythrocyte complement receptor type 1 numbers were reduced in the patients, resulting in defective opsonization of IC and reduced red cell binding in vivo. These observations support the hypothesis that IC handling is abnormal in SLE.
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Complejo Antígeno-Anticuerpo/metabolismo , Lupus Eritematoso Sistémico/inmunología , Adulto , Femenino , Antígenos de Superficie de la Hepatitis B/metabolismo , Humanos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Receptores de Complemento 3b/análisis , Bazo/metabolismoRESUMEN
Immunocompromised patients are especially at risk for developing chronic hepatitis E virus (HEV) infection, which may result in progressive liver disease and cirrhosis. In addition, treatment of chronic HEV infection in these patients often includes dose reduction of immunosuppressive therapy and this may lead to severe flare-ups of the underlying condition or even rejection of transplant material. Therefore prevention of HEV transmission is being more and more recognised as an essential step to stop increasing HEV seroprevalence. The Dutch National Institute for Public Health and the Environment (RIVM) has recently warned immunocompromised patients following haematopoietic stem cell and solid organ transplantations for the risk of infection by HEV through eating of contaminated products from pig meat. Furthermore, the Dutch blood bank recently decided to start screening all blood products for HEV to prevent iatrogenic transmission of HEV. We describe two patients with HEV infection and discuss risk of infection for immunocompromised patients, transmission routes and the importance of prevention of iatrogenic transfusion related transmission.
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Virus de la Hepatitis E , Hepatitis E/transmisión , Huésped Inmunocomprometido , Femenino , Humanos , Cirrosis Hepática , Masculino , Persona de Mediana Edad , Estudios Seroepidemiológicos , Adulto JovenRESUMEN
OBJECTIVE: Tissue accumulation of (18)F-FDG is quantified as standardised uptake value (SUV), which may be expressed as the voxel maximum (SUVmax) or mean (SUVmean). SUVmax/SUVmean may be a marker of hepatic steatosis, while the coefficient of variation (CV) of SUV may be a marker of hepatic fat distribution heterogeneity (HFDH). Alternatively, they may reflect low signal-to-noise ratio ('noise') in obese persons in whom hepatic steatosis is common. The study aim was to compare the impact of body size on noise versus SUV and CT density (CTD). METHODS: Dynamic PET was performed (30×1min frames) following FDG injection in 60 patients undergoing routine PET/CT. Hepatic FDG clearance was measured using Patlak-Rutland graphical analysis with abdominal aorta as input. Noise was quantified as the standard deviation (SD) of the plot residuals (ignoring the first 2 frames), normalised to the intercept (NRMSD). SUVmax, SUVmean and CTD were measured from 60min whole body PET/CT. CV of SUV and SD of CTD were quantified in 28/60 patients using texture analysis. RESULTS: NRMSD correlated with weight (r=0.49; p<0.0001) and BMI (r=0.48; p=0.0001). SUVmax, SUVmean, SUVmax/SUVmean, CV of SUV, CTD, and SD of CTD all correlated strongly with weight and BMI (p<0.0001). However, they correlated weakly with NRMSD, the strongest being SUVmax (r=0.34; p=0.008) and SD of CTD (r=0.42; n=28; p=0.026). CONCLUSIONS: Noise is increased in overweight/obese persons but has little effect on SUV indices, CTD and their variabilities. SUVmax/SUVmean and CV of SUV are therefore, to some extent, markers of hepatic steatosis and HFDH, respectively.
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Hígado Graso/diagnóstico por imagen , Fluorodesoxiglucosa F18/farmacocinética , Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Adulto , Anciano , Femenino , Humanos , Grasa Intraabdominal/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Relación Señal-RuidoRESUMEN
The biodistribution and pharmacokinetics of (111)In-DTPA-labeled pegylated liposomes (IDLPL) were studied in 17 patients with locally advanced cancers. The patients received 65-107 MBq of IDLPL, and nuclear medicine whole body gamma camera imaging was used to study liposome biodistribution. The t(1/2beta) of IDLPL was 76.1 h. Positive tumor images were obtained in 15 of 17 studies (4 of 5 breast, 5 of 5 head and neck, 3 of 4 bronchus, 2 of 2 glioma, and 1 of 1 cervix cancer). The levels of tumor liposome uptake estimated from regions of interest on gamma camera images were approximately 0.5-3.5% of the injected dose at 72 h. The greatest levels of uptake were seen in the patients with head and neck cancers [33.0 +/- 15.8% ID/kg (percentage of injected dose/kg)]. The uptake in the lung tumors was at an intermediate level (18.3 +/- 5.7% ID/kg), and the breast cancers showed relatively low levels of uptake (5.3 +/- 2.6% ID/kg). These liposome uptake values mirrored the estimated tumor volumes of the various tumor types (36.2 +/- 18.0 cm3 for squamous cell cancer of the head and neck, 114.5 +/- 42.0 cm3 for lung tumors, and 234.7 +/- 101.4 cm3 for breast tumors). In addition, significant localization of the liposomes was seen in the tissues of the reticuloendothelial system (liver, spleen, and bone marrow). One patient with extensive mucocutaneous AIDS-related Kaposi sarcoma was also studied according to a modified protocol, and prominent deposition of the radiolabeled liposomes was demonstrated in these lesions. An additional two patients with resectable head and neck cancer received 26 MBq of IDLPL 48 h before undergoing surgical excision of their tumors. Samples of the tumor, adjacent normal mucosa, muscle, fat, skin, and salivary tissue were obtained at operation. The levels of tumor uptake were 8.8 and 15.9% ID/kg, respectively, with tumor uptake exceeding that in normal mucosa by a mean ratio of 2.3:1, in skin by 3.6:1, in salivary gland by 5.6:1, in muscle by 8.3:1, and in fat by 10.8:1. These data strongly support the development of pegylated liposomal agents for the treatment of solid tumors, particularly those of the head and neck.
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Neoplasias/metabolismo , Ácido Pentético/farmacocinética , Radiofármacos/farmacocinética , Adulto , Anciano , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Femenino , Humanos , Radioisótopos de Indio/farmacocinética , Liposomas , Masculino , Persona de Mediana Edad , Neoplasias/diagnóstico por imagen , Distribución Tisular , Tomografía Computarizada de Emisión de Fotón Único , Orina/químicaRESUMEN
Concomitant chemotherapy and radiotherapy (CCRT) has recently been shown to improve treatment outcome in a range of solid tumors. Pegylated liposomes have the potential to target drugs directly to tumors and may increase the efficacy and reduce the toxicity of CCRT by selectively delivering radiosensitizing agents to tumor, as opposed to normal, tissues. In these studies, we have assessed CCRT using pegylated liposome encapsulated doxorubicin (PLED) and pegylated liposome encapsulated cisplatin (PLEC) against KB head and neck cancer xenograft tumors in nude mice. The addition of low-dose (2 mg/kg) PLED (P < 0.001) and PLEC (P < 0.001) significantly increased the effect of 4.5 Gy, but not 9 Gy, single-fraction radiotherapy (SFRT). Both PLED and PLEC were significantly more effective than their unencapsulated counterparts in increasing the effect of SFRT. In addition, PLED (P < 0.001) and PLEC (P < 0.05) significantly increased the effect of fractionated radiotherapy (9 Gy in 3 fractions) in two different dosing schedules (2 mg/kg single dose or three sequential doses of 0.67 mg/kg). Unencapsulated diethylenetriaminepentaacetic acid and pegylated liposomal diethylenetriaminepentaacetic acid were used as controls to test the effect of the liposome vehicle and showed no interaction with 4.5 Gy or 9 Gy SFRT (P > 0.1). CCRT was well-tolerated, with no evidence of increased local or systemic toxicity, as compared with radiotherapy alone. This study is the first to demonstrate the value of pegylated liposomes as vehicles for the delivery of radiosensitizing drugs in CCRT strategies.
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Antineoplásicos/administración & dosificación , Cisplatino/administración & dosificación , Doxorrubicina/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Liposomas/química , Polietilenglicoles/química , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Animales , Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Terapia Combinada , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Doxorrubicina/uso terapéutico , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
Renal transplantation is an ever-increasing procedure. Baseline DTPA renography is routinely performed in these patients in many centers to assess transplant perfusion and function. This report describes 2 cases of unusual appearance at renography resulting from the native polycystic kidneys.
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Trasplante de Riñón/diagnóstico por imagen , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Humanos , Trasplante de Riñón/fisiología , Riñón Poliquístico Autosómico Dominante/cirugía , Cuidados Posoperatorios , Renografía por Radioisótopo , Radiofármacos , Pentetato de Tecnecio Tc 99mRESUMEN
Apoptosis via CD95 and its ligand is an important mechanism that prevents uncontrolled proliferation of activated lymphocytes and regulates lymphocyte homeostasis. The apoptosis receptor CD95 is a transmembrane protein with an intracellular domain well conserved between CD95 and tumor necrosis factor receptor I, another apoptosis-inducing protein. Because of its functional importance, this domain was designated the death domain. We describe the molecular analysis of the CD95 death domain in a family with autoimmune lymphoproliferative syndrome (Canale-Smith syndrome), T-cell lymphoma, and Hodgkin's disease. A functional defect in apoptosis was detected in cells from the index patient, a 5-year-old girl suffering from Canale-Smith syndrome and a T-cell lymphoma, as well as in her father, who had a history of splenomegaly and mild hemolysis, and her paternal uncle who had been cured of Hodgkin's disease (HD). Expansion of double-negative T cells (CD4-CD8-) was only seen in the index patient. All family members with a functional defect in apoptosis were heterozygous for a point mutation in the death domain of CD95 (A1009G, E256G). We conclude that, within the same family, a defect in apoptosis due to a mutation in the CD95 death domain can be associated with diverse clinical phenotypes, including mild, reversible symptoms and different malignancies.
Asunto(s)
Apoptosis/genética , Enfermedades Autoinmunes/patología , Enfermedad de Hodgkin/patología , Linfoma de Células T/patología , Trastornos Linfoproliferativos/patología , Receptor fas/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Secuencia de Bases , Preescolar , Cartilla de ADN , Femenino , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/inmunología , Humanos , Inmunofenotipificación , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/inmunología , Masculino , Linaje , Mutación PuntualRESUMEN
STUDY OBJECTIVE: The aim was to evaluate the limitation on the measurement of the clearance rate of a small solute, 99mTc DTPA, from intravascular to extravascular spaces imposed by diffusion of the solute back into blood during the period of measurement. DESIGN: The technique for measuring clearance also generates the regional plasma volume from which the solute is cleared. Back diffusion would result in an overestimation of this plasma volume. By applying the same technique to 99mTc labelled human serum albumin, which is not cleared over the period of measurement, a separate estimate of plasma volume can be made. SUBJECTS: The subjects were eight patients undergoing routine 99mTc DTPA renography for suspected outflow obstruction. MEASUREMENTS AND RESULTS: The ratio of plasma volumes based respectively on 99mTc DTPA and human serum albumin in a region of interest below the kidney was 1.04 (SD 0.09). The technique requires a region of interest over the cardiac blood pool from which the blood level of 99mTc DTPA is continuously monitored. When a correction was made for extravascular 99mTc DTPA in this cardiac region of interest, the ratio was unchanged: 0.97 (0.12). CONCLUSION: The technique is capable of measuring the clearance of 99mTc DTPA although, because of its small molecular size, the transfer rate is blood flow dependent, ie, its PS product is greater than its clearance.
Asunto(s)
Permeabilidad Capilar , Compuestos de Organotecnecio/farmacocinética , Ácido Pentético/farmacocinética , Humanos , Matemática , Métodos , Volumen Plasmático , Albúmina Sérica/farmacocinética , Pentetato de Tecnecio Tc 99mRESUMEN
Little clinical attention has been paid to the quantification of microvascular permeability to small hydrophilic solutes, probably because of a paucity of non-invasive techniques. We describe a technique using the gamma camera which measures the clearance of 99mTc DTPA, a molecule similar in size to sucrose, from the intravascular to the extravascular space in the lumbar tissues below the kidneys. This regional clearance (PSr) is analogous to the permeability-surface area (PS) product, a well established concept for describing solute transfer across the capillary. We found a value in subjects with normal renal function of 1.0 (SD 0.2) ml.min-1.100 ml-1 tissue, which is broadly similar to the values anticipated from published values of the extraction fraction of 51Cr EDTA and plasma flow of resting human skeletal muscle. We also describe an index, the t95, of whole body microvascular permeability. This is the time at which the second exponential of the bi-exponential plasma 99mTc DTPA clearance curve becomes equal to 95% of the total curve. The index reflects the rate of equilibration of DTPA between intravascular and extravascular spaces, and should reflect whole body microvascular permeability. The t95 showed a significant inverse correlation with regional clearance (t95 = -12 PSr + 98 min; r = -0.61; n = 60; p less than 0.001) confirming their mutual dependence on capillary DTPA transfer. These non-invasive techniques, with their advantages of simplicity, could prove useful in a variety of clinical settings.