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BACKGROUND: Metastatic basal cell carcinoma (mBCC) is a rare condition with no effective second-line treatment options. Cemiplimab is an immune checkpoint inhibitor that blocks the binding of programmed cell death-1 (PD-1) to its ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2). Here, we present the final analysis of cemiplimab in patients with mBCC after first-line hedgehog pathway inhibitor (HHI) treatment (NCT03132636). PATIENTS AND METHODS: In this open-label, single-arm, phase II study, adults with mBCC and Eastern Cooperative Oncology Group performance status ≤1, post-HHI treatment, received cemiplimab 350 mg intravenously every 3 weeks for ≤93 weeks or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Duration of response (DOR) was a key secondary endpoint. Other secondary endpoints were ORR per investigator assessment, progression-free survival (PFS), overall survival (OS), complete response rate, safety, and tolerability. RESULTS: Fifty-four patients were enrolled: 70% were male and the median age of patients was 64 [interquartile range (IQR) 57.0-73.0] years. The median duration of follow-up was 8 months (IQR 4-21 months). The ORR per ICR was 22% [95% confidence interval (CI) 12% to 36%], with 2 complete responses and 10 partial responses. Among responders, the median time to response per ICR was 3 months (IQR 2-7 months). The estimated median DOR per ICR was not reached [95% CI 10 months-not evaluable (NE)]. The disease control rate was 63% (95% CI 49% to 76%) per ICR and 70% (95% CI 56% to 82%) per investigator assessment. The median PFS per ICR was 10 months (95% CI 4-16 months); the median OS was 50 months (95% CI 28 months-NE). The most common treatment-emergent adverse events were fatigue [23 (43%)] and diarrhoea [20 (37%)]. There were no treatment-related deaths. CONCLUSIONS: Cemiplimab demonstrated clinically meaningful antitumour activity, including durable responses, and an acceptable safety profile in patients with mBCC who had disease progression on or intolerance to HHI therapy.
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Anticuerpos Monoclonales Humanizados , Antineoplásicos , Carcinoma Basocelular , Neoplasias Cutáneas , Adulto , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Proteínas Hedgehog , Ligandos , Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/inducido químicamente , Progresión de la Enfermedad , Amidas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: The clinical implementation of immunotherapy has broadened the therapeutic options for recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Until 2016, the only molecularly targeted therapy was epidermal growth factor receptor (EGFR) blockade. However, immune checkpoint inhibition has recently become part of first-line treatment in recurrent and/or metastatic HNSCC. OBJECTIVES: The occurrence of abscopal effects of radiotherapy and synergisms between immunotherapy and chemotherapy as well as the phenomenon of pseudoprogression in HNSCC were investigated. MATERIALS AND METHODS: Key publications of recent clinical trials and preclinical studies on the underlying biological mechanisms were analyzed. RESULTS: As already observed in other tumor entities, synergistic effects upon combination of immunotherapy with radio- and/or chemotherapy are observed in the clinical management of recurrent and/or metastatic HNSCC, and this is mediated by (re)activation of host antitumor immune mechanisms. In selected patients, this may be radiologically detected as pseudoprogression. Reliable biomarkers for these phenomena have not yet been clinically established. CONCLUSIONS: For recurrent and/or metastatic HNSCC, the occurrence of systemic effects upon radiochemoimmunotherapy in the clinic is on the rise. Hence, the identification of biomarkers for abscopal effects of radiotherapy and unexpected synergisms between chemotherapy and immunotherapy as well as for pseudoprogression is gaining in importance.
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Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Inmunoterapia/métodos , Terapia Molecular Dirigida , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Factores Inmunológicos , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismoRESUMEN
Background: Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy. Patients and methods: In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients. Results: Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as 'non-responders' were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8-7.1) and 12.8 months (95% confidence interval, 9.8-15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway. Conclusion: The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/patología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Paclitaxel/administración & dosificación , Sirolimus/administración & dosificación , Sirolimus/análogos & derivados , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Some oncology outpatients experience a higher number of and more severe symptoms during chemotherapy (CTX). However, little is known about whether this high risk phenotype persists over time. Latent transition analysis (LTA) was used to examine the probability that patients remained in the same symptom class when assessed prior to the administration of and following their next dose of CTX. For the patients whose class membership remained consistent, differences in demographic and clinical characteristics, and quality of life (QOL) were evaluated. The Memorial Symptom Assessment Scale (MSAS) was used to evaluate symptom burden. LTA was used to identify subgroups of patients with distinct symptom experiences based on the occurrence of the MSAS symptoms. Of the 906 patients evaluated, 83.9% were classified in the same symptom occurrence class at both assessments. Of these 760 patients, 25.0% were classified as Low-Low, 44.1% as Moderate-Moderate and 30.9% as High-High. Compared to the Low-Low class, the other two classes were younger, more likely to be women and to report child care responsibilities, and had a lower functional status and a higher comorbidity scores. The two higher classes reported lower QOL scores. The use of LTA could assist clinicians to identify higher risk patients and initiate more aggressive interventions.
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Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Atención Ambulatoria , Femenino , Estado de Salud , Humanos , Masculino , Salud Mental , Persona de Mediana Edad , Pacientes Ambulatorios/estadística & datos numéricos , Fenotipo , Calidad de Vida , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. PATIENTS AND METHODS: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. RESULTS: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). CONCLUSIONS: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.
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Carcinoma Adenoide Quístico/tratamiento farmacológico , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Factores de Transcripción NFI/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-myb/genética , Adulto , Anciano , Axitinib , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Cromosomas Humanos Par 4/genética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imidazoles/efectos adversos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
Barrett's metaplasia is a well-recognized risk factor for esophageal adenocarcinoma. It is believed to develop in response to the injurious effects of gastroesophageal reflux. Following subtotal esophagectomy and reconstruction with a gastric conduit, many patients experience profound reflux into the remnant esophagus. Barrett's-like epithelium has been described in these patients, and they have been identified as a potential human model in which to study the early events in the development of metaplasia. This phenomenon also raises clinical concerns about the long-term fate of the esophageal remnant following surgery and the potential for further malignant change. This systematic review summarizes the literature on the prevalence and timing of Barrett's metaplasia occurring after esophagectomy, reviews the evidence regarding risk factors and malignant progression in such patients, and considers the implications for clinical practice.
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Esófago de Barrett/etiología , Esofagectomía/efectos adversos , Adenocarcinoma/complicaciones , Adenocarcinoma/etiología , Adenocarcinoma/patología , Esófago de Barrett/patología , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/etiología , Neoplasias Esofágicas/patología , Esófago/patología , Humanos , Metaplasia/etiologíaAsunto(s)
Antineoplásicos/uso terapéutico , Carcinoma Basocelular/tratamiento farmacológico , Proteínas Hedgehog/antagonistas & inhibidores , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anilidas/farmacología , Anilidas/uso terapéutico , Antineoplásicos/farmacología , Compuestos de Bifenilo/farmacología , Compuestos de Bifenilo/uso terapéutico , Carcinoma Basocelular/mortalidad , Carcinoma Basocelular/patología , Femenino , Estudios de Seguimiento , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Piridinas/farmacología , Piridinas/uso terapéutico , Estudios Retrospectivos , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patologíaRESUMEN
Social Workers (SWs) are vital members of the multidisciplinary health care teams at Hemophilia Treatment Centers (HTCs) across the US. However, little research has been done to identify the demographics and qualifications of HTC SWs. In response to this lack of data, a subcommittee from the Social Work Working Group sponsored by the National Hemophilia Foundation conducted a national online survey in 2010. The authors attempted to ascertain the demographics and characteristics of SWs who work at HTCs across the country. The purpose of this article is to report the results of this online survey and evaluate the parameters of SW demographics in HTCs. Electronic surveys were sent to 143 HTC SWs. Ten were excluded and 100 were completed and returned, yielding a 75% response rate. The great majority of HTC SWs are women and almost half are middle-aged (aged 40-59). They represent a highly educated, very experienced group of professionals. When asked why respondents stayed in their positions at the HTCs, answers appeared to highly correlate to factors related to the HTC multidisciplinary team model. The high survey response rate of 75% reflects the interest of HTC SWs in obtaining data that describe and quantify their qualifications. This information may serve as validation of the haemophilia SW role in times of funding cuts. It may also give a basis for the recruitment and retention of SWs in the haemophilia field.
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Recolección de Datos , Demografía , Hemofilia A/terapia , Servicio Social/estadística & datos numéricos , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Salarios y Beneficios , Servicio Social/economía , Estados UnidosRESUMEN
BACKGROUND AND AIMS: We have previously shown that a maternal low protein (LP) diet during pregnancy in the rat results in adverse ventricular remodeling and contractile deficiencies of the neonatal rat heart. Since pathological cardiac hypertrophy is associated with increased expression of genes involved in glucose handling, this study was undertaken to examine if maternal LP diet alters the expression of genes encoding for some key components of glucose metabolism and uptake, and of the insulin receptor (IR) signal transduction in the heart of male offspring. METHODS AND RESULTS: We determined the effect of maternal LP and normal diet (90 and 180 g/casein/kg respectively) on IR ß-subunit, insulin receptor substrate (IRS)-1, phosphotyrosyl protein phosphatase (PTP) 1B, GLUT4 and phosphatidylinositol (PI) 3-kinase in male rat offspring at 24 h and at 1, 4 and 8 wks post-partum. Quantitative real-time RT-PCR revealed significant age-dependent increases in the expression of IR ß-subunit, IRS-1, PTP1B, GLUT4 and PI3-kinase in the LP group with concomitant increases in corresponding protein abundance at 4 wks of age. These changes were associated with increases in left ventricular (LV) internal diameters as well as increases in LV wall thickness. CONCLUSION: A maternal LP diet can induce increases in the gene expression and protein levels of key components of glucose metabolism and the IR signal transduction pathway in the neonatal rat heart, which may be related to accelerated energy supply, demand and utilization for ventricular remodeling due to compromised contractile performance during early life.
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Dieta con Restricción de Proteínas/efectos adversos , Glucosa/metabolismo , Corazón/fisiopatología , Fenómenos Fisiologicos Nutricionales Maternos , Animales , Western Blotting , Cardiomegalia/fisiopatología , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Expresión Génica , Transportador de Glucosa de Tipo 4/genética , Transportador de Glucosa de Tipo 4/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Desnutrición/metabolismo , Fosfatidilinositol 3-Quinasa/genética , Fosfatidilinositol 3-Quinasa/metabolismo , Embarazo , Proteína Tirosina Fosfatasa no Receptora Tipo 1/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 1/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Transducción de SeñalRESUMEN
PURPOSE: Interfraction and intrafraction variation in anatomic structures is a significant challenge in contemporary radiotherapy. The objective of this work is to develop a novel tool for deformable structure dosimetry, using a tissue-equivalent deformable gel dosimeter that can reproducibly simulate targets subject to deformation. This will enable direct measurement of integrated doses delivered in different deformation states, and the verification of dose deforming algorithms. METHODS: A modified version of the nPAG polymer gel has been used as a deformable 3D dosimeter and phantom to investigate doses delivered to deforming tissue-equivalent geometry. The deformable gel (DEFGEL) dosimeter/phantom is comprised of polymer gel in a latex membrane, moulded (in this case) into a cylindrical geometry, and deformed with an acrylic compressor. Fifteen aluminium fiducial markers (FM) were implanted into DEFGEL phantoms and the reproducibility of deformation was determined via multiple computed tomography (CT) scans in deformed and nondeformed states before and after multiple (up to 150) deformations. Dose was delivered to the DEFGEL phantom in three arrangements: (i) without deformation, (ii) with deformation, and (iii) cumulative exposures with and without deformation, i.e., dose integration. Irradiations included both square field and a stereotactic multiple dynamic arc treatment adapted from a patient plan. Doses delivered to the DEFGEL phantom were read out using cone beam optical CT. RESULTS: Reproducibility was verified by observation of interscan shifts of FM locations (as determined via CT), measured from an absolute reference point and in terms of inter-FM distance. The majority (76%) of points exhibited zero shift, with others shifting by one pixel size consistent with setup error as confirmed with a control sample. Comparison of dose profiles and 2D isodose distributions from the three arrangements illustrated complex spatial redistribution of dose in all three dimensions occurring as a result of the change in shape of the target between irradiations, even for a relatively simple deformation. Discrepancies of up to 30% of the maximum dose were evident from dose difference maps for three orthogonal planes taken through the isocenter of a stereotactic field. CONCLUSIONS: This paper describes the first use of a tissue-equivalent, 3D dose-integrating deformable phantom that yields integrated or redistributed dosimetric information. The proposed methodology readily yields three-dimensional (3D) dosimetric data from radiation delivery to the DEFGEL phantom in deformed and undeformed states. The impacts of deformation on dose distributions were readily seen in the isodose contours and line profiles from the three arrangements. It is demonstrated that the system is potentially capable of reproducibly emulating the physical deformation of an organ, and therefore can be used to evaluate absorbed doses to deformable targets and organs at risk in three dimensions and to validate deformation algorithms applied to dose distributions.
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Geles/química , Geles/efectos de la radiación , Radiometría/instrumentación , Tomografía Computarizada por Rayos X/métodos , Módulo de Elasticidad , Ensayo de Materiales , Dosis de Radiación , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
PURPOSE: The use of time-resolved four-dimensional computed tomography (4D-CT) in radiotherapy requires strict quality assurance to ensure the accuracy of motion management protocols. The aim of this work was to design and test a phantom capable of large amplitude motion for use in 4D-CT, with particular interest in small lesions typical for stereotactic body radiotherapy. METHODS: The phantom of "see-saw" design is light weight, capable of including various sample materials and compatible with several surrogate marker signal acquisition systems. It is constructed of polymethylmethacrylate (Perspex) and its movement is controlled via a dc motor and drive wheel. It was tested using two CT scanners with different 4D acquisition methods: the Philips Brilliance Big Bore CT (helical scan, pressure belt) and a General Electric Discovery STE PET∕CT (axial scan, infrared marker). Amplitudes ranging from 1.5 to 6.0 cm and frequencies of up to 40 cycles per minute were used to study the effect of motion on image quality. Maximum intensity projections (MIPs), as well as average intensity projections (AIPs) of moving objects were investigated and their quality dependence on the number of phase reconstruction bins assessed. RESULTS: CT number discrepancies between moving and stationary objects were found to have no systematic dependence on amplitude, frequency, or specific interphase variability. MIP-delineated amplitudes of motion were found to match physical phantom amplitudes to within 2 mm for all motion scenarios tested. Objects undergoing large amplitude motions (>3.0 cm) were shown to cause artefacts in MIP and AIP projections when ten phase bins were assigned. This problem can be mitigated by increasing the number of phase bins in a 4D-CT scan. CONCLUSIONS: The phantom was found to be a suitable tool for evaluating the image quality of 4D-CT motion management technology, as well as providing a quality assurance tool for intercenter∕intervendor testing of commercial 4D-CT systems. When imaging objects with large amplitudes, the completeness criterion described here indicates the number of phase bins required to prevent missing data in MIPs and AIPs. This is most relevant for small lesions undergoing large motions.
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Tomografía Computarizada Cuatridimensional/instrumentación , Neoplasias/diagnóstico por imagen , Neoplasias/cirugía , Fantasmas de Imagen , Radiocirugia/métodos , Artefactos , Neoplasias/patología , Carga TumoralRESUMEN
PURPOSE: Strategies for dose accumulation in deforming anatomy are of interest in radiotherapy. Algorithms exist for the deformation of dose based on patient image sets, though these are sometimes contentious because not all such image calculations are constrained by physical laws. While tumor and organ motion has been a key area of study for a considerable amount of time, deformation is of increasing interest. In this work, we demonstrate a full 3D experimental validation of results from a range of dose deformation algorithms available in the public domain. METHODS: We recently developed the first tissue-equivalent, full 3D deformable dosimetric phantom-"DEFGEL." To assess the accuracy of dose-warping based on deformable image registration (DIR), we have measured doses in undeformed and deformed states of the DEFGEL dosimeter and compared these to planned doses and warped doses. In this way we have directly evaluated the accuracy of dose-warping calculations for 11 different algorithms. We have done this for a range of stereotactic irradiation schemes and types and magnitudes of deformation. RESULTS: The original Horn and Schunck algorithm is shown to be the best performing of the 11 algorithms trialled. Comparing measured and dose-warped calculations for this method, it is found that for a 10 × 10 mm(2) square field, γ(3%∕3mm) = 99.9%; for a 20 × 20 mm(2) cross-shaped field, γ(3%∕3mm) = 99.1%; and for a multiple dynamic arc (0.413 cm(3) PTV) treatment adapted from a patient treatment plan, γ(3%∕3mm) = 95%. In each case, the agreement is comparable to-but consistently â¼1% less than-comparison between measured and calculated (planned) dose distributions in the absence of deformation. The magnitude of the deformation, as measured by the largest displacement experienced by any voxel in the volume, has the greatest influence on the accuracy of the warped dose distribution. Considering the square field case, the smallest deformation (â¼9 mm) yields agreement of γ(3%∕3mm) = 99.9%, while the most significant deformation (â¼20 mm) yields agreement of γ(3%∕3mm) = 96.7%. CONCLUSIONS: We have confirmed that, for a range of mass and density conserving deformations representative of those observable in anatomical targets, DIR-based dose-warping can yield accurate predictions of the dose distribution. Substantial differences can be seen between the results of different algorithms indicating that DIR performance should be scrutinized before application todose-warping. We have demonstrated that the DEFGEL deformable dosimeter can be used to evaluate DIR performance and the accuracy of dose-warping results by direct measurement.
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Imagenología Tridimensional/métodos , Radiometría/métodos , Algoritmos , Electrones , Geles/química , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Fantasmas de Imagen , Fotones , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , Radioterapia Conformacional/métodos , Reproducibilidad de los ResultadosRESUMEN
Metronidazole (MTR) is frequently used for the treatment of Blastocystis infections, but with variable effectiveness, and often with treatment failures as a possible result of drug resistance. We have developed two Blastocystis MTR-resistant (MTR(R)) subtype 4 WR1 lines (WR1-M4 and WR1-M5), with variable susceptibility to a panel of anti-protozoal agents including various 5-nitroimidazoles, nitazoxanide and furazolidone. WR1-M4 and WR1-M5 were developed and assessed over an 18-month period and displayed persistent MTR resistance, being more than 2.5-fold less susceptible to MTR than the parent isolate. The MTR(R) lines grew with a similar g time to WR1, but were morphologically less consistent with a mixture of size. All Blastocystis isolates and the MTR(R) lines were most susceptible to the 5-nitroimidazole drug ronidazole. WR1-M5 was apparently cross-resistant to satranidazole and furazolidone, and WR1-M4 was cross-resistant to nitazoxanide. These MTR(R) lines now provide a valuable tool for the continued assessment of the efficacy and mechanism of action of new and established drugs against a range of Blastocystis sp. subtypes, in order to identify a universally effective drug and to facilitate understanding of the mechanisms of drug action and resistance in Blastocystis.
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Antiprotozoarios/farmacología , Blastocystis/efectos de los fármacos , Resistencia a Medicamentos , Metronidazol/farmacología , AnimalesRESUMEN
A commercially available motion phantom (QUASAR, Modus Medical) was modified for programmable motion control with the aim of reproducing patient respiratory motion in one dimension in both the anterior-posterior and superior-inferior directions, as well as, providing controllable breath-hold and sinusoidal patterns for the testing of radiotherapy gating systems. In order to simulate realistic patient motion, the DC motor was replaced by a stepper motor. A separate 'chest-wall' motion platform was also designed to accommodate a variety of surrogate marker systems. The platform employs a second stepper motor that allows for the decoupling of the chest-wall and insert motion. The platform's accuracy was tested by replicating patient traces recorded with the Varian real-time position management (RPM) system and comparing the motion platform's recorded motion trace with the original patient data. Six lung cancer patient traces recorded with the RPM system were uploaded to the motion platform's in-house control software and subsequently replicated through the phantom motion platform. The phantom's motion profile was recorded with the RPM system and compared to the original patient data. Sinusoidal and breath-hold patterns were simulated with the motion platform and recorded with the RPM system to verify the systems potential for routine quality assurance of commercial radiotherapy gating systems. There was good correlation between replicated and actual patient data (P 0.003). Mean differences between the location of maxima in replicated and patient data-sets for six patients amounted to 0.034 cm with the corresponding minima mean equal to 0.010 cm. The upgraded motion phantom was found to replicate patient motion accurately as well as provide useful test patterns to aid in the quality assurance of motion management methods and technologies.
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Neoplasias/radioterapia , Fantasmas de Imagen , Técnicas de Imagen Sincronizada Respiratorias/métodos , Algoritmos , Simulación por Computador , Humanos , Movimiento (Física) , Planificación de la Radioterapia Asistida por Computador , Programas InformáticosRESUMEN
The 50th annual National Scientific Conference of the Australian Society for Medical Research was held in Cairns, Queensland, 13-16 November 2011. The theme, 'Indigenous Health: ACTION on Prevention' highlighted the direct action being undertaken by health and medical researchers, as well as allied health professionals, to improve long-term health outcomes for Indigenous Australians.
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Empleos Relacionados con Salud , Servicios de Salud del Indígena , Garantía de la Calidad de Atención de Salud , Sociedades Médicas , Investigación sobre Servicios de Salud , Humanos , Queensland , InvestigadoresRESUMEN
Multi-disciplinary collaborative care for pregnant women with complex and emergent conditions is essential. Logistical planning, clear communication and human factor awareness are all non-clinical skills which need to be utilised in order to maximise outcomes. We describe the case of a proximal aortic dissection in the late third trimester of pregnancy diagnosed in a peripheral hospital that was transferred to a cardiothoracic centre for successful operative management 160 km away. This required the time-sensitive mobilisation and liaison of a receiving cardiothoracic, anaesthesiology and perfusionist team in conjunction with obstetric and midwifery support from an affiliated maternity hospital, as well as the national neonatal transport team. We emphasise the importance of multidisciplinary team management in complex cases and how imperative good inter-disciplinary communication is to ensure safe inter-hospital transfer.
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Two, once daily (q.d.) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease (COPD): the ß(2)-agonist indacaterol and the anticholinergic tiotropium. This blinded study compared the efficacy of these two agents and assessed their safety and tolerability. Patients with moderate-to-severe COPD were randomised to treatment with indacaterol 150 µg q.d. (n=797) or tiotropium 18 µg q.d. (n=801) for 12 weeks. After 12 weeks, the two treatments had similar overall effects on "trough" (24 h post-dose) forced expiratory volume in 1 s. Indacaterol-treated patients had greater improvements in transition dyspnoea index (TDI) total score (least squares means 2.01 versus 1.43; p<0.001) and St George's Respiratory Questionnaire (SGRQ) total score (least squares means 37.1 versus 39.2; p<0.001; raw mean change from baseline -5.1 versus -3.0), and were significantly more likely to achieve clinically relevant improvements in these end-points (indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ, both p<0.001). Adverse events were recorded for 39.7% and 37.2% of patients in the indacaterol and tiotropium treatment groups, respectively. The most frequent adverse events were COPD worsening, cough and nasopharyngitis. Both bronchodilators demonstrated spirometric efficacy. The two treatments were well tolerated with similar adverse event profiles. Compared with tiotropium, indacaterol provided significantly greater improvements in clinical outcomes.
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Broncodilatadores/administración & dosificación , Indanos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinolonas/administración & dosificación , Derivados de Escopolamina/administración & dosificación , Antagonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Antagonistas de Receptores Adrenérgicos beta 2/efectos adversos , Anciano , Broncodilatadores/efectos adversos , Antagonistas Colinérgicos/administración & dosificación , Antagonistas Colinérgicos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Indanos/efectos adversos , Masculino , Registros Médicos , Persona de Mediana Edad , Quinolonas/efectos adversos , Derivados de Escopolamina/efectos adversos , Índice de Severidad de la Enfermedad , Espirometría , Bromuro de Tiotropio , Resultado del TratamientoRESUMEN
To assess the effect of lesion motion and respiration rate on Standardised Uptake Value (SUV) and the ability of 4D PET to restore any loss in SUV and distortion of lesion volume on two PET/CT systems. A Perspex phantom with four cylindrical reservoirs filled with (18)F-FDG was used in this study. The cylinders measured 5, 10, 15, and 20 mm in diameter. A GE Discovery STE8 (GE Medical Systems Milwaukee, WI) and a Siemens Biograph 64/40 (Siemens Medical Solutions, Erlangen, Germany) scanner was used to acquire a stationary un-gated PET scan of the phantom. Multiple 10 min list mode 4D PET scans were acquired using the Varian RPM on the GE camera and the Anzai Gating system on the Siemens camera. The phantom was scanned at five different respiratory rates and motion amplitudes in a sinusoidal fashion, 15 RPM/1 cm, 15 RPM/2 cm, 15 RPM/4 cm, 30 RPM/2 cm and 7.5 RPM/2 cm (RPM-respirations per minute). Each scan was reconstructed into ten bins and as an un-gated static image. The SUVmax, SUVmean and volume were measured for all four reservoirs using Siemens TrueD analysis software. With increasing lesion movement the SUVmax and SUVmean decreased and the volume increased with the SUVmax in the smallest lesion underestimated by up to a factor of four. The SUVmax, SUVmean and volume were mostly recovered using 4D imaging regardless of amount of lesion displacement. The larger lesions showed better count recovery and volume correction than the smaller lesions. The respiratory rate had no effect of SUV or volume. Un-gated imaging of moving lesions decreases apparent SUV in small lesions significantly and overestimates volumes. 4D PET scanning recovers most of the apparent loss in SUV and distortion of volumes.