Effect of PTK/ZK on the Angiogenic Switch in Head and Neck Tumors

Transformation of small avascular masses of tumor cells into rapidly progressive cancers is triggered by the angiogenic switch, a process that involves vascular endothelial growth factor (VEGF) signaling. We have shown that VEGF enhances the survival and angiogenic potential of endothelial cells by activating the Bcl-2-CXCL8 signaling axis. The purpose of this study was to evaluate the effect of a small-molecule inhibitor of VEGF receptors (PTK/ZK) on the initial stages of head and neck tumor angiogenesis. In vitro, PTK/ZK blocked head and neck tumor cell (OSCC3 or UM-SCC-17B)-induced Bcl-2 and CXCL8 expression in endothelial cells. Oral administration of PTK/ZK decreased xenograft head and neck tumor microvessel density, and inhibited Bcl-2 and CXCL8 expression in tumor-associated endothelial cells. Analysis of these data demonstrates that PTK/ZK blocks downstream targets of VEGF signaling in endothelial cells, and suggests that PTK/ZK may inhibit the angiogenic switch in head and neck tumors. Abbreviations: HDMEC, human dermal microvascular endothelial cells; VEGF, vascular endothelial growth factor; CXCL8, CXC ligand-8; PTK/ZK, PTK787/ZK222584.

A for stage III and IV squamous carcinoma of the head and neck: a Trans-Tasman Radiation Oncology Group Study

Purpose: The aims of this randomized controlled trial were to determine whether there were differences in the disease-free survival (DFS) and toxicity between conventional radiotherapy (CRT) and a continuous 3 week accelerated radiotherapy regimen (ART) in stage III and IV squamous cell carcinoma of the oral cavity, oropharynx, larynx and hypopharynx. Patients and methods: Patients from 14 centres throughout Australia and New Zealand were randomly assigned to either CRT, using a single 2 Gy/day to a dose of 70 Gy in 35 fractions in 49 days or to ART, using 1.8 Gy twice a day to a dose of 59.4 Gy in 33 fractions in 24 days. Treatment allocation was stratified for site and stage. The accrual began in 1991 and the trial was closed in 1998 when the target of 350 patients was reached. Results: The median potential follow-up time was 53 months (range, 14-101). The DFS at 5 years was 41% (95% CI, 33-50%) for ART and 35% (95% CI, 27-43%) for CRT (P = 0.323) and the hazard ratio was 0.87 in favour of ART (95% CI, 0.66-1.15). The 5-year disease-specific survival rates were 40% for CRT and 46% for ART (P = 0.398) and the loco-regional control was 47% for CRT vs. 52% for ART (P = 0.300). The respective hazard ratios were 0.88 (95% CI, 0.65-1.2) and 0.85 (0.62-1.16), favouring the accelerated arm. In the ART arm, confluent mucositis was more severe (94 vs. 71%; P < 0.001) and peaked about 3 weeks earlier than in the CRT arm, but healing appeared complete in all cases. There were statistically significant reductions in the probability of grade 2 or greater late soft tissue effects over time in the ART arm (P < 0.05), except for the mucous membrane where late effects were similar in both arms. Conclusions: Differences in DFS, disease-specific survival and loco-regional control have not been demonstrated. ART resulted in more acute mucosal toxicity, but this did not result in greater prolongation of the treatment time compared with the CRT arm. There were less late effects in the ART arm, with the exception of late mucosal effects. This trial has confirmed that tumour cell repopulation occurs during conventionally fractionated radiotherapy for head and neck cancer. However, it has also provided additional evidence that overall improvements in the therapeutic ratio using accelerated fractionation strategies are seriously constrained by the need to limit total doses to levels that do not exceed acute mucosal tolerance. The accelerated schedule tested has been shown in this trial to be an acceptable alternative to conventionally fractionated irradiation to 70 Gy. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.

Applying statistical approaches in the dissection of genes versus environment for asthma and allergic disease

Now that some of the genes involved in asthma and allergy have been identified, interest is turning to how genetic predisposition interacts with exposure to environmental risk factors. These questions are best answered by studies in which both genotypes and other risk factors are measured, but even simpler studies, in which family history is used as a proxy for genotype, have made suggestive findings. For example, early breast feeding may increase the risk of allergic disease in genetically susceptible children, and decrease the risk of 'sporadic' allergy. This review also addresses the overall importance of genetic causes of allergic disease in the general population.

An inverse design of an open, head/neck RF coil for MRI

Radio-frequency (RF) coils are a necessary component of magnetic resonance imaging (MRI) systems. When used in transmit operation, they act to generate a homogeneous RF magnetic field within a volume of interest and when in receive operation, they act to receive the nuclear magnetic resonance signal from the RF-excited specimen. This paper outlines a procedure for the design of open RF coils using the time-harmonic inverse method. This method entails the calculation of an ideal current density on a multipaned planar surface that would generate a specified magnetic field within the volume of interest. Because of the averaging effect of the regularization technique in the matrix solution, the specified magnetic field is shaped within an iterative procedure until the generated magnetic field matches the desired magnetic field. The stream-function technique is used to ascertain conductor positions and a method of moments package is then used to finalize the design. An open head/neck coil was designed to operate in a clinical 2T MRI system and the presented results prove the efficacy of this design methodology.

Myoelectric manifestations of sternocleidomastoid and anterior scalene muscle fatigue in chronic neck pain patients

Objective: This study compares myoelectric manifestations of fatigue of the sternocleidomastoid (SCM) and anterior scalene (AS) muscles between 10 chronic neck pain subjects and 10 normal matched controls. Methods: Surface electromyography (sEMG) signals were recorded from the sternal bead of SCM and AS muscles bilaterally during submaximal isometric cervical flexion contractions at 25 and 50% of the maximum voluntary contraction (MVC). The mean frequency, average rectified value and conduction velocity of the sEMG signal were calculated to quantify myoelectric manifestations of muscle fatigue. Results: For both the SCM and AS muscles, the Mann-Whitney U test indicated that the initial value and slope of the mean frequency in neck pain patients were greater than in healthy subjects (P < 0.05). This was significant both at 25 and 50% of MVC. Conclusions: These results suggest: (a) a predominance of type-II fibres in the neck pain patients and/or (b) greater fatigability of the superficial cervical flexors in neck pain patients. These results are in agreement with previous muscle biopsy studies in subjects with neck pain, which identified transformation of slow-twitch type-I fibres to fast-twitch type-IIB fibres, as well as the clinical observation of reduced endurance in the cervical flexors in neck pain patients. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.

Statistical analysis of quality control measurements in IMRT for head and neck and prostate cancer

Intensity Modulated Radiotherapy (IMRT) is a technique introduced to shape more precisely the dose distributions to the tumour, providing a higher dose escalation in the volume to irradiate and simultaneously decreasing the dose in the organs at risk which consequently reduces the treatment toxicity. This technique is widely used in prostate and head and neck (H&N) tumours. Given the complexity and the use of high doses in this technique it’s necessary to ensure as a safe and secure administration of the treatment, through the use of quality control programmes for IMRT. The purpose of this study was to evaluate statistically the quality control measurements that are made for the IMRT plans in prostate and H&N patients, before the beginning of the treatment, analysing their variations, the percentage of rejected and repeated measurements, the average, standard deviations and the proportion relations.

Mid-Term Results of EVAR in Severe Proximal Aneurysm Neck Angulation.

OBJECTIVE: To determine if mid-term outcome following endovascular aneurysm repair (EVAR) with the Endurant Stent Graft (Medtronic, Santa Rosa, CA, USA) is influenced by severe proximal neck angulation. METHODS: A retrospective case-control study was performed using data from a prospective multicenter database. All measurements were obtained using dedicated reconstruction software and center-lumen line reconstruction. Patients with neck length >15 mm, infrarenal angle (β) >75°, and/or suprarenal angle (α) >60°, or neck length >10 mm with β >60°, and/or α >45° were compared with a matched control group. Primary endpoint was primary clinical success. Secondary endpoints were freedom from rupture, type 1A endoleak, stent fractures, freedom from neck-related reinterventions, and aneurysm-related adverse events. Morphological neck variation over time was also assessed. RESULTS: Forty-five patients were included in the study group and were compared with a matched control group with 65 patients. Median follow-up time was 49.5 months (range 30.5-58.4). The 4-year primary clinical success estimates were 83% and 80% for the angulated and nonangulated groups (p = .42). Proximal neck angulation did not affect primary clinical success in a multivariate model (hazard ratio 1.56, 95% confidence interval 0.55-4.41). Groups did not differ significantly in regard to freedom from rupture (p = .79), freedom from type 1A endoleak (p = .79), freedom from neck-related adverse events (p = .68), and neck-related reinterventions (p = .68). Neck angle reduction was more pronounced in patients with severe proximal neck angulation (mean Δα -15.6°, mean Δβ -30.6°) than in the control group (mean Δα -0.39°, mean Δβ -5.9°) (p < .001). CONCLUSION: Mid-term outcomes following EVAR with the Endurant Stent Graft were not influenced by severe proximal neck angulation in our population. Despite the conformability of the device, moderate aortic neck remodeling was identified in the group of patients with angulated neck anatomy on the first computed tomography scan after implantation with no important further remodeling afterwards. No device integrity failures were encountered.

Contribuição para a adaptação cultural do Neck Disability Index e caraterização da prática de fisioterapia em pacientes com dor crónica cervical

RESUMO: Objetivo: Este trabalho teve como objetivo contribuir para o processo de adaptação cultural do Neck Disability Index (NDI), através da análise da sua unidimensionalidade e do estudo da sua fiabilidade (consistência interna e fiabilidade teste-reteste), validade de constructo e poder de resposta. De igual forma pretendeu-se caraterizar a intervenção realizada pela fisioterapia e os resultados obtidos em pacientes com Dor Cervical Crónica (DCC). Introdução: A dor cervical é um problema cada vez mais comum nos países industrializados, constituindo uma das três condições mais frequentemente reportadas por queixas de origem músculo-esquelética. A sua incidência é um fenómeno em crescimento, com custos implicados para a sociedade. Desta forma reconhece-se a importância de um instrumento que monitorize a evolução da incapacidade funcional associada à DCC. O NDI é atualmente o instrumento de avaliação mais recomendado para avaliar a incapacidade funcional associada à dor cervical. Foi traduzido e adaptado à língua portuguesa, mas à data não foi realizada nenhuma avaliação das suas propriedades psicométricas. Por outro lado, apesar de a literatura referir que os serviços de Fisioterapia são extremamente procurados por indivíduos com DCC, em Portugal, a informação sobre a sua prática nesta condição clínica é escassa ou mesmo inexistente. Assim, e sendo a incapacidade nas atividades funcionais uma das variáveis de maior impacto da DCC e ao mesmo tempo um dos resultados principais da intervenção da Fisioterapia, importa por um lado possuir instrumentos capazes de avaliar o nível de incapacidade funcional e a sua mudança, e por outro, aferir qual a intervenção realizada pela Fisioterapia e quais os resultados obtidos. Metodologia: Realizou-se um estudo de coorte prospetivo com uma amostra de conveniência, do tipo não probabilístico, constituída por 88 pacientes com DCC de origem músculo-esquelética e causa não traumática referenciados para 6 serviços de fisioterapia / medicina física e de reabilitação de clínicas e centros de reabilitação, sendo elegíveis todos os pacientes que cumprissem os critérios de inclusão e exclusão estabelecidos. Os pacientes foram avaliados em três momentos pré-definidos: antes do início das sessões de fisioterapia ou na 1ª semana de tratamento; 4 a 7 dias após a 1ª avaliação; e 7 semanas após o início da fisioterapia. Para verificação da unidimensionalidade do NDI, procedeu-se a uma Análise Fatorial Exploratória. As propriedades psicométricas do NDI avaliadas foram a Fiabilidade (consistência interna e fiabilidade teste-reteste), a Validade de Constructo e o Poder de Resposta. Posteriormente procedeu-se à caraterização da prática da fisioterapia quanto às modalidades utilizadas, número de sessões de tratamento e duração do episódio de cuidados. Adicionalmente descreveu-se os resultados obtidos após a intervenção da fisioterapia ao nível da dor e incapacidade. Resultados: os resultados obtidos foram positivos e significativos, com a confirmação da unidimensionalidade do NDI, sendo que em todos os critérios seguidos o fator mínimo retido foi de um. Na avaliação da consistência interna o valor obtido foi acima do mínimo aceitável (α Cronbach = 0,77), enquanto o valor de fiabilidade teste-reteste foi elevado (CCI =0,95). De igual forma, os resultados foram positivos para a validade de constructo, obtendo-se uma associação positiva do NDI com a Escala Numérica da dor (END). O valores de poder de resposta reportaram uma Área Abaixo da Curva de 0,63 (IC 95%=0,51-0,75), com valor de Diferença Mínima Clinicamente importante de 5,5 pontos (sensibilidade = 69,6%; especificidade = 43,6%). Relativamente á intervenção de fisioterapia em casos de DCC verificou-se que as características da prática da fisioterapia reportadas neste relatório são de difícil comparação ou análise dada a escassez ou inexistência de trabalhos publicados sobre este assunto em pacientes com DCC. No entanto, neste estudo, encontraram-se reduções significativas na intensidade da dor e incapacidade funcional após a intervenção de fisioterapia (z= -7,16; p<0,001 e t= 10,412, p<0,05, respetivamente). Conclusão: Os resultados do presente estudo revelam que o NDI-VP possui uma boa Fiabilidade, Validade de Constructo e Poder de Resposta. Revela ainda que a intervenção da fisioterapia em casos de DCC, apesar da escassez de trabalhos publicados, proporciona uma redução significativa dos níveis de dor e incapacidade em pacientes com DCC.--------------- ABSTRACT:Objective: the aim of this study was to contribute for the process of cultural adaption of the Neck Disability Index (NDI), through the analysis of his unidimensionality and the study of his reliability (internal consistency and test-retest reliability), construct validity and responsiveness. At the same time it pretends to characterize the intervention performed by physical therapy and the results in patients with Chronic Neck Pain (CNP). Introduction: neck pain is a common problem in the industrialized countries, since is one of the three most reported conditions by complaints with musculoskeletal origin. His incidence is a growth phenomena that implicate great costs to society. Therefore the importance of an instrument that monitories the evolution of the functional disability associated to CNP is recognized. Nowadays, NDI is the instrument most recommended to evaluate functional disability associated to neck pain. It has been translated and adapted to portuguese but, till now, no evaluation of his psychometric proprieties has been completed. In the other hand, despite literature refers that physical therapy services are extremely searched by patients with neck pain, in Portugal, the information about practice in this clinical condition is very few or inexistent. Therefore, and since disability in the functional activities is one of the variables with most impact of CNP and, at the same time, one of the main results of physical therapy interventions, it’s important to have instruments capable of evaluate the level of functional disability and his change, and also calculate which intervention of physical therapy is most appropriate and his results. Methodology: it was used a prospective cohort study with a convenience sample, non-probabilistic, consisting of 88 patients with CNP of musculoskeletal origin and non-traumatic cause, referred to 6 physical therapy services of clinics and rehabilitation centers, and fulfilled the inclusion and exclusion criteria established. Patients were evaluated in three pre-defined moments: before the beginning of physical therapy or during the first week of treatment; 4 to 7 days after the first evaluation; and 7 weeks after beginning of physical therapy. To verify NDI unidimensionality, we run an Exploratory Factorial Analysis. NDI psychometric proprieties evaluated were reliability (internal consistency and test-retest reliability), construct validity and responsiveness. Subsequently, it was proceeded the characterization the practice of physical therapy regarding to the modalities used, the number of treatment sessions and duration of the episode of care. Additionally it was described the results obtained after the intervention of the physical therapy, the level of pain and the disability. Results: results were positive and significant, with the confirmation of the NDI unidimensionality, since in every followed criteria the minimal retained factor was one. In the evaluation of internal consistency the value was above the minimal accepted (α Cronbach = 0,77), and the test-retest reliability value was high (CCI =0,95). Results were positive to construct validity, with an positive association of the NDI with Numeric Rating Scale (NRS). Responsiveness values reported an Area Under Curve (AUC) of 0,63 (IC 95%=0,51-0,75) with a Minimal Important Detectable Change (MIDC) of 5,5 points (sensitivity = 69,9%; specificity = 43,6%). Regarding physical therapy interventions in CNP, it was verified that the physical therapy characteristics reported are difficult to compare or analyze since there are very few published studies about this topic. However, in this study, significant reductions were founded in pain intensity and functional disability after intervention(z= -7,16; p<0,001 and t= 10,412, p<0,05, respectively).Conclusion: present study results reveals that NDI has an good reliability, construct validity and responsiveness. It also reveals that physical therapy intervention in CNP, beside few studies published, result in a significant reduction of pain and disability levels in patients with CNP.