Quality-of-life measurement in patients undergoing radiation therapy for head and neck cancer: a Hong Kong experience

The aims of this study are (1) to establish a reliable and valid quality-of-life (QOL) questionnaire for Chinese patients with head and neck (H&N) cancer who are treated with radiation therapy and (2) to evaluate the impact of the immediate side effects of treatment on the QOL of these patients. The 39-item "Quality of Life Radiation Therapy Instrument with Head and Neck Companion Module" (QOL-RTI/H&N) was translated into Chinese. In the reliability evaluation phase (study module 1), the questionnaire was administered twice to 56 H&N cancer patients, 7 days apart, during the second and third week of radiation therapy. In the validity evaluation phase (study module 2), 138 patients completed the QOL-RTI/H&N before starting and at the end of radiation therapy. Sixty-nine of these 138 patients also completed the QOL-RTI/H&N during the second week of their radiation therapy, at the same time as completing the Functional Assessment of Cancer Therapy-Head and Neck (FACT-H&N) questionnaire. Cronbach alpha coefficients were 0.88 for the general-tool QOL-RTI and 0.90 for the H&N subscale. Test-retest reliability was satisfactory with intraclass correlation coefficients of 0.89 for the general-tool QOL-RTI and 0.75 for the H&N subscale. The instrument can discriminate between patients with stage I or II disease and those with stage III or IV disease (P < .05). Concurrent validity was established by the good agreement with the FACT-H&N (r = 0.86, P < .001). A highly significant deterioration was in the QOL from the baseline to the end of treatment (mean difference for general tool = 1.95, P < .001; mean difference for H&N subscale = 4.85, P < .001). The Chinese QOL-RTI/H&N is a reliable and valid tool for determining the QOL in H&N cancer patients receiving radiation therapy. The immediate side effects of treatment had a significantly negative impact on the patients' QOL. The impact was relatively large for the functional and treatment-site aspects.

A microfluidic system for testing the responses of head and neck squamous cell carcinoma tissue biopsies to treatment with chemotherapy drugs

Tumors are heterogeneous masses of cells characterized pathologically by their size and spread. Their chaotic biology makes treatment of malignancies hard to generalize. We present a robust and reproducible glass microfluidic system, for the maintenance and “interrogation” of head and neck squamous cell carcinoma (HNSCC) tumor biopsies, which enables continuous media perfusion and waste removal, recreating in vivo laminar flow and diffusion-driven conditions. Primary HNSCC or metastatic lymph samples were subsequently treated with 5-fluorouracil and cisplatin, alone and in combination, and were monitored for viability and apoptotic biomarker release ‘off-chip’ over 7 days. The concentration of lactate dehydrogenase was initially high but rapidly dropped to minimally detectable levels in all tumor samples; conversely, effluent concentration of WST-1 (cell proliferation) increased over 7 days: both factors demonstrating cell viability. Addition of cell lysis reagent resulted in increased cell death and reduction in cell proliferation. An apoptotic biomarker, cytochrome c, was analyzed and all the treated samples showed higher levels than the control, with the combination therapy showing the greatest effect. Hematoxylin- and Eosin-stained sections from the biopsy, before and after maintenance, demonstrated the preservation of tissue architecture. This device offers a novel method of studying the tumor environment, and offers a pre-clinical model for creating personalized treatment regimens.

Quick chip assay using locked nucleic acid modified epithelial cell adhesion molecule and nucleolin aptamers for the capture of circulating tumor cells

The role of circulating tumor cells (CTCs) in disease diagnosis, prognosis, monitoring of the therapeutic efficacy, and clinical decision making is immense and has attracted tremendous focus in the last decade. We designed and fabricated simple, flat channel microfluidic devices polydimethylsiloxane (PDMS based) functionalized with locked nucleic acid (LNA) modified aptamers (targeting epithelial cell adhesion molecule (EpCAM) and nucleolin expression) for quick and efficient capture of CTCs and cancer cells. With optimized flow rates (10 μl/min), it was revealed that the aptamer modified devices offered reusability for up to six times while retaining optimal capture efficiency (>90%) and specificity. High capture sensitivity (92%) and specificity (100%) was observed in whole blood samples spiked with Caco-2 cells (10-100 cells/ml). Analysis of blood samples obtained from 25 head and neck cancer patients on the EpCAM LNA aptamer functionalized chip revealed that an average count of 5 ± 3 CTCs/ml of blood were captured from 22/25 samples (88%). EpCAM intracellular domain (EpICD) immunohistochemistry on 9 oral squamous cell carcinomas showed the EpICD positivity in the tumor cells, confirming the EpCAM expression in CTCs from head and neck cancers. These microfluidic devices also maintained viability for in vitro culture and characterization. Use of LNA modified aptamers provided added benefits in terms of cost effectiveness due to increased reusability and sustainability of the devices. Our results present a robust, quick, and efficient CTC capture platform with the use of simple PDMS based devices that are easy to fabricate at low cost and have an immense potential in cancer diagnosis, prognosis, and therapeutic planning.

Development of microfluidic-based analytical methodology for studying the effects of chemotherapy agents on cancer tissue

Whilst a multitude of techniques have been employed to study the biology of tumour tissue and its response to chemotherapeutic reagents, most current methodologies do not capture the sophistication of the in vivo environment. Microfluidics however offers the ability to maintain and interrogate primary tissue samples in an environment with biomimetic flow characteristics. In this study head and neck squamous cell carcinoma (HNSCC) tumour biopsies have been used to investigate the performance of a microfluidic device for generating clinically-useful information. The response of fresh and cryogenically-frozen primary HNSCC or metastatic lymph node samples to chemotherapy drugs (cisplatin, 5-flurouracil or docetaxel), alone and in combination, were monitored for both proliferation (water-soluble tetrazolium salt metabolism) and cell death biomarker release (lactate dehydrogenase, LDH) “off-chip”. The frozen tissue showed no significant difference in terms of either proliferation or LDH release in comparison with the matched fresh samples. Administration of all drugs caused cell death, in a dose-response manner, with the combination showing the greatest amount of cytotoxicity particularly at days 8 and 9; correlating well with published clinical data. The system described here offers an innovative method for studying the tumour microenvironment in vitro and, through incorporation of relevant analytical modules, provides the basis of a pre-clinical device that can be used to define personalised treatment regimens.

Factors associated with breast and cervical cancer screening behaviours

To investigate the factors associated with the use of screening mammography for breast cancer and cervical smear tests for cervical cancer, a theoretical framework was used comprising elements from the Health Belief Model, the Theory of Reasoned Action, and illness representations from the self-regulatory model. Items reflecting older women’s illness representations about cancer and cancer screening were derived from an earlier qualitative study. Using a highly structured interview schedule, telephone interviews were conducted with 1,200 women aged 50-70 years. There were considerable similarities between the factors associated with both mammography and cervical smear test behaviours. The factors associated with screening mammography behaviour were: perceived barriers, perceived benefits, social influence, the illness representations, and marital status. The factors associated with cervical smear test behaviour were: perceived barriers, perceived benefits, emotions as a cause of cancer, feeling frightened of cancer, the illness representations, having a usual general practitioner, and being younger.

The impact of computer display height and desk design on 3D posture during information technology work by young adults

Computer display height and desk design to allow forearm support are two critical design features of workstations for information technology tasks. However there is currently no 3D description of head and neck posture with different computer display heights and no direct comparison to paper based information technology tasks. There is also inconsistent evidence on the effect of forearm support on posture and no evidence on whether these features interact. This study compared the 3D head, neck and upper limb postures of 18 male and 18 female young adults whilst working with different display and desk design conditions. There was no substantial interaction between display height and desk design. Lower display heights increased head and neck flexion with more spinal asymmetry when working with paper. The curved desk, designed to provide forearm support, increased scapula elevation/protraction and shoulder flexion/abduction.

Ets2 maintains hTERT gene expression and breast cancer cell proliferation by interacting with c-Myc

Human telomerase reverse transcriptase (hTERT) underlies cancer cell immortalization, and the expression of hTERT is regulated strictly at the gene transcription. Here, we report that transcription factor Ets2 is required for hTERT gene expression and breast cancer cell proliferation. Silencing Ets2 induces a decrease of hTERT gene expression and increase in human breast cancer cell death. Reconstitution with recombinant hTERT rescues the apoptosis induced by Ets2 depression. In vitro and in vivo analyses show that Ets2 binds to the EtsA and EtsB DNA motifs on the hTERT gene promoter. Mutation of either Ets2 binding site reduces the hTERT promoter transcriptional activity. Moreover, Ets2 forms a complex with c-Myc as demonstrated by co-immunoprecipitation and glutathione S-transferase pulldown assays. Immunological depletion of Ets2, or mutation of the EtsA DNA motif, disables c-Myc binding to the E-box, whereas removal of c-Myc or mutation of the E-box also compromises Ets2 binding to EtsA. Thus, hTERT gene expression is maintained by a mechanism involving Ets2 interactions with the c-Myc transcription factor and the hTERT gene promoter, a protein-DNA complex critical for hTERT gene expression and breast cancer cell proliferation.

Saw palmetto supplement use and prostate cancer risk

Saw palmetto is an herb used to treat the symptoms of benign prostatic hyperplasia. In vitro studies have found that saw palmetto inhibits growth of prostatic cancer cells and may induce apoptosis. To evaluate whether saw palmetto supplements are associated with a reduced risk of prostate cancer, we conducted a prospective cohort study of 35,171 men aged 50-76 yr in western Washington state. Subjects completed questionnaires between 2000 and 2002 on frequency of use of saw palmetto supplements and saw palmetto-containing multivitamins over the previous 10 yr in addition to other information on supplement intake, medical history, and demographics. Men were followed through December 2003 (mean of 2.3 yr of follow-up) via the western Washington Surveillance, Epidemiology, and End Results cancer registry, during which time 580 developed prostate cancer. Ten percent of the cohort used saw palmetto at least once per week for a year in the 10 yr before baseline. No association was found between this level of use of saw palmetto and risk of prostate cancer development [hazard ratio (HR) = 0.95; 95% confidence interval = 0.74-1.23] or with increasing frequency or duration of use. In this free-living population, use of commercial saw palmetto, which varies widely in dose and constituent ratios, was not associated with prostate cancer risk.

Regressive logistic and proportional hazards disease models for within-family analyses of measured genotypes, with application to a CYP17 polymorphism and breast cancer

Various statistical methods have been proposed to evaluate associations between measured genetic variants and disease, including some using family designs. For breast cancer and rare variants, we applied a modified segregation analysis method that uses the population cancer incidence and population-based case families in which a mutation is known to be segregating. Here we extend the method to a common polymorphism, and use a regressive logistic approach to model familial aggregation by conditioning each individual on their mother's breast cancer history. We considered three models: 1) class A regressive logistic model; 2) age-of-onset regressive logistic model; and 3) proportional hazards familial model. Maximum likelihood estimates were calculated using the software MENDEL. We applied these methods to data from the Australian Breast Cancer Family Study on the CYP17 5UTR TC MspA1 polymorphism measured for 1,447 case probands, 787 controls, and 213 relatives of case probands found to have the CC genotype. Breast cancer data for first- and second-degree relatives of case probands were used. The three methods gave consistent estimates. The best-fitting model involved a recessive inheritance, with homozygotes being at an increased risk of 47% (95% CI, 28-68%). The cumulative risk of the disease up to age 70 years was estimated to be 10% or 22% for a CYP17 homozygote whose mother was unaffected or affected, respectively. This analytical approach is well-suited to the data that arise from population-based case-control-family studies, in which cases, controls and relatives are studied, and genotype is measured for some but not all subjects.

Psychological impact of breast and prostate cancer on patients and partners

Aims to identify and describe the psychological experiences of breast and prostate cancer patients and their partners, in terms of adjustment, coping and support issues.

Hormonal breast and prostate cancer cytotoxic agents

Details 13 novel hormone compounds, designed and synthesised for the purpose of aiding the detection and treatment of breast and prostate cancers. Cellular and electromechanical studies of 3 of these synthesised hormones indicate a potential for human application.