Vestibular rehabilitation following the removal of an acoustic neuroma : a systematic review of randomized trials

An acoustic neuroma (also known as a vestibular schwannoma) is an intracranial tumour of the vestibular nerve that is commonly treated by surgical resection. Following resection of an acoustic neuroma, patients may experience a range of symptoms that include deficits in gaze stability, mobility and balance. Vestibular rehabilitation may be useful in reducing the severity and minimizing the impact of these symptoms.

Upper-body morbidity after breast cancer : incidence and evidence for evaluation, prevention, and management within a prospective surveillance model of care

The purpose of this paper is to review the incidence of upper-body morbidity (arm and breast symptoms, impairments, and lymphedema), methods for diagnosis, and prevention and treatment strategies. It was also the purpose to highlight the evidence base for integration of prospective surveillance for upper-body morbidity within standard clinical care of women with breast cancer. Between 10% and 64% of women report upper-body symptoms between 6 months and 3 years after breast cancer, and approximately 20% develop lymphedema. Symptoms remain common into longer-term survivorship, and although lymphedema may be transient for some, those who present with mild lymphedema are at increased risk of developing moderate to severe lymphedema. The etiology of morbidity seems to be multifactorial, with the most consistent risk factors being those associated with extent of treatment. However, known risk factors cannot reliably distinguish between those who will and will not develop upper-body morbidity. Upper-body morbidity may be treatable with physical therapy. There is also evidence in support of integrating regular surveillance for upper-body morbidity into the routine care provided to women with breast cancer, with early diagnosis potentially contributing to more effective management and prevention of progression of these conditions.

Validity and use of the UV index : Report from the UVI working group, Schloss Hohenkammer, Germany, 5-7 December 2011

The adequacy of the UV Index (UVI), a simple measure of ambient solar ultraviolet (UV) radiation, has been questioned on the basis of recent scientific data on the importance of vitamin D for human health, the mutagenic capacity of radiation in the UVA wavelength, and limitations in the behavioral impact of the UVI as a public awareness tool. A working group convened by ICNIRP and WHO met to assess whether modifications of the UVI were warranted and to discuss ways of improving its effectiveness as a guide to healthy sun-protective behavior. A UV Index greater than 3 was confirmed as indicating ambient UV levels at which harmful sun exposure and sunburns could occur and hence as the threshold for promoting preventive messages. There is currently insufficient evidence about the quantitative relationship of sun exposure, vitamin D, and human health to include vitamin D considerations in sun protection recommendations. The role of UVA in sunlight-induced dermal immunosuppression and DNA damage was acknowledged, but the contribution of UVA to skin carcinogenesis could not be quantified precisely. As ambient UVA and UVB levels mostly vary in parallel in real life situations, any minor modification of the UVI weighting function with respect to UVA-induced skin cancer would not be expected to have a significant impact on the UV Index. Though it has been shown that the UV Index can raise awareness of the risk of UV radiation to some extent, the UVI does not appear to change attitudes to sun protection or behavior in the way it is presently used. Changes in the UVI itself were not warranted based on these findings, but rather research testing health behavior models, including the roles of self-efficacy and self-affirmation in relation to intention to use sun protection among different susceptible groups, should be carried out to develop more successful strategies toward improving sun protection behavior. Health Phys. 103(3):301-306; 2012

Genetic association of the KLK4 locus with risk of prostate cancer

The Kallikrein-related peptidase, KLK4, has been shown to be significantly overexpressed in prostate tumours in numerous studies and is suggested to be a potential biomarker for prostate cancer. KLK4 may also play a role in prostate cancer progression through its involvement in epithelial-mesenchymal transition, a more aggressive phenotype, and metastases to bone. It is well known that genetic variation has the potential to affect gene expression and/or various protein characteristics and hence we sought to investigate the possible role of single nucleotide polymorphisms (SNPs) in the KLK4 gene in prostate cancer. Assessment of 61 SNPs in the KLK4 locus (±10 kb) in approximately 1300 prostate cancer cases and 1300 male controls for associations with prostate cancer risk and/or prostate tumour aggressiveness (Gleason score <7 versus ≥7) revealed 7 SNPs to be associated with a decreased risk of prostate cancer at the Ptrend<0.05 significance level. Three of these SNPs, rs268923, rs56112930 and the HapMap tagSNP rs7248321, are located several kb upstream of KLK4; rs1654551 encodes a non-synonymous serine to alanine substitution at position 22 of the long isoform of the KLK4 protein, and the remaining 3 risk-associated SNPs, rs1701927, rs1090649 and rs806019, are located downstream of KLK4 and are in high linkage disequilibrium with each other (r2≥0.98). Our findings provide suggestive evidence of a role for genetic variation in the KLK4 locus in prostate cancer predisposition.

Combined expression of KLK4, KLK5, KLK6, and KLK7 by ovarian cancer cells leads to decreased adhesion and paclitaxel-induced chemoresistance.

OBJECTIVE: Chemoresistance is a critical feature of advanced ovarian cancer with only 30% of patients surviving longer than 5 years. We have previously shown that four kallikrein-related (KLK) peptidases, KLK4, KLK5, KLK6 and KLK7 (KLK4-7), are implicated in peritoneal invasion and tumour growth, but underlying mechanisms were not identified. We also reported that KLK7 overexpression confers chemoresistance to paclitaxel, and cell survival via integrins. In this study, we further explored the functional consequenses of overexpression of all four KLKs (KLK4-7) simultaneously in the ovarian cancer cell line, OV-MZ-6, and its impact on integrin expression and signalling, cell adhesion and survival as contributors to chemoresistance and metastatic progression. METHODS: Quantitative gene and protein expression analyses, confocal microscopy, cell adhesion and chemosensitivity assays were performed. RESULTS: Expression of α5β1/αvβ3 integrins was downregulated upon combined stable KLK4-7 overexpression in OV-MZ-6 cells. Accordingly, the adhesion of these cells to vitronectin and fibronectin, the extracellular matrix binding proteins of α5β1/αvβ3 integrins and two predominant proteins of the peritoneal matrix, was decreased. KLK4-7-transfected cells were more resistant to paclitaxel (10-100 nmol/L: 38-54%), but not to carboplatin, which was associated with decreased apoptotic stimuli. However, the KLK4-7-induced paclitaxel resistance was not blocked by the MEK1/2 inhibitor, U0126. CONCLUSIONS: This study demonstrates that combined KLK4-7 expression by ovarian cancer cells promotes reduced integrin expression with consequently less cell-matrix attachment, and insensitivity to paclitaxel mediated by complex integrin and MAPK independent interactions, indicative of a malignant phenotype and disease progression suggesting a role for these KLKs in this process.

Standardising radiation therapy undergraduate competency levels

QUT Bachelor of Radiation Therapy students progress from first visiting a radiation therapy department to graduation and progression into the NPDP over a span of three years. Although there are clear guidelines as to expected competency level post-NPDP, there is still a variety of perceived levels prior to this. Staff and students feedback both suggest that different centres and within centres different staff have differing opinions of these levels. Indeed, many staff members object to the use of the word “competency” for a pre-NPODP undergraduate, preferring the term “achievement”. While it is acknowledged that students progress at different rates, it is vitally important for equity that staff expectations of students at different academic levels are identical. Provision of guidelines for different stages of progression are essential for equitable assessment and most assessments, including the NRTAT are complemented by statements to enable level to be determined. For the University-specific competency assessments some level of consensus between clinical staff is required, especially where students are placed at a large number of different placement sites. Aims The main aim of this initial study is to gauge staff opinions of levels of student progression in order to judge cross-centres consistency. A secondary objective is to evaluate the degree of correlation between staff seniority and perception of student levels. Informal feedback suggests that staff at or just post NPDP level have a different perception of student competency expectations than more senior staff. If these perceptions change with level it will make agreement of guidelines statements more challenging. Study Methods A standard evaluation questionnaire was provided to RT staff participating in ongoing updates to clinical assessment. As part of curriculum development staff were asked to provide anonymous and optional answers to further questions in order to audit current practice. This involved assigning level of student progression to different statements relating to tasks or competencies. After data collation, scores were assigned to level and totals used to rank statements according to perceived student level. Descriptive statistical analysis was used to identify which statements were easier to assign to student level and which were more ambiguous. Further sub-analysis was performed for each category of staff seniority to judge differences in perception. Strength of correlation between seniority and expectation was calculated to confirm or contradict the informal feedback. Results By collating different staff perceptions of competencies for different student levels commonly agreed statements can be used to define achievement level. This presentation outlines the results of the audit including statements that most staff perceived as relevant to a specific student group and statements that staff found to be harder to attribute. Strength of correlation between staff perception and seniority will be outlined where statistically significant.

Reply to William B. Grant

THE UVI working group acknowledges the contribution of Vitamin D to bone health as stated in our paper. However, we concluded that an optimal level of Vitamin D for humans has not yet been established with any certainty...

The N550K/H mutations in FGFR2 confer differential resistance to PD173074, dovitinib and ponatinib ATP-competitive inhibitors

We sought to identify fibroblast growth factor receptor 2 (FGFR2) kinase domain mutations that confer resistance to the pan-FGFR inhibitor, dovitinib, and explore the mechanism of action of the drug-resistant mutations. We cultured BaF3 cells overexpressing FGFR2 in high concentrations of dovitinib and identified fourteen dovitinib-resistant mutations, including the N550K mutation observed in 25% of FGFR2mutant endometrial cancers (EC). Structural and biochemical in vitro kinase analyses, together with BaF3 proliferation assays, showed that the resistance mutations elevate the intrinsic kinase activity of FGFR2. BaF3 lines were used to assess the ability of each mutation to confer cross-resistance to PD173074 and ponatinib. Unlike PD173074, ponatinib effectively inhibited all the dovitinib-resistant FGFR2 mutants except the V565I gatekeeper mutation, suggesting ponatinib but not dovitinib targets the active conformation of FGFR2 kinase. EC cell lines expressing wild-type FGFR2 were relatively resistant to all inhibitors. Whereas EC cell lines expressing mutated FGFR2 showed differential sensitivity. Within the FGFR2mutant cell lines, 3/7 showed marked resistance to PD173074 and relative resistance to dovitinib and ponatinib. This suggests that alternative mechanisms distinct from kinase domain mutations are responsible for intrinsic resistance in these three EC lines. Finally, overexpression of FGFR2N550K in JHUEM-2 cells (FGFR2C383R) conferred resistance (~5 fold) to PD173074, providing independent data that FGFR2N550K can be associated with drug resistance. Biochemical in vitro kinase analyses also shows ponatinib is more effective than dovitinib at inhibiting FGFR2N550K. We propose tumors harboring mutationally activated FGFRs should be treated with FGFR inhibitors that specifically bind the active kinase.

A systematic review on quality of life among patients at 1 year after treatment for head and neck cancer

Introduction: Although advances in treatment modalities have improved the survival of head and neck (H&N) cancer patients over recent years, survivors’ quality of life (QoL) could be impaired for a number of reasons. The investigation of QoL determinants can inform the design of supportive interventions for this population. Objectives: To examine the QoL of H&N cancer survivors at 1 year after treatment and to identify potential determinants affecting their QoL. Methods: A systematic search of literature was done in December 2011 in five databases: Pubmed, Medline, Scopus, Sciencedirect and CINAHL, using combined search terms ‘head and neck cancer’, ‘quality of life’, ‘health-related quality of life’ and ‘systematic review’. The methodological qualities of selected studies were assessed by two reviewers using predefined criteria. The study characteristics and results were abstracted and summarized. Results: Thirty-seven studies met all inclusion criteria with methodological quality from moderate to high. The global QoL of H&N cancer survivors returned to baseline at 1 year after treatment. Significant improvement showed in emotional functioning while physical functioning, xerostomia, sticky/insufficient saliva, and fatigue were consistently worse at 12 months compared with baseline. Age, cancer sites and stages, social support, smoking, presence of feeding tube are significant QoL determinants at 12 months. Conclusions: Although the global QoL of H&N cancer survivors recover by 12 months after treatment, problems with physical functioning, fatigue, xerostomia and sticky saliva persist. Regular assessment should be carried out to monitor these problems. Further research is required to develop appropriate and effective interventions for this population.

Do nursing interventions targeting concurrent symptoms hold promise for managing fatigue in patients with advanced cancer?

TO THE EDITOR: It was with great interest that I read two recent articles by de Raaf et al1, and Bruera et al2. These authors are to be congratulated for completing two of the very few high quality randomized trials that evaluate complex interventions for managing fatigue in patients with advanced cancer. de Raaf et al conducted a non-blinded RCT with 152 patients with advanced cancer and reported significant reduction of fatigue in patients who received a nurse-led monitoring and protocol-guided treatment of physical symptoms compared with those who received usual care1. Patients who received this intervention experienced a significant improvement over time in general fatigue, at one-month follow-up and two-month follow-up. Another recent RCT conducted with 141 patients with advanced cancer by Bruera et al2 did not find any benefits of a nursing telephone intervention that involved systematic symptom assessment/management, medication review, psychosocial support and patient education in fatigue reduction, compared to those who received a control telephone intervention conducted by a non-professional...

Polymorphisms of the SIPA1 gene and sporadic breast cancer susceptibility

Background The novel breast cancer metastasis modulator gene signal-induced proliferation-associated 1 (Sipa1) underlies the breast cancer metastasis efficiency modifier locus Mtes 1 and has been shown to influence mammary tumour metastatic efficiency in the mouse, with an ectopically expressing Sipa1 cell line developing 1.5 to 2 fold more surface pulmonary metastases. Sipa1 encodes a mitogen-inducible GTPase activating (GAP) protein for members of the Ras-related proteins; participates in cell adhesion and modulates mitogen-induced cell cycle progression. Germline SIPA1 SNPs showed association with positive lymph node metastasis and hormonal receptor status in a Caucasian cohort. We hypothesized that SIPA1 may also be correlated to breast carcinoma incidence as well as prognosis. Therefore, this study investigated the potential relationship of SIPA1 and human breast cancer incidence by a germline SNP genotype frequency association study in a case-control Caucasian cohort in Queensland, Australia. Methods The SNPs genotyped in this study were identified in a previous study and the genotyping assays were carried out using TaqMan SNP Genotyping Assays. The data were analysed with chi-square method and the Monte Carlo style CLUMP analysis program. Results Results indicated significance with SIPA1 SNP rs3741378; the CC genotype was more frequently observed in the breast cancer group compared to the disease-free control group, indicating the variant C allele was associated with increased breast cancer incidence. Conclusion This observation indicates SNP rs3741378 as a novel potential sporadic breast cancer predisposition SNP. While it showed association with hormonal receptor status in breast cancer group in a previous pilot study, this exonic missense SNP (Ser (S) to Phe (F)) changes a hydrophilic residue (S) to a hydrophobic residue (F) and may significantly alter the protein functions of SIPA1 in breast tumourgenesis. SIPA1 SNPs rs931127 (5' near gene), and rs746429 (synonymous (Ala (A) to Ala (A)), did not show significant associations with breast cancer incidence, yet were associated with lymph node metastasis in the previous study. This suggests that SIPA1 may be involved in different stages of breast carcinogenesis and since this study replicates a previous study of the associated SNP, it implicates variants of the SIPA1 gene as playing a potential role in breast cancer.

Focussing on genomic and phenomic correlations in respiration of non-melanotic skin cancers

In recent years, with the development of techniques in modern molecular biology, it has become possible to study the genetic basis of carcinogenesis down to the level of DNA sequence. Major advances have been made in our understanding of the genes involved in cell cycle control and descriptions of mutations in those genes. These developments have led to the definition of the role of specific oncogenes and tumour suppressor genes in several cancers, including, for example, colon cancers and some forms of breast cancer. Work reported from our laboratory has led to the identification of a number of candidate genes involved in the development of non-melanotic skin cancers. In this chapter, we attempt to further explain the observed (phenomic) alterations in metabolic pathways associated with oxygen consumption with the changes at the genetic level.

Genetic polymorphisms in DPF3 associated with risk of breast cancer and lymph node metastases

Background Several studies have identified rare genetic variations responsible for many cases of familial breast cancer but their contribution to total breast cancer incidence is relatively small. More common genetic variations with low penetrance have been postulated to account for a higher proportion of the population risk of breast cancer. Methods and Results In an effort to identify genes that influence non-familial breast cancer risk, we tested over 25,000 single nucleotide polymorphisms (SNPs) located within approximately 14,000 genes in a large-scale case-control study in 254 German women with breast cancer and 268 age-matched women without malignant disease. We identified a marker on chromosome 14q24.3-q31.1 that was marginally associated with breast cancer status (OR = 1.5, P = 0.07). Genotypes for this SNP were also significantly associated with indicators of breast cancer severity, including presence of lymph node metastases ( P = 0.006) and earlier age of onset ( P = 0.01). The association with breast cancer status was replicated in two independent samples (OR = 1.35, P = 0.05). High-density association fine mapping showed that the association spanned about 80 kb of the zinc-finger gene DPF3 (also known as CERD4 ). One SNP in intron 1 was found to be more strongly associated with breast cancer status in all three sample collections (OR = 1.6, P = 0.003) as well as with increased lymph node metastases ( P = 0.01) and tumor size ( P = 0.01). Conclusion Polymorphisms in the 5' region of DPF3 were associated with increased risk of breast cancer development, lymph node metastases, age of onset, and tumor size in women of European ancestry. This large-scale association study suggests that genetic variation in DPF3 contributes to breast cancer susceptibility and severity.

An assessment of MMP and TIMP gene expression in cell lines and stroma : tumour differences in microdissected breast cancer biopsies

To examine matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinases (TIMP) mRNA levels in archival breast cancer biopsies, we employed microdissection to separate tumour tissue from the surrounding breast tissue, or stroma and RT-PCR to determine gross qualitative and small quantitative differences in the patterns of expression. In this study, a significant correlation (p < 0.05, by Mann-Whitney U analysis) between TIMP-2 expression and lymph node involvement was identified, while MMP-11 and TIMP-1 expression patterning also significantly (p < 0.05) differed between those tumours showing calcification and those that did not. When compared by Spearmans’ ρ correlation analysis, a significant association (p < 0.05, ρ = 0.404) was identified in the pattern of MMP-2 and MMP-9 gene expression. In this study, the use of microdissection and a systematic strategy of RT-PCR analysis have allowed us to investigate localized MMP and MMP inhibitor expression within breast tumours. We have identified patterns of gene expression that may further reveal aspects of breast carcinogenesis, and a robust method for examining changes in clinically important genes using archival biopsies and across stroma-tumour boundaries.

Differential gene expression in breast cancer cell lines and stroma-tumor differences in microdissected breast cancer biopsies revealed by display array analysis

To examine gene-expression patterning in late-stage breast cancer biopsies, we used a microdissection technique to separate tumor from the surrounding breast tissue or stroma. A DD-PCR protocol was then used to amplify expressed products, which were resolved using PAGE and used as probe to hybridize with representative human arrays and cDNA libraries. The probe derived from the tumor–stroma comparison was hybridized with a gene array and an arrayed cDNA library derived from a GCT of bone; 21 known genes or expressed sequence tags were detected, of which 17 showed differential expression. These included factors associated with epithelial to mesenchymal transition (vimentin), the cargo selection protein (TIP47) and the signal transducer and activator of transcription (STAT3). Northern blot analysis was used to confirm those genes also expressed by representative breast cancer cell lines. Notably, 6 genes of unknown function were restricted to tumor while the majority of stroma-associated genes were known. When applied to transformed breast cancer cell lines (MDA-MB-435 and T47D) that are known to have different metastatic potential, DD array analysis revealed a further 20 genes; 17 of these genes showed differential expression. Use of microdissection and the DD-PCR array protocol allowed us to identify factors whose localized expression within the breast may play a role in abnormal breast development or breast carcinogenesis.