Australian Association for Exercise and Sport Science position stand : optimising cancer outcomes through exercise

Cancer represents a major public health concern in Australia. Causes of cancer are multifactorial with lack of physical activity being considered one of the known risk factors, particularly for breast and colorectal cancers. Participating in exercise has also been associated with benefits during and following treatment for cancer, including improvements in psychosocial and physical outcomes, as well as better compliance with treatment regimens, reduced impact of disease symptoms and treatment-related side effects, and survival benefits for particular cancers. The general exercise prescription for people undertaking or having completed cancer treatment is of low to moderate intensity, regular frequency (3-5 times/week) for at least 20 minutes per session, involving aerobic, resistance or mixed exercise types. Future work needs to push the boundaries of this exercise prescription, so that we can better understand what constitutes optimal, desirable and necessary frequency, duration, intensity and type, and how specific characteristics of the individual (e.g., age, cancer type, treatment, presence of specific symptoms) influence this prescription. What follows is a summary of the cancer and exercise literature, in particular the purpose of exercise following diagnosis of cancer, the potential benefits derived by cancer patients and survivors from participating in exercise programs, and exercise prescription guidelines and contraindications or considerations for exercise prescription with this special population. This report represents the position stand of the Australian Association of Exercise and Sport Science on exercise and cancer recovery and has the purpose of guiding Accredited Exercise Physiologists in their work with cancer patients.

Incomplete pregnancy and risk of ovarian cancer : results from two Australian case-control studies and systematic review

Although full-term pregnancies reduce the risk of ovarian cancer, it has not been conclusively established whether incomplete pregnancies also influence risk. We investigated the relationship between a history of incomplete pregnancy and incident epithelial ovarian cancer among over 4,500 women who participated in two large Australian population-based case-control studies in 1990-1993 and 2002-2005. They provided responses to detailed questions about their reproductive histories and other personal factors. Summary odds ratios (OR) and confidence intervals (CI) derived from each study using the same covariates were aggregated. We found no significant associations between the number of incomplete pregnancies and ovarian cancer, for parous (OR = 0.98, 95% CI: 0.89, 1.08) or nulliparous (OR = 1.06, 95% CI: 0.75, 1.48) women, nor for the number of spontaneous or induced abortions and ovarian cancer for parous women (OR = 0.95, 95% CI 0.82, 1.09; OR = 1.08, 95% CI: 0.86, 1.36) or nulliparous women (OR = 1.2, 95% CI: 0.6, 2.4; OR = 0.8, 95% CI: 0.47, 1.38), respectively. A systematic review of 37 previous studies of the topic confirmed our findings that a history of incomplete pregnancy does not influence a woman’s risk of epithelial ovarian cancer.

Depression, anxiety and body image after treatment for invasive stage one epithelial ovarian cancer

Background: Diagnosis of epithelial ovarian cancer (EOC) in young women has major implications including those to their reproductive potential. We evaluated depression, anxiety and body image in patients with stage I EOC treated with fertility sparing surgery (FSS) or radical surgery (RS). We also investigated fertility outcomes after FSS.----- Methods: A retrospective study was undertaken in which 62 patients completed questionnaires related to anxiety, depression, body image and fertility outcomes. Additional information on adjuvant therapy after FSS and RS and demographic details were abstracted from medical records. Both bi and multivariate regression models were used to assess the relationship between demographic, clinical and pathological results and scores for anxiety, depression and body image.----- Results: Thirty-nine patients underwent RS and the rest, FSS. The percentage of patients reporting elevated anxiety and depression (subscores ≥ 11) were 27 % and 5% respectively. The median (inter quartile range) score for body image scale (BIS) was 6 (3-15). None of the demographic or clinical factors examined showed significant association with anxiety and BIS with the exception of ‘time since diagnosis’. For depression, post-menopausal status was the only independent predictor. Among those 23 patients treated by FSS, 14 patients tried to conceive (7 successful), resulting in 7 live births, one termination of pregnancy and one miscarriage.----- Conclusion: This study shows that psychological issues are common in women treated for stage I EOC. Reproduction after FSS is feasible and lead to the birth of healthy babies in about half of patients who wished to have another child. Further prospective studies with standardised instruments are required.

Latitude variation in pancreatic cancer mortality in Australia

Objectives: Ecological studies support the hypothesis that there is an association between vitamin D and pancreatic cancer (PaCa) mortality, but observational studies are somewhat conflicting. We sought to contribute further data to this issue by analyzing the differences in PaCa mortality across the eastern states of Australia and investigating if there is a role of vitamin D-effective ultraviolet radiation (DUVR), which is related to latitude. ---------- Methods: Mortality data from 1968 to 2005 were sourced from the Australian General Record of Incidence and Mortality books. Negative binomial models were fitted to calculate the association between state and PaCa mortality. Clear sky monthly DUVR in each capital city was also modeled. ---------- Results: Mortality from PaCa was 10% higher in southern states than in Queensland, with those in Victoria recording the highest mortality risk (relative risk, 1.13; 95% confidence interval, 1.09-1.17). We found a highly significant association between DUVR and PaCa mortality, with an estimated 1.5% decrease in the risk per 10-kJ/m2 increase in yearly DUVR. ---------- Conclusions: These data show an association between latitude, DUVR, and PaCa mortality. Although this study cannot be used to infer causality, it supports the need for further investigations of a possible role of vitamin D in PaCa etiology.

Repeat participation in colorectal cancer screening utilizing fecal occult blood testing : a community-based project in a rural setting

Background and Aim: To investigate participation in a second round of colorectal cancer screening using a fecal occult blood test (FOBT) in an Australian rural community, and to assess the demographic characteristics and individual perspectives associated with repeat screening. ---------- Methods: Potential participants from round 1 (50–74 years of age) were sent an intervention package and asked to return a completed FOBT (n = 3406). Doctors of participants testing positive referred to colonoscopy as appropriate. Following screening, 119 participants completed qualitative telephone interviews. Multivariable logistic regression models evaluated the association between round-2 participation and other variables.---------- Results: Round-2 participation was 34.7%; the strongest predictor was participation in round 1. Repeat participants were more likely to be female; inconsistent screeners were more likely to be younger (aged 50–59 years). The proportion of positive FOBT was 12.7%, that of colonoscopy compliance was 98.6%, and the positive predictive value for cancer or adenoma of advanced pathology was 23.9%. Reasons for participation included testing as a precautionary measure or having family history/friends with colorectal cancer; reasons for non-participation included apathy or doctors’ advice against screening.---------- Conclusion: Participation was relatively low and consistent across rounds. Unless suitable strategies are identified to overcome behavioral trends and/or to screen out ineligible participants, little change in overall participation rates can be expected across rounds.

Correlation of the expression of human kallikrein-related peptidases 4 and 7 with the prognosis in oral squamous cell carcinoma

Background Very few articles have been written about the expression of kallikreins (KLK4 and KLK7) in oral cancers. Therefore, the purpose of this study was to examine and report on their prognostic potential. Methods Eighty archival blocks of primary oral cancers were sectioned and stained for KLK4 and KLK7 by immunohistochemistry. The percentage and the intensity of malignant keratinocyte staining were correlated with patient survival using Cox regression analysis. Results Both kallikreins were expressed strongly in the majority of tumor cells in 68 of 80 cases: these were mostly moderately or poorly differentiated neoplasms. Staining was particularly intense at the infiltrating front. Patients with intense staining had significantly shorter overall survival (p < .05). Conclusion This is the first observation on the patient survival influenced by kallikrein expression in oral carcinoma. The findings are consistent with those for carcinomas at other sites, in particular the prostate and ovary. KLK4 and/or KLK7 immunohistochemistry seems to have diagnostic and prognostic potential in this disease.

PCR bias Toward the wild-type k-ras and p53 sequences: Implications for PCR detection of mutations and cancer diagnosis

PCR-based cancer diagnosis requires detection of rare mutations in k- ras, p53 or other genes. The assumption has been that mutant and wild-type sequences amplify with near equal efficiency, so that they are eventually present in proportions representative of the starting material. Work on factor IX suggests that this assumption is invalid for one case of near- sequence identity. To test the generality of this phenomenon and its relevance to cancer diagnosis, primers distant from point mutations in p53 and k-ras were used to amplify wild-type and mutant sequences from these genes. A substantial bias against PCR amplification of mutants was observed for two regions of the p53 gene and one region of k-ras. For k-ras and p53, bias was observed when the wild-type and mutant sequences were amplified separately or when mixed in equal proportions before PCR. Bias was present with proofreading and non-proofreading polymerase. Mutant and wild-type segments of the factor V, cystic fibrosis transmembrane conductance regulator and prothrombin genes were amplified and did not exhibit PCR bias. Therefore, the assumption of equal PCR efficiency for point mutant and wild-type sequences is invalid in several systems. Quantitative or diagnostic PCR will require validation for each locus, and enrichment strategies may be needed to optimize detection of mutants.

Compilation of somatic mutations of the CDKN2 gene in human cancers : non-random distribution of base substitutions

The CDKN2 gene, encoding the cyclin-dependent kinase inhibitor p16, is a tumour suppressor gene that maps to chromosome band 9p21-p22. The most common mechanism of inactivation of this gene in human cancers is through homozygous deletion; however, in a smaller proportion of tumours and tumour cell lines intragenic mutations occur. In this study we have compiled a database of over 120 published point mutations in the CDKN2 gene from a wide variety of tumour types. A further 50 deletions, insertions, and splice mutations in CDKN2 have also been compiled. Furthermore, we have standardised the numbering of all mutations according to the full-length 156 amino acid form of p16. From this study we are able to define several hot spots, some of which occur at conserved residues within the ankyrin domains of p16. While many of the hotspots are shared by a number of cancers, the relative importance of each position varies, possibly reflecting the role of different carcinogens in the development of certain tumours. As reported previously, the mutational spectrum of CDKN2 in melanomas differs from that of internal malignancies and supports the involvement of UV in melanoma tumorigenesis. Notably, 52% of all substitutions in melanoma-derived samples occurred at just six nucleotide positions. Nonsense mutations comprise a comparatively high proportion of mutations present in the CDKN2 gene, and possible explanations for this are discussed.

The CDKN2A (p16) gene and human cancer

CDKN2A, the gene encoding the cell-cycle inhibitor p16CDKN2A, was first identified in 1994. Since then, somatic mutations have been observed in many cancers and germline alterations have been found in kindreds with familial atypical multiple mole/melanoma (FAMMM), also known as atypical mole syndrome. In this review we tabulate the known mutations in this gene and discuss specific aspects, particularly with respect to germline mutations and cancer predisposition.

CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.

Haplotype analysis of two recurrent CDKN2A mutations in 10 melanoma families : evidence for common founders and independent mutations

Germ-line mutations in CDKN2A have been shown to predispose to cutaneous malignant melanoma. We have identified 2 new melanoma kindreds which carry a duplication of a 24bp repeat present in the 5' region of CDKN2A previously identified in melanoma families from Australia and the United States. This mutation has now been reported in 5 melanoma families from 3 continents: Europe, North America, and Australasia. The M53I mutation in exon 2 of CDKN2A has also been documented in 5 melanoma families from Australia and North America. The aim of this study was to determine whether the occurrence of the mutations in these families from geographically diverse populations represented mutation hotspots within CDKN2A or were due to common ancestors. Haplotypes of 11 microsatellite markers flanking CDKN2A were constructed in 5 families carrying the M53I mutation and 5 families carrying the 24bp duplication. There were some differences in the segregating haplotypes due primarily to recombinations and mutations within the short tandem-repeat markers; however, the data provide evidence to indicate that there were at least 3 independent 24bp duplication events and possibly only 1 original M53I mutation. This is the first study to date which indicates common founders in melanoma families from different continents.

Molecular classification of cutaneous malignant melanoma by gene expression profiling

The most common human cancers are malignant neoplasms of the skin. Incidence of cutaneous melanoma is rising especially steeply, with minimal progress in non-surgical treatment of advanced disease. Despite significant effort to identify independent predictors of melanoma outcome, no accepted histopathological, molecular or immunohistochemical marker defines subsets of this neoplasm. Accordingly, though melanoma is thought to present with different 'taxonomic' forms, these are considered part of a continuous spectrum rather than discrete entities. Here we report the discovery of a subset of melanomas identified by mathematical analysis of gene expression in a series of samples. Remarkably, many genes underlying the classification of this subset are differentially regulated in invasive melanomas that form primitive tubular networks in vitro, a feature of some highly aggressive metastatic melanomas. Global transcript analysis can identify unrecognized subtypes of cutaneous melanoma and predict experimentally verifiable phenotypic characteristics that may be of importance to disease progression.