Pattern of Local Recurrence After Conservative Surgery and Radiotherapy for Soft Tissue Sarcoma

Purpose: Over the past three decades our centre has adopted a policy of conservative surgery followed by adjuvant radicaldose radiotherapy for medium-and high-grade soft tissue sarcomas. For all cases of local recurrence following this treatment we aimed to define the spatial relationship between sites of recurrence and the positions of the phase 1 and 2 radiotherapy volumes

Summer distribution and movements of narwhals (Monodon monoceros) in Eclipse Sound and adjacent waters, North Baffin Island, N.W.T.

Each year from 1987 to 1991 and in 1993, 3-6 helicopter surveys were flown in August to study the distribution and movements of narwhals (Monodon monoceros) in their summering grounds in western Eclipse Sound, Milne Inlet, Koluktoo Bay and Tremblay Sound. Their summer distribution is influenced by ice cover. They prefer waters that while giving them shelter from the wind, are over deep bottoms. Narwhals associate with ice in Eclipse Sound, a large expanse of water, while it persists, but do not frequent Tremblay Sound, a narrow fjord, when it has ice cover. When Eclipse Sound is ice-free, narwhals frequent smaller water bodies. Favoured areas in the ice-free season have in common the characteristics of being steep-sided and deep. Narwhals associate in small groups, but these groups aggregate to form larger herds that generally move together. In the short term, movements and distribution are greatly affected by the near presence of killer whales (Orcinus orca), which narwhals seek to avoid

The Two-Tier Fecal Occult Blood Test: Cost-Effective Screening

The two-tier test represents a strategy combining HO Sensa and Hemeselect fecal occult blood tests (FOBTs) with the aim of greater specificity and consequent economic advantages. If patients register a positive result on any HO Sensa guaiac test, they are once again tested by a hemoglobin-specific Hemeselect test. This concept was applied to a multicentre study involving persons 40 years or older. One component of the study enrolled 573 high risk patients while the second arm recruited an additional 1301 patients (52% asymptomatic/48% symptomatic) stratified according to personal history and symptoms. The two-tier test produced fewer false positives than traditional tests in both groups evaluated in the study. In the high risk group, specificity (88.7% for two-tier versus 80.6% for Hemoccult and 69.5% for HO Sensa) was higher and false positive rates were lower (11.3% for two-tier versus 19.5% for Hemoccultand 30.5% for HO Sensa) for the two-tier test versus Hemoccult and HO Sensa FOBTs (95% CI for all colorectal cancers [CRCs] and polyps greater than 1 cm, α=0.05 ). No significant differences in sensitivity were observed between tests in the same group. Also, in the high risk group, benefits of the two-tier test outweighed the costs. Due to the small number of cancers and polyps in the second arm of the study, presentation of data is meant to be descriptive and representative of trends in a ‘normal’ population. Nevertheless, specificity of the two-tier test was higher (96.8% for two-tier versus 87.2% for Hemoccult and 69.5% for HO Sensa) and false positive rate lower (3.2% for two-tier versus 12.8% for Hemoccult and 22.3% for HO Sensa) than either the Hemoccult or HO Sensa FOBT (95% CI for all CRCs and polyps greater than 1 cm). This initial study, focusing on the cost-benefit relationship of increased specificity, represents a new way of economically evaluating existing FOBTs

Clinical translation of [18F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer

Background: Effective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy. Results: Breast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Conclusion: This study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer

Statistical expression deconvolution from mixed tissue samples

Motivation: Global expression patterns within cells are used for purposes ranging from the identification of disease biomarkers to basic understanding of cellular processes. Unfortunately, tissue samples used in cancer studies are usually composed of multiple cell types and the non-cancerous portions can significantly affect expression profiles. This severely limits the conclusions that can be made about the specificity of gene expression in the cell-type of interest. However, statistical analysis can be used to identify differentially expressed genes that are related to the biological question being studied

The effect of the stromal component of breast tumours on prediction of clinical outcome using gene expression microarray analysis

INTRODUCTION: The aim of this study was to examine the effect of the cellular composition of biopsies on the error rates of multigene predictors of response of breast tumours to neoadjuvant adriamycin and cyclophosphamide (AC) chemotherapy. MATERIALS AND METHODS: Core biopsies were taken from primary breast tumours of 43 patients prior to AC, and subsequent clinical response was recorded. Post-chemotherapy (day 21) samples were available for 16 of these samples. Frozen sections of each core were used to estimate the proportion of invasive cancer and other tissue components at three levels. Transcriptional profiling was performed using a cDNA array containing 4,600 elements. RESULTS: Twenty-three (53%) patients demonstrated a 'good' and 20 (47%) a 'poor' clinical response. The percentage invasive tumour in core biopsies collected from these patients varied markedly. Despite this, agglomerative clustering of sample expression profiles showed that almost all biopsies from the same tumour aggregated as nearest neighbours. SAM (significance analysis of microarrays) regression analysis identified 144 genes which distinguished high- and low-percentage invasive tumour biopsies at a false discovery rate of not more than 5%. The misclassification error of prediction of clinical response using microarray data from pre-treatment biopsies (on leave-one-out cross-validation) was 28%. When prediction was performed on subsets of samples which were more homogeneous in their proportions of malignant and stromal cells, the misclassification error was considerably lower (8%–13%, p < 0.05 on permutation). CONCLUSION: The non-tumour content of breast cancer samples has a significant effect on gene expression profiles. Consideration of this factor improves accuracy of response prediction by expression array profiling. Future gene expression array prediction studies should be planned taking this into account

Evaluation of the current knowledge limitations in breast cancer research: a gap analysis

BACKGROUND A gap analysis was conducted to determine which areas of breast cancer research, if targeted by researchers and funding bodies, could produce the greatest impact on patients. METHODS Fifty-six Breast Cancer Campaign grant holders and prominent UK breast cancer researchers participated in a gap analysis of current breast cancer research. Before, during and following the meeting, groups in seven key research areas participated in cycles of presentation, literature review and discussion. Summary papers were prepared by each group and collated into this position paper highlighting the research gaps, with recommendations for action. RESULTS Gaps were identified in all seven themes. General barriers to progress were lack of financial and practical resources, and poor collaboration between disciplines. Critical gaps in each theme included: (1) genetics (knowledge of genetic changes, their effects and interactions); (2) initiation of breast cancer (how developmental signalling pathways cause ductal elongation and branching at the cellular level and influence stem cell dynamics, and how their disruption initiates tumour formation); (3) progression of breast cancer (deciphering the intracellular and extracellular regulators of early progression, tumour growth, angiogenesis and metastasis); (4) therapies and targets (understanding who develops advanced disease); (5) disease markers (incorporating intelligent trial design into all studies to ensure new treatments are tested in patient groups stratified using biomarkers); (6) prevention (strategies to prevent oestrogen-receptor negative tumours and the long-term effects of chemoprevention for oestrogen-receptor positive tumours); (7) psychosocial aspects of cancer (the use of appropriate psychosocial interventions, and the personal impact of all stages of the disease among patients from a range of ethnic and demographic backgrounds). CONCLUSION Through recommendations to address these gaps with future research, the long-term benefits to patients will include: better estimation of risk in families with breast cancer and strategies to reduce risk; better prediction of drug response and patient prognosis; improved tailoring of treatments to patient subgroups and development of new therapeutic approaches; earlier initiation of treatment; more effective use of resources for screening populations; and an enhanced experience for people with or at risk of breast cancer and their families. The challenge to funding bodies and researchers in all disciplines is to focus on these gaps and to drive advances in knowledge into improvements in patient care

Chemotherapy-Response Monitoring of Breast Cancer Patients Using Quantitative Ultrasound-Based Intra-Tumour Heterogeneities

© 2017 The Author(s). Anti-cancer therapies including chemotherapy aim to induce tumour cell death. Cell death introduces alterations in cell morphology and tissue micro-structures that cause measurable changes in tissue echogenicity. This study investigated the effectiveness of quantitative ultrasound (QUS) parametric imaging to characterize intra-tumour heterogeneity and monitor the pathological response of breast cancer to chemotherapy in a large cohort of patients (n = 100). Results demonstrated that QUS imaging can non-invasively monitor pathological response and outcome of breast cancer patients to chemotherapy early following treatment initiation. Specifically, QUS biomarkers quantifying spatial heterogeneities in size, concentration and spacing of acoustic scatterers could predict treatment responses of patients with cross-validated accuracies of 82 ± 0.7%, 86 ± 0.7% and 85 ± 0.9% and areas under the receiver operating characteristic (ROC) curve of 0.75 ± 0.1, 0.80 ± 0.1 and 0.89 ± 0.1 at 1, 4 and 8 weeks after the start of treatment, respectively. The patients classified as responders and non-responders using QUS biomarkers demonstrated significantly different survivals, in good agreement with clinical and pathological endpoints. The results form a basis for using early predictive information on survival-linked patient response to facilitate adapting standard anti-cancer treatments on an individual patient basis

Self-reported sleep duration and quality and cardiovascular disease and mortality: A dose-response meta-analysis

Background-There is growing evidence that sleep duration and quality may be associated with cardiovascular harm and mortality. Methods and Results-We conducted a systematic review, meta-analysis, and spline analysis of prospective cohort studies that evaluate the association between sleep duration and quality and cardiovascular outcomes. We searched MEDLINE and EMBASE for these studies and extracted data from identified studies. We utilized linear and nonlinear dose-response meta-analysis models and used DerSimonian-Laird random-effects meta-analysis models of risk ratios, with inverse variance weighting, and the I2statistic to quantify heterogeneity. Seventy-four studies including 3 340 684 participants with 242 240 deaths among 2 564 029 participants who reported death events were reviewed. Findings were broadly similar across both linear and nonlinear dose-response models in 30 studies with >1 000 000 participants, and we report results from the linear model. Self-reported duration of sleep >8 hours was associated with a moderate increased risk of all-cause mortality, with risk ratio, 1.14 (1.05-1.25) for 9 hours, risk ratio, 1.30 (1.19-1.42) for 10 hours, and risk ratio, 1.47 (1.33-1.64) for 11 hours. No significant difference was identified for periods of selfreported sleep <7 hours, whereas similar patterns were observed for stroke and cardiovascular disease mortality. Subjective poor sleep quality was associated with coronary heart disease (risk ratio, 1.44; 95% confidence interval, 1.09-1.90), but no difference in mortality and other outcomes. Conclusions-Divergence from the recommended 7 to 8 hours of sleep is associated with a higher risk of mortality and cardiovascular events. Longer duration of sleep may be more associated with adverse outcomes compared with shorter sleep durations