3,657 research outputs found
Mechanical suppression of osteolytic bone metastases in advanced breast cancer patients: A randomised controlled study protocol evaluating safety, feasibility and preliminary efficacy of exercise as a targeted medicine
Background: Skeletal metastases present a major challenge for clinicians, representing an advanced and typically incurable stage of cancer. Bone is also the most common location for metastatic breast carcinoma, with skeletal lesions identified in over 80% of patients with advanced breast cancer. Preclinical models have demonstrated the ability of mechanical stimulation to suppress tumour formation and promote skeletal preservation at bone sites with osteolytic lesions, generating modulatory interference of tumour-driven bone remodelling. Preclinical studies have also demonstrated anti-cancer effects through exercise by minimising tumour hypoxia, normalising tumour vasculature and increasing tumoural blood perfusion. This study proposes to explore the promising role of targeted exercise to suppress tumour growth while concomitantly delivering broader health benefits in patients with advanced breast cancer with osteolytic bone metastases.
Methods: This single-blinded, two-armed, randomised and controlled pilot study aims to establish the safety, feasibility and efficacy of an individually tailored, modular multi-modal exercise programme incorporating spinal isometric training (targeted muscle contraction) in 40 women with advanced breast cancer and stable osteolytic spinal metastases. Participants will be randomly assigned to exercise or usual medical care. The intervention arm will receive a 3-month clinically supervised exercise programme, which if proven to be safe and efficacious will be offered to the control-arm patients following study completion. Primary endpoints (programme feasibility, safety, tolerance and adherence) and secondary endpoints (tumour morphology, serum tumour biomarkers, bone metabolism, inflammation, anthropometry, body composition, bone pain, physical function and patient-reported outcomes) will be measured at baseline and following the intervention.
Discussion: Exercise medicine may positively alter tumour biology through numerous mechanical and nonmechanical mechanisms. This randomised controlled pilot trial will explore the preliminary effects of targeted exercise on tumour morphology and circulating metastatic tumour biomarkers using an osteolytic skeletal metastases model in patients with breast cancer. The study is principally aimed at establishing feasibility and safety. If proven to be safe and feasible, results from this study could have important implications for the delivery of this exercise programme to patients with advanced cancer and sclerotic skeletal metastases or with skeletal lesions present in haematological cancers (such as osteolytic lesions in multiple myeloma), for which future research is recommended.
Trial registration: anzctr.org.au, ACTRN-12616001368426. Registered on 4 October 2016
Clinical and epidemiological issues and applications of mammographic density
The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the authorMammographic density, the amount of radiodense tissue on a mammogram, is a strong risk factor for breast cancer, with properties that could be an asset in screening and prevention
programmes. Its use in risk prediction contexts is currently limited, however,
mainly due to di culties in measuring and interpreting density.
This research investigates rstly, the properties of density as an independent marker of
breast cancer risk and secondly, how density should be measured.
The rst question was addressed by analysing data from a chemoprevention trial, a trial
of hormonal treatment, and a cohort study of women with a family history of breast
cancer . Tamoxifen-induced density reduction was observed to be a good predictor of
breast cancer risk reduction in high-risk una ected subjects. Density and its changes
did not predict risk or treatment outcome in subjects with a primary invasive breast
tumour. Finally absolute density predicted risk better than percent density and showed
a potential to improve existing risk-prediction models, even in a population at enhanced
familial risk of breast cancer.
The second part of thesis focuses on density measurement and in particular evaluates
two fully-automated volumetric methods, Quantra and Volpara. These two methods
are highly correlated and in both cases absolute density (cm3) discriminated cases from
controls better than percent density. Finally, we evaluated and compared di erent measurement
methods. Our ndings suggested good reliability of the Cumulus and visual
assessments. Quantra volumetric estimates appeared negligibly a ected by measurement
error, but were less variable than visual bi-dimensional ones, a ecting their ability
to discriminate cases from controls. Overall, visual assessments showed the strongest
association with breast cancer risk in comparison to computerised methods.
Our research supports the hypothesis that density should have a role in personalising
screening programs and risk management. Volumetric density measuring methods,
though promising, could be improved.Cancer Research U
Short-term changes in ultrasound tomography measures of breast density and treatment-associated endocrine symptoms after tamoxifen therapy
Although breast density decline with tamoxifen therapy is associated with greater therapeutic benefit, limited data suggest that endocrine symptoms may also be associated with improved breast cancer outcomes. However, it is unknown whether endocrine symptoms are associated with reductions in breast density after tamoxifen initiation. We evaluated treatment-associated endocrine symptoms and breast density change among 74 women prescribed tamoxifen in a 12-month longitudinal study. Treatment-associated endocrine symptoms and sound speed measures of breast density, assessed via novel whole breast ultrasound tomography (m/s), were ascertained before tamoxifen (T0) and at 1-3 (T1), 4-6 (T2), and 12 months (T3) after initiation. CYP2D6 status was genotyped, and tamoxifen metabolites were measured at T3. Using multivariable linear regression, we estimated mean change in breast density by treatment-associated endocrine symptoms adjusting for age, race, menopausal status, body mass index, and baseline density. Significant breast density declines were observed in women with treatment-associated endocrine symptoms (mean change (95% confidence interval) at T1:-0.26 m/s (-2.17,1.65); T2:-2.12 m/s (-4.02,-0.22); T3:-3.73 m/s (-5.82,-1.63); p-trend = 0.004), but not among women without symptoms (p-trend = 0.18) (p-interaction = 0.02). Similar declines were observed with increasing symptom frequency (p-trends for no symptoms = 0.91; low/moderate symptoms = 0.03; high symptoms = 0.004). Density declines remained among women with detectable tamoxifen metabolites or intermediate/efficient CYP2D6 metabolizer status. Emergent/worsening endocrine symptoms are associated with significant, early declines in breast density after tamoxifen initiation. Further studies are needed to assess whether these observations predict clinical outcomes. If confirmed, endocrine symptoms may be a proxy for tamoxifen response and useful for patients and providers to encourage adherence
Deep learning in breast cancer screening
Breast cancer is the most common cancer form among women worldwide and the incidence
is rising. When mammography was introduced in the 1980s, mortality rates decreased by
30% to 40%. Today all women in Sweden between 40 to 74 years are invited to screening
every 18 to 24 months. All women attending screening are examined with mammography,
using two views, the mediolateral oblique (MLO) view and the craniocaudal (CC) view,
producing four images in total. The screening process is the same for all women and based
purely on age, and not on other risk factors for developing breast cancer.
Although the introduction of population-based breast cancer screening is a great success,
there are still problems with interval cancer (IC) and large screen detected cancers (SDC),
which are connected to an increased morbidity and mortality. To have a good prognosis, it
is important to detect a breast cancer early while it has not spread to the lymph nodes,
which usually means that the primary tumor is small. To improve this, we need to
individualize the screening program, and be flexible on screening intervals and modalities
depending on the individual breast cancer risk and mammographic sensitivity. In Sweden,
at present, the only modality in the screening process is mammography, which is excellent
for a majority of women but not for all.
The major lack of breast radiologists is another problem that is pressing and important to
address. As their expertise is in such demand, it is important to use their time as efficiently
as possible. This means that they should primarily spend time on difficult cases and less
time on easily assessed mammograms and healthy women.
One challenge is to determine which women are at high risk of being diagnosed with
aggressive breast cancer, to delineate the low-risk group, and to take care of these different
groups of women appropriately. In studies II to IV we have analysed how we can address
these challenges by using deep learning techniques.
In study I, we described the cohort from which the study populations for study II to IV
were derived (as well as study populations in other publications from our research group).
This cohort was called the Cohort of Screen Aged Women (CSAW) and contains all
499,807 women invited to breast cancer screening within the Stockholm County between
2008 to 2015. We also described the future potentials of the dataset, as well as the case
control subset of annotated breast tumors and healthy mammograms. This study was
presented orally at the annual meeting of the Radiological Society of North America in
2019.
In study II, we analysed how a deep learning risk score (DLrisk score) performs compared
with breast density measurements for predicting future breast cancer risk. We found that the
odds ratios (OR) and areas under the receiver operating characteristic curve (AUC) were
higher for age-adjusted DLrisk score than for dense area and percentage density. The
numbers for DLrisk score were: OR 1.56, AUC, 0.65; dense area: OR 1.31, AUC 0.60,
percent density: OR 1.18, AUC, 0.57; with P < .001 for differences between all AUCs).
Also, the false-negative rates, in terms of missed future cancer, was lower for the DLrisk
score: 31%, 36%, and 39% respectively. This difference was most distinct for more
aggressive cancers.
In study III, we analyzed the potential cancer yield when using a commercial deep
learning software for triaging screening examinations into two work streams – a ‘no
radiologist’ work stream and an ‘enhanced assessment’ work stream, depending on the output score of the AI tumor detection algorithm. We found that the deep learning
algorithm was able to independently declare 60% of all mammograms with the lowest
scores as “healthy” without missing any cancer. In the enhanced assessment work stream
when including the top 5% of women with the highest AI scores, the potential additional
cancer detection rate was 53 (27%) of 200 subsequent IC, and 121 (35%) of 347 next-round
screen-detected cancers.
In study IV, we analyzed different principles for choosing the threshold for the continuous
abnormality score when introducing a deep learning algorithm for assessment of
mammograms in a clinical prospective breast cancer screening study. The deep learning
algorithm was supposed to act as a third independent reader making binary decisions in a
double-reading environment (ScreenTrust CAD). We found that the choice of abnormality
threshold will have important consequences. If the aim is to have the algorithm work at the
same sensitivity as a single radiologist, a marked increase in abnormal assessments must be
accepted (abnormal interpretation rate 12.6%). If the aim is to have the combined readers
work at the same sensitivity as before, a lower sensitivity of AI compared to radiologists is
the consequence (abnormal interpretation rate 7.0%). This study was presented as a poster
at the annual meeting of the Radiological Society of North America in 2021.
In conclusion, we have addressed some challenges and possibilities by using deep learning
techniques to make breast cancer screening programs more individual and efficient. Given
the limitations of retrospective studies, there is a now a need for prospective clinical studies
of deep learning in mammography screening
The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme--a multicentre retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone.
BACKGROUND: Digital breast tomosynthesis (DBT) is a three-dimensional mammography technique with the potential to improve accuracy by improving differentiation between malignant and non-malignant lesions. OBJECTIVES: The objectives of the study were to compare the diagnostic accuracy of DBT in conjunction with two-dimensional (2D) mammography or synthetic 2D mammography, against standard 2D mammography and to determine if DBT improves the accuracy of detection of different types of lesions. STUDY POPULATION: Women (aged 47-73 years) recalled for further assessment after routine breast screening and women (aged 40-49 years) with moderate/high of risk of developing breast cancer attending annual mammography screening were recruited after giving written informed consent. INTERVENTION: All participants underwent a two-view 2D mammography of both breasts and two-view DBT imaging. Image-processing software generated a synthetic 2D mammogram from the DBT data sets. RETROSPECTIVE READING STUDY: In an independent blinded retrospective study, readers reviewed (1) 2D or (2) 2D + DBT or (3) synthetic 2D + DBT images for each case without access to original screening mammograms or prior examinations. Sensitivities and specificities were calculated for each reading arm and by subgroup analyses. RESULTS: Data were available for 7060 subjects comprising 6020 (1158 cancers) assessment cases and 1040 (two cancers) family history screening cases. Overall sensitivity was 87% [95% confidence interval (CI) 85% to 89%] for 2D only, 89% (95% CI 87% to 91%) for 2D + DBT and 88% (95% CI 86% to 90%) for synthetic 2D + DBT. The difference in sensitivity between 2D and 2D + DBT was of borderline significance (p = 0.07) and for synthetic 2D + DBT there was no significant difference (p = 0.6). Specificity was 58% (95% CI 56% to 60%) for 2D, 69% (95% CI 67% to 71%) for 2D + DBT and 71% (95% CI 69% to 73%) for synthetic 2D + DBT. Specificity was significantly higher in both DBT reading arms for all subgroups of age, density and dominant radiological feature (p < 0.001 all cases). In all reading arms, specificity tended to be lower for microcalcifications and higher for distortion/asymmetry. Comparing 2D + DBT to 2D alone, sensitivity was significantly higher: 93% versus 86% (p < 0.001) for invasive tumours of size 11-20 mm. Similarly, for breast density 50% or more, sensitivities were 93% versus 86% (p = 0.03); for grade 2 invasive tumours, sensitivities were 91% versus 87% (p = 0.01); where the dominant radiological feature was a mass, sensitivities were 92% and 89% (p = 0.04) For synthetic 2D + DBT, there was significantly (p = 0.006) higher sensitivity than 2D alone in invasive cancers of size 11-20 mm, with a sensitivity of 91%. CONCLUSIONS: The specificity of DBT and 2D was better than 2D alone but there was only marginal improvement in sensitivity. The performance of synthetic 2D appeared to be comparable to standard 2D. If these results were observed with screening cases, DBT and 2D mammography could benefit to the screening programme by reducing the number of women recalled unnecessarily, especially if a synthetic 2D mammogram were used to minimise radiation exposure. Further research is required into the feasibility of implementing DBT in a screening setting, prognostic modelling on outcomes and mortality, and comparison of 2D and synthetic 2D for different lesion types. STUDY REGISTRATION: Current Controlled Trials ISRCTN73467396. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 4. See the HTA programme website for further project information.This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 4. See the HTA programme website for further project information.Gilbert FJ, Tucker L, Gillan MGC, Willsher P, Cooke J, Duncan KA, et al. The TOMMY trial: a comparison of TOMosynthesis with digital MammographY in the UK NHS Breast Screening Programme – a multicentre retrospective reading study comparing the diagnostic performance of digital breast tomosynthesis and digital mammography with digital mammography alone. Health Technol Assess 2015;19(4). © Queen’s Printer and Controller of HMSO 2015. This work was produced by Gilbert et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK
Advancing combined radiological and optical scanning for breast-conserving surgery margin guidance
Breast cancer is one of the most common types of cancer worldwide, and standard-of-care for early-stage disease typically involves a lumpectomy or breast-conserving surgery (BCS). BCS involves the local resection of cancerous tissue, while sparring as much healthy tissue as possible. State-of-the-art methods for intraoperatively evaluating BCS margins are limited. Approximately 20% of BCS cases result in a tissue resection with cancer at or near the resection surface (i.e., a positive margin). A two-fold increase in ipsilateral breast cancer recurrence is associated with the presence of one or more positive margins. Consequently, positive margins often necessitate costly re-excision procedures to achieve a curative outcome. X-ray micro-computed tomography (CT) is emerging as a powerful ex vivo specimen imaging technology, as it provides robust three-dimensional sensing of tumor morphology rapidly. However, X-ray attenuation lacks contrast between soft tissues that are important for surgical decision making during BCS. Optical structured light imaging, including spatial frequency domain imaging and active line scan imaging, can act as adjuvant tools to complement micro-CT, providing wide field-of-view, non-contact sensing of relevant breast tissue subtypes on resection margins that cannot be differentiated by micro-CT alone. This thesis is dedicated to multimodal imaging of BCS tissues to ultimately improve intraoperative BCS margin assessment, reducing the number of positive margins after initial surgeries and thereby reducing the need for costly follow-up procedures. Volumetric sensing of micro-CT is combined with surface-weighted, sub-diffuse optical reflectance derived from high spatial frequency structured light imaging. Sub-diffuse reflectance plays the key role of providing enhanced contrast to a suite of normal, abnormal benign, and malignant breast tissue subtypes. This finding is corroborated through clinical studies imaging BCS specimen slices post-operatively and is further investigated through an observational clinical trial focused on combined, intraoperative micro-CT and optical imaging of whole, freshly resected BCS tumors. The central thesis of this work is that combining volumetric X-ray imaging and sub-diffuse optical scanning provides a synergistic multimodal imaging solution to margin assessment, one that can be readily implemented or retrofitted in X-ray specimen imaging systems and that could meaningfully improve surgical guidance during initial BCS procedures
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