Measurement of Tumor Extent and Effects of Breast Compression in Digital Mammography and Breast Tomosynthesis

Breast cancer is the most common form of cancer affecting women in the western countries. Today x-ray digital mammography (DM) of the breast is commonly used for early detection of breast cancer. However, the sensitivity of mammography is limited, mainly due to the fact that a 3D volume is projected down to a 2D image. This problem can be partially solved by a tomographic technique. Breast tomosynthesis (BT) reduces the detrimental effect of the projected anatomy. Tumor size is an important predictor of prognosis and treatment effect. We hypothesized that the tumor outline would be better defined in BT and therefore tumor measurement in BT would be more accurate compared with DM. The results showed that breast tumor size measured on BT correlated better with the size measured by the pathologists on the surgical specimens compared with measurement on DM. Breast compression is important in mammography both to improve image quality and to reduce the radiation dose to the breast, but it also has a negative consequence as some women refrain from mammography due to the pain associated with the examination. Since BT is a 3D technique, it was hypothesized that less breast compression force can be applied. The results indicated that less compression force is possible without significantly compromising the diagnostic quality of the image and that the patient comfort was improved. An applied breast compression force as used in mammography results in a pressure distribution over the breast. The pressure distribution was assessed using thin pressure sensors attached to the compression plate. The results showed that the pressure distribution was heterogeneous in appearance and varied widely between different breasts. In almost half of the subjects most of the pressure was over the juxtathoracic part of the breast and the pectoral muscle with little or no pressure over the rest of the breast. Another concern regarding breast compression is the question whether the resulting pressure might damage tumors, causing a shedding of malignant cells into the blood system. Peripheral venous blood samples were drawn before and after breast compression and analyzed for circulating tumor cells. The study found no elevated number of circulating cancer cells in peripheral blood after breast compression. Future analysis of samples from veins draining the breast are needed to study if circulating tumor cells are being trapped in the lung capillaries

Zebularine induces long-term survival of pancreatic islet allotransplants in streptozotocin treated diabetic rats.

Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed

Compression forces used in the Norwegian Breast Cancer Screening Program

Objectives: Compression is used in mammography to reduce breast thickness, which is claimed to improve image quality and reduce radiation dose. In the Norwegian Breast Cancer Screening Program (NBCSP), the recommended range of compression force for full field digital mammography is 11-18 kg (108-177 Newton [N]). This is the first study to investigate the compression force used in the program. Methods: The study included information from 17,951 randomly selected women screened with FFDM at 14 breast centres in the NBCSP, January-March 2014. We investigated the applied compression force on left breast in craniocaudal (CC) and mediolateral oblique (MLO) view for breast centres, mammography machines within the breast centres and for the radiographers. Results: The mean compression force for all mammograms in the study was 116N and ranged from 91 to 147N between the breast centres. The variation in compression force was wider between the breast centres than between mammography machines (range 137-155N) and radiographers (95-143N) within one breast centre. Approximately 59% of the mammograms in the study complied with the recommended range of compression force. Conclusions: A wide variation in applied compression force was observed between the breast centres in the NBCSP. This variation indicates a need for evidence-based recommendations for compression force aimed at optimizing the image quality and individualising breast compression. Advances in knowledge: There was a wide variation in applied compression force between the breast centres in the NBCSP. The variation was wider between the breast centres than between mammography machines and radiographers within one breast centre

Cancer recurrence times from a branching process model

As cancer advances, cells often spread from the primary tumor to other parts of the body and form metastases. This is the main cause of cancer related mortality. Here we investigate a conceptually simple model of metastasis formation where metastatic lesions are initiated at a rate which depends on the size of the primary tumor. The evolution of each metastasis is described as an independent branching process. We assume that the primary tumor is resected at a given size and study the earliest time at which any metastasis reaches a minimal detectable size. The parameters of our model are estimated independently for breast, colorectal, headneck, lung and prostate cancers. We use these estimates to compare predictions from our model with values reported in clinical literature. For some cancer types, we find a remarkably wide range of resection sizes such that metastases are very likely to be present, but none of them are detectable. Our model predicts that only very early resections can prevent recurrence, and that small delays in the time of surgery can significantly increase the recurrence probability.Comment: 26 pages, 9 figures, 4 table

Optimization of breast tomosynthesis: Computer simulations of image acquisition and glandular dose

Breast tomosynthesis (BT) is an X-ray imaging technique recently introduced as an alternative or complement to standard digital mammography (DM) in breast imaging and breast cancer screening. In BT, a set of projection images is acquired over a limited angular range and reconstructed into a volume of slice images. The method includes many possible combinations of acquisition parameters that have to be optimized for best possible clinical performance and outcome. The visibility of breast cancer lesions is important in this context. Compared to DM images, the reconstructed BT volume provides additional information on depth, reducing the superposition of breast tissue, which may hide true lesions or appear as false positive findings. Thus, the BT volume also contains information about the distribution of dense tissue within the breast, which is of interest when estimating the radiation dose from DM and BT exposure.In this thesis, a simulation procedure was developed for the optimization of image acquisition and estimation of individual glandular dose in BT. The procedure was shown to be useful in generating BT images with realistic sharpness, though with higher image noise and contrast than experimentally acquired images (Paper I). The procedure was used to investigate the influence of angular range, distribution of projection images, and dose distribution on simulated microcalcifications in reconstructed BT volumes. Image acquisitions with very high central dose yielded significantly lower visibility than acquisitions with more uniform dose distributions, and the depth resolution increased with wider angular range (Paper II).A method for localizing dense tissue from reconstructed BT volumes was verified using the simulation procedure (Paper III). A prototype software program was used for automatic and objective estimation of breast density in BT, with similar performance as DM (Paper IV). Using software breast phantoms recreated from reconstructed BT volumes, the glandular dose could be estimated with good overall accuracy for breast phantoms with different amounts and distributions of dense tissue (Paper V).The developed simulation procedure has been a useful tool for optimizing acquisition parameters and estimating glandular dose in BT. The procedure could potentially be developed for further evaluation of the imaging chain and estimation of individual glandular dose in human cases

Novel treatments of glioblastoma in experimental models

One of the major problems with malignant brain tumours, such as glioblastoma multiforme, is that despite being able to remove the major bulk of the tumour through surgery and treating the patients with chemotherapy and radiotherapy, we know that tumour cells have already spread throughout the brain. Furthermore, we now know that the glioblastoma cells effectively suppress the patients’ own anti-tumour response. One key part of the immune response, the complement system, acts as a functional bridge between innate and adaptive immunity. Here we wanted to further investigate the complement system in both glioblastoma patients and in laboratory animals by looking at the role of CRP and C1-inhibitor (C1-INH). In order not to rely solely on old glioblastoma models, which have been passed in vitro for decades, we also developed a new glioblastoma model.Initially we studied an experimental treatment, ITPP, which had previously shown promising results in other cancer models. This was done using the old glioblastoma model RG2. Subsequently we went on to develop a new GFPpositive glioblastoma model called NS1. The NS1 cell line was then used to further investigate the role of the complement system, both in vitro and in vivo, by treating the cells and animals with anti-C1-INH and anti-CRP. The in vivo experiments involved intratumoral treatment of both intracranial and subcutaneous tumours. Additionally, tumour material from glioblastoma patients was examined on the gene and protein level and compared to tumour data available from public databases.Treatment with ITPP showed no survival advantage in the RG2 model, and the route of ITPP administration did not affect outcome. The NS1 model turned out to generate infiltrative CNS tumours with perivascular growth and characteristics of a glioblastoma upon histopathological examination. With MRI tumour could easily be detected within 14 days after inoculation. We could demonstrate a significantly increased survival in vivo in animals inoculated intracerebrally with NS1 glioblastoma cells pre-coated with anti-C1-INH antibodies. On the contrary no effect of coating glioblastoma cells with anti-CRP antibodies prior to intracranial inoculation was seen. In the subcutaneous NS1 tumour model, intratumoral anti-C1-INH treatment showed a significant survival advantage andthere was a significant decrease in tumour size over time following treatment with anti-C1-INH. Using data fram a publicly available database and our own mRNA material from glioblastoma patients, we found an upregulation ofC1-INH in human glioblastoma cells. Furthermore, by using immunohistochemistry, we could demonstrate the presence of both C1-INH and CRP on glioma cells in vitro from humans and rats.We could conclude that C1-INH seems to play an important role in glioblastoma. This could possibly be explained by effects on the complement system, but also other effects are possible, since C1-INH has many biological functions. The exact role and mechanisms of anti-C1-INH treatment are topics for future studies

Changes in breast density over serial mammograms : A case-control study

Purpose: In addition to a breast density category, temporal changes in breast density have gained attention as a dynamic breast cancer risk marker. This case-control study aimed to investigate a potential change in breast density preceding tumor development and the relationship of this potential change to prognostic pathological tumor variables. Method: A total of 51 consecutive, eligible-for-analyses, biopsy-proven breast cancers were diagnosed between 1 st of August and 31 st of December 2014 at Skåne University Hospital, Sweden. Mammogram data and patient- and tumor characteristics were retrieved retrospectively from medical charts. Breast density was quantitatively estimated using LIBRA (a free open source software package). The cases were matched for year of birth, number of screening rounds, and date for first and last mammograms with controls from the Malmö Breast Tomosynthesis Screening Trial in a 1:2 ratio, resulting in median time between mammograms of 4.5 (1.3–11.9) years for cases and 4.7 (1.4–11.1) years for controls, averaging approximately three screening rounds (1–6 rounds). Results: We detected a statistically significant difference in breast density change over time, with cases showing an increase in breast density (1.7 %) as compared to controls (-0.3 %) (p = 0.045). We found that in women with breast cancer, older women (≥ 55 years) experienced a higher breast density increase compared to younger women (5.1 % vs. 0.3 %, p = 0.002). Conclusions: There was a statistically significant difference in density change, where women with breast cancer showed an increased density over time, which was particularly evident in women > 55 years of age

Comparison between software volumetric breast density estimates in breast tomosynthesis and digital mammography images in a large public screening cohort

Objectives: To compare software estimates of volumetric breast density (VBD) based on breast tomosynthesis (BT) projections to those based on digital mammography (DM) images in a large screening cohort, the Malmö Breast Tomosynthesis Screening Trial (MBTST). Methods: DM and BT images of 9909 women (enrolled 2010–2015) were retrospectively analysed with prototype software to estimate VBD. Software calculation is based on a physics model of the image acquisition process and incorporates the effect of masking in DM based on accumulated dense tissue areas. VBD (continuously and categorically) was compared between BT [central projection (mediolateral oblique view (MLO)] and two-view DM, and with radiologists’ BI-RADS density 4th ed. scores. Agreement and correlation were investigated with weighted kappa (κ), Spearman’s correlation coefficient (r), and Bland–Altman analysis. Results: There was a high correlation (r = 0.83) between VBD in DM and BT and substantial agreement between the software breast density categories [observed agreement, 61.3% and 84.8%; κ = 0.61 and ĸ = 0.69 for four (a/b/c/d) and two (fat involuted vs. dense) density categories, respectively]. There was moderate agreement between radiologists’ BI-RADS scores and software density categories in DM (ĸ = 0.55) and BT (ĸ = 0.47). Conclusions: In a large public screening setting, we report a substantial agreement between VBD in DM and BT using software with special focus on masking effect. This automated and objective mode of measuring VBD may be of value to radiologists and women when BT is used as the primary breast cancer screening modality. Key Points: • There was a high correlation between continuous volumetric breast density in DM and BT.• There was substantial agreement between software breast density categories (four groups) in DM and BT; with clinically warranted binary software breast density categories, the agreement increased markedly.• There was moderate agreement between radiologists’ BI-RADS scores and software breast density categories in DM and BT