• TEN-YEAR RISK OF FALSE POSITIVE SCREENING MAMMOGRAMS AND CLINICAL BREAST EXAMINATIONS

    The New England Journal of Medicine
    ©Copyright, 1998, by the Massachusetts Medical Society
    VOLUME 338 A PRIL 16, 1998 NUMBER 16

    J OANN G. E LMORE , M.D., M.P.H., M ARY B. B ARTON , M.D., M.P.P., V ICTORIA M. M OCERI , P H .C., S ARAH P OLK , B.A., P HILIP J. A RENA , M.D., AND S UZANNE W. F LETCHER , M.D.

    A BSTRACT Background The cumulative risk of a false positiveresult of a breast-cancer screening test is unknown. Methods We performed a 10-year retrospective co-hort study of breast-cancer screening and diagnosticevaluations among 2400 women who were 40 to 69years old at study entry. Mammograms or clinicalbreast examinations that were interpreted as indeter-minate, aroused a suspicion of cancer, or promptedrecommendations for additional workup in women inwhom breast cancer was not diagnosed within thenext year were considered to be false positive tests. Results A total of 9762 screening mammogramsand 10,905 screening clinical breast examinationswere performed, for a median of 4 mammograms and5 clinical breast examinations per woman over the 10-year period. Of the women who were screened, 23.8percent had at least one false positive mammogram,13.4 percent had at least one false positive breast ex-amination, and 31.7 percent had at least one falsepositive result for either test. The estimated cumula-tive risk of a false positive result was 49.1 percent (95percent confidence interval, 40.3 to 64.1 percent) after10 mammograms and 22.3 percent (95 percent confi-dence interval, 19.2 to 27.5 percent) after 10 clinicalbreast examinations. The false positive tests led to870 outpatient appointments, 539 diagnostic mam-mograms, 186 ultrasound examinations, 188 biopsies,and 1 hospitalization. We estimate that among wom-en who do not have breast cancer, 18.6 percent (95percent confidence interval, 9.8 to 41.2 percent) willundergo a biopsy after 10 mammograms, and 6.2 per-cent (95 percent confidence interval, 3.7 to 11.2 per-cent) after 10 clinical breast examinations. For every$100 spent for screening, an additional $33 was spentto evaluate the false positive results.

    To read the rest of the study, click here to download the PDF.

  • EVALUATION OF THE ABILITY OF DIGITAL INFRARED IMAGING TO DETECT VASCULAR CHANGES IN EXPERIMENTAL ANIMAL TUMOURS

    Int. J. Cancer: 108, 790–794 (2004)

    © 2003 Wiley-Liss, Inc.

    Publication of the International Union Against Cancer

    Infrared imaging has frequently been used in the past to detect changes in skin surface temperature associated with breast cancer. Usually a 1–2° C elevation in skin surfacet em-perature is observed at the tumour periphery, and it has been proposed that this change is due to hypervascularity resulting from tumour-associated angiogenesis. In our study, we used the rat mammary adenocarcinoma 13762 MAT, a tumour that has been used to identify antiangiogenic drugs, to investigate whether infrared imaging can detect angiogenesis in malignant tumours. If successful, it was hoped that this technique would represent a simple, noninvasive, procedure for monitoring the activity of antiangiogenic drugs. To read the rest of this article, click here to download the PDF file of this study.

  • Breast Thermography is a Noninvasive Prognostic Procedure that Predicts Tumor Growth Rate in Breast Cancer Patients

    Ann N Y Acad Sci. 1993 Nov 30;698:153-8.

    Breast thermography is a noninvasive prognostic procedure that predicts tumor growth rate in breast cancer patients.

    Head JF, Wang F, Elliott RL.

    Source

    Elliott Mastology Center, Baton Rouge, Louisiana 70816.

    Abstract

    Our recent retrospective analysis of the clinical records of patients who had breast thermography demonstrated that an abnormal thermogram was associated with an increased risk of breast cancer and a poorer prognosis for the breast cancer patient. This study included 100 normal patients, 100 living cancer patients, and 126 deceased cancer patients. Abnormal thermograms included asymmetric focal hot spots, areolar and periareolar heat, diffuse global heat, vessel discrepancy, or thermographic edge sign. Incidence and prognosis were directly related to thermographic results: only 28% of the noncancer patients had an abnormal thermogram, compared to 65% of living cancer patients and 88% of deceased cancer patients. Further studies were undertaken to determine if thermography is an independent prognostic indicator. Comparison to the components of the TNM classification system showed that only clinical size was significantly larger (p = 0.006) in patients with abnormal thermograms. Age, menopausal status, and location of tumor (left or right breast) were not related to thermographic results. Progesterone and estrogen receptor status was determined by both the cytosol-DCC and immunocytochemical methods, and neither receptor status showed any clear relationship to the thermographic results. Prognostic indicators that are known to be related to tumor growth rate were then compared to thermographic results. The concentration of ferritin in the tumor was significantly higher (p = 0.021) in tumors from patients with abnormal thermograms (1512 +/- 2027, n = 50) compared to tumors from patients with normal thermograms (762 +/- 620, n = 21). Both the proportion of cells in DNA synthesis (S-phase) and proliferating (S-phase plus G2M-phase, proliferative index) were significantly higher in patients with abnormal thermograms. The expression of the proliferation-associated tumor antigen Ki-67 was also associated with an abnormal thermogram. The strong relationships of thermographic results with these three growth rate-related prognostic indicators suggest that breast cancer patients with abnormal thermograms have faster-growing tumors that are more likely to have metastasized and to recur with a shorter disease-free interval.

  • Circadian Rhythm Chaos: A New Breast Cancer Marker

    Int J Fertil Womens Med. 2001 Sep-Oct;46(5):238-47.

    Circadian rhythm chaos: a new breast cancer marker.

    Keith LG, Oleszczuk JJ, Laguens M.

    Source

    Department of Obstetrics and Gynecology, Northwestern University Medical School, Chicago, Illinois, USA.

    Abstract

    The most disappointing aspect of breast cancer treatment as a public health issue has been the failure of screening to improve mortality figures. Since treatment of late-stage cancer has indeed advanced, mortality can only be decreased by improving the rate of early diagnosis. From the mid-1950s to the mid-1970s, it was expected that thermography would hold the key to breast cancer detection, as surface temperature increases overlying malignant tumors had been demonstrated by thermographic imaging. Unfortunately, detection of the 1-3 degrees C thermal differences failed to bear out its promise in early identification of cancer. In the intervening two-and-a-half decades, three new factors have emerged: it is now apparent that breast cancer has a lengthy genesis; a long-established tumor-even one of a certain minimum size-induces increased arterial/capillary vascularity in its vicinity; and thermal variations that characterize tissue metabolism are circadian (“about 24 hours”) in periodicity. This paper reviews the evidence for a connection between disturbances of circadian rhythms and breast cancer. Furthermore, a scheme is proposed in which circadian rhythm “chaos” is taken as a signal of high risk for breast cancer even in the absence of mammographic evidence of neoplasm or a palpable tumor. Recent studies along this line suggest that an abnormal thermal sign, in the light of our present knowledge of breast cancer, is ten times as important an indication as is family history data.

  • The Evolving Role of the Dynamic Thermal Analysis in the Early Detection of Breast Cancer

    The evolving role of the dynamic thermal analysis in the early detection of breast cancer

    M Salhab, W Al Sarakbi and K Mokbel

    St George’s and The Princess Grace Hospitals, London, UK

    International Seminars in Surgical Oncology 2005, 2:8doi:10.1186/1477-7800-2-8

    The electronic version of this article is the complete one and can be found online at: http://www.issoonline.com/content/2/1/8

    Received: 6 April 2005
    Accepted: 8 April 2005
    Published: 8 April 2005

    © 2005 Salhab et al; licensee BioMed Central Ltd.
    This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    It is now recognised that the breast exhibits a circadian rhythm which reflects its physiology. There is increasing evidence that rhythms associated with malignant cells proliferation are largely non-circadian and that a circadian to ultradian shift may be a general correlation to neoplasia.

    Cancer development appears to generate its own thermal signatures and the complexity of these signatures may be a reflection of its degree of development.

    The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity. Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer.

    This article focuses on dynamic thermal analysis as an evolving method in breast cancer detection in pre-menopausal women with dense breast tissue. Prospective multi-centre trials are required to validate this promising modality in screening.

    The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy.

    Keywords:

    Circadian rhythm; breast cancer; screening and dynamic thermal analysis

    Introduction

    Breast cancer is one of the most common cancers, it is estimated that one in eight women in the USA will develop breast cancer during their lifetime [14]. Furthermore, 25–30% of breast cancers are found in pre-menopausal women [1]. Currently mammography is the best available approach for the early detection of breast cancer in the general population with a sensitivity of 75–90% [2]. However, the positive predictive value is only 25% [3,4].

    In addition to mammography, non invasive new modalities have been developed to allow the early detection of breast cancer in all age groups and more importantly in young women with dense breast tissue and women who have high risk of developing breast cancer such as, women with strong family history and carriers of BRCA1 and/or BRCA2 genes.

    Currently, magnetic resonance imaging (MRI) is being studied for the early detection of breast cancer. Its sensitivity in high risk women has been found to be much higher than mammography but with a lower specificity [5,6]. Kriege et al observed a higher sensitivity for MRI in detection of breast cancer in women with a genetic predisposition or at high risk compared to (71% vs. 41 %) but with lower specificity (90% vs. 95%) [6].

    Electrical impedance scanning (EIS) is another modality under development for breast cancer detection especially in young women with dense breasts [7]. The basic science behind its use is the fact that malignant tumours have lower electrical impedance than the surrounding normal tissue. However, separation between malignant and benign lesions needs further investigations [8].

    Furthermore, mammary ductoscopy (MD) and visualization of mammary ducts and proteomics of nipple aspirate fluid (NAF) and serum are promising screening modalities that require further evaluation [9,10].

    The limitations of mammography as a screening modality especially in young women with dense breasts necessitated the development of novel and more effective screening strategies with a high sensitivity and specificity.

    This article focuses on the dynamic thermal analysis as an evolving non invasive and a safe method in breast cancer detection in pre-menopausal women with dense breast tissue and women at high risk due to family history or genetic predisposition.

    Breast and circadian rhythm [1]

    It is now recognised that the establishment and growth of a tumour depend on neovascularization. This successful recruitment of new blood vessels into a tumour; also known as angiogenesis is dependent on angiogenic growth factors produced by the tumour cells [11]. Such new vessels grow adjacent to the tumour presumably to increase its nutrient supply [12]. These new vessels lack smooth muscles rendering them unreceptive to control by epinephrine [13,14]. The lack of receptivity produce a more constant blood flow, thus increasing the local temperature.

    Earlier technology for assessing thermal abnormalities in the breast focussed on the presence of the abnormal temperature as a crucial marker [1517]. In a study conducted by Gantherine et al, 21.3% of patients who had abnormal thermograms but no abnormality on physical examination and mammography developed breast cancer within the next 3 years [17]. In another study of women who had thermal abnormalities on initial examination using infrared technology, long term follow up (2–10 years) revealed that 33% of these women developed breast cancer, a rate six times higher than that expected in the normal population [18]. This relationship between breast skin temperature and breast cancer was thoroughly examined by Gros et al [15,16]. They found that the differences between the characteristics of rhythmic changes in skin temperature of clinically healthy and cancerous breasts were real and measurable. Despite these interesting observations thermography as a general screening tool for the detection of women at risk of breast cancer did not find a wide spread acceptance due to low sensitivity of the test and the subjective nature of the test interpretations.

    The superficial thermal patterns measured on the surface of the breast seem to be related to tissue metabolism and vascularization within the underlying tissue. Such thermal patterns change significantly as a result of normal phenomena including menstrual cycle, pregnancy and more importantly the pathologic process itself. Additionally, cancer development represents the summation of a large number of mutations that occur over years, each with its own particular histologic phenotype [1923].

    Such changes appear to generate their own thermal signature and the complexity of these signatures may be a reflection of their degree of development [2428].

    Temperature in a normal breast increases from the skin into the deep tissue and heat conductivity in the healthy breasts is constant in most cases and generally can be characterized in terms of circadian rhythm periodicity [29]. In contrast, the rhythms associated with malignant cells proliferation are largely non circadian and suggest that a circadian to ultradian shift may be a general correlation to neoplasia. Heat production by the tumour under the influence of angiogenesis should be therefore re-examined in terms of absence of normal circadian fluctuations. Due to the increased blood flow and the lack of receptivity in the newly formed vessels in malignancy, temperature production exhibits circadian rhythmic variations to a far lesser degree than is evident in the healthy breasts [13]. It has been found that independent of a tumour’s size, relatively small tumours (>/= 0.5 cm in diameter), poorly vascularized rapidly growing tumors can produce increases in regional heat. The explanation for this effect is unclear but it may be due to the chronic inflammatory response around developing breast tumours. With increasing evidence that inflammation can enhance tumor growth and is associated with a poor prognosis, this suggestion implies that thermal analysis may have considerable value [30].

    Furthermore, the unique relationship between the thermal circadian rhythm and mitotic activity could be considered as a first warning of tumour development, which can be detected using a safe and non-invasive technology. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis [31].

    Dynamic thermal analysis

    Recent technological advances have facilitated the recording of circadian rhythm variations of the breast and analysing the recorded data using highly complicated computer statistical software. A miniaturized microprocessor has been developed to record and store thermal information collected from eight separate sites of each breast. Sensors are placed in anatomically critical positions elicited by data obtained from tumour registries as to where cancers are most likely to develop.

    In the First Warning System (FWS, Lifeline Biotechnologies, Florida, USA), thermal data are collected every five minutes for a period of 48 hours during which time women are encouraged to maintain their daily activities. 9000 pieces of data are recorded by microprocessors during the test period and analysed using specially developed statistical software. Temperature points from each contralateral sensor are plotted against each other to form a thermal motion picture of a lesion’s physiological activity.

    Such a technology was first used by Farrar et al who examined a cohort of 138 women who had been scheduled for open breast biopsies based on the finding of physical examination and mammography [14]. A total of 23 women (17%) were found to have breast cancer, of these, 20 (87%) were characterized by the monitor as being high risk. The other 3 patients (13%) who were missed by the monitor had ductal carcinoma. Mammography was positive or suspicious in only 19 patients (83%). Of the 4 cancers missed by mammography (3 of them were pre menopausal), the monitor correctly characterized 3 women as being high risk. Figures 1 and 2 demonstrate the thermal graphs in two patients with a fibroadenoma (Fig. 1) and a T1 breast cancer (Fig. 2). A neural net algorithm was subsequently developed and evaluated by the authors because of its value in analysing the non-linear data such as these recorded by the breast’s monitors. Using this neural net algorithm reduced the number of false positives (18% vs. 30%)) and improved sensitivity (91% vs. 87%).

    Figure 1.

    Dynamic thermal analysis in a patient with fibroadenoma.

    Salhab et al. International Seminars in Surgical Oncology 2005 2:8 doi:10.1186/1477-7800-2-8
    Download authors’ original image

     

    Figure 2.

    Dynamic thermal analysis in a patient with T1 breast cancer.

    Salhab et al. International Seminars in Surgical Oncology 2005 2:8 doi:10.1186/1477-7800-2-8
    Download authors’ original image

     

    One of the main challenges to this technology is the false positive cases; confusion could be created in these women who are characterized as being positive or high risk by dynamic thermal analysis in the absence of physical and mammographical signs. This group of women may or may not have cancer in its earliest stages. Further retrospective analysis of the thermal data using a refined neural net algorithm may increase the sensitivity and reduce the number of false positives. Also this group of patients may well benefit from the new advances in the nipple aspirate fluid analysis and proteomic profiling technologies. Research is currently ongoing on this subject and the initial results are promising [9].

    The Future

    Dynamic thermal analysis of the breast is a safe, non invasive approach that seems to be sensitive for the early detection of breast cancer especially in young women where the conventional mammography is of limited value. Such a technology could become the initial breast screening test in pre-menopausal women and those who are classified as positive can then be selected for anatomical imaging with mammography, MRI and/or ultrasonography. Further refinement of the neural net algorithm is required in order to shorten the period of data recording and improve specificity. Prospective multi-centre trials are then required to validate these promising observations. The issue of false positives require further investigation using molecular genetic markers of malignancy and novel techniques such as mammary ductoscopy [10].

    Finally, a better understanding of the circadian rhythm biology [1,30] and clearer definition of the thermal activity boundaries for various pathological conditions of the breast will open the door to a new and more precise screening method for breast cancer.

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  • Advanced Integrated Technique in Breast Cancer Thermography

    J Med Eng Technol. 2008 Mar-Apr;32(2):103-14.

    Advanced integrated technique in breast cancer thermography.

    Ng EY, Kee EC.

    Source

    School of Mechanical and Aerospace Engineering, College of Engineering, Nanyang Technological University, 639798, Singapore. mykng@ntu.edu.sg

    Abstract

    Thermography is a passive and non-contact imaging technique used extensively in the medical arena, but in relation to breast care, it has not been accepted as being on a par with mammography. This paper proposes the analysis of thermograms with the use of artificial neural networks (ANN) and bio-statistical methods, including regression and receiver operating characteristics (ROC). It is desired that through these approaches, highly accurate diagnosis using thermography techniques can be achieved. The suggested method is a multi-pronged approach comprising of linear regression, radial basis function network (RBFN) and ROC analysis. It is a novel, integrative and powerful technique that can be used to analyse large amounts of complicated measured data such as temperature values extracted from abnormal and healthy breast thermograms. The use of regression allows the correlation between the variables and the actual health status of the subject, which is decided by other traditional means such as the gold standard of mammography for breast cancer detection. This is important as it helps to select the appropriate variables to be used as inputs for building the neural network. RBFN is next trained to produce the desired outcome that is either positive or negative. When this is done, the RBFN possess the ability to predict the outcome when there are new input variables. The advantages of using RBFN include fast training of superior classification and decision-making abilities as compared to other networks such as backpropagation. Lastly, ROC is applied to evaluate the sensitivity, specificity and accuracy of the outcome for the RBFN test files. The proposed technique has an accuracy rate of 80.95%, with 100% sensitivity and 70.6% specificity in identifying breast cancer. The results are promising as compared to clinical examination by experienced radiologists, which has an accuracy rate of approximately 60-70%. To sum up, technological advances in the field of infrared thermography over the last 20 years warrant a re-evaluation of the use of high-resolution digital thermographic camera systems in the diagnosis and management of breast cancer. Thermography seeks to identify the presence of a tumour by the elevated temperature associated with increase blood flow and cellular activity. Of particular interest would be investigation in younger women and men, for whom mammography is either unsuitable or of limited effectiveness. The paper evaluated the high-definition digital infrared thermographic technology and knowledge base; and supports the development of future diagnostic and therapeutic services in breast cancer imaging. Through the use of integrative ANN and bio-statistical methods, advances are made in thermography application with regard to achieving a higher level of consistency. For breast cancer care, it has become possible to use thermography as a powerful adjunct and biomarker tool, together with mammography for diagnosis purposes.

  • Screening for Breast Cancer

    JAMA. 2005 Mar 9;293(10):1245-56.

    Screening for breast cancer.

    Elmore JG, Armstrong K, Lehman CD, Fletcher SW.

    Source

    Department of Medicine, University of Washington School of Medicine, Seattle, USA. jelmore@u.washington.edu

    Abstract

    CONTEXT:

    Breast cancer screening in community practices may be different from that in randomized controlled trials. New screening modalities are becoming available.

    OBJECTIVES:

    To review breast cancer screening, especially in the community and to examine evidence about new screening modalities.

    DATA SOURCES AND STUDY SELECTION:

    English-language articles of randomized controlled trials assessing effectiveness of breast cancer screening were reviewed, as well as meta-analyses, systematic reviews, studies of breast cancer screening in the community, and guidelines. Also, studies of newer screening modalities were assessed.

    DATA SYNTHESIS:

    All major US medical organizations recommend screening mammography for women aged 40 years and older. Screening mammography reduces breast cancer mortality by about 20% to 35% in women aged 50 to 69 years and slightly less in women aged 40 to 49 years at 14 years of follow-up. Approximately 95% of women with abnormalities on screening mammograms do not have breast cancer with variability based on such factors as age of the woman and assessment category assigned by the radiologist. Studies comparing full-field digital mammography to screen film have not shown statistically significant differences in cancer detection while the impact on recall rates (percentage of screening mammograms considered to have positive results) was unclear. One study suggested that computer-aided detection increases cancer detection rates and recall rates while a second larger study did not find any significant differences. Screening clinical breast examination detects some cancers missed by mammography, but the sensitivity reported in the community is lower (28% to 36%) than in randomized trials (about 54%). Breast self-examination has not been shown to be effective in reducing breast cancer mortality, but it does increase the number of breast biopsies performed because of false-positives. Magnetic resonance imaging and ultrasound are being studied for screening women at high risk for breast cancer but are not recommended for screening the general population. Sensitivity of magnetic resonance imaging in high-risk women has been found to be much higher than that of mammography but specificity is generally lower. Effect of the magnetic resonance imaging on breast cancer mortality is not known. A balanced discussion of possible benefits and harms of screening should be undertaken with each woman.

    CONCLUSIONS:

    In the community, mammography remains the main screening tool while the effectiveness of clinical breast examination and self-examination are less. New screening modalities are unlikely to replace mammography in the near future for screening the general population.