Non-randomness of the anatomical distribution of tumors

Akt activation has been found in various human cancers, while experimental studies have suggested that Akt plays an important role in the development of tumor angiogenesis and lymphangiogenesis. Immunohistochemical analyses for VEGF-C and Akt and the lymphatic endothelial specific marker D2-40 were performed on a series of 242 invasive ductal carcinomas of the breast, in which VEGF-A expression and microvessel density (MVD) had been determined previously. Lymphatic vessel density (LVD) was estimated in three hot spots. A significant correlation was observed between the VEGF-C expression and LVD (p=0.0026) and between LVD and the lymph node status (p<0.0001). The VEGF-C expression, however, did not correlate significantly with the lymph nodes status, while a high VEGF-C expression was associated with a smaller tumor size (p=0.0188). There was a significant correlation between VEGF-C and VEGF-A expression (p=0.0079) and between LVD and MVD (p=0.0008). The VEGF-C expression correlated with MVD (p<0.0001), while the VEGF-A expression correlated with LVD (p=0.0155). The Akt expression correlated with VEGF-A (p=0.0173) and -C expression (p=0.0056) as well as MVD (p=0.0482) and LVD (p=0.0012), while the correlation of Akt expression to VEGF-C expression and LVD was stronger than that to VEGF-A expression and MVD. Although the patients with a high LVD have a poorer disease-free survival than those with a low LVD (p=0.0005), a multivariate analysis determined the lymph node status and MVD to be independently significant factors for the disease-free survival. In conclusion, the correlation of both VEGF-C and VEGF-A to LVD and MVD suggested the two growth factors to be involved in both angiogenesis and lymphangiogenesis in breast cancer. The correlation of the Akt expression to the VEGF-A and -C expression as well as MVD and LVD, thus, suggested Akt activation to contribute to both angiogenesis and lymphangiogenesis via VEGF-A and -C expression in breast cancer.

Recent studies have drawn attention to intratumoral microvessel density (MVD) as a prognostic factor in invasive breast cancer. Various methods have been applied to assess MVD and the prognostic value of MVD in different studies varies considerably. Counting of microvessels in the most highly vascularized area (hot spot) of a tumour is the method most widely used. In this study we compared three counting methods. To assess MVD in 112 cases of invasive breast cancer with long-term follow-up we performed microvessel counting in the hot spot of the tumour in four and 10 fields of vision (HS-MVD4 and HS-MVD10) and microvessel counting in 10 fields of vision distributed systematically over the whole tumour area (global MVD). The HS-MVD4, HS-MVD10 and global MVD showed good correlations with each other. HS-MVD4 provided the highest number of microvessels (median value 71) followed by HS-MVD10 and global MVD, with median values of 58 and 39, respectively. HS-MVD4 showed the best prognostic value for overall survival (P = 0.0001) whereas HS-MVD10 showed less (P = 0.01) and the global MVD showed no (P = 0.75) prognostic value. In univariate analysis, the HS-MVD4 was the second strongest prognostic factor after tumour size. In multivariate survival analysis, the HS-MVD4, mitotic activity index (MAI), lymph node status and tumour size were found to be independent prognostic factors. When combining MVD4 and MAI in lymph node negative patients, none of the patients with low MVD (< 71/mm2) and a low MAI (< 10 per 10 HPF) died, in contrast to patients with a high MVD or high MAI who have a 10-year survival of 57%. These data suggest that the hot spot MVD in four fields of vision is a major independent prognostic factor for overall survival in invasive breast cancer. For the first time, it is shown that hot spot MVD provides additional prognostic information to well established factors like lymph node status and the MAI, and may therefore be useful for designing treatment strategies in invasive breast cancer.

In some studies of breast cancer, quantitation of immunohistochemically highlighted microvessel 'hot spots' has been shown to be a powerful prognostic tool. However, the antibody used, the number and size of the 'hot spots' assessed, and the stratification of patients into high and low vascular groups vary between studies. Furthermore, little is known about the relationship between microvessel density and other vascular parameters. These uncertainties and the laborious nature of the technique make it unsuitable for diagnostic practice. Both manual and computerized image analysis techniques were used in this study to examine the relationship between microvessel density and the vascular parameters in different sized microscopic fields in a pilot series of 30 invasive breast carcinomas. Automated pixel analysis of immunohistochemical staining, Chalkley point counting, and observer subjective vascular grading were also assessed as more rapid methods of measuring tumour vascularity. A Chalkley count was also performed on a further 211 invasive breast carcinomas. Significant correlations were observed between manual microvessel density and luminal perimeter (r = 0.6, P = 0.0004), luminal area (r = 0.56, P = 0.002), and microvessel number (r = 0.57, P = 0.0009) by computerized analysis. There were also significant correlations between the microscopic hot spots of 0.155 mm2 and 0.848 mm2 for microvessel number (r = 0.81, P < 0.00005), luminal perimeter (r = 0.78, P < 0.00005), and luminal area (r = 0.65, P = 0.0001). In addition, a significant correlation was observed between microvessel density and both subjective vascular grade (P = 0.002) and Chalkley count (P = 0.0001). A significant reduction in overall survival was observed between patients stratified by Chalkley count in both a univariate (P = 0.02) and a multivariate (P = 0.05) analysis in the 211 invasive breast carcinomas. These findings show that Chalkley counting is a rapid method of quantifying tumour angiogenesis and gives independent prognostic information which might be useful in diagnostic practice.

Abundant evidence has shown that tumor growth and metastasis are dependent upon tumor angiogenesis (TA). TA refers to the growth of new vessels toward and within the tumor. Until TA occurs, tumors grow no larger than 2-4 mm in diameter. Also, TA is necessary at the beginning and at the end of the metastatic cascade of events. Thus, it seems reasonable that increasing intratumoral microvascular density (iMVD) might correlate with greater tumor aggressiveness, such as a higher frequency of metastases and/or decreased survival. Indeed, in 1991 my colleagues and I reported a statistically significant association between greater incidence of metastases in patients with breast carcinoma and increasing iMVD. Microvessel density was measured with a light microscope in a single area of invasive tumor (200x field or 0.74 mm2) representative of the highest microvessel density (neovascular "hot spot"). This was done after endothelial cells, lining the microvessels, had been highlighted with anti-factor VIII-related antigen/von Willebrand's factor (F8RA/vWF). Subsequent studies by other investigators, using either anti-F8RA/vWF or other relatively vessel-specific reagents such as anti-CD31, have shown that the association of greater tumor aggressiveness with increasing iMVD exists not only in breast carcinoma, but also in other solid tumors. This article reviews the methods of highlighting intratumoral vessels and describes the techniques for counting these vessels for assessing iMVD.

e21166 Background: We aimed to investigate whether a relation exists between primary tumor localization at breast and metastasis sites in breast cancer patients. Methods: Data of metastatic breast cancer patients being followed at Hacettepe University Institute of Oncology, Department of Medical Oncology between years 1987 and 2010 were analysed retrospectively. Metastasis sites and primary tumor localizations at breast were evaluated with chi-square test. Results: There were 129 (10.6%) metastatic breast cancer patients diagnosed at the admission or during the follow up period within 1,218 patients. The 13 (10%) patients had primary tumor at inner upper quadrant, 78 (60.4%) at upper outer quadrant, 11 (8.52%) at rero-areolar region, and 10 (7.75%) at inferior outer quadrant. Ten patients (7.75% ) had extensive tumors consisting of all quadrants and 4 (3.1%) had inflammatory breast cancer. The most frequent sites of metastasis were bone (n=43, 33.3%), lung (16, 12.4%) and liver (13, 10%). The 45 (34.9%) patients had metastases at multiple visceral sites. Bone and multiple visceral metastasis were the most frequent pattern of metastasis for all regions of primary tumor localizations. Isolated bone metastasis were less frequent at outer upper quadrant tumors compared to other regions of primary tumor localizations (p=0.043). Metastases at multiple visceral sites were more frequent at outer upper quadrant tumors compared to other primary tumor localizations, but statistical difference was not at significance level (p=0.106). Conclusions: It was shown that breast cancer patients had primary tumors at upper outer quadrant had less isolated bone and more frequent multiple visceral metastases.

The potential role and status of IL-17 family cytokines in breast cancer

Stromal cells, within and around the tumor, as well as tumor cells are both involved in angiogenesis which is an important step in tumor growth and metastasis. Among such stromal cells, macrophages are known to play various roles in tumor angiogenesis and have thus been called tumor-associated macrophages (TAMs). The TAM density, vascular endothelial growth factor (VEGF) expression and the microvessel density (MVD) were immunohistochemically evaluated in 249 paraffin-embedded sections of invasive ductal carcinoma of the breast. The TAM density and MVD were assessed as the average density of three hot spots at a magnification of x400 and x200, respectively. The TAM density showed a significant correlation with both the VEGF expression and MVD, while a significant correlation was also found between the VEGF expression and MVD. The TAM density was also associated with the nuclear grade, estrogen receptor status and MIB-1 count. Patients with a high TAM density had a significantly (p=0.0025) worse disease-free survival (DFS) prognosis than those with a low TAM density, while univariate analyses also indicated both the MVD (p<0.0001) and VEGF expression (p=0.0152) to be prognostic factors for DFS. A multivariate analysis indicated MVD (p=0.0057), as well as lymph node metastasis and the MIB-1 count, to be independently significant prognostic factors for DFS. In conclusion, the present study demonstrated a close association between TAM infiltration and both the VEGF expression and MVD. The prognostic significance of MVD was the strongest among these three factors in breast cancer. These findings suggested that the prognostic implications of TAM infiltration are due to the involvement of TAMs in tumor angiogenesis.

Chronic infection and other risk factors of cancer in China and other countries

The worldwide burden of cancer and other non-communicable diseases (NCDs) is increasing. In 2005, NCDs were estimated to have caused more than 60% (35 million) of all deaths worldwide. For cancer an estimated 7.6 million deaths occurred in 2008 (around 20% of all NCD deaths). Without prevention or control the total cancer deaths is projected to rise to 13.1 million by 2030 whilst incidence will rise from 12.7 million in 2008 to 21.3 in 2030 based on demographic changes alone. The greatest percent increases will be in countries falling within the low and medium Human Development Index (HDI) categories. This phenomenon is mainly a consequence of the epidemiologic transition, i.e., a shift from infectious diseases to NCDs. Wider adoption of specific aspects of westernized lifestyles would translate to still greater increases in certain cancer types. In many countries the burden of cancer and other NCDs will therefore add to communicable diseases and malnutrition to impose a “double burden” on the poorest. These trends represent major challenges to health, poverty, sustainable development and equality. One consequence, especially in the lower HDI countries, is the implausibility of treating our way out of the cancer epidemic. Large variations in the type and number of cancers are observed in different regions of the world. Within high- and very high-HDI countries, prostate and breast cancers are the most common in males and females respectively, with lung and colorectal cancers ranking next in both sexes. Within low-HDI countries lung and breast cancers remain among the most common, but cancers of the cervix, stomach, liver, and Kaposi sarcoma are also among the leading types – all of which are cancers with infection-related aetiology. Medium-HDI countries are intermediate with respect to their patterns of cancer burden, reflecting an on-going transition from infection-related cancers to those most associated with a westernized lifestyle. The three most common types of cancer in medium-HDI countries are lung, stomach and liver cancers in males, and breast, cervix and lung cancer in females. In face of these increases in burden and variations in types of cancer, both primary and secondary cancer prevention offer many opportunities through implementing existing knowledge about environmental and lifestyle risk factors and using the natural history of the disease to establish screening and early detection. Reducing tobacco consumption through primary prevention has the capacity to contribute globally to the largest number of cancer deaths avoided; implementation of the international treaty of the WHO Framework Convention on Tobacco Control is vital. Effective tobacco control efforts have resulted in substantial declines in tobacco-related cancer deaths in the USA and several European countries demonstrating the effectiveness of a range of control methods. In relation to diet there are a number of clear potentially modifiable risk factors. Obesity is associated with an increased risk of breast, colorectal, endometrium, kidney, oesophageal and pancreatic cancers. Physical inactivity is also associated with breast, colorectal and endometrium cancer. Much less is known about specific nutrients or dietary components, although alcohol is associated with increased risks of liver, aero-digestive tract, breast and colorectal cancers; the consumption of red and processed meats as well as a diet low in fibre has also been associated with colorectal cancer. Recent estimates reported about 2 million cancer cases per year (16% of the global cancer burden) attributable to chronic infections, principally human papillomavirus (HPV); hepatitis B virus (HBV) and hepatitis C virus (HCV); and Helicobacter pylori (H. pylori). The contribution is substantially larger in low-resource countries (that include low- and medium-HDI countries) (26%) than in high-resource countries (8%) making the prevention or eradication of these infections a powerful tool to overcome inequalities in cancer incidence between poor and rich populations. Priorities include vaccination against HBV and HPV and avoidance of HCV transmission. Environmental causes of cancer, encompassing environmental contaminants or pollutants (e.g. radon, indoor and outdoor air pollution), naturally occurring toxins (e.g. aflatoxins, arsenic), occupationally-related exposures (e.g. asbestos) and radiation (X-rays and gamma radiation, as well as sunlight and UV tanning devices) can make substantial contributions to specific cancers or cancer clusters on a smaller scale. These exposures can also be amenable to low-cost modification by regulation, thus reducing the burden of some very lethal cancers with straightforward operable measures. The majority of cancers have a long latent phase and are preceded by pre-neoplastic lesions. Early detection and treatment of cancer or precancerous lesions resulted in substantial declines in cancer mortality in high-resource countries and would greatly improve survival in low-resource countries where access to expensive cancer treatment is limited. Firm evidence of efficacy of screening programmes in the reduction of cancer mortality exists for three cancer sites: the cervix uteri, breast, and colon-rectum. In relation to the lower HDI countries in particular there is a need to evaluate alternatives to mammographic screening for early detection of breast cancer. These may initially include improvements in breast awareness among women and health workers; facilitation of access of women with clinically detectable lumps to high-quality diagnostic facilities and of women with breast cancer to effective systemic treatment. Whilst much can be achieved based on current knowledge there is an important caveat. Namely, that knowing the cause does not automatically translate to having a strategy for prevention. For example, it is likely that a large proportion of stomach cancer could be prevented by H. pylori control, but currently neither a mechanism to achieve this, nor the effectiveness if achieved, is known. In analogous fashion far more research is required into behavioural change in relation to lifestyle factors such as diet, obesity and physical activity. Even for existing prevention strategies additional work is needed on their implementation into health care settings, particularly in lower HDI countries. At the same time, for a number of major cancers (e.g., colon, prostate, kidney, pancreas, brain, lympho-haematological malignancies) research is needed to identify as yet unknown risk factors. Finally, there is a remarkable opportunity for the recent advances in understanding the molecular basis of carcinogenesis to provide new tools and insights into aetiology and prevention. Among these opportunities are: improved exposure assessment; elucidation of mechanistic pathways related to defined exposures; identification of molecular markers which indicate risk of disease progression; and stratification of cancer cases by molecular subtype in relation to specific exposures. This broader concept of translational cancer research and its potential to inform cancer prevention stands at an exciting but critical point in time. It is only by complementing efforts to improve treatment with those aimed at prevention that the impending epidemic of this disease can be addressed. Citation Format: Christopher Paul Wild. Preventable exposures associated with human cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY14-01. doi:10.1158/1538-7445.AM2013-SY14-01

Relationship of Baseline Tumor Angiogenesis with Kinetics of Inflammatory Markers in DLBCL

Introduction: Invasive ductal carcinoma (IDC) is the most common type of breast malignancy, making about 75% of all breast cancer cases, usually the management for IDC contains breast-conserving therapy (BCT) which is a treatment strategy that removes the tumor while preserving as much as possible from breast tissue. There is still a debate how the tumor’s location affects survival. This study aims to evaluate survival rates for IDC patients treated with BCT alone across different breast quadrants which improves patients outcomes and inrich our medical understanding. Method: SEER Program was used to obtain the data, retrospectively. Patients diagnosed with infiltrating duct breast carcinoma treated with breast conserving therapy alone were included from (2000-2021). Patients were categorised into four groups based on the location of the tumor within the breast (upper outer quadrant , upper inner quadrant , lower inner quadrant, lower outer quadrant). All patients received BCT according to SEER breast cancer surgery codes (20-24). Relative survival rates were compared using Kaplan-Meier, log-rank analysis. IBM SPSS Statistics 27.0.1 was used to conduct the statistical analysis. Results: A total of 36443 cases of IDC and treated with BCT alone were identified. Among the groups , 9.57%(n=3491) have a tumor located in lower inner quadrant, 21.55% (n=7854) in the upper inner quadrant, 57.47% (n=20947) in the upper outer quadrant, and 11.39% (n=4151) in the lower outer quadrant .Among all tumor locations, 5- years relative survival was the highest for patients with tumors in the upper inner quadrant (95.3%), followed by upper outer quadrant (94.1%), then came Lower outer quadrant (92.5%),and lastly came lower inner quadrant (92.2%), with (p -value &amp;lt; .001). Conclusion: Overall, patients who are diagnosed with invasive ductal carcinoma and treated with breast conserving therapy only showed better survival when tumors were located in the upper inner quadrant. In contrast patients with tumors in the (lower inner quadrant) showed the lowest survival rates among all quadrants . Our findings confirm that there is a significant difference in survival rates between different quadrants, it could be an entry for several researches and to spot the light on the importance of tumor location in IDC, and different management patterns. Citation Format: Abdulah Jariri. The impact of tumor location on survival rates in invasive ductal carcinoma for patients who undergo breast-conserving therapy [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-08-30.

Microvessel density (MVD) is a measure of the extent of new blood vessel growth or angiogenesis, which is required for tumor progression. Increased MVD in primary breast cancers appears to adversely affect disease-free survival and overall survival in patients with breast cancer. However, the clinical implications of angiogenesis in breast cancer metastases have not been well studied. The purpose of this study was to compare intratumoral MVD in primary breast cancer tissues with MVD in axillary lymph node metastases and to evaluate the relationships among primary- and metastatic-tumor MVD, disease-free survival, and overall survival in patients with lymph node-positive, stage II breast cancer who were treated with adjuvant chemotherapy in Cancer and Leukemia Group B Protocol 8082. Immunostaining for factor VIII-related antigen was performed on tissue sections from 47 primary tumors and 91 axillary lymph nodes containing metastases from 110 patients with lymph node-positive breast cancer. Sections were examined for the presence or absence of focal areas of relatively intense neovascularization (vascular hot spots), and a quantitative assessment of intratumoral MVD was performed. The presence of vascular hot spots in axillary lymph node metastases, but not primary breast cancers, was associated with statistically significantly decreased disease-free survival (P =.006) and overall survival (P =.004) by univariate analysis. Similarly, increased MVD in metastases, but not in primary tumors, was statistically significantly associated with diminished overall survival in these patients (P =.02). In multivariate analysis, the number of positive axillary lymph nodes and the presence of vascular hot spots in axillary lymph node metastases predicted decreased disease-free survival (P =.0001 and.02, respectively) and overall survival (P =.0001 and.007, respectively). All P values were two-sided. This pilot study suggests that assessing neovascularization in axillary lymph node metastases may provide clinically useful information regarding survival in patients with primary breast cancer.

Aim: Angiogenesis plays an important role in tumour growth and has been shown to occur around both in situ and invasive tumours. The degree of angiogenesis within tumours depends on...

In this study on the determination of intratumoral microvessel density (MVD) in breast cancer, we have investigated the influence of the observer experience and the microscopic field size. We have used the sample set reported on earlier in the J Natl Cancer Inst 87: 1797-1798, 1995. This case-control study has shown a positive association of high MVD and unfavorable outcome when comparing node-negative pT1-2 breast carcinoma (NNBC) patients with a disease-free period of over ten years with those with an early distant relapse. Tumor sections of both outcome groups (favorable: n = 19; unfavorable: n = 19) were immunostained for factor VIII related-antigen (FVIII r-Ag). Microvessels were counted in the areas of most intense vascularization ('hot spots'), both at magnification x 200 (field size of 0.61 square mm) and x 400 (field size of 0.15 square mm), by one inexperienced and three experienced observers. Microphotographs of individual vascular hot spots were analyzed using overlays resembling the two field sizes. The main results obtained are: i) a confirmation of the prognostic value of microvessel density in the case-control sample set (n = 38) was established by all experienced but not by the unexperienced investigator; ii) both at x 200 and x 400 magnification, angiogenesis quantification in vascular hot spots contained prognostic information. The results of this study indicate that the selection of vascular hot spots in tumor sections immunostained for an antigen expressed on endothelial cells is more prone to inter-observer variability and more dependent on training than the counting of the microvessels within predefined hot spots itself. The microscopic magnification and resulting field size do not influence the prognostic significance of MVD in NNBC. This information validates the development of more objective methods of measuring the amount of angiogenesis within malignant tissue. This will allow more accurate implementation of the angiogenesis parameter in multiparametric and prospective prognostic factor studies in NNBC.

Falls, strokes and dementia can be predicted and their occurrence can be delayed or even prevented by treatment of risk factors. The value of screening self-referred adults is unknown. To assess whether a screening program of self-referred adults provides new and valuable medical information on risk factors for falls, stroke and dementia. We examined 514 self-referred people (59% women, mean age 68+/-8 years (range 44-89) and 14+/-3 years of education) in our "Brain Screen" program. Participants completed detailed questionnaires and underwent a neurological examination, computerized gait analysis, carotid Duplex, serum lipid and homocysteine levels, a computerized neuropsychological battery (NeuroTrax) and the Mini-Mental State Exam. Information that was detected by "Brain Screen" was compared with the self-reported data. Unknown vascular risk factors detected by ""Brain Screen" included: high cholesterol in 44%, homocysteine > 10 micromol/L in 20%, >1 mm carotid intima-media thickness in 13%, and carotid narrowing (> 30%) in 2.2%. Unknown risk factors for falls were detected in 66% of the subjects who never fell. Of the 205 subjects (44%) who complained of memory decline, 28% had objective memory disturbances compared with their age group. Mild cognitive impairment (amnestic MCI) was clinically diagnosed in 17% of the population and dementia in 5%. Screening self-referred adults for falls, strokes and dementia risk factors detected significant unknown risk factors that can be treated in more than one-third of the participants. A national "Brain Screen" program can have significant impact on the health of the aging population.