This study compared the expression of E-cadherin, β-catenin, and MUC1 in multicentric/multifocal breast cancers versus unifocal breast cancers of identical tumor size and grade. The study found significantly downregulated expression of E-cadherin in multicentric/multifocal cancers compared to unifocal cancers. In contrast, no significant differences were seen in β-catenin expression between the two groups. Within the unifocal group, E-cadherin and β-catenin expression were positively correlated, but this was not seen in the multicentric/multifocal group. The results suggest multicentric/multifocal and unifocal breast cancers differ in E-
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Assessment of preoperative exercise capacity in hepatocellular carcinoma pati...Enrique Moreno Gonzalez
Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Assessment of preoperative exercise capacity in hepatocellular carcinoma pati...Enrique Moreno Gonzalez
Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy.
The KRAS-Variant and miRNA Expression in RTOG Endometrial Cancer Clinical Tri...UCLA
The KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Differentiation of irradiation and cetuximab induced skin reactions in patien...Enrique Moreno Gonzalez
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
Low expression of the X-linked ribosomal protein S4 in human serous epithelia...Enrique Moreno Gonzalez
The X-linked ribosomal protein S4 (RPS4X), which is involved in cellular translation and proliferation, has previously been identified as a partner of the overexpressed multifunctional protein YB-1 in several breast cancer cells. Depletion of RPS4X results in consistent resistance to cisplatin in such cell lines.
In this session, H. Kim Lyerly, MD, FACS, Director of the Center of Applied Therapeutics at Duke University, discussed research in tumor dormancy in breast cancer. Topics included the role of disseminated tumor cells, the bone marrow, and the potential for immune responses to control or prevent recurrences. Q&A period followed
Exploring chemo-resistance in NSCLC - Dr Martin BarrHannahMcCarthy31
Dr Martin Barr is a Clinical Scientist at St James's Hospital and Adjunct Assistant Professor at Trinity College Dublin. Dr Barr's research interests are chemotherapy resistance in Non-Small Cell Lung Cancer (NSCLC), in vivo and in vitro models, Liquid Biopsy and EGFR-mutant NSCLC.
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Claudin 1 expression in basal-like breast cancer is related to patient ageEnrique Moreno Gonzalez
Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype. In these tumors, the claudin 1.
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
The KRAS-Variant and miRNA Expression in RTOG Endometrial Cancer Clinical Tri...UCLA
The KRAS-variant may be a genetic marker of risk for type 2 endometrial cancers. In addition, tumor miRNA expression appears to be associated with patient age, lymphovascular invasion and the KRAS-variant, supporting the hypothesis that altered tumor biology can be measured by miRNA expression, and that the KRAS-variant likely impacts endometrial tumor biology.
hMSH2 Gly322Asp (rs4987188) Single nucleotide polymorphism and the risk of br...Agriculture Journal IJOEAR
Aim: Breast cancer is the most common cancer in women both in the developed and less developed world. The reported study was designed to explore associations between hMSH2 - Gly322Asp (1032G>A, rs4987188) single nucleotide polymorphism (SNP) and the risk of breast carcinoma in the Polish women.
Material and methods: Blood samples were obtained from women with breast cancer (n=225), treated at the Department of Oncological Surgery and Breast Diseases, Polish Mother’s Memorial Hospital – Research Institute between the years 2005 and 2012. A control group included 220 cancer-free women. Genomic DNA was isolated and the SNP Gly322Asp of hMSH2 was determined by High-Resolution Melter method. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each genotype and allele.
Results: This study revealed that single nucleotide polymorphism Gly322Asp of hMSH2 is associated with both breast cancer risk and grading. Moreover, it can be linked with breast carcinoma tumor size and lymph node status. The Asp allele in patients may be a risk factor for breast carcinoma (OR 5.12; 95% CI 3.77 –6.97, p<.0001).
Conclusions: Gly322Asp single nucleotide polymorphism of hMSH2 may be a risk factor of breast cancer in the Polish women.
Differentiation of irradiation and cetuximab induced skin reactions in patien...Enrique Moreno Gonzalez
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
Low expression of the X-linked ribosomal protein S4 in human serous epithelia...Enrique Moreno Gonzalez
The X-linked ribosomal protein S4 (RPS4X), which is involved in cellular translation and proliferation, has previously been identified as a partner of the overexpressed multifunctional protein YB-1 in several breast cancer cells. Depletion of RPS4X results in consistent resistance to cisplatin in such cell lines.
In this session, H. Kim Lyerly, MD, FACS, Director of the Center of Applied Therapeutics at Duke University, discussed research in tumor dormancy in breast cancer. Topics included the role of disseminated tumor cells, the bone marrow, and the potential for immune responses to control or prevent recurrences. Q&A period followed
Exploring chemo-resistance in NSCLC - Dr Martin BarrHannahMcCarthy31
Dr Martin Barr is a Clinical Scientist at St James's Hospital and Adjunct Assistant Professor at Trinity College Dublin. Dr Barr's research interests are chemotherapy resistance in Non-Small Cell Lung Cancer (NSCLC), in vivo and in vitro models, Liquid Biopsy and EGFR-mutant NSCLC.
Objective: The association between telomerase reverse transcriptase (TERT) promoter mutation and outcome of melanoma is unclear and controversial. We aim to conduct a meta-analysis and investigate whether the TERT promoter mutation is a prognostic factor of melanoma.
Study Design: Appropriate studies were searched in 3 databases: PubMed, Web of Science, and Embase. Pooled hazard ratios (HRs) were counted through random effects model.
Results: Heterogeneity was moderate in overall survival (OS) (I2=43.7%, p=0.059) and low in disease-free survival (DFS) (I2=0.0%, p=0.587). Sensitivity analysis indicated that the removal of any of the study did not affect the final results. Evidence for publication bias was not found (Begg’s test, p=0.281; Egger’s test, p=0.078). The pooled OS HRs from combined effects analysis was determined (HR 1.07; 95% CI 0.83–1.39, p=0.585), together with the pooled HRs of DFS (HR 1.65; 95% CI 1.02–2.66, p=0.042). TERT promoter mutation predicted a good outcome in meta-static melanoma patients (HR 0.66; 95% CI 0.46–0.96, p=0.042). The pooled HRs of combined mutation in TERT promoter and BRAF (HR 6.27; 95% CI 2.7–14.58, p=0.000) predicted a bad outcome in melanoma patients.
Conclusion: TERT promoter mutation significantly predicted poor DFS outcome but, on the contrary, predicted a good outcome in metastatic melanoma patients. The combined TERT promoter and BRAF mutation was a significant independent factor of OS in melanoma patients.
Keywords: melanoma; meta-analysis; mutation; prognosis; promoter regions, genetic; skin neoplasms; telomerase; TERT promoter mutation; TERT protein, human
Claudin 1 expression in basal-like breast cancer is related to patient ageEnrique Moreno Gonzalez
Defects in tight junctions, gate-keepers of the integrity of the epidermal barrier function, are known to contribute to cancer development. As such, enhancing our understanding of how the expression of proteins involved in these junctions is regulated in cancer, remains a priority. Although the expression of one of these proteins, claudin 1, is down regulated in most invasive human breast cancers (HBC), we have recently shown that high levels of claudin 1, characterized tumors belonging to the very aggressive basal-like breast cancer (BLBC) subtype. In these tumors, the claudin 1.
Cancer testis antigens and NY-BR-1 expression in primary breast cancer: prog...Enrique Moreno Gonzalez
Cancer–testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
Toward Integrated Clinical and Gene Expression Profiles for Breast Cancer Pro...CSCJournals
Breast cancer patients with the same diagnostic and clinical prognostic profile can have markedly different clinical outcome. This difference is possibly caused by the limitation of current breast cancer prognostic indices, which group molecularly distinct patients into similar clinical classes based mainly on morphological of disease. Traditional clinical based prognosis models were discovered contain some restriction to address the heterogeneity of breast cancer. The invention of microarray technology and its ability to simultaneously interrogate thousands genes has changed the paradigm of molecular classification of human cancers as well as it shifted clinical prognosis model to broader prospect. Numerous studies have revealed the potential value of gene expression signatures in examining the risk of disease recurrence. However, currently most of these studies attempted to implement genetic marker based prognostic models to replace the traditional clinical markers, yet neglecting the rich information contain in clinical information. Therefore, this research took an effort to integrate both clinical and microarray data in order to obtain accurate breast cancer prognosis, by taking into account that these data complements each other. This article presents a review of the development of breast cancer prognosis models, concentrating precisely on clinical and gene expression profiles. The literature is reviewed in an explicit machine learning framework, which include the elements of feature selection and classification techniques.
Coexistence of carcinoma and tuberculosis in the breast: A rarity.KETAN VAGHOLKAR
Coexistence of carcinoma and tuberculosis in the same breast is extremely rare. The presence of two lesions in the same organ poses both a diagnostic as well as a therapeutic challenge to the surgeon. The case report highlights both the aspects of management.
The LANCET Oncology is the world-leading clinical oncology research journal globally (2021 Journal Citation Reports®, Clarivate 2022) With an Impact Factor of 54·433.
Publisher: Elsevier's Oncology Journal Network
Total Indexing – 11
Some Indexing sites are – Scopus , MEDLINE ,PubMed , Chemical Abstracts , Essential Science Indicators ,etc .
Editor :David Collingridge, Editor-in-Chief , gained a PhD in Tumour Biology from the Gray Cancer Institute/University College London (UK) and held research posts in the Department of Therapeutic Radiology, Yale University (USA) and in the PET Oncology Group, Imperial College School of Medicine, Hammersmith Hospital (UK)
Odontogenic ameloblast-associated protein (ODAM) inhibits growth and migratio...Enrique Moreno Gonzalez
The Odontogenic Ameloblast-associated Protein (ODAM) is expressed in a wide range of
normal epithelial, and neoplastic tissues, and we have posited that ODAM serves as a novel
prognostic biomarker for breast cancer and melanoma. Transfection of ODAM into breast
cancer cells yields suppression of cellular growth, motility, and in vivo tumorigenicity.
Herein we have extended these studies to the effects of ODAM on cultured melanoma cell
lines.
Diagnosed with breast cancer while on a family historyscreen.docxduketjoy27252
Diagnosed with breast cancer while on a family history
screening programme: an exploratory qualitative study
A. CLEMENTS, bsc, senior research nurse, Cancer Research UK Primary Care Education Research Group,
University of Oxford, Department of Primary Health Care, Oxford, B.J. HENDERSON, phd, research psycholo-
gist, Institute of Medical & Social Care Research, Ardudwy, Normal Site, University of Wales, Bangor, Gwynedd,
S. TYNDEL, ba, research officer, Cancer Research UK Primary Care Education Research Group, University of
Oxford, Department of Primary Health Care, Oxford, G. EVANS, md frcp, consultant in medical genetics,
Department of Clinical Genetics, St Mary’s Hospital, Manchester, K. BRAIN, phd, senior research fellow,
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, J. AUSTOKER, phd,
director, Cancer Research UK Primary Care Education Research Group, University of Oxford, Department of
Primary Health Care, Oxford, & E. WATSON, phd, deputy director, Cancer Research UK Primary Care Educa-
tion Research Group, University of Oxford, Department of Primary Health Care, Oxford, UK for the PIMMS Study
Management Group*
CLEMENTS A., HENDERSON B.J., TYNDEL S., EVANS G., BRAIN K., AUSTOKER J. & WATSON E. FOR
THE PIMMS STUDY MANAGEMENT GROUP (2008) European Journal of Cancer Care 17, 245–252
Diagnosed with breast cancer while on a family history screening programme: an exploratory qualitative study
Mammographic screening is offered to many women under 50 in the UK who are at moderate or high risk of
developing breast cancer because of their family history of the disease. Little is understood about the impact
of screening on the emotional well-being of women with a family history of breast cancer. This qualitative
study explores the value that women at increased risk placed on screening, both pre- and post-cancer diagnosis
and the impact of the diagnosis. In-depth interviews were undertaken with 12 women, aged 35–50, diagnosed
with breast cancer while on an annual mammographic screening programme. Women described the strong
sense of reassurance gained from screening prior to diagnosis. This faith in screening was reinforced by early
detection of their cancer. Reactions to diagnosis ranged from devastation to relief at having finally developed
a long-expected condition. Despite their positive attitudes about screening, not all women wanted to continue
with surveillance. For some, prophylactic mastectomy was preferable, to reduce future cancer risk and to
alleviate anxieties about the detection of another cancer at each subsequent screen. This study illustrates the
positive yet diverse attitudes towards mammographic screening in this group of women with a family history
of breast cancer.
Keywords: breast cancer, early screening programme, family history, qualitative.
Correspondence address: Alison Clements, Cancer Research UK Primary Care Education Research Group, University of Oxford, Department of Pr.
Diagnosed with breast cancer while on a family historyscreen.docxlynettearnold46882
Diagnosed with breast cancer while on a family history
screening programme: an exploratory qualitative study
A. CLEMENTS, bsc, senior research nurse, Cancer Research UK Primary Care Education Research Group,
University of Oxford, Department of Primary Health Care, Oxford, B.J. HENDERSON, phd, research psycholo-
gist, Institute of Medical & Social Care Research, Ardudwy, Normal Site, University of Wales, Bangor, Gwynedd,
S. TYNDEL, ba, research officer, Cancer Research UK Primary Care Education Research Group, University of
Oxford, Department of Primary Health Care, Oxford, G. EVANS, md frcp, consultant in medical genetics,
Department of Clinical Genetics, St Mary’s Hospital, Manchester, K. BRAIN, phd, senior research fellow,
Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, J. AUSTOKER, phd,
director, Cancer Research UK Primary Care Education Research Group, University of Oxford, Department of
Primary Health Care, Oxford, & E. WATSON, phd, deputy director, Cancer Research UK Primary Care Educa-
tion Research Group, University of Oxford, Department of Primary Health Care, Oxford, UK for the PIMMS Study
Management Group*
CLEMENTS A., HENDERSON B.J., TYNDEL S., EVANS G., BRAIN K., AUSTOKER J. & WATSON E. FOR
THE PIMMS STUDY MANAGEMENT GROUP (2008) European Journal of Cancer Care 17, 245–252
Diagnosed with breast cancer while on a family history screening programme: an exploratory qualitative study
Mammographic screening is offered to many women under 50 in the UK who are at moderate or high risk of
developing breast cancer because of their family history of the disease. Little is understood about the impact
of screening on the emotional well-being of women with a family history of breast cancer. This qualitative
study explores the value that women at increased risk placed on screening, both pre- and post-cancer diagnosis
and the impact of the diagnosis. In-depth interviews were undertaken with 12 women, aged 35–50, diagnosed
with breast cancer while on an annual mammographic screening programme. Women described the strong
sense of reassurance gained from screening prior to diagnosis. This faith in screening was reinforced by early
detection of their cancer. Reactions to diagnosis ranged from devastation to relief at having finally developed
a long-expected condition. Despite their positive attitudes about screening, not all women wanted to continue
with surveillance. For some, prophylactic mastectomy was preferable, to reduce future cancer risk and to
alleviate anxieties about the detection of another cancer at each subsequent screen. This study illustrates the
positive yet diverse attitudes towards mammographic screening in this group of women with a family history
of breast cancer.
Keywords: breast cancer, early screening programme, family history, qualitative.
Correspondence address: Alison Clements, Cancer Research UK Primary Care Education Research Group, University of Oxford, Department of Pr.
Similar to Multicentric and multifocal versus unifocal breast cancer: differences in the expression of E-cadherin suggest differences in tumor biology (20)
Gene expression analysis of a Helicobacter pyloriinfected and high-salt diet-...Enrique Moreno Gonzalez
Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.
The life in sight application study (LISA): design of a randomized controlled...Enrique Moreno Gonzalez
It is widely recognized that spiritual care plays an important role in physical and psychosocial well-being of cancer patients, but there is little evidence based research on the effects of spiritual care. We will conduct a randomized controlled trial on spiritual care using a brief structured interview scheme supported by an e-application. The aim is to examine whether an assisted reflection on life events and ultimate life goals can improve quality of life of cancer patients.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...Enrique Moreno Gonzalez
Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Cholestasis induces reversible accumulation of periplakin in mouse liverEnrique Moreno Gonzalez
Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in noncutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation car...Enrique Moreno Gonzalez
Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
Impaired mitochondrial beta-oxidation in patients with chronic hepatitis C: r...Enrique Moreno Gonzalez
Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Intraepithelial lymphocyte distribution differs between the bulb and the seco...Enrique Moreno Gonzalez
Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb. We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects.
Sticky siRNAs targeting survivin and cyclin B1 exert an antitumoral effect on...Enrique Moreno Gonzalez
Melanoma represents one of the most aggressive and therapeutically challenging malignancies as it often gives rise to metastases and develops resistance to classical chemotherapeutic agents. Although diverse therapies have been generated, no major improvement of the patient prognosis has been noticed. One promising alternative to the conventional therapeutic approaches currently available is the inactivation of proteins essential for survival and/or progression of melanomas by means of RNA interference. Survivin and cyclin B1, both involved in cell survival and proliferation and frequently deregulated in human cancers, are good candidate target genes for siRNA mediated therapeutics.
Association between variations in the fat mass and obesity-associated gene an...Enrique Moreno Gonzalez
It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk.
The cysteinyl leukotriene 2 receptor contributes to all-trans retinoic acid-i...Enrique Moreno Gonzalez
Cysteinyl leukotrienes (CysLTs) are potent pro-inflammatory mediators that are increased in samples from patients with inflammatory bowel diseases (IBDs). Individuals with IBDs have enhanced susceptibility to colon carcinogenesis. In colorectal cancer, the balance between the pro-mitogenic cysteinyl leukotriene 1 receptor (CysLT1R) and the differentiation-promoting cysteinyl leukotriene 2 receptor (CysLT2R) is lost. Further, our previous data indicate that patients with high CysLT1R and low CysLT2R expression have a poor prognosis. In this study, we examined whether the balance between CysLT1R and CysLT2R could be restored by treatment with the cancer chemopreventive agent all-trans retinoic acid (ATRA).
Clinical features and outcome of cryptogenic hepatocellular carcinoma compare...Enrique Moreno Gonzalez
Cryptogenic hepatocellular carcinoma (HCC) is thought to arise due to non-alcoholic fatty liver disease (NAFLD). This study investigated the prevalence, clinical features, and outcomes of cryptogenic HCC and compared them with those of HCC related to hepatitis B virus infection (HBV-HCC), hepatitis C virus infection (HCV-HCC), and alcohol (ALCHCC) in Korea.
Fatty liver index correlates with non-alcoholic fatty liver disease, but not ...Enrique Moreno Gonzalez
Fatty liver index (FLI) was recently established to predict non-alcoholic fatty liver disease (NAFLD) in general population, which is known to be associated with coronary artery atherosclerotic disease (CAD).
This study aims to investigate whether FLI correlates with NAFLD and with newly diagnosed CAD in a special Chinese population who underwent coronary angiography.
Antibiotic exposure and the development of coeliac disease: a nationwide case...Enrique Moreno Gonzalez
The intestinal microbiota has been proposed to play a pathogenic role in coeliac disease (CD). Although antibiotics are common environmental factors with a profound impact on intestinal microbiota, data on antibiotic use as a risk factor for subsequent CD development are scarce.
Implication from thyroid function decreasing during chemotherapy in breast ca...Enrique Moreno Gonzalez
Thyroid hormones have been shown to regulate breast cancer cells growth, the absence or reduction of thyroid hormones in cells could provoke a proliferation arrest in G0-G1 or weak mitochondrial activity, which makes cells insensitive to therapies for cancers through transforming into low metabolism status. This biological phenomenon may help explain why treatment efficacy and prognosis vary among breast cancer patients having hypothyroid, hyperthyroid and normal function. Nevertheless, the abnormal thyroid function in breast cancer patients has been considered being mainly caused by thyroid diseases, few studied influence of chemotherapy on thyroid function and whether its alteration during chemotherapy can influence the respose to chemotherapy is still unclear. So, we aimed to find the alterations of thyroid function and non-thyroidal illness syndrome (NTIS) prevalence druing chemotherapy in breast cancer patients, and investigate the influence of thyroid hormones on chemotherapeutic efficacy.
Optimal schedule of Bacillus Calmette-Guerin for non-muscle-invasive bladder ...Enrique Moreno Gonzalez
To explore the necessity of maintenance, efficacy of low-dose and superiority of various combination therapies of Bacillus Calmette-Guérin (BCG) in treatment of superficial bladder cancer (BCa).
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
2. Multicentric and multifocal versus unifocal breast
cancer: differences in the expression of E-cadherin
suggest differences in tumor biology
Tobias Weissenbacher1,6*
Email: tobias.weissenbacher@med.uni-muenchen.de
Eva Hirte1
Email: evahirte@t-online.de
Christina Kuhn1
Email: christina.kuhn@med.uni-muenchen.de
Wolfgang Janni2
Email: wolfgang.janni@uniklinik-ulm.de
Doris Mayr3
Email: doris.mayr@med.uni-muenchen.de
Uwe Karsten5
Email: uwe.karsten@glykotope.com
Brigitte Rack1
Email: brigitte.rack@med.uni-muenchen.de
Klaus Friese1
Email: klaus.friese@med.uni-muenchen.de
Udo Jeschke1
Email: udo.jeschke@med.uni.muenchen.de
Sabine Heublein1
Email: sabine.heublein@med.uni-muenchen.de
Darius Dian1
Email: darius.dian@med.uni.muenchen.de
Nina Ditsch4
Email: nina.ditsch@med.uni-muenchen.de
1
Frauenklinik, Klinikum der Ludwig-Maximilians-Universität, Innenstadt,
München, Germany
2
Frauenklinik, Heinrich-Heine-Universität, Düsseldorf, Germany
3
Pathologisches Institut, Ludwig-Maximilians-Universität, München, Germany
3. 4
Frauenklinik, Klinikum der Ludwig-Maximilians-Universität, Groβhadern,
München, Germany
5
Glycotope GmbH, Berlin, Germany
6
Department of Gynecology and Obstetrics, Campus Innenstadt Ludwig-
Maximilian-University Munich, Maistr. 11, Munich D-80337, Germany
*
Corresponding author. Department of Gynecology and Obstetrics, Campus
Innenstadt Ludwig-Maximilian-University Munich, Maistr. 11, Munich D-80337,
Germany
Abstract
Background
The aim of this study was to evaluate the expression of the cell adhesion-related
glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in
comparison to unifocal disease in order to identify potential differences in the biology of
these tumor types.
Methods
A retrospective analysis was performed on the expression of MUC1, β-catenin and E-
cadherin by immunohistochemistry on tumor tissues of a series of 112 breast cancer patients
(total collective) treated in Munich between 2000 and 2002. By matched-pair analysis, 46
patients were entered into two comparable groups of 23 patients after categorizing them as
having multicentric/multifocal or unifocal breast cancer. Matching criteria were tumor size,
histology grade and lymph node status; based on these criteria, patients were distributed
equally between the two groups (p = 1.000 each). Data were analyzed with the Kruskal-
Wallis and the Mann–Whitney tests.
Results
In the matched groups, we found a significantly down-regulated expression of E-cadherin in
multicentric/multifocal breast cancer compared to unifocal disease (p = 0.024). The total
collective showed even higher significance with a value of p < 0.0001. In contrast, no
significant differences were observed in the expression of β-catenin between
multicentric/multifocal and unifocal tumors (p = 0.636 and p = 0.914, respectively). When
comparing the expression of MUC1, E-cadherin and β-catenin within the unifocal group, we
found a significant positive correlation between E-cadherin and β-catenin (p = 0.003). In the
multicentric/multifocal group we observed, in contrast to the unifocal group, a significant
decrease of MUC1 expression with increased grading (p = 0.027).
Conclusion
This study demonstrates that multicentric/multifocal and unifocal breast cancers with
identical TNM-staging clearly differ in the expression level of E-cadherin. We suggest that
4. the down-regulation of E-cadherin in multicentric/multifocal breast cancer is causally
connected with the worse prognosis of this tumor type.
Keywords
Breast cancer, MUC-1, Multicentric, Multifocal, Tumor biology, E-cadherin, β-catenin
Background
Tumor-node-metastasis (TNM) staging has been the standard method for breast cancer
classification for more than fifty years. During this time, however, the classification
procedure has changed substantially. In 2003, the 6th edition of the TNM classification was
established [1-3]. The T category has maintained its prognostic relevance throughout these
changes [3]. The prognosis of breast cancer patients depends on two different types of
factors: tumor size as a time-dependent marker of tumor biology, and biological factors (i.e.,
histological grade) which represent tumor aggressiveness [4]. Other prognostic factors
include the estrogen and progesterone receptor status as well as the relative number of mitotic
figures (MF/10HPF) [5,6]. Treatment plans are following worldwide prevailing suggestions,
including those of the TNM system. However, the TNM classification has changed, and
treatment recommendations and the treatments themselves have been modified. Breast-
conserving treatment, once a controversial issue, is now an established alternative to modified
radical mastectomy for surgically manageable breast cancer.
In a recent study we have demonstrated that focality is an independent prognostic factor by
comparing multicentric/multifocal and unifocal breast cancer [7]. Therefore, additional
biological factors seem to play an important but not well understood role in
multicentric/multifocal breast cancers.
The above-mentioned established prognostic factors [4,8,9] as well as potential new factors,
such as the E-cadherin-related transcriptional repressor Snail or the c-Jun activation domain-
binding protein-1 (Jab1), are multifunctional signaling proteins. The E-cadherin/catenin
complex is known to be a potent inhibitor of cancer progression [10-13].
The disconnection of cell-cell adhesions is a fundamental step in the progression of cancer
and metastasis that is mediated by a variety of membrane proteins. The transmembrane
protein E-cadherin, which is responsible for calcium-dependent cell adhesions, is a widely
studied tumor suppressor. It is expressed predominantly in epithelial cells, and its
extracellular region has a Ca2+
-dependent homophilic adhesion function. Loss of E-cadherin
has been reported to induce epithelial-mesenchymal transition in several cancers [14-16].
Epithelial mucin-1 (MUC1) is a complex transmembrane glycoprotein. The larger, heavily
glycosylated domain of the MUC molecule is extracellularly expressed [17] MUC1 exerts a
number of different functions [18-23]. MUC1 undergoes characteristic modifications of its
glycosylation and cellular localization during malignant transformation [24]. Many
monoclonal antibodies have been developed to MUC1 [17]. A novel antibody, PankoMab,
was developed against a tumor-associated epitope of MUC1 [19]. In a previous paper,
PankoMab was examined in patients with breast cancer in comparison with two other known
antibodies. PankoMab was unique to the effect that its staining was correlated with the
estrogen receptor expression [20].
5. The glycoprotein β-catenin interacts with both E-cadherin and MUC1. The interaction
between MUC1 and E-cadherin is mediated by β-catenin-binding and interrupts E-cadherin-
mediated cell-cell adhesions. Signal transduction through β-catenin (the so-called Wnt/β-
catenin signaling pathway) has already been thoroughly investigated [21]. This signal
transduction regulates the expression of a number of genes essential for cell differentiation
and proliferation. Alterations in this pathway are implicated in diseases such as cancer [22].
The aim of this study was to compare the expression of MUC1, E-cadherin and β-catenin in
multicentric/multifocal tumors with their expression in unifocal tumors of identical tumor
size according to TNM staging in order to detect potential differences.
Methods
Patients
Two groups were framed and investigated. Based on a consecutive patient cohort consisting
of 112 patients documented and surgically treated for primary breast cancer between 2000
and 2002 at the Department of Gynecology of the University Hospital in Munich-Innenstadt,
57 unifocal breast cancer patients and 55 patients with multicentric/multifocal disease formed
our total collective (TC). From the same patient cohort, two equivalent groups of 23 breast
cancer patients with multicentric/multifocal vs. unifocal tumors were selected using a
matched paired analysis (MG) (see Statistical Analysis section below). The Institutional
Review Board of the Ludwig Maximilians University Munich, Germany, approved the study
and all the patients gave informed consent.
Unifocality versus multicentricity/multifocality were determined by clinical examination,
ultrasound and X-ray. In addition, in a few cases nuclear magnetic resonance imaging
(NMRI), galactography or pneumocystography was performed if necessary. These techniques
were used in a few cases, in which additional information regarding focality was necessary.
Moreover, those cases which failed to confirm multicentricity/multifocality with respect to
the final histological examination were excluded.
Data were contemporaneously gathered for the unifocal and multicentric/multifocal tumors.
To be eligible, patients were required to be free of disease, and they must have been treated at
the study site at the time of primary diagnosis of resectable breast cancer. The tumor stage at
primary diagnosis was classified according to the UICC TNM classification [23]. Tumor
grading by WHO (Nottingham grading respectively to Elston & Ellis modification of Bloom-
Richardson grading [25] was used., and match criteria were tumor size, histology grade and
lymph node status, all of which were equally distributed between the two groups (p = 1.0).
The total collective was not matched. We used this group to validate the results of the
matched group.
Surgical treatment
The primary surgical treatment consisted of either breast conservation or modified radical
mastectomy. Routine axillary dissections were performed on levels I and II lymph nodes,
while level III lymph nodes were only excised in cases expressing macroscopic metastatic
lesions of the lower levels. For the diagnosis of lymph node metastasis, single embedded
lymph nodes were screened at up to three levels.
6. The guidelines for chemotherapy and cytostatic regimes changed substantially also within the
observation time of the study. Therefore the authors did not include oncological treatment
details.
Immunohistochemistry
Immunohistochemistry was performed using a combination of pressure cooker heating for
antigen retrieval and the standard streptavidin-biotin-peroxidase complex with the use of the
mouse IgG-Vectastain Elite ABC kit (Vector Laboratories, Burlingame, CA, USA). Table 1
lists the mouse monoclonal antibodies used for these experiments.
Table 1 Antibodies employed
Antigen Antibody/clone Isotype Dilution Source
E-cadherin HECD-1 Mouse IgG1 1:80 Merck, Darmstadt, Germany
β-catenin polyclonal Rabbit IgG 1:100 Diagnostic BioSystems, Pleasanton, CA,
USA
MUC1 mPankoMab Mouse IgG1 1:550 Glycotope, Berlin, Germany
Formalin-fixed paraffin embedded tissue sections were dewaxed using xylol for 15 min,
rehydrated in an descending series of alcohols (100%, 96%, and 70%), and subjected to
epitope retrieval for 5 min in a pressure cooker using sodium citrate buffer (pH 6.0). After
cooling, sections were washed twice in PBS. Endogenous peroxidase activity was quenched
by immersion in 3% hydrogen peroxide in methanol for 20 min. Non-specific binding of the
primary antibodies was blocked by pretreatment of the sections with diluted normal serum
(10 ml PBS containing 150 µl horse serum; Vector Laboratories, Servion, Switzerland) for 20
min. Sections were then incubated with the primary antibodies at room temperature for 60
min. After washing with PBS, sections were incubated in diluted biotinylated secondary
antiserum (10 ml PBS containing 50 µl horse serum; Vector Laboratories) for 30 min at room
temperature. After incubation with the avidin-biotin peroxidase complex (diluted in 10 ml
PBS, Vector Laboratories) for 30 min and repeated washing steps with PBS, visualization
was performed with DAB substrate (Dako, Glostrup, Denmark) for 2 min. Sections were
counterstained with Mayer‘s hematoxylin and dehydrated in an ascending series of alcohols
(50–98%), followed by xylol. Finally, sections were embedded, but mounted and covered.
Negative controls were performed by replacing the primary antibody with normal horse
serum. Immunohistochemical staining was performed using an appropriate positive control.
The intensity and distribution patterns of specific immunohistochemical staining were
evaluated using the semi-quantitative immuno-reactive score (IRS). This score was calculated
by multiplying the staining intensity (graded as 0 = no, 1 = weak, 2 = moderate and 3 =
strong staining) with the percentage of positively stained cells (0 = no staining, 1 = <10% of
cells, 2 = 11-50% of cells, 3 = 51-80% of cells and 4= >81% of cells stained). The slides
were examined by two independent observers. Sections were examined using a Leitz
microscope (Wetzlar, Germany) with a 3CCD color camera (JVC, Victor Company of Japan,
Japan).
Statistical analysis
Data were entered into the database in a coded fashion. Our total collective of 112 patients
included 57 unifocal breast cancer patients and 55 cases of multicentric/multifocal tumors.
7. Because of the uneven distribution of prognostic factors in our original patient group of 46
cases that met the match criteria, a matched pair analysis was performed. A total of 23 pairs
of patients, each consisting of one patient with unifocal and one with multicentric/multifocal
tumor lesions, were selected according to the highest degree of equivalence in the following
hierarchical and sequential order: tumor size at the time of primary diagnosis, histology
grading, and lymph node status. Each parameter was required to have a p value > 0.50 to
achieve intergroup homogeneity. We deliberately matched patients based on the criteria at the
time of primary diagnosis. The computer software ‘Statistical Package for the Social Sciences
15.0′ (SPSS Inc., Chicago, IL, USA) was used to perform statistical analyses. We used
Kruskal-Wallis one-way analysis of variance to analyze our data, which is a non-parametric
method for testing equality of population medians among groups. It is an extension of the
Mann–Whitney U test to 3 or more groups.
For survival analysis median immunoreactivity levels, as determined by the IR-score, of each
marker were employed to split the collective into low vs. high expressing cases. The
following thresholds were used: E-Cadherin ≥ IRS 8, beta-Catenin (membrane staining) ≥
IRS 8, beta-Catenin (cytoplasma staining) ≥ IRS 4, MUC1 (membrane staining) ≥ IRS 8,
MUC1 (cytoplasma staining) ≥ IRS 1. Kaplan-Meier survival curves were drawn to compare
survival times of uni- vs. multifocal/-centric tumors and of high vs low expressing cases,
respectively. Differences in overall and relapse-free survival were tested for significance by
applying the chi-square statistic of the log rank test.
P values below 0.05 were considered significant.
Results
All matching criteria (tumor size, histology grade and lymph node status) were equally
distributed between the two groups (p = 1.0).
No significant difference was observed between the two groups in terms of age (p = 0.104 in
the matched group and p = 0.533 in the total collective) or menopausal status (MG: p = 0.291
and TC: p = 0.503). Regarding histological types of tumors, the total collective (TC)
demonstrated a statistically significant difference with p = 0.003 (see below), whereas no
significant difference was found in the matched group (p = 0.120). Table 2 shows the primary
patient characteristics of both groups.
8. Table 2 Patient characteristics
Total Collective
Multicentric/multifocal (%) Unifocal (%) P-Value
Number of patients 55 57
Age 60.6 58.9 .533
Lymph node Metastases .150
Absent (N0) 27 (50.0) 35 (62.5)
1-3 axillary LNM (pN1bi) 4(7.4) 7 (12.5)
1-3 axillary LNM (pN1biii) 18 (33.3) 8 (14.3)
1-3 axillary LNM (pN1biv) 0 3 (5.4)
4-9 axillary LNM (pN2) 1 (1.9) 1 (1.8)
Unknown (pNx) 5 (9.1) 3 (5.3)
Histological Type .003
Ductal 35 (66) 39 (69.6)
Lobular 11 (20.8) 3 (5.4)
Ductal-lobular 4 (7.5) 3 (5.4)
Mucinous 1 (1.9) 2 (3.6)
Medullary 1 (1.9) 4 (7.1)
Micropapillary 1 (1.9) 2 (3.6)
Tubulary 0 3 (5.4)
Not specified 2 (3.6) 1 (1.8)
Menopausal Status .503
Premenopausal 13 (47.9) 16 (37.5)
Postmenopausal 37 (52.1) 36 (62.5)
Matched Group
Multicentric/multifocal (%) Unifocal (%) P-Value
Number of patients 23 23
Age 57 68 .104
Histological Type .120
Ductal 16 (69.6) 15 (65.2)
Lobular 5 (21.7) 3 (13.0)
Ductal-lobular 2 (8.7) 1 (4.3)
Medullary 0 1 (4.3)
Micropapillary 0 2 (8.7)
Not specified 0 1 (4.3)
Menopausal Status .291
Premenopausal 4 (18.8) 6 (26.1)
Perimenopausal 0 1 (4.3)
Postmenopausal 18 (81.8) 14 (60.9)
Unknown 1 (4.3) 2 (8.7)
Looking at the total collective, 55 patients were included in the multicentric/multifocal group
and 57 in the unifocal group. This group was not matched, so statistical analysis was
performed according the matching criteria of tumor size, lymph node status and
histopathological grading. Tumor size (p = 0.113), lymph node involvement (p = 0.150), and
9. histopathological grading (p = 0.068) did not show any significant correlation with
multicentric/multifocal tumors versus unifocal tumors.
According to the histological tumor type, a significant difference was observed in the
incidence of invasive lobular cancer in the multicentric/multifocal group in comparison to the
unifocal group. Of 14 patients suffering from invasive lobular cancer, 11 had
multicentric/multifocal disease, whereas only 3 had unifocal breast cancer. The results were
different for invasive ductal tumors; out of 74 patients with invasive ductal cancer, 35 had
multicentric/multifocal disease, and 39 had unifocal breast cancer. Looking at the matched
group, five patients had lobular multicentric/multifocal breast cancer (21.7%), and three
patients (13.6%) had a lobular unifocal disease. Also, ductal carcinomas did not differ
significantly. Sixteen patients (69.6%) in the multicentric/multifocal matched group had
ductal breast cancer, compared with 15 patients (68.2%) in the unifocal group.
Regarding the expression of E-cadherin, lobular cancers were not included in the statistical
analysis of the two groups. The total collective examined therefore included 54 unifocal and
44 multicentric/multifocal cancer tissues. Compared to the multicentric/multifocal group, E-
cadherin expression was significantly higher in the unifocal group, with a p-value of <0.0001.
MG in this case included 32 patients (16 pairs). E-cadherin expression was also significantly
higher in the unifocal matched group with p = 0.024 (Figure 1).
Figure 1 E-cadherin expression in the total collective (A, B) and in the matched group
(C, D) of unifocal (A, C) and multicentric/multifocal (B, D) breast cancer; magnification
25× lens. Semiquantitative evaluation of staining results (IR score) is presented in box plots
(E- G) for the total collective and in the box plots (H-J) for the matched group with respect
to differences between G2 and G3-tumors. The boxes represent the range between the 25th
and 75th percentiles with a horizontal line at the median. The bars delineate the 5th and 95th
percentiles. The circles indicate values more than 1.5 box lengths away from the median.
Looking at the grading within the total collectivegroup as well as unifocal tumors, G2
(moderately differentiated) tumors exhibited higher E-cadherin expression compared to
multifocal tumors (p = 0.001), as did G3 (poorly differentiated)tumors (p = 0.037). The
matched pair group underlined these results for G2 tumors and revealed higher E-cadherin
expression in unifocal tumors compared with multicentric/multifocal tumors. The p-value
was 0.055 for G2 tumors, whereas G3 tumors failed to demonstrate significance with p =
0.261 (Fig. 1).
No significant differences in β-catenin expression patterns were observed between
multicentric/multifocal and unifocal tumors (p = 0.914) when comparing the total collective,
and the difference was also not significant for the matched pairs (p = 0.636). Furthermore, β-
catenin expression showed no significant correlation with histology grade within the total
collective either for multicentric/multifocal breast cancers (p = 0.564) or for unifocal disease
(data not shown, p = 0.635).
However, the cytoplasm ß-catenin was associated significantly with a reduced overall
survival (OS) in unifocal tumors (p = 0.032). Interestingly, no differences were found
concerning survival in mulicentric/multifocal tumors (Figure 2A).
10. Figure 2 A: Cytoplasmic ß-catenin expression related to the overall survival (OS) in
unifocal and multicentric/multifocal tumors. B: PankoMab epitope on the membrane
related to the overall survival (OS) in unifocal and multicentric/multifocal tumors.
The MUC1 expression also failed to demonstrate a significant difference between unifocal
and multicentric/multifocal disease in both the MG (p = 0.840) and the TC group (p = 0.183).
Analyzing differences with respect to histology grade, no differences in MUC1 expression
were observed in the total collective among G1, G2 and G3 unifocal tumors (p = 0.840). In
contrast, MUC1 expression in multicentric/multifocal tumors was significantly dependent on
histology grade (decreasing from G1 to G3 at p = 0.027) (Figure 3).
Figure 3 MUC1 (mPankoMab) membrane expression in the total collective of
multicentric/multifocal breast cancer in a G1 tumor (A), a G2 tumor (B), and a G3
tumor (C); magnification 25× lens. The box plots (D, E) present a semiquantitative
evaluation of staining results (IR score). The boxes represent the range between the 25th and
75th percentiles with a horizontal line at the median. The bars delineate the 5th and 95th
percentiles.
The PankoMab epitope was demonstrated no difference according to the histology grade
when looking at the cytoplasm staining. When looking at the overall survival (OS), the
PankoMab epitope on the membrane was associated with a better outcome, however only
significant in G2 and G3-unifocal tumors (Figure 2B).
In other words, less differentiated multicentric/multifocal tumors exhibited partial loss of
MUC1 expression.
Discussion
We investigated in a previous study the prognostic differences between
multicentric/multifocal and unifocal breast cancer [7]. In that study, patients were entered by
matched-pair analysis into two comparable groups of 288 patients after categorizing them as
having multicentrical/multifocal or unifocal breast cancers. Matching criteria were tumor
size, histology grade and hormone receptor status, which were equally distributed between
both groups (p = 1.000 each). We demonstrated that multicentric/multifocal breast cancer is
associated with a worse prognosis compared to unifocal disease with an identical tumor size
[7]. However, Vlastots et al. investigated breast cancer patients with early-stage disease and
did not find an increased risk of poor outcome with respect to multicentricity. According to
the authors, this study supports the current tumor, node, metastasis staging system [26].
On the contrary, Tot et al. also demonstrated recently, that multifocality represents a negative
prognostic parameter associated in this study with significantly increased lymphnode
metastasis (LNM) [27]. These findings were confirmed by Tot et al. in further studies, that
demonstrated multifocality being associated with an increased risk of LNM [28,29].
According to our study-collective of 112 patients, 55 patients were included in the
multicentric/multifocal group and 57 in the unifocal group. This total collective was not
matched, and statistical analysis was performed according the matching criteria of tumor size,
lymph node status and histopathological grading. Our results did however not demonstrate
11. any significant correlation of lymph node metastasis when comparing multicentric/multifocal
and unifocal tumors. This result however has to be interpreted in a critical manner to the
effect that the total collective however includes patients who were matched according to the
lymph nodes status.
However, it remained unclear whether the tendency of breast cancer tumors to metastasize
was a reflection of the total tumor load or whether biological differences play a decisive role.
The 10-year survival rate was investigated by Boyages et al. who found – especially in
tumors > 2 cm – that the aggregate size of every focus should be considered along with other
prognostic factors when comparing multifocal and unifocal breast cancer [30].
Aim of this manuscript was, to evaluate differences in tumor biology, that might help
explaining the above mentioned differences. Tot et al. investigated multifocal and unifocal
breast cancer according to the immunophenotype (estrogen and progesterone receptor
expression, HER2 overexpression and expression of basal-like markers, CK5/6, CK14, and
epidermal growth factor receptor). The auhors found higher rates of LNM in the multifocal
group, interestingly no differences with respect to molecular phenotype [29]. These findings
were underlined by Pekar et al. who also demonstrated that diffuse or multifocal distribution
of the invasive component is associated with cancer-related death independent of the
molecular phenotype [31].
Bassarova et al. [32] investigated the cadherin/catenin immunophenotype of multicentric
tumor foci and bilateral breast cancer. They found a greater similarity of the primary tumor to
its corresponding metastatic tumor than to the contralateral primary tumor regarding the
cadherin/catenin immunophenotype [32]. Although different histological subtypes were
examined (pleomorphic lobular, invasive ductal of usual type, atypical medullary carcinomas,
mucinous and invasive micro papillary carcinomas), differences in the tumor biology were
obvious and could be anticipated. The present study was intended to analyze some of the
potential factors involved.
β-catenin is involved in cell-cell adhesions and is a transcriptional regulator in the Wnt
signaling pathway [33], furthermore it is consequently involved in the development of human
malignancies. Lopez-Knowles et al. [34] investigated immunohistochemically the expression
of β-catenin in 292 patients with invasive ductal breast cancers. The authors demonstrated an
association between a high cytoplasmic expression of β-catenin and a high tumor grade (p =
0.004) and negative estrogen receptor values (p = 0.005), and the high expression of β-
catenin was thus associated with an adverse disease outcome.
We found no differences for the cytoplasmic ß-catenin as well as for the membrane ß-catenin
with respect to the grading. Moreover, the cytoplasmic ß-catenin was associated significantly
with a reduced OS in unifocal tumors (p = 0.032). Our data suggest a wnt signaling pathway
in unifocal tumors. However, this pathway might not play an important role in
multicentric/multifocal tumors. Therefore we assume differences in tumor biology between
uni- and multifocal tumors according to our results.
Niu et al. described an association between abnormal β-catenin expression, positive lymph
node status and high histological grade (p < 0.01) as well as a significant correlation between
positive Her2 expression and abnormal β-catenin expression [13]. Therefore, elevated β-
catenin expression appears to be linked with worse outcome for the patients. However,
differences concerning focality have not been investigated.
12. Recent research has underlined the importance of E-cadherin with respect to cell adhesion
mechanisms. Down-regulation of E-cadherin/catenin-mediated intercellular adhesion is
known to be an important step in the acquisition of malignancy and metastasis. According to
Baranwal [14], down-regulation of E-cadherin is associated with worse outcome and
enhanced aggressiveness of the tumor. Klopp et al. [35] also stated that decreased expression
of E-cadherin is associated with breast cancer progression and resistance to therapy. Finally,
loss of E-cadherin expression is a hallmark of epithelial-mesenchymal transition (EMT),
which is associated with a worse prognosis [16]. In contrast, up regulation of E-
cadherin/catenin complex, which acts as a suppressor of tumor progression, has been
accomplished with a series of agents, some of which can be used therapeutically [36].
Our finding of a significantly reduced expression of E-cadherin in multicentric/multifocal
tumours underline and reinforce our view of a more aggressive behavior of this tumor type.
Since loss of E-cadherin is a marker of EMT, it might be worthwhile to examine other EMT
markers such as MMPs, which lead to E-cadherin degradation [37], or vimentin in
multicentric/multifocal versus unifocal breast tumors..
MUC1 is a multifunctional epithelial glycoprotein known to be overexpressed in most
epithelial cancers. MUC1 can promote proliferation and metastasis, whereas down regulation
of MUC1 expression inhibits cell migration by inducing β-catenin relocation from the
nucleus to the cytoplasm and increases E-cadherin/catenin complex formation [38]. In
addition, MUC1 is coexpressed and complexed with STAT1 (Khodarev et al.[39]), and it is
associated with decreased recurrence-free and overall survival. This may explain why
intracellular expression of MUC1 is associated with worse prognosis [40], whereas
membrane (or overall) expression of MUC1 is generally correlated with a better outcome
[41].
Using the anti-MUC1 antibody mPankoMab, which recognizes a special, tumor-associated
MUC1 epitope [19], we previously observed a correlation between MUC1 and the expression
of the ER receptor [42]. In the present study, we did not observe differences in MUC1
expression between multicentric/multifocal and unifocal breast cancer (p = 0.183). However,
when looking at the histopathological grading, multicentric/multifocal carcinomas showed a
statistically significant decrease in staining with increased histology grade (p = 0.027) which
was in contrast to the MUC1 expression in unifocal breast cancer of different grade.
According to the cytoplasmic PankoMab-staining no differences were found with respect to
the histology grade. When looking at the overall survival (OS) the PankoMab epitope on the
membrane was however associated with a better outcome, nevertheless only significant in G2
and G3 unifocal tumors (p = 0.038).
Conclusions
In summary, differences regarding tumo rbiology are obvious as fore the wnt signaling
pathway might play an important role in unifocal tumors and the PankoMab epitope on the
membrane associated with a better outcome in G2 and G3 unifocal tumors.
Due to the small collective used for this study, we have not confirmed and extended our
earlier results which demonstrated that multicentric/multifocal tumors as compared to
unifocal breast tumors correlate with a reduced survival and relapse-free interval (Additional
13. file 1: Figure S1).Instead, we analyzed membrane associated breast cancer markers as
molecules to discriminate with respect to focality between both entities. These results
indicate that the breast tumor biology differs depending on focality and suggest a tendency
for enhanced EMT in multicentric/multifocal breast cancer. Further research is necessary on
the tumor biology of multicentric and multifocal tumors.
Competing interest
Uwe Karsten is an employee of Glycotope GmbH which mad and provided the PankoMab
antibody. All other authors declare no competing interest.
Authors’ contributions
TW designed the study and performed collection, analysis and interpretation of data and
drafted the manuscript for publication. EH, CK and UK participated in the design of the
study, and were involved in the immunhistochemistry. WJ, SH, ND, BR essentially were
involved in the analysis and interpretation of the data and also approved the English. UJ, DD
and FK performed participant inclusion, collected samples and contributed substantially to
acquisition of data. DD helped substantially to draft the manuscript. All conceived of the
study, participated in its design and coordination, helped with data interpretation and drafting
of the manuscript. All authors read and approved the final manuscript.
Acknowledgement
We would like to thank Dr. Steven S. Witkin (Weill Cornell Medical College, New York,
USA) for his help with the manuscript.
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17. Additional file
Additional_file_1 as JPEG
Additional file 1: Figure S1 Kaplan-Meier survival curves were drawn to compare Overall
survival (OS) and relapse free survival (RFS) in unifocal and multicentric/multifocal tumors.