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Supplementary Information - PDF file 145K, Supplementary Material and Methods; Supplementary Figure Legend S1 (Proliferation of tumor-specific CD4 T cells by matured DC pulsed with autologous tumor lysate.); Supplementary Figure Legend S2 (In breast tumors TEM and CD11c+ are distinct cell subsets.); Supplementary Tables S1 (Clinical and pathological features of tumors and patients (n=40)); Supplementary Tables S2 (CD11c+ DC and TEM from breast tumors were exposed to autologous CFSE-labeled T cells and their proliferation assessed five days later by flow cytometry.); Supplementary References

Supplementary figures - PDF file 1536K, Figure S1. Proliferation of tumor-specific CD4 T cells by matured DC pulsed with autologous tumor lysate; Figure S2. In breast tumors TEM and CD11c+ are distinct cell subsets

Supplementary Figure 7 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Supplementary Figure Legends 1-9 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Supplementary Figure 1 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Supplementary Figures 2-6 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Supplementary Figure 8 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Supplementary Figure 9 from Proangiogenic Factor PlGF Programs CD11b+ Myelomonocytes in Breast Cancer during Differentiation of Their Hematopoietic Progenitors

Background Increasing data support the role of BCSCs in recurrence and resistance to chemotherapy. However, detecting these cells specifically and targeting them therapeutically remain challenging. We set to identify miRNAs involved in chemoresistance of BCSCs in vitro and the results were assessed in the sera of healthy donors and breast cancer patients treated with neoadjuvant chemotherapy (NAC). Methods In vitro experiments were conducted in the MCF7 cell line grown as mammospheres (MS) in order to enrich a BCSC phenotype. After treatment with 5FU or Paclitaxel (Pac), microRNA profile of chemoresistant cells was analyzed by microarray. The results were compared to miRNAs found in immortalized non-tumorigenic MCF10A cells in order to exclude miRNAs related to normal stem cells. A signature of 6 miRNAs was identified. miR-363-3p, appearing the most relevant, was chosen for further assessment. By RT-qPCR, miR363-3p levels were 20- and 100-fold higher in ALDH+ sorted cells compared to ALDH- MCF7 and MDA-MB-231 cells, respectively. Moreover, overexpression of miR363-3p in MCF7 cells correlated with an increased number of ALDH+ cells and 1.5 more MS formed. In contrast, downregulation of miR363-3p levels induced a decrease in MS size and 2-fold reduction in number. Consistently, miR-363-3p downregulation decreased tumor growth and metastasis of MCF7 cells in an intraductal human-in-mice transplantation model. miRNA was quantified by RT-qPCR in tissue and sera collected prospectively from 40 breast cancer patients before and after NAC (anthracycline-taxane) and also from 25 healthy donors. Results Fifty percent of the patients had luminal A and B tumors (n=20), 32,5% (n=13) had triple negative breast cancer (TNBC), and 17.5% (n=7) had HER2 positive BC. Excluding one patient, who refused the surgical resection, 40% achieved pathological complete response (pCR). Six patients presented disease recurrence. In patients’ tumor before and after NAC, a higher level of miR363-3p was observed compared with benign tissue. In sera of the BC patients, miR363-3p levels were significantly higher than that of healthy donors. After NAC, the levels of miR363-3p remained high among patients who relapsed, whereas they were equivalent to the healthy donors in patients who remained in remission. No correlation between Ki-67, grade 1 or 2 and miR363-3p levels was observed. However, in grade 3 BC, low level of miR363-3p before and after NAC was correlated with pCR and remission. The level of miR363-3p correlated with remission and pCR in patients with TNBC and HER2 BC. Conclusions Assessment in the sera of patients and healthy donors confirms our previous data supporting the role of miR363-3p as predictive factor of resistance to neoadjuvant chemotherapy and disease recurrence. Further investigations are warranted to confirm the role of miR363-3p as a biomarker and potential therapeutic target. Citation Format: Stephanie Renaud, Athina Stravodimou, Maryse Fiche, Ioannis Xenarios, Scabia Valentina, Valerian Dormoy, Marie Galmiche, Cathrin Brisken, Jean-Francois Delaloye, Assia Treboux, Jean-Yves Meuwly, Nicolas Mermod, Khalil Zaman. miR363-3p mediates maintenance of breast cancer stem cells (BCSCs) and predicts resistance to neoadjuvant chemotherapy and disease recurrence [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-22.

BackgroundThe aim of the study was to identify risk factors for positive surgical margins in breast-conserving surgery for breast cancer and to evaluate the influence of surgical experience in obtaining complete resection.MethodsAll lumpectomies for invasive breast carcinoma and ductal carcinoma in situ (DCIS) between April 2008 and March 2010 were selected from the database of a single institution. Re-excision rates for positive margins as well as patient and histopathologic tumor characteristics were analyzed. Surgical experience was staged by pairs made of Resident plus Specialist or Consultant. Two periods were defined. During period A, the majority of operations were performed by Residents under supervision of Specialist or Consultant. During period B, only palpable tumors were operated by Residents.ResultsThe global re-excision rate was 27% (50 of 183 patients). The presence of DCIS increased the risk for positive margins: 60% (nine of 15 patients) in the case of sole DCIS compared to 26% (41 of 160 patients) for invasive cancer (p = 0.005) and 35% (42 of 120 patients) in the case of peritumoral DCIS compared to 11% (seven of 62 patients) in the case of sole invasive cancer (p = 0.001). Re-excision rate decreased from 36% (23 of 64 patients) during period A to 23% (27 of 119 patients) during period B (p = 0.055). There was no significant difference between the surgical pairs.ConclusionIn our study, DCIS was the only risk factor for positive surgical margins. Breast-conserving surgery for non-palpable tumors should be performed by Specialists, however, palpable tumors can be safely operated by Residents under supervision.

Objective To examine the protective role of relationship satisfaction on body image in women with breast cancer throughout the first year post-surgery. Methods Seventy-four Swiss patients engaged in a relationship filled out a questionnaire assessing body image disturbance 2 weeks, 3 months, and 1 year after surgery. A univariate latent change score model was used to analyze the evolution of body image disturbance and the contribution of relationship satisfaction to body image disturbance. Results Women who were satisfied with their relationship reported less body image disturbance than did dissatisfied women at 2 weeks post-surgery. Being married was also associated with less body image disturbance at that time. The protective effect of these relational variables was still observable 1 year later. Changes in body image disturbance over time were explained by the negative impacts of mastectomy and chemotherapy. Conclusions How women perceive the impact of breast cancer treatment on their body may be partly determined by the quality of the relational context in which they live.

The purpose of this study is to obtain a consensus for the therapy of B3 lesions. The first International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions) including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), papillary lesions (PL), benign phyllodes tumors (PT), and radial scars (RS) took place in January 2016 in Zurich, Switzerland organized by the International Breast Ultrasound School and the Swiss Minimally Invasive Breast Biopsy group—a subgroup of the Swiss Society of Senology. Consensus recommendations for the management and follow-up surveillance of these B3 lesions were developed and areas of research priorities were identified. The consensus recommendation for FEA, LN, PL, and RS diagnosed on core needle biopsy or vacuum-assisted biopsy (VAB) is to therapeutically excise the lesion seen on imaging by VAB and no longer by open surgery, with follow-up surveillance imaging for 5 years. The consensus recommendation for ADH and PT is, with some exceptions, therapeutic first-line open surgical excision. Minimally invasive management of selected B3 lesions with therapeutic VAB is acceptable as an alternative to first-line surgical excision.

The aim of this study was to assess, in the immediate postsurgical period, the influence of attachment avoidance and anxiety on distress and body image disturbances in women facing breast cancer. Seventy-five women participated in the study 3 weeks after surgery. Questionnaires were used to assess study variables. To predict distress and body image disturbances, we controlled for several variables known to influence adjustment to the stress of breast cancer. The results of hierarchical regression analyses show that attachment explains the outcomes above and beyond other influential variables. Insecurely attached women are especially vulnerable to the stress of the disease.

This study describes women's sexual functioning in the early weeks of breast cancer treatment and the possible sexual changes that women may experience compared with pre-treatment functioning. Seventy-five patients filled out a questionnaire on sexual functioning and participated in a semi-structured interview on changes in sexual life and intimacy after treatment. Sixty-two women were sexually active before treatment; three post-treatment patterns of sexual behaviour were identified: 22.6% of these women were as active as before treatment, 35.5% stopped any sexual activity and 41.9% experienced quantitative and qualitative changes. Analyses showed that each pattern had specific characteristics regarding current sexual functioning, the kinds of changes reported (e.g. decreased frequency and increased tenderness) and the reasons for these changes (e.g. tiredness and sex not a priority). Even in the immediate post-surgical period, women may react in very different ways to treatment in terms of sexual functioning. Most women experience changes, but cessation of sexual activity is not inevitable. Positive changes (growing tenderness and affection) also exist. These important interindividual differences require a person-centred approach when the topic of sexuality is being addressed, and practitioners need to be sensitive to individual perceptions of change. Early detection of sexual changes may prevent the crystallisation of difficulties over time.

Tumor-associated macrophages (TAM) are well known as a key player in the tumor microenvironment, which support cancer progression. More recently, a lineage of monocytes characterized by the expression of the TIE-2/Tek angiopoietin receptor identified a subset of circulating and tumor-associated monocytes endowed with proangiogenic activity. TIE-2 expressing monocytes (TEM) were found both in humans and mice. Here, we review the phenotypes and functions of TEM reported so far in human cancer and their potential use as markers of cancer progression and metastasis. Finally, we discuss the therapeutic approaches currently used or proposed to target TEM.

Purpose: Tumor-associated TIE-2–expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs. Experimental Design: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas. Results: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells. Conclusions: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response. Clin Cancer Res; 19(13); 3439–49. ©2013 AACR.

We examined the evolution of the subjective burden of romantic partners caring for women with non-metastatic breast cancer and investigated the moderating role of couple satisfaction on caring stress. Forty-seven partners filled out questionnaires 3 and 12 months after surgery. Using a stress process model, we examined caring stressors and moderating factors (couple satisfaction, coping and social support) as predictors of subjective burden. Results showed that subjective burden decreases over time and that the couple satisfaction largely explains it above and beyond other influential variables. Partners dissatisfied with their couple relationship are especially vulnerable to the stress of caregiving.

Summary Seventy-five percent of breast cancers are estrogen receptor α positive (ER + ). Research on these tumors is hampered by lack of adequate in vivo models; cell line xenografts require non-physiological hormone supplements, and patient-derived xenografts (PDXs) are hard to establish. We show that the traditional grafting of ER + tumor cells into mammary fat pads induces TGFβ/SLUG signaling and basal differentiation when they require low SLUG levels to grow in vivo. Grafting into the milk ducts suppresses SLUG; ER + tumor cells develop, like their clinical counterparts, in the presence of physiological hormone levels. Intraductal ER + PDXs are retransplantable, predictive, and appear genomically stable. The model provides opportunities for translational research and the study of physiologically relevant hormone action in breast carcinogenesis.

Breast cancer is a reality for 5000 women in Switzerland every year and, when these women are in a committed relationship, represents a critical event for their partners as well. For this reason, there is now a consensus in the literature to consider breast cancer as an event involving couples as much as women alone. Research should also take into account women and partners and should be extended to couples as a unit. Up to now, it has been difficult to draw a synthesis from the data available in the body of writings on the impact of cancer on couples, as methodologies have been diverse and vary between studies. Thus, the goal of this chapter is first of all to present the advantages and limitations of the two main methods of assessment that are used in the domain of couple relationships: questionnaires and observation. The necessity to combine the different methods is then discussed. At last, comments will be illustrated with a project conducted in Switzerland funded by the Swiss National Science Foundation that formed part of the National Centre of Competence in Research (NCCR) “LIVES – Overcoming Vulnerability: Life Course Perspectives” and which examined couples facing breast cancer using a mixed method approach.

We recently reported that nuclear grading in prostate cancer is subject to a strong confirmation bias induced by the tumor architecture. We now wondered whether a similar bias governs nuclear grading in breast carcinoma. An unannounced test was performed at a pathology conference. Pathologists were asked to grade nuclei in a PowerPoint presentation. Circular high power fields of 27 invasive ductal carcinomas were shown, superimposed over low power background images of either tubule-rich or tubule-poor carcinomas. We found (a) that diagnostic reproducibility of nuclear grades was poor to moderate (weighed kappa values between 0.07 and 0.54, 27 cases, 44 graders), but (b) that nuclear grades were not affected by the tumor architecture. We speculate that the categorized grading in breast cancer, separating tubule formation, nuclear pleomorphism, and mitotic figure counts in a combined three tier score, prevents the bias that architecture exerts on nuclear grades in less well-controlled situations.

This study aimed to assess the psychometric robustness of the French version of the Supportive Care Needs Survey and breast cancer (BC) module (SCNS-SF34-Fr and SCNS-BR8-Fr). Breast cancer patients were recruited in two hospitals (in Paris, France and Lausanne, Switzerland) either in ambulatory chemotherapy or radiotherapy, or surgery services. They were invited to complete the SCNS-SF34-Fr and SCNS-BR8-Fr as well as quality of life and patient satisfaction questionnaires. Three hundred and eighty-four (73% response rate) BC patients returned completed questionnaires. A five-factor model was confirmed for the SCNS-SF34-Fr with adequate goodness-of-fit indexes, although some items evidenced content redundancy, and a one-factor was identified for the SCNS-BR8-Fr. Internal consistency and test-retest estimates were satisfactory for most scales. The SCNS-SF34-Fr and SCNS-BR8-Fr scales demonstrated conceptual differences with the quality of life and satisfaction with care scales, highlighting the specific relevance of this assessment. Different levels of needs could be differentiated between groups of BC patients in terms of age and level of education (P < 0.001). The SCNS-SF34-Fr and SCNS-BR8-Fr present adequate psychometric properties despite some redundant items. These questionnaires allow for the crucial endeavour to design appropriate care services according to BC patients' characteristics.

Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps. Although dissemination of tumour cells seems to be an early and frequent event, the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites. Prevalent target sites are characteristic of many tumour entities, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.

Tumor-mobilized bone marrow–derived CD11b+ myeloid cells promote tumor angiogenesis, but how and when these cells acquire proangiogenic properties is not fully elucidated. Here, we show that CD11b+ myelomonocytic cells develop proangiogenic properties during their differentiation from CD34+ hematopoietic progenitors and that placenta growth factor (PlGF) is critical in promoting this education. Cultures of human CD34+ progenitors supplemented with conditioned medium from breast cancer cell lines or PlGF, but not from nontumorigenic breast epithelial lines, generate CD11b+ cells capable of inducing endothelial cell sprouting in vitro and angiogenesis in vivo. An anti–Flt-1 mAb or soluble Flt-1 abolished the generation of proangiogenic activity during differentiation from progenitor cells. Moreover, inhibition of metalloproteinase activity, but not VEGF, during the endothelial sprouting assay blocked sprouting induced by these proangiogenic CD11b+ myelomonocytes. In a mouse model of breast cancer, circulating CD11b+ cells were proangiogenic in the sprouting assays. Silencing of PlGF in tumor cells prevented the generation of proangiogenic activity in circulating CD11b+ cells, inhibited tumor blood flow, and slowed tumor growth. Peripheral blood of breast cancer patients at diagnosis, but not of healthy individuals, contained elevated levels of PlGF and circulating proangiogenic CD11b+ myelomonocytes. Taken together, our results show that cancer cells can program proangiogenic activity in CD11b+ myelomonocytes during differentiation of their progenitor cells in a PlGF-dependent manner. These findings impact breast cancer biology, detection, and treatment. Cancer Res; 71(11); 3781–91. ©2011 AACR.

Breast cancer is a public health issue in numerous countries. Multidisciplinary collaboration is required for patient care, research, and also education of future physicians. This paper uses Kern's framework for curriculum design to demonstrate how a breast diseases module for undergraduate medical students created in 1993 evolved over 15 years. The main outcomes of program refinements were better integrated course content, the development of electronic course documents, and implementation of computer-aided small group learning. A main future challenge is to further develop efficient instructional strategies in line with well-defined learning needs for undergraduate students.

Objective. MegaFas Ligand (MFL) is a recombinant molecule that efficiently triggers apoptosis after binding to the Fas receptor expressed on target cells. The purpose of this study was to determine the potency of MFL in vitro and efficacy in vivo for intraperitoneal treatment of mice implanted with human ovarian carcinoma cells. Methods. The potency of MFL was compared to that of other Fas agonists in a cytotoxicity assay on SKOV-3 cells. The potency of MFL was further determined by measuring apoptosis in combination with cisplatin. The efficacy of MFL was determined in vivo using peritoneal xenograft models of human ovarian carcinoma. Results. In vitro, MFL induced significantly higher levels of apoptosis than other Fas agonists, and was able to overcome the resistance of the ovarian cancer cell line SKOV-3 to Fas agonist antibody. MFL exerted an enhanced cytotoxic effect when combined with platinum-based drugs, leading to significantly more apoptosis than by incubation with MFL or these drugs alone. Treatment of mice xenografted with SKOV-3 and HOC79 ovarian tumors by intraperitoneal administration of MFL alone or in combination with cisplatin resulted in a significant decrease in peritoneal tumor nodules and ascitic cells, and prolongation of survival as compared to non-treated mice. The beneficial effects of MFL treatment occurred in the absence of severe toxicity. Conclusion. MFL is a novel pro-apoptotic molecule that is able to efficiently induce apoptosis in ovarian cancer cells as well as to potentiate the activity of chemotherapeutic agents in vitro and in vivo.

Objective The purpose of the study was to assess the feasibility of intraoperative sentinel node (SN) detection using injection of patent blue dye and radioactive tracer beneath the tumor of patients with endometrial carcinoma. Methods Hysteroscopy was used for injection of 2 ml of patent-V blue, followed by 20–50 MBq technetium-99 m-labelled nanocolloids into the subendometrial layer underlying the tumor of 60 patients with endometrial cancer. Then SN biopsy, pelvic and paraaortic lymphadenectomy, hysterectomy and bilateral salpingo-oophorectomy were carried out through laparotomy or laparoscopy. Results Sixty patients aged 43 years to 87 years (median age 65 years) were enrolled in this study. Sentinel nodes were identified in 49 of 60 patients (82%). The mean number of SN retrieved was 3.7 per patient (range, 1 to 8). Sixteen patients (33%) had SN in both pelvic and paraaortic areas. No patient had SN only at the paraaortic level. Metastatic disease was found in 9 patients (15%). In 8 of them at least one SN was positive. Conclusion Intraoperative sentinel node detection is feasible in patients with endometrial carcinoma using hysteroscopy for injection of blue dye and technetium-99 m beneath the tumor. This technique may actually enhance the chances of detecting metastatic disease, while reducing the extent of the surgery.

Angiogenesis plays a key role in tumor growth and cancer progression. TIE-2-expressing monocytes (TEM) have been reported to critically account for tumor vascularization and growth in mouse tumor experimental models, but the molecular basis of their pro-angiogenic activity are largely unknown. Moreover, differences in the pro-angiogenic activity between blood circulating and tumor infiltrated TEM in human patients has not been established to date, hindering the identification of specific targets for therapeutic intervention. In this work, we investigated these differences and the phenotypic reversal of breast tumor pro-angiogenic TEM to a weak pro-angiogenic phenotype by combining Boolean modelling and experimental approaches. Firstly, we show that in breast cancer patients the pro-angiogenic activity of TEM increased drastically from blood to tumor, suggesting that the tumor microenvironment shapes the highly pro-angiogenic phenotype of TEM. Secondly, we predicted in silico all minimal perturbations transitioning the highly pro-angiogenic phenotype of tumor TEM to the weak pro-angiogenic phenotype of blood TEM and vice versa. In silico predicted perturbations were validated experimentally using patient TEM. In addition, gene expression profiling of TEM transitioned to a weak pro-angiogenic phenotype confirmed that TEM are plastic cells and can be reverted to immunological potent monocytes. Finally, the relapse-free survival analysis showed a statistically significant difference between patients with tumors with high and low expression values for genes encoding transitioning proteins detected in silico and validated on patient TEM. In conclusion, the inferred TEM regulatory network accurately captured experimental TEM behavior and highlighted crosstalk between specific angiogenic and inflammatory signaling pathways of outstanding importance to control their pro-angiogenic activity. Results showed the successful in vitro reversion of such an activity by perturbation of in silico predicted target genes in tumor derived TEM, and indicated that targeting tumor TEM plasticity may constitute a novel valid therapeutic strategy in breast cancer., Author Summary Tumor vascularization is essential for tumor growth and cancer progression. In breast cancer, monocytes are angiogenic, i.e. able to induce tumor vascularization. In patients, blood circulating monocytes drastically increase their angiogenic activity when reaching the tumor, suggesting that the tumor microenvironment shapes their angiogenic activity. The identification of the tumor signals inducing the angiogenic activity of monocyte is of paramount significance because it represents the rationale for anti-angiogenic therapies in breast cancer. This goal was achieved by constructing an integrative model of monocyte behavior based on experimental data. The model predicted treatments abrogating the angiogenic activity of monocytes, which were experimentally validated in monocytes isolated from patient breast carcinoma. Importantly, these treatments reverted angiogenic monocytes into immunological potent cells. The main outcome of this modeling strategy for experimental and clinical oncology is the identification of effective treatments abrogating the angiogenic activity of monocytes and thus simultaneously revealing their functional plasticity.

Das Konsensusmeeting wurde am 5. Juni 2004 im BrustCentrum Zurich-Bethanien als Veranstaltung der Arbeitsgemeinschaft Gynakologische Onkologie (AGO) durchgefuhrt. Das Expertenpanel war interdisziplinar und national ausgewogen zusammengesetzt und diskutierte an der Veranstaltung mit den anwesenden Teilnehmern die offenen Punkte anhand von vorbereiteten Konsensusstatements. Das vorliegende Konsensuspapier wurde von den vier Studienleitern zusammengestellt und den Panelmitgliedern in schriftlicher Form zur definitiven Genehmigung prasentiert und stellt in der jetzigen Form einen Konsens dieses Panels dar und nicht nur einen solchen der AGO, obwohl an dem von der AGO organisierten Meeting viele AGO-Mitglieder und -Vorstandsmitglieder beteiligt waren. Warum ist ein solches Papier notig? Die Nachfrage fur klare Statements kam von den Kolleginnen und Kollegen, die Patientinnen mit Mammakarzinom operieren bzw. therapieren. Nach Abschluss der schweizerischen Multizenterstudie (AGO-Studien I und II) Ende 2003 stieg das Bedurfnis nach Klarheit, was aktuell nach nationalen und internationalen Erfahrungen fur die Sentinelchirurgie beim Mammakarzinom gilt. Das vorliegende Papier gliedert sich in 9 Teile: 1. Grundlagen, Definitionen, Begriffe, Erklarungen; 2. Strukturvoraussetzungen (Anforderungen an Operateure und die Behandlungsteams); 3. Indikationen und Kontraindikationen; 4. Operationstechnik und Identifikation des Sentinellymphknotens; 5. Histopathologische Aufarbeitung; 6. Nachsorge; 7. Dokumentation; 8. Patientinnenaufklarung; 9. Offene Fragen. I. Grundlagen, Definitionen und Begriffe

This prospective study evaluates bone marrow scintigraphy (BMS) in detecting bone metastases from primary breast cancer when performed in complement to conventional bone scan (BS). Sixty women predominantly with low-stage disease underwent BS followed by BMS within 1-35 days using BW250/183 antigranulocyte antibodies. A receiver operating characteristic (ROC) analysis was performed to compare BS to BS+BMS on a patient-by-patient basis using a 'gold standard' composed of subsequent computed tomography, magnetic resonance imaging, X-ray or BS examinations and at least a 12 month follow-up. Metastases were present in eight out of 60 patients (13%). Specificity was improved by BS+BMS compared to BS alone (90%, 65%) as well as positive predictive value (62%, 27%), accuracy (87%, 72%), positive (10.4, 2.4) and negative (0.20, 0.00) likelihood ratios. Sensitivity (100%, 88%) and negative predictive value (100%, 97%) were similar for BMS+BS and BS alone. As a result of BMS, clinical management was modified in 15 patients (25%). In conclusion, BMS supplements BS by improving specificity, positive predictive value and accuracy in detecting breast cancer bone metastases. The ROC curves show improved specificity for BS+BMS at the same sensitivity compared to BS alone. Consequently, BMS may be useful in low-stage subjects with positive or equivocal BS for metastases.

Although the incidence of ovarian cancer is low, mortality from this cancer is high due to discovery at a late stage in the majority of cases. So it seems worthwhile to detect ovarian cancer at an early stage. The clinical presentation is nonspecific, thus screening tools have been evaluated. The most efficient screening technique includes two steps: evaluation of CA-125 and then sonography in case of abnormal results of CA-125. Two main studies have been performed in large populations. The PLCO-study has led to negative results: no reduction in ovarian cancer mortality in the screening group with an important increase in surgical morbidity. The final results of the UKCTOCS-study will be known in two years. Currently these data can't allow the realization of ovarian cancer screening in the general population, mainly due to their natural history.

Estrogens and progesterones are major drivers of breast development but also promote carcinogenesis in this organ. Yet, their respective roles and the mechanisms underlying their action in the human breast are unclear. Receptor activator of nuclear factor kB ligand (RANKL) has been identified as a pivotal paracrine mediator of progesterone function in mouse mammary gland development and mammary carcinogenesis. Whether the factor has the same role in humans is of clinical interest because an inhibitor for RANKL, denosumab, is already used for the treatment of bone disease and might benefit breast cancer patients. We show that progesterone receptor (PR) signaling failed to induce RANKL in PR + breast cancer cell lines and in dissociated, cultured breast epithelial cells. In clinical specimens from healthy donors and intact breast tissue microstructures, hormone response was maintained and RANKL expression was under progesterone control, which increased RNA stability. RANKL was sufficient to trigger cell proliferation and was required for progesterone-induced proliferation. The findings were validated in vivo where RANKL protein expression in the breast epithelium correlated with serum progesterone levels and the protein was expressed in a subset of luminal cells that express PR. Thus, important hormonal control mechanisms are conserved across species, making RANKL a potential target in breast cancer treatment and prevention. Copyright 2013 by the American Association for the Advancement of Science; all rights reserved., National Center of Competence in Research Molecular Oncology, Oncosuisse (SNF-3100A0112090/SNF-31003-138065); Marie-Curie incoming fellowship; European Union (115188)

BACKGROUND: This study assessed whether breast cancer (BC) patients express similar levels of needs for equivalent severity of symptoms, functioning difficulties, or degrees of satisfaction with care aspects. BC patients who did (or not) report needs in spite of similar difficulties were identified among their sociodemographic or clinical characteristics. PATIENTS AND METHODS: Three hundred and eighty-four (73% response rate) BC patients recruited in ambulatory or surgery hospital services completed the European Organisation for Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ)-C30 quality of life [health-related quality of life (HRQOL)], the EORTC IN-PATSAT32 (in-patient) or OUT-PATSAT35 (out-patient) satisfaction with care, and the supportive care needs survey short form 34-item (SCNS-SF34) measures. RESULTS: HRQOL or satisfaction with care scale scores explained 41%, 45%, 40% and 22% of variance in, respectively, psychological, physical/daily living needs, information/health system, and care/support needs (P < 0.001). BC patients' education level, having children, hospital service attendance, and anxiety/depression levels significantly predicted differences in psychological needs relative to corresponding difficulties (adjusted R(2) = 0.11). Medical history and anxiety/depression levels significantly predicted differences in information/health system needs relative to degrees of satisfaction with doctors, nurses, or radiotherapy technicians and general satisfaction (adjusted R(2) = 0.12). Unmet needs were most prevalent in the psychological domains across hospital services. CONCLUSIONS: Assessment of needs, HRQOL, and satisfaction with care highlights the subgroups of BC patients requiring better supportive care targeting.

Reconstructive surgery takes an important place in breast cancer treatment. Immediate breast reconstruction is performed during the same operation as mastectomy. It is contraindicated following radiotherapy. Reconstruction performed after mastectomy is called differed breast reconstruction. It is completed 6 months after chemotherapy and 1 year after radiotherapy. Prosthetic breast reconstruction is indicated when tissues are of good qualities and breast are small. Autologous reconstruction is performed in case of radiotherapy or large breast. After breast reconstruction, imperfections can be corrected with autologous fat injection.

Several authors have demonstrated an increased number of mitotic figures in breast cancer resection specimen when compared with biopsy material. This has been ascribed to a sampling artifact where biopsies are (i) either too small to allow formal mitotic figure counting or (ii) not necessarily taken form the proliferating tumor periphery. Herein, we propose a different explanation for this phenomenon. Biopsy and resection material of 52 invasive ductal carcinomas was studied. We counted mitotic figures in 10 representative high power fields and quantified MIB-1 immunohistochemistry by visual estimation, counting and image analysis. We found that mitotic figures were elevated by more than three-fold on average in resection specimen over biopsy material from the same tumors (20±6 vs 6±2 mitoses per 10 high power fields, P=0.008), and that this resulted in a relative diminution of post-metaphase figures (anaphase/telophase), which made up 7% of all mitotic figures in biopsies but only 3% in resection specimen (P

Les anomalies mammographiques detectees le plus frequemment sont les masses, les calcifications ou la distorsion architecturale.

Die am haufigsten bei Mammographien festgestellten Anomalien sind Massen, Verkalkungen und Architekturstorungen.

Analyser l’influence des caracteres histologiques sur le taux des reprises chirurgicales pour tranches de section positives dans le cadre d’operations pour un cancer du sein en tenant compte de l’âge de la patiente, ainsi que de l’experience et de l’encadrement de l’operateur.

Cheap and massively parallel methods to assess the DNA-binding specificity of transcription factors are actively sought, given their prominent regulatory role in cellular processes and diseases. Here we evaluated the use of protein-binding microarrays (PBM) to probe the association of the tumor suppressor AP2α with 6000 human genomic DNA regulatory sequences. We show that the PBM provides accurate relative binding affinities when compared to quantitative surface plasmon resonance assays. A PBM-based study of human healthy and breast tumor tissue extracts allowed the identification of previously unknown AP2α target genes and it revealed genes whose direct or indirect interactions with AP2α are affected in the diseased tissues. AP2α binding and regulation was confirmed experimentally in human carcinoma cells for novel target genes involved in tumor progression and resistance to chemotherapeutics, providing a molecular interpretation of AP2α role in cancer chemoresistance. Overall, we conclude that this approach provides quantitative and accurate assays of the specificity and activity of tumor suppressor and oncogenic proteins in clinical samples, interfacing genomic and proteomic assays.

24 patients with advanced epithelial ovarian cancer, who demonstrated a clinical complete or partial response to the induction of intravenous chemotherapy, underwent implantation of a subcutaneous semipermanent port-and-catheter system (Port-A-Cath) for intraperitoneal chemotherapy, which consisted of carboplatin 300 mg/m2 every 4 weeks. The median survival was 27.4 months for minimal residual disease versus 8 months for bulky disease (p = 0.0054). The median progression-free interval was 15.7 months for minimal residual disease versus 1.8 months for bulky disease (p = 0.008). There were 3 complications (12.5%) related to the catheter: 1 perforation of the large bowel and 2 catheter inflow obstructions. Myelosuppression, especially a grade 3 leucopenia in 5 patients (25%) and a grade 4 thrombopenia in 3 patients (15%), was the dose-limiting toxicity. Even with maximum cytoreductive surgery and second-line intraperitoneal carboplatin-based chemotherapy, the 5-year progression-free survival (4.1%) remains very small.