Predictive Potential of RNA Polymerase B (II) Subunit 1 (RPB1) Cytoplasmic Aggregation for Neoadjuvant Chemotherapy Failure.

We aimed to investigate the contribution of co-translational protein aggregation to the chemotherapy resistance of tumor cells. Increased co-translational protein aggregation reflects altered translation regulation that may have the potential to buffer transcription under genotoxic stress. As an indicator for such an event, we followed the cytoplasmic aggregation of RPB1, the aggregation-prone largest subunit of RNA polymerase II, in biopsy samples taken from patients with invasive carcinoma of no special type. RPB1 frequently aggregates co-translationally in the absence of proper HSP90 chaperone function or in ribosome mutant cells as revealed formerly in yeast. We found that cytoplasmic foci of RPB1 occur in larger sizes in tumors that showed no regression after therapy. Based on these results, we propose that monitoring the cytoplasmic aggregation of RPB1 may be suitable for determining-from biopsy samples taken before treatment-the effectiveness of neoadjuvant chemotherapy.

Does Diffusely Infiltrating Lobular Carcinoma of the Breast Arise from Epithelial-Mesenchymal Hybrid Cells?

Classic diffusely infiltrating lobular carcinoma has imaging features divergent from the breast cancers originating from the terminal ductal lobular units and from the major lactiferous ducts. Although the term "invasive lobular carcinoma" implies a site of origin within the breast lobular epithelium, we were unable to find evidence supporting this assumption. Exceptional excess of fibrous connective tissue and the unique cell architecture combined with the aberrant features at breast imaging suggest that this breast malignancy has not originated from cells lining the breast ducts and lobules. The only remaining relevant component of the fibroglandular tissue is the mesenchyme. The cells freshly isolated and cultured from diffusely infiltrating lobular carcinoma cases contained epithelial-mesenchymal hybrid cells with both epithelial and mesenchymal properties. The radiologic and histopathologic features of the tumours and expression of the mesenchymal stem cell positive markers CD73, CD90, and CD105 all suggest development in the direction of mesenchymal transition. These hybrid cells have tumour-initiating potential and have been shown to have poor prognosis and resistance to therapy targeted for malignancies of breast epithelial origin. Our work emphasizes the need for new approaches to the diagnosis and therapy of this highly fatal breast cancer subtype.

Review of the scientific literature on the use of automated breast ultrasound for screening / Az automatizált emloultrahang-daganatszurés szakirodalmi áttekintése

Several technological developments have been carried out recently to improve the effectiveness of breast cancer screening. Most of them have emerged as a complementary method to mammography. Automated breast ultrasound is one of these technologies. The objective of this study is to provide an overview on guidelines and recommenda-tions related to the application of automated breast ultrasound as a screening modality and to summarize the scien-tific literature. Targeted literature review was performed to collect information. We searched in publicly available databases for guidelines and recommendations as well as scientific publications on screening and early detection. We found substantial amount of information about automated breast ultrasound mainly for patients with dense breast; however, breast cancer screening guidelines have not yet incorporated this technology. 9 clinical studies were in-cluded in the review, most of them were single-arm studies with relatively short follow-up time. Most of them were performed in the USA. Results were presented mainly for short-term outcomes of breast cancer screening: sensitiv-ity, specificity, tumor detection rate and recall rate. The opportunity for retrospective evaluation of the images and the reproducibility are considered the most important advantages. Evidence suggest that the cancer detection rate can be improved compared to mammography alone in women with dense breast. The main disadvantages of this technology are the high recall and false positive rates. Further scientific evidence is required to reduce uncertainty related to the use of automated breast ultrasound for breast cancer screening.

New trends in the surgical treatment of axilla in breast cancer / Új trendek az axilla sebészi kezelésében emlorák esetén

Oncosurgical treatment of breast tumors involves the removal of metastatic axillary lymph nodes. In the last 30 years, the diagnosis and treatment of axillary lymph nodes have also undergone significant changes. The introduction of sentinel lymph node biopsy in 1993 made axillary block dissection with high morbidity safely omitted in a significant proportion of patients, and similarly, the staging of breast tumors and thus oncology and complex treatment became significantly more accurate. Shortly after the introduction of sentinel lymph node biopsy, intraoperative examination of sentinel lymph nodes (e.g. imprint cytology) also appeared, which significantly reduced the number of surgeries performed in the two sessions, thereby significantly reducing patient burden and surgical costs. The results of our study indicate that axillary block dissection is required in the treatment of axilla in an ever-decreasing group of patients and this proportion will decrease further in the future, with the increasing use of alternative axillary radiotherapy. The imprint cytological examination of sentinel lymph nodes taking into account current guidelines, no longer provides demonstrable benefits and its routine use is not justified. According to the latest international recommendations, intraoperative examination of the sentinel lymph node may be indicated in connection with mastectomy (when postoperative radiotherapy is not planned) and after neoadjuvant treatment. Our results suggest that the detection of suspected lymph nodes during preoperative axillary ultrasound may predict the stage of the disease. Based on our research results confirm that in patients receiving neoadjuvant therapy, in addition to the preoperative size of the tumour (≤20 mm, P = 0.002), the preoperative size of the lymph node (≤15 mm, P = 0.04) may also be used to predict that the stage of the disease is N0-1.

Use of Diagnostic Imaging Modalities in Modern Screening, Diagnostics and Management of Breast Tumours 1st Central-Eastern European Professional Consensus Statement on Breast Cancer.

Breast radiologists and nuclear medicine specialists updated their previous recommendation/guidance at the 4th Hungarian Breast Cancer Consensus Conference in Kecskemét. A recommendation is hereby made that breast tumours should be screened, diagnosed and treated according to these guidelines. These professional guidelines include the latest technical developments and research findings, including the role of imaging methods in therapy and follow-up. It includes details on domestic development proposals and also addresses related areas (forensic medicine, media, regulations, reimbursement). The entire material has been agreed with the related medical disciplines.

[Radiology/Nuclear Medicine Group. Use of imaging methods in the current screening, diagnostics and treatment of breast cancer - Professional guidelines. 4th Breast Cancer Consensus Conference]. / A képalkotó vizsgálómódszerek alkalmazása az emlodaganatok korszeru szurésében, diagnosztikájában és ellátásában ­ Szakmai útmutató a IV. Emlorák Konszenzus Konferencia alapján.

Breast radiologists and nuclear medicine specialists have updated their previous recommendation/guidance at the 4th Hungarian Breast Cancer Consensus Conference. They suggest to adopt this actual protocol for the screening, diagnostics and treatment of breast tumors from now on. This recommendation includes the description of the newest technologies, the recent results of scientific research, as well as the role of imaging methods in the therapeutic processes and the followup. Suggestions for improvement of the current Hungarian practice and other related issues as forensic medicine, media connections, regulations, and reimbursement are also detailed. The guidance has been in agreement with the related medical disciplines.

Apocrine Encapsulated Papillary Carcinoma of the Breast: The First Reported Case with an Infiltrative Component.

Apocrine encapsulated papillary carcinoma (EPC) of the breast is a rare neoplasm, and only 10 cases have been reported in the literature to date. Although EPC by definition lacks a peripheral myoepithelial layer, all previously published apocrine EPC cases were clinically indolent and lacked a conventional invasive component. Herein, we report the 11th case of apocrine EPC, which had a conventional invasive carcinoma component and provides evidence of the malignant potential of this entity. We postulate that apocrine EPC is most likely a morphological variant of conventional EPC, with the same unpredictable malignant potential as non-apocrine cases.

Position paper on screening for breast cancer by the European Society of Breast Imaging (EUSOBI) and 30 national breast radiology bodies from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Israel, Lithuania, Moldova, The Netherlands, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, Switzerland and Turkey.

EUSOBI and 30 national breast radiology bodies support mammography for population-based screening, demonstrated to reduce breast cancer (BC) mortality and treatment impact. According to the International Agency for Research on Cancer, the reduction in mortality is 40 % for women aged 50-69 years taking up the invitation while the probability of false-positive needle biopsy is <1 % per round and overdiagnosis is only 1-10 % for a 20-year screening. Mortality reduction was also observed for the age groups 40-49 years and 70-74 years, although with "limited evidence". Thus, we firstly recommend biennial screening mammography for average-risk women aged 50-69 years; extension up to 73 or 75 years, biennially, is a second priority, from 40-45 to 49 years, annually, a third priority. Screening with thermography or other optical tools as alternatives to mammography is discouraged. Preference should be given to population screening programmes on a territorial basis, with double reading. Adoption of digital mammography (not film-screen or phosphor-plate computer radiography) is a priority, which also improves sensitivity in dense breasts. Radiologists qualified as screening readers should be involved in programmes. Digital breast tomosynthesis is also set to become "routine mammography" in the screening setting in the next future. Dedicated pathways for high-risk women offering breast MRI according to national or international guidelines and recommendations are encouraged. KEY POINTS: • EUSOBI and 30 national breast radiology bodies support screening mammography. • A first priority is double-reading biennial mammography for women aged 50-69 years. • Extension to 73-75 and from 40-45 to 49 years is also encouraged. • Digital mammography (not film-screen or computer radiography) should be used. • DBT is set to become "routine mammography" in the screening setting in the next future.

[Use of imaging methods in the current screening, diagnostics and treatment of breast cancer - Professional guidelines. 3rd Breast Cancer Consensus Meeting]. / A képalkotó vizsgálómódszerek alkalmazása az emlõdaganatok korszerû szûrésében, diagnosztikájában és ellátásában - Szakmai útmutató a III. Emlõrák Konszenzus Konferencia alapján.

Breast radiologists and nuclear medical specialists have refreshed their previous statement text during the 3rd Hungarian Breast Cancer Consensus Meeting. They suggest taking into consideration this actual protocol for the screening, diagnostics and treatment of breast tumors, from now on. This recommendation includes the description of the newest technologies, the recent results of scientific research, as well as the role of imaging methods in the therapeutic processes and the follow-up. Suggestions for improvement of the Hungarian current practice and other related issues as forensic medicine, media connections, regulations, and reimbursement are also detailed. The statement text has been cross-checked with the related medical disciplines.

[Latest international guidelines for screening, prevention and treatment of familial breast cancer - implications for the relevant practice in Hungary]. / Az örökletes emlorák szurésének, megelozésének és kezelésének új nemzetközi irányvonalai - hazai vonatkozásokkal.

INTRODUCTION: Screening, prevention and treatment of familial breast cancer require a multidisciplinary approach. New guidelines were published in the United Kingdom for the management of familial breast cancer. AIM: The authors summarise these new guidelines and analyse the relevant practice in Hungary. METHOD: Relevant guidelines of the National Institute for Health and Care Excellence and Familial Breast Cancer Report (NHS Scotland) are described. RESULTS: New guidelines will increase the number of genetic tests as well as genetic counselling. An increase in the number of breast magnetic resonance imaging is expected, too. Chemoprevention can be offered for individuals with medium risk and above. Promising trials are underway with platinum based chemotherapy and polyADP-ribose polimerase inhibitors for the systemic treatment of familial breast cancer. The increase in the number of genetic tests, counselling, and breast magnetic resonance imaging may have a significant impact on health care budget. CONCLUSIONS: These guidelines will change some aspects of the current management of familial breast cancer. Orv. Hetil., 2016, 157(28), 1117-1125.

One-Year Neoadjuvant Endocrine Therapy in Breast Cancer.

The evaluation of the effects of 1-year endocrine therapy (NET) was aimed at. A retrospective analysis of 42 cases with 46 stage II-III invasive, hormone receptor-positive, HER2-negative breast cancers was performed. One-year NET was planned with letrozole (n = 33, postmenopausal group), or with goserelin plus letrozole (n = 7) or with goserelin plus tamoxifen (n = 2) (premenopausal group). Surgery was performed in accordance with the initial stage and the response to therapy. With regard to the tumor remaining in the surgical specimen, risk groups were constructed: Group 1: stage 0, pathological complete regression (pCR); Group 2: stages IA-IIA; Group 3: stages ≥ IIB + cases with clinical progression. Due to local progression, NET was replaced by neoadjuvant chemotherapy in three patients (four tumors). In two postmenopausal patients, letrozole was replaced by tamoxifen because of the insufficient treatment effect. In 19/42 cases, breast-conserving surgery was performed. Within Group 1, there was no cancer in four cases, while only DCIS remained in 2 (pCR: 13 %); Groups 2 and 3 comprised 25 and 15 cases, respectively. The likeliness of a good response (Groups 1 and 2 vs. Group 3) to NET was increased by 7 % for every 1 % increase of the expression of ER (OR = 1.070; 95 % CI: 1.007-1.138, p = 0.029). Progression-free survival differed according to treatment response (p = 0.001). The post-therapy Ki67 value of ≤ 15 % had only a marginal effect on survival. No other associations were detected between the tumor characteristics and the therapeutic response or survival. Long-duration NET is effective and safe in cases of hormone-sensitive breast cancer.

Radioguided occult lesion localisation versus wire-guided lumpectomy in the treatment of non-palpable breast lesions.

The purpose of this study was to compare the two methods-guidewire localisation and the radioguided occult lesion localisation-used in the localisation and surgical removal of non-palpable breast tumours. This retrospective study enrolled patients diagnosed with nonpalpable malignant breast tumours. In this study either guidewire localisation (GWL, n = 69) or radioguided occult lesion localisation (ROLL, n = 321) was used for the detection and removal of the tumours. The two methods were compared with regards to preoperative localisation time, operating time, removed specimen volume, the pathological tumour size, the presence of positive surgical margins and postoperative complications. Furthermore, we have also investigated other factors that could have an impact on the frequency of positive resection margins. The localisation time was significantly shorter in the ROLL group, both with ultrasound guidance (5.7 ± 1.44 min vs. 21.6 ± 2.37 min, p = 0.05) and with radiographic guidance (21.8 ± 3.1 min vs. 41.6 ± 3.75 min, p = 0.021) as well. No significant difference was observed between the two methods in terms of operating time, removed specimen volume and pathological tumour size, or the presence of positive resection margins, or the occurrence of postoperative wound infections. The size of the tumour (ROLL, GWL grps), the presence of a multifocal tumour (ROLL grp), the presence of an extensive in situ breast carcinoma around the invasive cancer (ROLL, GWL grps) and the volume of the removed breast specimen (GWL grp) significantly increased the frequency of positive resection margins. We recommend the use of the ROLL method for the removal of nonpalpable breast tumours as it has a much shorter localisation time, and it is a simpler surgical technique as well.

Tumor topoisomerase II alpha status and response to anthracycline-based neoadjuvant chemotherapy in breast cancer.

OBJECTIVES: Individualized chemotherapy for breast cancer improves the outcome. Anthracyclines target the enzyme topoisomerase IIα (TOP2A). We set out to perform a retrospective study of the presence of gene abnormalities and the expression of TOP2A in a cohort of breast cancer patients treated with neoadjuvant anthracycline-based chemotherapy. METHODS: Forty-three patients with 45 breast cancers were treated with neoadjuvant docetaxel-epirubicin with/without capecitabine chemotherapy. The TOP2A status of the cancers, determined retrospectively by fluorescent in situ hybridization and immunohistochemistry, was analyzed in relation to the standard clinical and pathological data. RESULTS: Clinically and pathologically complete remission (pCR) was achieved in 15 (33.3%) and 9 (20%) cases, respectively. The TOP2A gene was amplified in 2 human epidermal growth factor receptor 2 (HER2)-positive cancers (8%), and 32 (84.2%) overall exhibited TOP2A expression in >15% of the cells. The expression of TOP2A exhibited a strong correlation with the expression of Ki67 (R = 0.743, p < 0.001), and was negatively correlated with estrogen receptors (ER; R = 0.404, p = 0.012) and progesterone receptors (R = 0.430, p = 0.007). The expression of TOP2A was not related to the amplification of the TOP2A gene or the HER2 status of the tumor. The proportions of Ki67- and TOP2A-positive tumor cells were significantly reduced after chemotherapy (56.1 ± 23.6 vs. 19.0 ± 27.7%, p = 0.004, and 41.0 ± 27.9 vs. 12.7 ± 24.8%, p < 0.001, respectively). The development of pCR was related to a high grade (p = 0.054), ER negativity (p = 0.027) and high TOP2A expression (p = 0.037). The expression of TOP2A was an independent predictor of pCR (OR = 1.460, for every 10% increase, 95% CI: 1.016-2.096, p = 0.041). After a median follow-up time of 31.0 months, neither relapse-free survival nor overall survival was related to the tumor response. CONCLUSIONS: TOP2A expression is a marker of the tumor's proliferation rate and sensitivity to anthracycline-based chemotherapy, and does not depend on the amplification of its gene.

Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer.

OBJECTIVES: To perform a protocol-specified analysis of the dose-dense adriamycin-paclitaxel-cyclophosphamide (ddATC) study. METHODS: Survival and late toxicity were analyzed in 55 patients enrolled to receive 4 x adriamycin 60 mg/m(2), 4 x paclitaxel 200 mg/m(2), 4 x cyclophosphamide 800 mg/m(2), every 2 weeks, with cardioxane and filgrastim support. Kaplan-Meier curves were used to analyze relapse-free survival (RFS), distant disease-free survival (DDFS), and overall survival (OS). Survival analyses were performed according to the presence of casting-type calcifications on the mammogram. RESULTS: After a median follow-up time of 78.5 (64.3-100.0) months, 29 (52.7%) patients were free of relapse (local, regional, distant or contralateral breast cancer), 34 (61.8%) patients were free of distant metastases, and 36 patients (65.5%) survived. The median times of RFS, DDFS and OS were not yet reached at 100.0 months. The median RFS, DDFS and OS times among breast cancer patients with tumors not associated with casting-type calcifications were >100.0 months, the corresponding parameters among patients with tumors accompanied by casting calcifications were 11.5 (p < 0.001), 11.5 (p < 0.001) and 29.6 months (p = 0.035), respectively. None of the patients developed myelodysplastic syndrome or leukemia. No cardiac failure occurred during the follow-up period. CONCLUSIONS: Our results indicate that adjuvant sequential ddATC is an efficient and less toxic chemotherapy regimen in high-risk breast cancer. The presence of casting-type calcifications on the mammogram points to a special biologic nature with very poor prognosis.

Importance of sentinel lymph node biopsy in surgical therapy of in situ breast cancer.

The aim of this retrospective study was to determine the rate of sentinel lymph node (SLN) positivity in patients with a final diagnosis of ductal in situ cancer (DCIS) of the breast. Between October 2002 and January 2007, 57 patients with DCIS underwent wide excision after radio-guided lesion localization; 53 of them (53/57, 93%) had participated in simultaneous SLN mapping. SLNs were analysed by 250-micron step-sectioning with haematoxylin and eosin staining and immunohistochemical evaluation. The histologic investigation verified pure breast DCIS in 44 cases (44/57, 77.2%), DCIS with microinvasion in eight cases (8/57, 14%) and lobular in situ breast cancer in five cases (5/57, 8.8%). SLNs were identified in 49 cases (49/53, 92.5%) and removed in 48 cases (48/53, 90.6%), i.e. an average of 1.6 SLNs per patient. In four patients (4/53, 7.6%), the SLN biopsy was unsuccessful because of the failure of the radiocolloid substance to migrate. In these cases, axillary sampling was performed. In one case (1/53, 1.9%), only a parasternal SLN was detected; this was not removed. Histologic analysis of the SLNs and the axillary lymph nodes with haematoxylin and eosin or cytokeratin immunohistochemistry did not prove the presence of metastases. The international data and our present results suggest that routine SLN biopsy is not to be recommended in pure DCIS cases. If the final histology verifies an invasive or microinvasive tumour, or if mastectomy is to be performed, SLN mapping is suggested.

Tumor characteristics in screen-detected and symptomatic breast cancers.

The natural course of early breast cancer has changed as a result of the introduction of mammographic screening. The present aim was a prospective analysis of screen-detected and symptomatic operable breast cancers in the era of mammographic service screening. The mode of detection (screen-detected, symptomatic or interval cancer), the type of mammographic image and other characteristics (the invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status and the presence of lymphovascular invasion) of 569 invasive breast cancers were studied. Screen-detected cancers were significantly more frequently of grade I, < 10 mm of size and node-negative (p < 0.001, respectively). Symptomatic/interval cancers were significantly more frequently of grade 3, >20 mm of size (p < 0.001), and exhibited lymphovascular invasion (p = 0.001). Screening-detection of the tumor favored breast-conserving surgery, sentinel lymph node biopsy and the avoidance of chemotherapy (p < 0.001). Cancers associated with casting-type calcifications on the mammogram were typically of ductal type (p = 0.043), of grade 2-3, estrogen receptor and progesterone receptor-negative and HER2-positive (p < 0.001). Interval cancers occurred significantly more often at a younger age and remained mammographically occult as compared with other cancers. Mammographic screen-detected cancers demonstrate more favorable prognostic features, and need less extensive treatment than symptomatic or interval cancers. The mammographic appearance of the tumor reflects its biological behavior, and this should be considered in the management optimization.

Casting-type calcifications on the mammogram suggest a higher probability of early relapse and death among high-risk breast cancer patients.

INTRODUCTION: A retrospective analysis of the relation between the presence of casting-type calcifications on the mammogram and the prognosis of breast cancer was performed. MATERIALS AND METHODS: The mammographic tumor features and other characteristics (invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status, presence of lymphovascular invasion) of 55 high-risk breast cancers were studied. RESULTS: After a median follow-up time of 29.1 months, the median relapse-free survival and overall survival times among breast cancer patients with tumors associated with casting calcifications were 26.6 and 29.6 months, respectively. The corresponding parameters among patients with tumors not accompanied by casting calcifications were 54.4 and > 58.5 months, respectively. Significant associations were found between the presence of casting calcifications and the risks of relapse (HR = 3.048, 95% CI: 1.116-8.323, p = 0.030) or death (HR = 3.504, 95% CI: 1.074-11.427, p = 0.038). Positive associations were found between casting calcifications and ER/PR negativity (p = 0.015 and p = 0.003, respectively) and HER2 overexpression (p = 0.019). DISCUSSION: Our findings support the theory that breast tumors associated with casting-type calcifications at mammography comprise a disease entity which exhibits significantly more aggressive behavior and a poorer outcome than do cancers with other mammographic tumor features.

[Importance of sentinel lymph node biopsy in surgical therapy of in situ breast cancer]. / Az orszem (sentinel) nyirokcsomó jelentôsége in situ emlocarcinoma sebészi kezelésében.

INTRODUCTION AND AIMS: The aim of this retrospective study was to determine the rate of sentinel lymph node (SLN) positivity in patients with a final diagnosis of ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Between October 2002 and January 2006, 47 patients with DCIS underwent wide excision after radio-guided lesion localisation; 44 of them (93.6%) had simultaneous SLN mapping. SLNs were analysed by 250 micron step-sectioning by H&E and immunohistochemical evaluation. RESULTS: The histological investigation verified pure breast DCIS in 36 cases (76.6%), DCIS with microinvasion in 7 cases (14.9%) and lobular in situ breast cancer in 4 cases (8.5%). SLNs were identified in 40 cases (91%) and removed in 39 cases: an average of 1.5 SLNs per patient. In 4 patients (9%) SLN biopsy was unsuccessful because of the lack of migration of radiocolloid substance. In these cases, axillary sampling was performed. In 1 case (2.3%), only a parasternal SLN was detected; this was not removed. Histological analysis of SLNs and axillary lymph nodes with haematoxylin and eosin or cytokeratin immunohistochemistry did not prove metastases. DISCUSSION AND CONCLUSION: On the basis of international data and our present results, routine SLN biopsy is not recommended in pure DCIS cases. If the final histology verifies an invasive or microinvasive tumour, or if mastectomy is to be performed, SLN mapping is suggested.