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This bibliography mostly straddles 2023–2024, covering the period since the summer 2023 publication of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by previously published items earlier not included. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2014, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (published by Purdue University) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography

Leaf chlorophyll content is a key indicator of plant physiological status in viticulture; therefore, regular evaluation to obtain data for nutrient supply and canopy management is of vital importance. The measurement of pigmentation is most frequently carried out with hand-held instruments, destructive off-site spectrophotometry, or remote sensing. Moreover, smartphone-based applications also ensure a promising way to collect colorimetric information that could correlate with pigmentation. In this study, four grapevine genotypes were investigated using smartphone-based RGB (Red, Green, Blue) and CIE-L*a*b* colorimetry and a portable chlorophyll meter. The objective of this study was to evaluate the correlation between leaf chlorophyll concentration and RGB- or CIE-L*a*b*-based color indices. A further aim was to find an appropriate model for discriminating between the genotypes by leaf coloration. For these purposes, fully developed leaves of ‘Chardonnay’, ‘Sauvignon blanc’, and ‘Pinot noir’ clones 666 and 777 were investigated with the Color Grab smartphone application to obtain RGB and CIE-L*a*b* values. Using these color values, chroma, hue, and a further 31 color indices were calculated. Chlorophyll concentrations were determined using an Apogee MC100 device, and the values were correlated with color values and color indices. The results showed that the chlorophyll concentration and color indices significantly differed between the genotypes. According to the results, certain color indices show a different direction in their relationship with leaf pigmentation for different grapevine genotypes. The same index showed a positive correlation for the leaf chlorophyll concentration for one variety and a negative correlation for another, which raises the possibility that the relationship is genotype-specific and not uniform within species. In light of this result, further study of the species specificity of the commonly used vegetation indices is warranted. Support Vector Machine (SVM) analysis of the samples based on color properties showed a 71.63% classification accuracy, proving that coloration is an important ampelographic feature for the identification and assessment of true-to-typeness.

Abstract Most invasive lobular breast carcinomas (ILBCs) are luminal‐type carcinomas with an HER2‐negative phenotype (ERBB2 or HER2 un‐amplified) and CDH1 mutations. Rare variants include ERBB2‐amplified subtypes associated with an unfavorable prognosis and less response to anti‐HER2 targeted therapies. We analyzed the clinicopathological and molecular features of ERBB2‐amplified ILBC and compared these characteristics with ERBB2‐unamplified ILBC. A total of 253 patients with ILBC were analyzed. Paraffin‐embedded formalin‐fixed tumor samples from 250 of these patients were added to a tissue microarray. Protein expression of prognostic, stem cell and breast‐specific markers was tested by immunohistochemistry (IHC). Hybrid capture‐based comprehensive genomic profiling (CGP) was performed for 10 ILBCs that were either fluorescent in situ hybridization (FISH) or IHC positive for HER2 amplification/overexpression and 10 ILBCs that were either FISH or IHC negative. Results were compared with a CGP database of 44,293 invasive breast carcinomas. The CGP definition of ERBB2 amplification was five copies or greater. A total of 17 of 255 ILBC (5%) were ERBB2 amplified. ERBB2‐amplified ILBC had higher tumor stage (p

Today’s exponential advancement of information and communication technologies is reconfiguring participatory urban development practices. The use of digital technology implies new forms of decentralised governance, collaborative knowledge production, and social activism. The digital transformation has the potential to overcome shortcomings in citizen participation, make participatory processes more deliberative, and enable collaborative approaches for making cities. While digital tools such as digital mapping, e-participation platforms, location-based games, and social media offer new opportunities for the various actors and may act as a catalyst for renegotiating urban space and collective goods, digitalisation can also perpetuate or even attenuate existing inequalities and exclusion. This editorial introduces the thematic issue “Citizen Participation, Digital Agency, and Urban Development” which focuses on the trajectories and (dis)continuities of citizen participation through digitalisation and elaborates this with examples from Europe and Asia on how the digital transformation impacts, challenges, or reproduces hegemonic power relations in urban development.

Abstract Background The doctor-patient relationship has changed a lot in the 21st century and the varying expectations of the patients play an important role in future professional medical care. The knowledge of patients’ needs is crucial in determining the learning outcomes in medical education. The objective of this study was to examine the expectations of the patients regarding professional and soft skills (e.g. communicational skills, empathy) of doctors and to get a deeper view. Methods Face-to face data collection through self-reported questionnaire in accredited health care institutions (GPs, hospitals, outpatient care) in Hungary was carried out in 2019. Descriptive statistics, independent sample t-tests, k-means cluster and gap matrices were performed to analyze the data. Results In total 1115 patients (male-female: 50–50%, age groups: between 18 and 30: 20%, between 31 and 60: 40% above 60: 40%) participated in the survey. They rated sixteen learning outcomes along with two dimensions: importance and satisfaction. Except for one learning outcome, patients rated the outcomes more important than they were satisfied with them (negative gap). Positive gap was registered only in the case of respecting individual specialty during patient care. Conclusions The results suggest the importance of learning outcomes in relation to the rate of satisfaction from the patients’ perspectives. In addition, the results support that patients’ need are not met in medical care. Patients’ ratings also make an emphasis on the fact that besides professional knowledge other learning outcomes are also important in health care which should have been emphasized as a basis in medical education.

IntroductionAn organized mental lexicon determines new information acquisition by orienting attention during language processing. Adult-like lexical-semantic knowledge organization has already been demonstrated in 24-month-olds. However, the outcomes of earlier studies have been contradictory in terms of the organizational capacities of 18-month-olds, thus our aim was to examine lexical-semantic organization in this younger age group. In prematurely born infants, audiovisual integration deficits have been found alongside disruptions in language perception. By including late preterm infants with corrected ages in our study, we aimed to test whether maturational differences influence lexical-semantic organization when vocabulary is growing rapidly.MethodsWe tested 47 late preterm and full-term 18- and 24-month-old infants by means of an infant-adapted target-absent task using a slightly modified version of the original visual world paradigm for eye tracker.ResultsWe found a longer fixation duration for the lexical and semantic distractors compared to the neutral pictures. Neither language proficiency nor age affected the looking time results. We found a dissociation by age between taxonomic and associative semantic relations. Maturational differences were detectable in the initial processing of taxonomic relations, as processing in the preterm group was slightly delayed and qualitatively different in the first half of the looking time. The size and composition of the expressive vocabulary differed only by age.DiscussionIn general, our study demonstrated a stable lexical-semantic organization between 18 and 24 months of age, regardless of maturational differences.

This bibliography mostly straddles 2022–2023, covering the period since the summer 2022 publication of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by previously published items earlier not included. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2014, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (published by Purdue University) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography

Abstract Breast cancer is a biologically diverse disease with treatment modalities selected based on tumor stage and tumor biology. Distinct intrinsic subtypes and surrogate biomarker profiles play a major role for therapeutic decisions. Response rates to systemic and local treatments as well as the interaction with epidemiological risk factors have been validated in clinical trials and translational studies. This retrospective study addresses the question how biomarker profiles and treatment modalities in the neoadjuvant chemotherapy setting have changed during the past 15 years and what prognostic impact these changes implicate. 342 female breast cancer stage I-IV patients receiving neoadjuvant chemotherapy between 2003 and 2017 were analyzed. Overall survival (OS) was correlated with preoperative clinical stage, postoperative pathological stage, treatment modalities and tumor biology before and after chemotherapy. Two subgroups were separated using an arbitrary cut-off year at 2009/2010, due to 2010 when platinum containing regimens were first administered. Median follow-up was 54 months. 57 (17%) patients died; recurrences occurred in 103 of 342 (30%) patients. Nodal stage and intrinsic subtypes (pre- and postoperative) significantly correlated with OS (p 30%), clinical metastatic stage and pathological tumor stage had prognostic impact on OS (p

A tervgazdasággal foglalkozó magyarországi szakirodalom fókuszában mind a rendszerváltás előtt, mind az azóta eltelt időszakban elsősorban az ipari vállalatok vizsgálata állt. Az agrárium szereplőivel alig foglalkoztak annak ellenére, hogy éppen ezen a területen került sor először a piaci mechanizmusok részleges korrekciójára. A jelen tanulmány egyrészt arra keresi a választ, hogy miért éppen az agrárgazdaságban indult meg a piac rehabilitálása, s meddig jutott el ez a folyamat. Másrészt pedig azt vizsgálja, hogy a piac működéséről felhalmozódott agrárgazdasági tapasztalatok milyen hatást gyakoroltak az 1960-as évek gazdasági reformmunkálataira/ új gazdasági mechanizmus előkészítő munkálatai során. Kísérlet a piac kiiktatására a Rákosi-korszakban Az 1945-49 közötti időszakkal foglalkozó kutatók között a mai napig intenzív vita folyik arról, hogy mikortól is lehet egyértelműen szovjet típusú berendezkedésről beszélni Magyarországon. Annak megítélésében már konszenzus alakult ki, hogy a fordulat nem egyidőben következett be a politikai és a gazdasági életben. Ez utóbbi területen az 1948. március 25-én kiadott, a 100-nál több munkást foglalkoztató üzemek államosításáról szóló minisztertanácsi rendelet hozott döntő fordulatot. (Pető 1998: 95-110.) Az államosítások révén lehetőség nyílt arra, hogy a piaci viszonyok kiiktatásával központilag irányított termelési és elosztási rendszerre térjenek át, ahol az állam tulajdonába került vállalatoknak kötelező tervutasításokkal előírták, hogy miből mennyit termeljenek. A szocializmus nagy előnyét abban jelölte meg a hivatalos ideológia, hogy a termelőeszközök magántulajdonának és a piacnak a felszámolásával lehetővé válik a népgazdasági méretekben való szervezettség, s ezáltal kiiktatódnak olyan problémák, mint a túltermelési válság, a munkanélküliség, stb. (Kornai 1993: 140-159.) A szovjet típusú tervgazdaság Magyarországon az ipar és a nagykereskedelem területén már az első ötéves terv 1950. évi elindulása előtt életbe lépett. Más volt a helyzet a mezőgazdaságban, ahol az 1940-es évek végén a magántulajdonra épülő parasztgazdaságok voltak túlnyomó többségben. (Szakács 1998: 311-329.) Közgazdasági környezetük azonban a korlátozott piacgazdaság jegyeit mutatta. A háború utáni rendkívüli helyzetben ugyanis a koalíciós pártok – átmeneti időre tervezve – fenntartottak egy sor hadigazdasági intézkedést, közülük legfontosabbnak a mezőgazdasági termények és állatok kötelező beszolgáltatása bizonyult. A háború alatt bevezetett ún. Jurcsek-féle beszolgáltatási rendszer fenntartását 1945-46 folyamán azzal indokolták a kormányzati erők, hogy az agrárszférát ért háborús károk és a lecsökkent termelés közepette a közélelmezés, valamint a fegyverszüneti egyezményben vállalt jóvátételi és seregellátási kötelezettségek teljesítése csak így biztosítható. (Erdmann 1993: 7-20.)

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2020-2021, covering the period since the publication in Fall of 2020 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved only recently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography

The content of 2,3-butanediol ((R,R) and meso isomers) and 1,2-propanediol in grape berries and “liquid samples” (all non-berry extracts) from the Tokaj wine region of Hungary was investigated. Our aim was to find out how the activity of Botrytis cinerea influences the concentrations of these compounds compared with healthy grapes. Based on the measured concentrations, we can make a distinction between healthy berries and noble, rotted, so-called aszú berries. We also investigated if there is a difference between finished aszú wines and liquids intended for aszú production. We wanted to investigate the amount and distribution of the stereoisomers of 2,3-butanediol and their proportions. The results of the HS-SPME-GC-FID analysis of the samples showed significant differences in the 2,3-butanediol content between healthy and botrytised, aszú berries and between liquid samples for aszú production and aszú wines. In the berry samples, meso-2,3-butanediol could not be detected, whereas in the liquid samples, we found good amounts of this isomer. This may be due to the fact that the appearance of the meso form of 2,3-butanediol is a consequence of alcoholic fermentation. Significant differences were found between wines from healthy grapes and wines from botrytised grapes in terms of the levo-2,3-butanediol content, so that from an analytical point of view, a difference can be made between wines from healthy and botrytised grapes. No significant differences were found between berry and liquid samples in terms of 1,2-propanediol concentrations during our tests.

Abstract Similar to the influenza A pandemic in 1918/1919, the new Coronavirus disease 2019 (COVID‐19) has spread globally. The causes of death in COVID‐19 are frequently compared to a seasonal influenza outbreak. Complete COVID‐19 autopsy studies were almost non‐existent in the first months of the outbreak and are still rare with respect to the number of deaths. It has been recently reported that capillary microthrombi are significantly more prevalent in patients with COVID‐19 than in patients with influenza A. To date, the contribution of macrothrombi, i.e. visible thrombi in pulmonary arteries, to the death of patients with influenza A in comparison to COVID‐19 remains unaddressed. Here, we report autopsy findings in 411 patients who died from the ‘Spanish’ influenza A pandemic between May 1918 and April 1919 at the University Hospital Zurich, Switzerland. We compare these results with influenza A autopsies from 2009 to 2020, other influenza A autopsy series and all COVID‐19 autopsies published to date. No descriptions of any macroscopic thromboembolic events were mentioned in influenza A autopsy reports. In 75 published COVID‐19 autopsies, pulmonary artery thrombosis/embolism was reported in 36%. The direct comparison of macroscopic autopsy findings suggests a significantly greater degree of grossly visible pulmonary macrothrombi in patients with COVID‐19 in comparison to influenza A autopsies even though most patients received empiric thromboprophylaxis. This is consistent with the concept of a SARS‐related de novo coagulopathy with generalised in situ clot formation, which could explain the high incidence of pulmonary thrombosis/embolism with or without underlying deep vein thrombosis and in the absence of a history of venous thromboembolic events.

Abstract Background A dual blockade against the novel immune checkpoint inhibitor lymphocyte activation gene-3 (LAG-3) and programmed cell death protein-1 (PD-1) is currently considered in advanced breast cancer. Nevertheless, PD-1 or LAG-3 expression within distant metastatic breast cancer tissue remains understudied. Methods To address this knowledge gap, we investigated the PD-1 and LAG-3 expression in combination with the CD8-based immune phenotype in intrapatient matched primary tumor distant metastases, representing 95 breast cancer patients with metastases occurring at four different anatomical locations. The immune phenotype was categorized into 2 categories: inflamed corresponding to the clinical category “hot” and exhausted or desert consistent with clinically “cold” tumors. Results Metastases of “cold” primary tumors always remained “cold” at their matched metastatic site. Expression of PD-1/LAG-3 was associated with a “hot” immune phenotype in both the primary tumors and metastases. We could not observe any association between the immune phenotype and the breast cancer molecular subtype. Brain and soft tissue metastases were more commonly inflamed with signs of exhaustion than other anatomical sites of metastases. Taken together, (i) the immune phenotype varied between sites of distant metastases, and (ii) PD-1+/LAG-3+ was strongly associated with a “hot” immune phenotype and (iii) was most prevalent in brain and soft tissue metastases among distant metastases. Conclusions Our data strongly support an integrated analysis of the immune phenotype together with the PD-1/LAG-3 expression in distant metastases to identify patients with inflamed but exhausted tumors. This may eventually improve the stratification and likelihood for advanced breast cancer patients to profit from immunotherapy.

Abstract Background The quality of medical education is a key factor. The fact that mostly physicians teach tomorrow’s physicians without acquiring pedagogical skills before becoming a teacher is a cause of concern. In Hungary, where traditional teaching methods are common, and teachers have not had pedagogical courses in medical education there has not been any research dealing with the issue. On the one hand, we aimed with this cross-sectional study to examine the attitudes of teachers towards learning outcomes of medical students to get a view about the opinions about their importance and rate of delivery. On the other hand, we analyzed the pedagogical skills of teachers from the students’ and teachers’ perspective in Hungary. Methods Data collection through self-reported questionnaires in online form in all the four Hungarian higher education institutions offering medical education was carried out among teachers and students with active student legal status in 2017. We validated the questionnaires of the two respondents’ groups. We used gap matrices to represent the correspondences of the delivery and perceived importance of the learning outcomes. We calculated averages of the pedagogical skills and compared them with t-tests. Results The response rates are 11.18% in case of the students (1505) and 24.53% in case of the teachers (439). The results indicate the lack of concordance between the rates of the learning outcomes in terms of their importance and delivery - no positive gap can be observed -, and the need for pedagogical skills among teachers and students. The opinions of students compared to teachers’ are all statistically higher according to the averages. Conclusions The study results underline the necessity of a transition and paradigm shift in medical education from delivering solely professional knowledge towards pedagogically prepared practice and patient oriented teaching methods as well as acquiring pedagogical knowledge as part of the training of medical teachers in Hungary.

Using a combination of two-photon imaging and single-cell electrophysiology, the authors discover that associative learning induces the emergence of a unique subset of neurons in the auditory cortex, exhibiting high-rate bursting responses to the learned complex sounds but not to any of the constituents.

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2019-2020, covering the period since the publication in Fall of 2019 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved onlyrecently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography

BackgroundLong-term sequelae of coronavirus disease 2019 (COVID-19), including the interaction between persisting viral-RNA and specific tissue involvement, pose a challenging issue. In this study, we addressed the chronological correlation (after first clinical diagnosis and postmortem) between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and organ involvement.MethodsThe presence of postmortem SARS-CoV-2 RNA from 35 complete COVID-19 autopsies was correlated with the time interval between the first diagnosis of COVID-19 and death and with its relationship to morphologic findings.ResultsSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA can be evident up to 40 days after the first diagnosis and can persist to 94 hours after death. Postmortem SARS-CoV-2 RNA was mostly positive in lungs (70%) and trachea (69%), but all investigated organs were positive with variable frequency. Late-stage tissue damage was evident up to 65 days after initial diagnosis in several organs. Positivity for SARS-CoV-2 RNA in pulmonary swabs correlated with diffuse alveolar damage (p = 0.0009). No correlation between positive swabs and other morphologic findings was present. Cerebral (p = 0.0003) and systemic hemorrhages (p = 0.009), cardiac thrombi (p = 0.04), and ischemic events (p = 0.03) were more frequent in the first wave, whereas bacterial pneumonia (p = 0.03) was more prevalent in the second wave. No differences in biometric data, clinical comorbidities, and other autopsy findings were found.ConclusionsOur data provide evidence not only of long-term postmortem persisting SARS-CoV-2 RNA but also of tissue damage several weeks after the first diagnosis of SARS-CoV-2 infection. Additional conditions, such as concomitant bacterial pulmonary superinfection, lung aspergillosis, thromboembolic phenomena, and hemorrhages can further worsen tissue damage.

Breast cancer remains the most prevalent malignancy in women in many countries around the world, thus calling for better imaging technologies to improve screening and diagnosis. Grating interferometry (GI)-based phase contrast X-ray CT is a promising technique which could make the transition to clinical practice and improve breast cancer diagnosis by combining the high three-dimensional resolution of conventional CT with higher soft-tissue contrast. Unfortunately though, obtaining high-quality images is challenging. Grating fabrication defects and photon starvation lead to high noise amplitudes in the measured data. Moreover, the highly ill-conditioned differential nature of the GI-CT forward operator renders the inversion from corrupted data even more cumbersome. In this paper, we propose a novel regularized iterative reconstruction algorithm with an improved tomographic operator and a powerful data-driven regularizer to tackle this challenging inverse problem. Our algorithm combines the L-BFGS optimization scheme with a data-driven prior parameterized by a deep neural network. Importantly, we propose a novel regularization strategy to ensure that the trained network is non-expansive, which is critical for the convergence and stability analysis we provide. We empirically show that the proposed method achieves high quality images, both on simulated data as well as on real measurements.

Grape (Vitis spp.) is one of the most important horticultural crops, cultivated worldwide on more than 7.3 million hectares for various purposes such as winemaking, fresh fruit consumption, rootstock, and ornamental plants. Based on the inter- and intraspecific morphological variability, several descriptor lists, manuals and ampelographic studies are available for identification. Among the organs, leaves have the most traits, while the young shoot, bunch and berry are also important in the characterization of the genotypes. Vitis species and cultivars are described by leaf morphological characterization developed in many ways for the identification of genotypes, to clarify synonymies and distinct clones or evaluate the diversity of wild Vitis taxa. Morphometric—also known as ampelometric—evaluation has an extensive background in the literature. However, for some reasons, only a part of the literature is cited, despite its significant scientific value. In this paper, we summarize the efforts of metric characterization of the grapevine leaf with the introduction of the scientific objectives and reviewing the studies showing the innovations in phenotyping during the past 120 years.

There are hundreds of morphologic and morphometric traits available to classify and identify grapevine (Vitis vinifera L.) genotypes, while statistical evaluation of those has certain limitations, especially when we have no information about the traits that are discriminative to a certain sample set. High numbers of investigated characters could cause redundancy, while reducing those numbers may result in data loss. Grapevine is one of the most important horticultural crops, with many cultivars in production. The characterization of the genotypes is of undeniably high importance. In this study, we analyzed a dataset of scientific and historical importance with 125 morphological traits of 97 grapevine cultivars described by Németh in 1966. However, the traits are not independent in a set of a large number of categorical traits with too few cultivars. Therefore, the number of traits was first reduced using a simple and effective algorithm to eliminate traits with redundant information content using the asymmetric measure of association Goodman and Kruskal’s λ. We reduced the number of traits from 125 to 59 without any information loss. For the classification, we applied a random forest (RF) method. In this way, 93% of the cultivars were correctly classified using only four traits of the data set. To our knowledge, only a few studies applied a trait elimination algorithm similar to ours in ampelography that can be used for other biological data sets of similar structure. The classification results give a morphological explanation to several cultivars from the Carpathian Basin, a territory where all three Vitis vinifera L. geographical groups, occidentalis, orientalis and pontica, are represented. We found that the information-loss-avoiding data reduction method we applied in our study solved the redundancy-caused interdependencies and provided a suitable dataset for classifying grapevine genotypes. For example, this method may successfully be applied in digital image analysis-based traditional morphometric investigations in ampelography.

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2018-2019, covering the period since the publication in Fall of 2018 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved only recently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography.

In the present study, we investigated the extent to which specific sulphur dioxide-producing wine yeasts produce SO2 during alcoholic fermentation and whether the SO2 they produce is sufficient to prevent oxidation during wine storage. Fermentation was carried out at 12 °C and 20 °C. After inoculation with yeast, the evolution of free and total sulphurous acid concentrations, acetaldehyde concentrations (11.6–46.9 mg L−1) and total polyphenol concentrations (137.4–244.7 mg L−1), including leucoanthocyanin and catechin concentrations (leucoanthocyanidin: 8.5–75.1 mg L−1; catechin: 70.8–115.4 mg L−1), were investigated during the storage of fermented wines. The amount of free sulphur dioxide was measured between 5 and 10 mg L−1. Total sulphuric acid ranged from 6 to 22 mg L−1, taking into account the results of the three years studied. The aim of our tests was to observe whether the use of sulphur-producing yeasts during the ageing of fermented wines showed any benefit. The results of all three vintages tested showed that neither the 12 °C nor the 20 °C fermented batches showed any advantage in using sulphur dioxide-producing yeasts. Our results show that there is no clear evidence that the yeast produces sufficient sulphur dioxide during fermentation and that there is no clear demonstrable benefit from its use.

Summary: Background: Older adult patients (ie, those aged ≥60 years) undergoing surgery for hip fracture repair frequently experience loss of muscle mass and strength due to poor mobility and delayed functional recovery. No proven treatment is currently available to enhance recovery of physical function in this growing patient population. This study aimed to investigate whether bimagrumab, a human monoclonal antibody targeting activin type 2 receptors, can improve post-surgical recovery. Methods: This multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial was done at 50 clinical research centres in 18 countries. Participants aged 60 years or older with a body-mass index of 15–35 kg/m2 who had undergone internal fixation or hemiarthroplasty for a proximal femoral fracture (confirmed by radiography) in the previous 6 weeks were eligible. Patients with a history of a high-energy subtrochanteric fracture or any other lower limb fracture in the past 6 months, or any major surgery of the lower limbs in the past 3 months were excluded. Participants were randomly assigned (2:1:2:2) via interactive response technology to receive intravenous treatment with placebo, bimagrumab 70 mg, bimagrumab 210 mg, or bimagrumab 700 mg every 4 weeks for 24 weeks. Participants, investigators, site personnel, and study sponsor personnel in participating countries were masked to treatment assignment. The primary endpoint was the change from baseline in total lean body mass, measured by dual-energy x-ray absorptiometry, at week 24 in the full analysis set, which included all randomised participants who had received at least one dose of the assigned treatment. Key secondary endpoints included changes in habitual gait speed (measured in m/s) and short physical performance battery score between baseline and 24 weeks. Safety and tolerability were assessed by recording adverse events and vital signs on weeks 4, 8, 12, 24, and 48, and by laboratory assessments and electrocardiography at the screening visit and on days 1, 84, and 168. Safety was assessed in all randomised participants who had received at least one dose of study drug, analysed according to treatment received. This study was registered with ClinicalTrials.gov, NCT02152761. Findings: Between Sept 16, 2014, and Dec 15, 2017, 384 patients were screened, of whom 250 patients were enrolled and randomly assigned to the placebo group (n=72), the bimagrumab 70 mg group (n=34), the bimagrumab 210 mg group (n=69), or the bimagrumab 700 mg group (n=75). A total of 207 (83%) participants completed the 24-week treatment period. There was a significant absolute increase in lean body mass from baseline compared with placebo (0·2 kg [SD 2·0]) in the bimagrumab 210 mg group (1·9 kg [1·7]; p

Background: SARS-CoV-2 infection (COVID-19 disease) can induce systemic vascular involvement contributing to morbidity and mortality. SARS-CoV-2 targets epithelial and endothelial cells through the ACE2 receptor. The anatomical involvement of the coronary tree is not explored yet. Methods: Cardiac autopsy tissue of the entire coronary tree (main coronary arteries, epicardial arterioles/venules, epicardial capillaries) and epicardial nerves were analyzed in COVID-19 patients (n = 6). All anatomical regions were immunohistochemically tested for ACE2, TMPRSS2, CD147, CD45, CD3, CD4, CD8, CD68 and IL-6. COVID-19 negative patients with cardiovascular disease (n = 3) and influenza A (n = 6) served as controls. Findings: COVID-19 positive patients showed strong ACE2 / TMPRSS2 expression in capillaries and less in arterioles/venules. The main coronary arteries were virtually devoid of ACE2 receptor and had only mild intimal inflammation. Epicardial capillaries had a prominent lympho-monocytic endotheliitis, which was less pronounced in arterioles/venules. The lymphocytic-monocytic infiltrate strongly expressed CD4, CD45, CD68. Peri/epicardial nerves had strong ACE2 expression and lympho-monocytic inflammation. COVID-19 negative patients showed minimal vascular ACE2 expression and lacked endotheliitis or inflammatory reaction. Interpretation: ACE2 / TMPRSS2 expression and lymphomonocytic inflammation in COVID-19 disease increases crescentically towards the small vessels suggesting that COVID-19-induced endotheliitis is a small vessel vasculitis not involving the main coronaries. The inflammatory neuropathy of epicardial nerves in COVID-19 disease provides further evidence of an angio- and neurotrophic affinity of SARS-COV2 and might potentially contribute to the understanding of the high prevalence of cardiac complications such as myocardial injury and arrhythmias in COVID-19. Funding: No external funding was necessary for this study.

PurposeDecades of quality control efforts have raised the standards of immunohistochemistry (IHC), the principle method used for biomarker testing in breast cancer; however, computational pathology and reverse transcription quantitative PCR (RT-qPCR) may also hold promise for additional substantial improvements.MethodsHerein, we investigated discrepancies in the assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and marker of proliferation Ki67 comparing routinely obtained IHC (and FISH) data (ORI) with the results of manual (REV) and semi-automated (DIA) re-evaluation of the original IHC slides and then with RNA expression data from the same tissue block using the MammaTyper® (MT) gene expression assay.ResultsCorrelation for ER and PR was high between ORI IHC and the other three study methods (REV, DIA and RT-qPCR). For HER2, 10 out of 96 discrepant cases can be detected between ORI and REV that involved at least one call in the equivocal category (except for one case). For Ki67, 22 (29.1%) cases were categorized differently by either REV alone (n = 17), DIA alone (n = 15) or both (n = 10) and 28 cases (29.2%) for RT-qPCR. Most of the discrepant Ki67 cases changed from low to high between the original and following assessment and belonged to the intermediate Ki67 expression range (between 9 and 30%).ConclusionsDetermination of the breast cancer biomarkers ER, PR, HER2 and Ki67 at the mRNA level shows high degree of correlation with IHC and compares well with correlations between original with subsequent independent manual or semi-automated IHC assessments. The use of methods with wider dynamic range and higher reproducibility such as RT-qPCR may offer more precise assessment of endocrine responsiveness, improve Ki67 standardization and help resolve HER2 cases that remain equivocal or ambiguous by IHC/FISH. In summary, our findings seem to configure RT-qPCR as a complementary method to be used in cases of either equivocal results or presenting, at the traditional determination assays, biomarkers expressions close to the cut-off values.

Background: Androgen receptor (AR) has been described to play a prominent role in male breast cancer (MBC). It maps on chromosome X, and recent reports indicate that X-chromosome polysomy is frequent in MBC. Since the response to anti-androgen therapy may depend on AR polysomy and on its overexpression similarly to prostate cancer, the aim of the present study was to investigate the DNA methylation level of AR and its coregulators, especially those mapped on the X-chromosome, that may influence the activity of AR in MBC.Methods: The DNA methylation level of AR, MAGEA2, MAGEA11, MAGEC1, MAGEC2, FLNA, HDAC6, and UXT, mapped on the X-chromosome, was evaluated by quantitative bisulfite-NGS. Bioinformatic analysis was performed in a Galaxy Project environment using BWA-METH, MethylDackel, and Methylation Plotter tools. The study population consisted of MBC (41 cases) compared with gynecomastia (17 cases).Results:MAGEA family members, especially MAGEA2, MAGEA11, MAGEC, and UXT and HDAC6 showed hypomethylation of several CpGs, reaching statistical significance by the Kruskal–Wallis test (p < 0.01) in MBC when compared to gynecomastia. AR showed almost no methylation at all.Conclusions: Our study demonstrated for the first time that MAGEA family members mapped on the X-chromosome and coregulators of AR are hypomethylated in MBC. This may lead to their overexpression, enhancing AR activity.

This paper aims to detect the effects of DMR (double reasoned maturation) method, and if it is able to increase the quality of Hungary’s most distributed white wine variety, Bianca. The resistant interspecific hybrid Bianca cultivar can accumulate high sugar content during ripening, but it is prone to drastic acid loss, which can lead to deficient microbiological stability of wines. The DMR method is suitable for achieving fruit with better sugar/acid ratio due to the shrinking of the berries. The DMR treatment was found to be a possible tool for avoiding rapid acid loss in Bianca juices. Early cutting of one-year-old wood and early harvest were found to be the ideal combination for increasing quality.

Nuclear magnetic resonance (NMR) spectroscopy is an innovative method for wine analysis. Every grapevine variety has a unique structural formula, which can be considered as the genetic fingerprint of the plant. This specificity appears in the composition of the final product (wine). In the present study, the originality of Hungarian wines was investigated with 1H NMR-spectroscopy considering 861 wine samples of four varieties (Cabernet Sauvignon, Blaufränkisch, Merlot, and Pinot Noir) that were collected from two wine regions (Villány, Eger) in 2015 and 2016. The aim of our analysis was to classify these varieties and region and to select the most important traits from the observed 22 ones (alcohols, sugars, acids, decomposition products, biogene amines, polyphenols, fermentation compounds, etc.) in order to detect their effect in the identification. From the tested four classification methods—linear discriminant analysis (LDA), neural networks (NN), support vector machines (SVM), and random forest (RF)—the last two were the most successful according to their accuracy. Based on 1000 runs for each, we report the classification results and show that NMR analysis completed with machine learning methods such as SVM or RF might be a successfully applicable approach for wine identification.

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2017-2018, covering the period since the publication in Fall of 2017 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved only recently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography.

Adenomyoepithelioma is a rare tumor of the breast with an unknown genetic basis. Here the authors perform a genomic analysis of adenomyoepitheliomas revealing that their repertoire of somatic mutations vary according to the estrogen receptor (ER) status, and that ER-negative tumors harbor recurrent mutations in HRAS and PI3K pathway genes.

Abstract Background Intra-tumoral heterogeneity has been recently addressed in different types of cancer, including breast cancer. A concept describing the origin of intra-tumoral heterogeneity is the cancer stem-cell hypothesis, proposing the existence of cancer stem cells that can self-renew limitlessly and therefore lead to tumor progression. Clonal evolution in accumulated single cell genomic alterations is a further possible explanation in carcinogenesis. In this study, we addressed the question whether intra-tumoral heterogeneity can be reliably detected in tissue-micro-arrays in breast cancer by comparing expression levels of conventional predictive/prognostic tumor markers, tumor progression markers and stem cell markers between central and peripheral tumor areas. Methods We analyzed immunohistochemical expression and/or gene amplification status of conventional prognostic tumor markers (ER, PR, HER2, CK5/6), tumor progression markers (PTEN, PIK3CA, p53, Ki-67) and stem cell markers (mTOR, SOX2, SOX9, SOX10, SLUG, CD44, CD24, TWIST) in 372 tissue-micro-array samples from 72 breast cancer patients. Expression levels were compared between central and peripheral tumor tissue areas and were correlated to histopathological grading. 15 selected cases additionally underwent RNA sequencing for transcriptome analysis. Results No significant difference in any of the analyzed between central and peripheral tumor areas was seen with any of the analyzed methods/or results that showed difference. Except mTOR, PIK3CA and SOX9 (nuclear) protein expression, all markers correlated significantly (p

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2016-2017, covering the period since the publication in Fall of 2016 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved only recently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography/

Abstract Background Accurate determination of the predictive markers human epidermal growth factor receptor 2 (HER2/ERBB2), estrogen receptor (ER/ESR1), progesterone receptor (PgR/PGR), and marker of proliferation Ki67 (MKI67) is indispensable for therapeutic decision making in early breast cancer. In this multicenter prospective study, we addressed the issue of inter- and intrasite reproducibility using the recently developed reverse transcription-quantitative real-time polymerase chain reaction-based MammaTyper® test. Methods Ten international pathology institutions participated in this study and determined messenger RNA expression levels of ERBB2, ESR1, PGR, and MKI67 in both centrally and locally extracted RNA from formalin-fixed, paraffin-embedded breast cancer specimens with the MammaTyper® test. Samples were measured repeatedly on different days within the local laboratories, and reproducibility was assessed by means of variance component analysis, Fleiss’ kappa statistics, and interclass correlation coefficients (ICCs). Results Total variations in measurements of centrally and locally prepared RNA extracts were comparable; therefore, statistical analyses were performed on the complete dataset. Intersite reproducibility showed total SDs between 0.21 and 0.44 for the quantitative single-marker assessments, resulting in ICC values of 0.980–0.998, demonstrating excellent agreement of quantitative measurements. Also, the reproducibility of binary single-marker results (positive/negative), as well as the molecular subtype agreement, was almost perfect with kappa values ranging from 0.90 to 1.00. Conclusions On the basis of these data, the MammaTyper® has the potential to substantially improve the current standards of breast cancer diagnostics by providing a highly precise and reproducible quantitative assessment of the established breast cancer biomarkers and molecular subtypes in a decentralized workup.

Abstract Ectopic breast tissue can persist in the axilla due to lack of involution of mammary glands along the mammary lines. It is rare in men, and the malignant transformation to breast cancer has occasionally been described. Differential diagnosis of any axillary tumor should include breast cancer arising at ectopic sites.

As the above title indicates, because of the publication schedule of Hungarian Cultural Studies this bibliography straddles 2015-2016, covering the period since the publication in Fall of 2015 of last year’s bibliography in this journal. Each year’s bibliography may also be supplemented by earlier items, which were retrieved only recently. Although this bibliography series can only concentrate on English-language items, occasional items of particular interest in other languages may be included. For a more extensive bibliography of Hungarian Studies from about 2000 to 2010, for which this is a continuing update, see Louise O. Vasvári, Steven Tötösy de Zepetnek, and Carlo Salzani. “Bibliography for Work in Hungarian Studies as Comparative Central European Studies.” CLCWeb: Comparative Literature and Culture (Library) (2011): http://docs.lib.purdue.edu/clcweblibrary/hungarianstudiesbibliography.

The aim of this study was to evaluate the relevance of the three-dimensional (3D) structure of breast microcalcifications (MC) as a predictor of malignancy using highly resolved micro-computed tomography (micro-CT) datasets of biopsy samples.The study included 28 women with suspicious MC in their mammogram undergoing vacuum-assisted biopsy. Directly after the intervention, the specimens were scanned in a micro-CT with an isometric spatial resolution of 9 μm. Datasets were analysed regarding the number, volume and morphology of suspicious non-monomorphic MC (fl-fine linear, fp-fine pleomorphic, ch-coarse heterogeneous) and the structure model index (SMI). Histological evaluation was performed according to the B-classification: normal tissue or benign (group A: B1, B2), unclear malignant potential or suspicious of malignancy (group B: B3, B4) and malignant lesions (group C: B5).In all groups, suspicious non-monomorphic MC were found: group A exhibited fp MC in 38.5% of samples, no fl/ch; group B: fl 14.3%, fp 28.6%, ch 14.3%; group C always had at least one type of suspicious non-monomorphic MC (fl (57.1%) or fp (57.1%)) in each sample. The different histologic groups showed a similar mean SMI (benign: 2.97 ± 0.31, malignant: 3.02 ± 0.10, unclear: 2.90 ± 0.28). Between the three groups, no significant differences were found regarding number, volume or SMI value of MC.3D structure based on the SMI of MC analysed with highest spatial resolution is not significantly associated with the B-classification of breast lesions. Thus, magnification views of MC may be omitted in the analysis of MC detected in mammograms.

Following publication of the original article [1], a typesetting mistake is reported. For Fig. 7b, a copy of Fig. 6b has been published. The correct Fig. 7b is given in this correction and the original article has been updated.

Adjuvant therapy comprising the HER2 receptor antagonist trastuzumab is associated with a significant improvement in disease-free and overall survival as compared to chemotherapy alone in localized HER2-positive breast cancer (BC). However, a subset of HER2-positive tumors seems to respond less favorably to trastuzumab. Various mechanisms have been proposed for trastuzumab resistance, such as high HER2 to Chromosome 17 FISH (HER2/CEP17) ratios and the possibility that single agent trastuzumab may not suffice to efficiently block HER2 downstream signaling thresholds. In a retrospective analysis we evaluated whether HER2/CEP17 ratios might have an impact on disease-free survival (DFS).Clinical records of Stage I-III BC patients with HER2-positive tumors were reviewed at our institution from 2007-2013. We analyzed demographics, tumor characteristics including tumor size and grade, lymph node involvement and estrogen receptor expression as well as treatment with respect to chemotherapeutic regimens from the clinical charts. HER2/CEP17 ratios were determined by routine pathology analysis using in situ fluorescent hybridization (FISH). Upon statistical preview we defined three groups of HER2 amplification based on FISH ratio (2.2 to 4, >4 to 8, >8), in order to evaluate an association between HER2 gene amplification and DFS with trastuzumab containing therapies. DFS was analyzed using Cox-regression.A total of 332 patients with HER2-positive BC were reviewed. Median age was 54 (range 23-89) years. The majority of tumors were classified T1 (50%) or T2 (39%), node negative (52%) and of high grade G3 histology (70%). We identified 312 (94%) tumors as immunohistochemistry (IHC) score 3+ and HER2/CEP17 ratios were available from 278 patients (84%). 30% (N = 84) had tumors with high HER2/CEP17 ratios (>8). Univariate analysis found no correlation between outcome, age, histological grade, sequence as well as anthracycline content of chemotherapy. However, a prognostic impact was detected for tumor size (p = 0.02), nodal status (p8 (p12) and DFS (p = 0.01).In early BC patients, tumors with high HER2 amplification ratios (>8), may less likely respond to standard trastuzumab-containing therapies. Although, we obtained a similar effect for high HER2 gene copy numbers, this provides only an indirect speculation and not a proof that high HER2/CEP17 ratios may induce HER2 resistance.

The latest guidelines of the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) to test Human Epidermal Growth Factor Receptor 2 (HER2) in breast cancer after being revised in 2008 underwent a second modification in October 2013. The modification includes changes in cut-offs: 10% strong membranous staining for score 3+ on immunohistochemistry (IHC) (previously 30%) and using the ratio of >2 or absolute gene-copy-number (6 or more) alone or in combination with each other by in-situ-hybridisation technology (previously >2.2 and average copy-number of 6 or more). Hereby we addressed the question, which impact the modified cut-offs had on overall HER2-positivity in a single institution.We prospectively analysed 617 consecutive diagnostic breast-cancer cases which underwent double HER2 testing by immunohistochemistry and fluorescent in-situ hybridisation (FISH), using the modified 2013 ASCO/CAP-guidelines for one year (October 2013-October 2014). Results were compared with HER2-test results on 1,528 consecutive diagnostic breast-cancer cases from two previous years (2011-2012), using the 2008 ASCO/CAP guidelines, also tested with IHC and FISH in each case.Between October 2013 and October 2014, overall HER2-positivity was 15.8% (98 of 617 cases were either IHC 3+ or FISH amplified). 79 of 617 cases (13%) were IHC 3+, 96 of 617 cases (15.5%) were FISH amplified. Equivocal cases were seen in 25 of 617 cases (4.1%). 22 of 25 equivocal cases (88%) in 2013-2014 were IHC 1+ or 2+. In 13 equivocal cases, there was a repeated IHC/FISH testing: 2 of 13 cases (15%) became FISH amplified, 1 of 13 cases (7.5%) became IHC 3+. In 2011-2012, overall HER2-positivity (IHC/FISH) was 13.8% (211 of 1,528 cases). 185 of 1,528 cases (12%) were 3+ on IHC, 181 of 1,522 cases (12%) were amplified by FISH. Six of 1,528 cases were equivocal by FISH, and interpreted as non-amplified (0.3%).Applying the modified ASCO/CAP guidelines from 2013 resulted in an increase (2%) in overall HER2-positivity rate compared to overall-HER2-positivity rate using the 2008 ASCO/CAP guidelines. The increased positivity rate was mainly due to more FISH-positive cases (3.5% more than until 2013). The high rate of equivocal cases (4.1%) did not contribute to increase in overall HER2-positivity, but resulted in delay in definitive HER2-status.

Proliferative activity (Ki-67 Labelling Index) in breast cancer increasingly serves as an additional tool in the decision for or against adjuvant chemotherapy in midrange hormone receptor positive breast cancer. Ki-67 Index has been previously shown to suffer from high inter-observer variability especially in midrange (G2) breast carcinomas. In this study we conducted a systematic approach using different Ki-67 assessments on large tissue sections in order to identify the method with the highest reliability and the lowest variability.Five breast pathologists retrospectively analyzed proliferative activity of 50 G2 invasive breast carcinomas using large tissue sections by assessing Ki-67 immunohistochemistry. Ki-67-assessments were done on light microscopy and on digital images following these methods: 1) assessing five regions, 2) assessing only darkly stained nuclei and 3) considering only condensed proliferative areas ('hotspots'). An individual review (the first described assessment from 2008) was also performed. The assessments on light microscopy were done by estimating. All measurements were performed three times. Inter-observer and intra-observer reliabilities were calculated using the approach proposed by Eliasziw et al. Clinical cutoffs (14% and 20%) were tested using Fleiss' Kappa.There was a good intra-observer reliability in 5 of 7 methods (ICC: 0.76-0.89). The two highest inter-observer reliability was fair to moderate (ICC: 0.71 and 0.74) in 2 methods (region-analysis and individual-review) on light microscopy. Fleiss'-kappa-values (14% cut-off) were the highest (moderate) using the original recommendation on light-microscope (Kappa 0.58). Fleiss' kappa values (20% cut-off) were the highest (Kappa 0.48 each) in analyzing hotspots on light-microscopy and digital-analysis. No methodologies using digital-analysis were superior to the methods on light microscope.Our results show that all methods on light-microscopy for Ki-67 assessment in large tissue sections resulted in a good intra-observer reliability. Region analysis and individual review (the original recommendation) on light-microscopy yielded the highest inter-observer reliability. These results show slight improvement to previously published data on poor-reproducibility and thus might be a practical-pragmatic way for routine assessment of Ki-67 Index in G2 breast carcinomas.

Reviewed by Zsuzsanna Varga

HER2 status assessment became a mandatory test assay in breast cancer, giving prognostic and predictive information including eligibility for adjuvant anti-HER2 therapy. Precise and reliable assessment of HER2 status is therefore of utmost importance. In this study we analyzed breast cancer samples by a novel technology for concomitant detection of the HER2 protein and gene copy number.Tissue microarrays containing 589 invasive breast cancer samples were analyzed with a double immunohistochemistry (IHC) and silver labeled in situ hybridization (SISH) assay simultaneously detecting HER2 protein and gene copy number in the same tumor cells. This bright-field assay was analyzed using scores according to the modified ASCO guidelines and the results were correlated with patient prognosis.Overall concordance rate between protein expression and the presence of gene amplification was 98%. Fifty-seven of 60 tumors (95%) with IHC score 3+, 6 of 10 tumors with IHC score 2+ (60%) and only 3 of 519 tumors (0.6%) with IHC score 0/1+ were amplified by SISH. Patients with gene amplification despite IHC score 0/1+ had a tendency for worse overall survival (p = 0.088, reaching nearly statistical significance) compared to IHC score 0/1+ without amplification. In contrast, there was no difference in overall survival in IHC score 3+/2+ tumors with and without gene amplification.The novel double IHC and SISH assay for HER2 is efficient in the identification of breast cancer with discordant HER2 protein and HER2 gene status, especially for the prognostically relevant groups of HER2 protein negative tumors with HER2 amplification and HER2 protein positive tumors without HER2 amplification. Breast cancer without HER2 amplification among IHC score 2+/3+ tumors (10% in our cohort) suggests that other mechanisms than gene amplification contribute to protein overexpression in these cells.

INTRODUCTION:The G protein-coupled estrogen receptor (GPER) is a novel estrogen receptor that mediates proliferative effects induced by estrogen but also by tamoxifen. The aim of our study was to analyze the frequency of GPER in a large collective of primary invasive breast carcinomas, with special emphasis on the subcellular expression and to evaluate the association with clinicopathological parameters and patient overall survival. METHODS:The tissue microarrays from formalin-fixed, paraffin embedded samples of primary invasive breast carcinomas (n = 981) were analyzed for GPER expression using immunohistochemistry. Expression data were compared to the clinicopathological parameters and overall survival. GPER localization was also analyzed in two immortalized breast cancer cell lines T47D and MCF7 by confocal immunofluorescence microscopy. RESULTS:A predominantly cytoplasmic GPER expression was found in 189 carcinomas (19.3%), whereas a predominantly nuclear expression was observed in 529 cases (53.9%). A simultaneous comparable positive expression of both patterns was found in 32 of 981 cases (3.2%), and negative staining was detected in 295 cases (30%). Confocal microscopy confirmed the occurrence of cytoplasmic and nuclear GPER expression in T47D and MCF7. Cytoplasmic GPER expression was significantly associated with non-ductal histologic subtypes, low tumor stage, better histologic differentiation, as well as Luminal A and B subtypes. In contrast, nuclear GPER expression was significantly associated with poorly differentiated carcinomas and the triple-negative subtype. In univariate analysis, cytoplasmic GPER expression was associated with better overall survival (p = 0.012). CONCLUSION:Our data suggest that predominantly cytoplasmic and/or nuclear GPER expression are two distinct immunohistochemical patterns in breast carcinomas and may reflect different biological features, reason why these patterns should be clearly distinguished in histological evaluations. Prospective studies will be needed to assess whether the expression status of GPER in breast carcinomas should be routinely observed by clinicians, for instance, before implementing endocrine breast cancer treatment.

AIM: Several multigene expression-based tests offering prognostic and predictive information in hormone-receptor positive early breast cancer were established during the last years. These tests provide prognostic information on distant recurrences and can serve as an aid in therapy decisions. We analyzed the recently validated reverse-transcription-quantitative-real-time PCR-based multigene-expression Endopredict (EP)-test on 34 hormone-receptor positive breast-cancer cases and compared the EP scores with the Oncotype DX Recurrence-scores (RS) obtained from the same cancer samples. METHODS: Formalin-fixed, paraffin-embedded invasive breast-cancer tissues from 34 patients were analyzed by the EP-test. Representative tumor blocks were analyzed with Oncotype DX prior to this study. Tumor tissue was removed from unstained slides, total-RNA was isolated and EP-analysis was performed blinded to Oncotype DX results. RESULTS: Extraction of sufficient amounts of RNA and generation of valid EP-scores were possible for all 34 samples. EP classified 11 patients as low-risk and 23 patients as high-risk. RS Score defined 15 patients as low-risk, 10 patients as intermediate-risk in and 9 patients as high-risk. Major-discrepancy occurred in 6 of 34 cases (18%): Low-risk RS was classified as high-risk by EP in 6 cases. Combining the RS intermediate-risk and high-risk groups to a common group, the concordance between both tests was 76%. Correlation between continuous EP and RS-scores was moderate (Pearson-coefficient: 0.65 (p