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Morphometric analysis is the quantification of shapes, which makes irregular shapes found in nature analyzable and comparable. Cave morphometry has been used for the genetic classification of caves, the digital reconstruction of their conduits, the decoding of their paleoenvironment, and other research purposes. Ratios and indices that have been derived from Euclidean geometry and application of fractal geometry onto karst features and topological parameters are the basic methodologies that have been used for shape quantification. This paper reviews the literature that focuses on methodologies used for morphometric analyses and the applications that these methodologies have found. [ABSTRACT FROM AUTHOR]

Caves serve as time capsules, preserving significant markers of tectonic activity and offering insights into geological history. Fault geometries and past activations found in caves can be correlated with known deformational events in the broader area, temporally delimiting the speleogenesis. More specifically, cave passage formation is suggested to be affected by the regional stress-field. The Asprorema Cave in Northern Greece is a typical example of a fracture guided cave, with passage geometry influenced by relative sidewall movements, revealing these discontinuities as faults. This study constructs the timeframe and conceptual model of speleogenesis in relation to tectonic events, geomorphological evolution and hydrological zones, and verifies its relation to the stress-field. Active tectonics, mineralogy and cave geomorphology are investigated. Results suggest syntectonic speleogenesis under phreatic and epiphreatic conditions. The absence of corrosion on fault slip surfaces implies recent activations post cave's shift to the vadose zone. Structural analysis identifies three main neotectonic phases: NNW-SSE striking faults (oldest group of structures), NE-SW striking faults with dextral strike-slip movement (post-middle Miocene), and NE-SW striking normal faults indicating extensional stress-regime (Quartenary). The last two phases affect cave passage shape causing wall displacement, highlighting passage formation along discontinuities perpendicular to the horizontal minimum stress axis. [ABSTRACT FROM AUTHOR]

Introduction: The pressure of the COVID-19 pandemic on healthcare systems led to limited roles of infectious diseases services, increased rates of irrational use of antimicrobials, and incidence of infections by multidrug-resistant microorganisms. The aim of the present study is to evaluate the incidence of antimicrobial resistance and the management of bloodstream infections before and during the COVID-19 pandemic at the University General Hospital of Alexandroupolis (Greece). Materials and Methods: This is a retrospective study conducted from January 2018 to December 2022. Data were collected from the University Microbiology Laboratory per semester regarding the isolated strains of Gram-positive and -negative bacteria in blood cultures and respiratory samples in hospitalized patients in medical and surgical wards and in the intensive care unit (ICU). Additionally, bloodstream infections with requested infectious disease consultations were reported (n = 400), determining whether these were carried out via telephone contact or at the patient's bedside. Demographic data, comorbidities, focus of infection, antimicrobial regimen, duration of treatment, length of hospitalization, and clinical outcome were analyzed. Results: A total of 4569 strains of Gram-positive and -negative bacteria were isolated. An increasing trend was reported compared to the pre-pandemic period in the incidence of resistant Gram-negative bacteria, particularly in ICUs. Prior antimicrobial use and the rate of hospital-acquired infections were increased significantly during the pandemic. In the pre-pandemic period 2018–2019, a total of 246 infectious disease consultations were carried out, while during the period 2020–2022, the number was 154, with the percentage of telephone consultations 15% and 76%, respectively. Detection of the source of infection and timely administration of appropriate antimicrobial agents were more frequently recorded before the pandemic, and 28-day mortality was significantly reduced in cases with bedside consultations. Conclusion: The empowering of infectious disease surveillance programs and committees, rational use of antimicrobials agents, and bedside infectious disease consultations are vital in order to reduce the impact of infections caused by multidrug-resistant strains. [ABSTRACT FROM AUTHOR]

Iron oxide deposits in the form of crusts are examined in the field and in the laboratory with scanning electron microscopy. Samples came from two caves developed in different geological settings but assumed by previous studies to be of hydrothermal-hypogene origin. The relation of iron oxide crusts to cave wall and ceiling morphology created by the cave's primary dissolution (speleogenesis), as well as to the formation of other speleothems, is investigated. Scanning electron microscope (SEM) elemental analysis showed a high iron content (20-78 % by weight) consistent with iron oxide minerals such as goethite, hematite, magnetite, etc. Three distinct types of iron oxide crusts were identified from the four samples that were analyzed: (1) high iron content crusts with some porosity formed on the host rock surface and discontinuities, (2) high iron content (but lower than type 1) crusts, including limestone clasts and pores originating from dissolved clasts, and (3) high iron content, significantly-porous crusts that are formed by a network of filaments that indicate microbial activity. The formation of these deposits in relation to other speleothems and to dissolution events is discussed. [ABSTRACT FROM AUTHOR]

The literature contains scant information on the relationship between tourists' gender and their attitudes toward food while vacationing. The present study had as its main aim to examine the role of gender in key behaviours concerning tourists' food choices and eating habits; in addition, our study evaluated the hypothesis that gender interacts with the "pandemic effect" in modifying tourists' food-related behaviour. By implementing a quantitative, exploratory, and descriptive methodology, an online questionnaire was developed based on existing literature. To this end, data derived from 474 female and 370 male tourists visiting Greece in 2019 (before) or in 2020 (during the COVID-19 pandemic) were analysed and evaluated. The results indicate that, compared to men, women were more motivated to taste local food, especially with respect to obtaining cultural experience and excitement, promoting interpersonal relations, and as a result of health concerns. In addition, they dined at facilities at their place of stay, as well as at Greek restaurants and taverns at a higher rate compared to men. Women also reported being more satisfied than men by their food experiences during their trips, and was found that during the pandemic they spent, on average, more on food than before. The study showed that the pandemic affected both genders; however, the most significant of the differences observed relates to the choice of dining facilities, in all likelihood, as a result of women being more sensitive to the risks of COVID-19. Overall, during the pandemic, women appeared more likely than men to adopt behaviours that are in line with the principles of sustainability, such as a positive attitude and motivation to consume foods produced locally in the country. Differences detected between genders can be used by various stakeholders as a benchmark to further improve the food services offered at tourist destinations. [ABSTRACT FROM AUTHOR]

Firn from an ice cave in the highest mountain of Greece, Mount Olympus, was sampled and analyzed to determine the tritium content in order to estimate rates of accumulation and to date the ice plug. The presence of a sharp raise of tritium content indicating the nuclear testing era was expected to be preserved into ice beds. Tritium concentrations were found to vary from 0.9 to 11 TU. This peak did not appear in the analyzed samples, providing an upper age limit of less than 50 years for the oldest sampled layer. It is suggested that the rate of melting is responsible for the absence of older firn layers. [ABSTRACT FROM AUTHOR]

Two of the most well-known caves of northern Greece, Petralona and Maaras, were morphometrically analyzed. They were strategically chosen for this morphometric study because they represent caves formed by different speleogenetic factors, resulting in patterns that clearly discriminate them from each other. Caves can display substantial variation in their patterns, depending on the local geology, hydrogeology, tectonics, and other factors. These qualitative parameters of speleogenesis, such as geological and hydrogeological controls, can be reflected in a cave's pattern. The different speleogenetic factors that create the patterns of the caves can be expressed in the mathematical indices, designating them as morphometrical tools for properly discriminating the two cave patterns. Petralona Cave falls into the category of a ramiform cave pattern. The cave's hypogenic origin is also supported by meso-scale cave morphology, and the hydrothermal activity of the surrounding area. On the other hand, Maaras Cave has a typical underground river pattern. The horizontal patterns of the two caves were morphometrically scrutinized using Euclidean and fractal geometry. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic has changed everyday reality and negatively impacted the global hospitality and tourism sectors. Even though food is an essential component of the tourist experience and the sustainable development of a region, research on the impact of COVID-19 on tourists' food-related behaviour remains scant. By implementing a quantitative approach, data obtained from 847 tourists visiting Greece before or during the pandemic were analysed in order to compare these two periods. Findings indicate that during the pandemic, tourists had a more positive attitude towards food than before the pandemic and were more motivated to consume local food. As a result, they spent more money on food and were keener to taste local food and visit Greek restaurants and taverns. Despite the restrictions, the level of food satisfaction remained the same. It seems that this is a case whereby the risk perceptions created by COVID-19 were eliminated. The demand for quality food experiences was mainly interpreted as a search for culture and consideration of health concerns. Specific trends have been revealed in tourists' food-related behaviours, which bear implications for a smooth transition to new and challenging circumstances. Researchers and food tourism stakeholders must set new goals, develop alternative forms of products and services based on sustainability, and, in general, adopt a new perspective to face future challenges. [ABSTRACT FROM AUTHOR]

Firn from an ice cave in the highest mountain of Greece, Mt. Olympos, was sampled and analysed to determine the tritium content in order to estimate rates of accumulation and to date the ice plug. The presence of a sharp raise of tritium content because of the nuclear testing era was expected to be preserved into ice beds. This peak did not appear in the analysed samples providing an age estimation of less than 50 years. It is suggested that the rate of melting is responsible for the absence of older firn layers. [ABSTRACT FROM AUTHOR]

Copyright of Acta Carsologica is the property of Scientific Research Centre of Slovenian Academy of Sciences & Arts and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The oxidation processes of white wines can occur during storage and commercialization due to several factors, and these can negatively affect the color, aroma, and quality of the wine. Wineries should have faster and simpler methods that provide valuable information on oxidation stability of wines and allow fast decision-making procedures, able to trigger suitable technological interventions. Using a portable prototype instrument for light irradiations at different wavelengths and times was considered and evaluated on sensorial, spectrophotometric, and colorimetric parameters of white wines. The sensorial analysis revealed that white and light blue were the most significant, after only 1 h of irradiation. The experimental results showed that hydrogen peroxide could enhance the effect of light treatment, allowing a contemporary evaluation of the oxidation stability of wine against light and chemical stresses. As expected, a good correlation (R2 > 0.89) between optical density at 420 nm and b* parameter was highlighted. The synergic effect of light and H2O2 was also studied on the hydrolyzable and condensed tannins’ additions to white wine. The proposed methodology could be used to evaluate the oxidative stability of white wines, but also to evaluate the effect of some oenological adjuvants on wine stability. [ABSTRACT FROM AUTHOR]

Copyright of Acta Carsologica is the property of Scientific Research Centre of Slovenian Academy of Sciences & Arts and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Cabazitaxel is a novel taxane that might be active in breast cancer resistant to first-generation taxanes.Methods: The purpose of the current multicentre phase II trial was to evaluate the activity and safety of cabazitaxel, as second-line treatment, in patients with human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) previously treated with taxanes. The primary endpoint was objective response rate (ORR).Results: Eighty-four patients were enrolled between October 2012 and November 2016. Taxane resistance to previous treatment was detected in 43 cases. The ORR was 22.6% in the intent-to-treat population, 23.3% in taxane-resistant and 20.5% in taxane-non-resistant cases. At a median follow-up of 39.6 months, the median progression-free survival and overall survival were 3.7 months (95% CI 2.2-4.4) and 15.2 months (95% CI 11.3-19.4), respectively. Regarding toxicity, grade 3-4 neutropenia was reported in 22.6% and febrile neutropenia in 6% of the patients, respectively. Two fatal events (one febrile neutropenia and one sepsis) were reported as being related to study treatment.Conclusions: This phase II trial suggests that cabazitaxel is active as second-line treatment in taxane-pretreated patients with HER2-negative MBC, with manageable toxicity. [ABSTRACT FROM AUTHOR]

Purpose: Neuromodulation, such as vagal nerve stimulation and intestinal electrical stimulation, has been introduced for the treatment of obesity and diabetes. Ideally, neuromodulation should be applied automatically after food intake. The purpose of this study was to develop a method of automatic food intake detection through dynamic analysis of heart rate variability (HRV). Materials and Methods: Two experiments were conducted: (1) a small sample series with a standard test meal and (2) a large sample series with varying meal size. Electrocardiograms (ECGs) were collected in the fasting and postprandial states. Each ECG was processed to compute the HRV. For each HRV segment, time- and frequency-domain features were derived and used as inputs to train and test an artificial neural network (ANN). The ANN was trained and tested with different cross-validation methods. Results: The highest classification accuracy reached with leave-one-subject-out-leave-one-sample-out cross-validation was 0.93 in experiment 1 and 0.88 in experiment 2. Retraining the ANN on recordings of a subject drastically increased the achieved accuracy for that subject to values of 0.995 and 0.95 in experiments 1 and 2, respectively. Conclusions: Automatic food intake detection by ANNs, using features from the HRV, is feasible and may have a great potential for neuromodulation-based treatments of meal-related disorders. [ABSTRACT FROM AUTHOR]

Background/Aim: PTEN-loss and PIK3CA mutations have been addressed as markers of PI3K activation in breast cancer. We evaluated these markers in early high-risk breast cancer (EBC) focusing on PTEN immunohistochemistry (IHC) issues, particularly in HER2-positive disease. Materials and Methods: We examined PTEN-loss and PIK3CA mutations in 1265 EBC patients treated with adjuvant chemotherapy within two clinical trials. Two different methods for the evaluation of PTEN IHC were used, one upfront binary (loss; no-loss) and the other initially multi-scale allowing for the classification of "grey zone" tumors with low and very low PTEN protein expression. Results: PTEN-loss (33.4% and 22.1%, depending on the IHC method) and PIK3CA mutations (29.6%) were associated with ER/PgR/HER2-negative and ER/PgR-positive disease, respectively. Concordance of the two IHC methods was moderate (Cohen's kappa 0.624). PTEN-loss discrepancy and intra-tumor heterogeneity concerned "grey zone" tumors that were prevalent among HER2-positive cancers. PTEN-loss independently conferred higher risk for relapse and death. Compared to single PIK3CA mutations, single PTEN-loss was independently associated with increased risk for relapse and death. Depending on the evaluation method, in HER2-positive cancer, PTEN-loss was without- or of marginal unfavorable prognostic significance. Conclusion: In EBC, PTEN-loss is an independent predictor of poor outcome. When occurring singly, PTEN-loss and PIK3CA mutations have opposite prognostic impact. In HER2-positive disease, assessment of PTEN-loss by IHC appears unreliable and the marker is without clear prognostic significance. [ABSTRACT FROM AUTHOR]

From the Early Villafranchian site of Milia (Grevena) in northern Greece a mandible fragment of a porcupine with part of the incisor has been recorded. Despite its fragmentary nature, morphologically the fossil has been referred unambiguously to the genus Hystrix; according to various size parameters it belongs to the species H. refossa. A compilation of all known porcupine fossils attributed to this species indicates that the find from Milia is the oldest record of H. refossa so far, the age of which is correlated with the early part of the informal Mammal Sub-Zone MN 16a. Age and location of the record suggest that--in parallel to the preceding species H. primigenia and H. depereti -- the porcupine species H. refossa spread from south-east Europe (Balkans) eventually over Europe. The Milia porcupine presumably inhabited vegetated river banks within a mosaic of open and forested terrain under warm and humid conditions. [ABSTRACT FROM AUTHOR]

In the current study, we performed a complete analysis, with four different methods, of all four HER family receptors, in a series of patients with metastatic breast cancer treated with trastuzumab-based regimens and evaluated their prognostic value. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 227 patients, considered to be HER2-positive when assessed at the local laboratories. We evaluated gene amplification, copy number variations (CNVs), mRNA and protein expression of all four HER family members. In addition, our analysis included the evaluation of several other factors by immunohistochemistry (IHC), such as pHER2Tyr1221/1222, pHER2Tyr877 and PTEN. Central review of HER2 status by IHC and fluorescence in situ hybridization revealed that of the 227 patients, only 139 (61.2%) were truly HER2-positive. Regarding the 191 patients treated with trastuzumab as first-line therapy, median time to progression (TTP) was 15.3 and 10.4 months for HER2-positive and HER2-negative participants, respectively, whereas median survival was 50.4 and 38.1 months, respectively. In HER2-positive patients, high HER3 mRNA expression was of favorable prognostic significance for TTP and survival (HR = 0.43, 95% CI 0.21–0.88, Wald’s p = 0.022 and HR = 0.43, 95% CI 0.21–0.88, p = 0.021, respectively), while EGFR copy gain and EGFR protein expression were associated with higher risk for disease progression in HER2-negative patients (HR = 3.53, 95% CI 1.19–10.50, p = 0.023 and HR = 3.37, 95% CI 1.12–10.17, p = 0.031, respectively). Positive HER3 protein expression was a favorable factor for TTP in HER2-negative patients (HR = 0.43, 95% CI 0.22–0.84, p = 0.014). In the multivariate analysis, only EGFR copy gain retained its prognostic significance for TTP in the HER2-negative population (HR = 3.96, 95% CI 1.29–12.16, p = 0.016), while high HER3 mRNA expression retained its favorable prognostic significance for TTP in the HER2-positive subgroup (HR = 0.47, 95% CI 0.23–0.99, p = 0.048). The present study suggests that EGFR copy gain represents a negative prognostic factor for TTP in HER2-negative patients with metastatic breast cancer treated with trastuzumab. In addition, high HER3 mRNA expression appears to be of favorable prognostic significance for TTP in HER2-positive patients. Given the small number of patients included in the current analysis and the retrospective nature of the study, our findings should be validated in larger cohorts. [ABSTRACT FROM AUTHOR]

Background: Tumor‐infiltrating lymphocytes (TILs) have been shown to be of prognostic value in several cancer types. In early breast cancer, TILs have a prognostic utility, as well, especially in HER2‐positive and triple‐negative breast cancer. TILs presence is broadly associated with improved survival; however, there is controversy regarding TILs subpopulations. Patients and methods: Early‐stage breast cancer patients treated with anthracycline‐based chemotherapy within two randomized trials were included in the study. We evaluated, by qRT‐PCR, 826 tumor tissue samples for mRNA expression of CD3, CD8, and FOXP3 for potential prognostic significance in terms of disease‐free survival (DFS) and overall survival (OS). Results: After a median follow‐up of 133.0 months, 255 patients (30.9%) had died and 314 (38.0%) had disease progression. In the univariate analysis, high CD3 and CD8 mRNA expression was found to be of favorable prognostic value for DFS (P = 0.007 and P = 0.016, respectively). In multivariate analyses, the association of high CD8 mRNA expression with increased DFS was retained (HR = 0.77, 95% CI 0.60‐0.998, Wald's P = 0.048), whereas that of high CD3 mRNA expression was of marginal statistical significance (HR = 0.77, 95% CI 0.59‐1.01, P = 0.059). Moreover, a significant interaction was observed between HER2 status and CD3 mRNA expression with respect to DFS (interaction P = 0.032). In the HER2‐positive subgroup, the hazard ratio associated with high CD3 mRNA expression was of greater magnitude (HR = 0.48, 95% CI 0.30‐0.76, P = 0.002) compared with the hazard ratio presented above, for the entire cohort. No significant findings were observed for FOXP3 in terms of DFS, while none of the studied markers were of prognostic value for OS. Conclusions: High CD3 and CD8 mRNA expression in early‐stage breast cancer patients is of prognostic value for decreased risk of relapse and, in the future, could potentially be of importance in deciding the most appropriate therapeutic strategy in light of the recent immune‐related treatment developments. We used CD3, CD8, and FOXP3 mRNA expression as markers for T cell infiltration, in early breast cancer patients treated with anthracycline‐based adjuvant chemotherapy. Results showed that high CD8 mRNA expression is associated with improved outcome in breast cancer and such prognostic value is more profound in the HER2‐positive subtype. [ABSTRACT FROM AUTHOR]

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values <0.05), with the exception of the one between VEGF-C and VEGFR1 (chi-square test, p = 0.15). Tumors with high VEGF-A protein expression, as compared to tumors with low expression were more frequently ER/PgR-negative (33.3% vs. 20.8%, chi-square test, p = 0.009) and HER2-positive (44.8% vs. 20.6%, p<0.001). In addition, tumors with high VEGFR1 expression, were more frequently HER2-positive (32.8% vs. 19.6%, p<0.001), while tumors with high VEGFR3 expression were more frequently ER/PgR-negative (24.9% vs. 17.0%, p = 0.024) and HER2-positive (26.9% vs. 14.8%, p = 0.001). High VEGF-A and VEGF-C protein expression was associated with increased DFS in the entire cohort (HR = 0.57, 95% CI 0.36–0.92, Wald’s p = 0.020 and HR = 0.71, 95% CI 0.52–0.96, p = 0.025, respectively), as well as in specific subtypes/subgroups, such as HER2-positive (VEGF-A, HR = 0.32, 95% CI 0.14–0.74, p = 0.008) and triple-negative (VEGF-C, HR = 0.44, 95% CI 0.21–0.91, p = 0.027) patients. High vs. low VEGFR1 expression was an unfavorable factor for DFS in triple-negative patients (HR = 2.74, 95% CI 1.26–5.98, p = 0.011), whereas the opposite was observed among the ER/PgR-positive patients (HR = 0.69, 95% CI 0.48–0.98, p = 0.041). Regarding OS, high VEGF-C protein expression was associated with increased OS in the entire cohort (HR = 0.64, 95% CI 0.46–0.89, Wald’s p = 0.008), as well as in in specific subtypes/subgroups, such as ER/PgR-negative (HR = 0.37, 95% CI 0.20–0.71, p = 0.003) and triple-negative (HR = 0.42, 95% CI 0.19–0.90, p = 0.026) patients. In conclusion, high expression of angiogenesis-related proteins is associated with adverse clinicopathological parameters in early-stage breast cancer patients and may be surrogate markers of biologically distinct subgroups of ER/PgR-negative or triple-negative tumors with superior outcome. Further validation of our findings in independent cohorts is needed. [ABSTRACT FROM AUTHOR]

Copyright of Paläontologische Zeitschrift is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background-Aim: To evaluate the prognostic role of elaborate molecular clusters encompassing cyclin D1, cyclin E1, p21, p27 and p53 in the context of various breast cancer subtypes. Methods: Cyclin E1, cyclin D1, p53, p21 and p27 were evaluated with immunohistochemistry in 1077 formalin-fixed paraffin-embedded tissues from breast cancer patients who had been treated within clinical trials. Jaccard distances were computed for the markers and the resulted matrix was used for conducting unsupervised hierarchical clustering, in order to identify distinct groups correlating with prognosis. Results: Luminal B and triple-negative (TNBC) tumors presented with the highest and lowest levels of cyclin D1 expression, respectively. By contrast, TNBC frequently expressed Cyclin E1, whereas ER-positive tumors did not. Absence of Cyclin D1 predicted for worse OS, while absence of Cyclin E1 for poorer DFS. The expression patterns of all examined proteins yielded 3 distinct clusters; (1) Cyclin D1 and/or E1 positive with moderate p21 expression; (2) Cyclin D1 and/or E1, and p27 positive, p53 protein negative; and, (3) Cyclin D1 or E1 positive, p53 positive, p21 and p27 negative or moderately positive. The 5-year DFS rates for clusters 1, 2 and 3 were 70.0%, 79.1%, 67.4% and OS 88.4%, 90.4%, 78.9%, respectively. Conclusions: It seems that the expression of cell cycle regulators in the absence of p53 protein is associated with favorable prognosis in operable breast cancer. [ABSTRACT FROM AUTHOR]

Background: The shift towards an earlier diagnosis of breast cancer (BC) highlights the need for biomarkers that would identify patients at risk for relapse and metastatic spread and indicate the potential value of additional treatment strategies. Osteopontin (OPN) is a matricellular protein that has been suggested to be a potential biomarker in BC. In the present study, we used archived BC patient samples to assess the clinical utility of OPN.Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 975 patients were collected from two large phase III randomized adjuvant chemotherapy trials (HE10/97 and HE10/00) that included patients with high risk BC. All tissue samples were assessed for ER, PgR, Ki67 and HER2 protein expression. OPN protein and mRNA expression was evaluated using immunohistochemistry and quantitative reverse transcription-polymerase chain reaction, respectively.Results: OPN mRNA expression data were available for 814 patients, whereas OPN protein expression data were available for 546 patients. The majority of patients were ER/PgR-positive (78.3%), HER2-negative (76.5%) and Ki67-positive (55.2%) and had received adjuvant radiation therapy (76.8%) and hormonal therapy (81.1%). OPN mRNA expression was significantly associated with age (60.9% in high OPN tumors vs. 54.1% in low OPN tumors, p = 0.047), ER/PgR-negative status (25.7 vs. 17.2%, p = 0.004) and BC subtypes (p = 0.021). In addition, high OPN mRNA expression was significantly associated with reduced DFS (HR 1.26, 95% CI 1.00-1.59, Wald's p = 0.050) and OS (HR 1.37, 95% CI 1.05-1.78, p = 0.019), while it retained its prognostic significance for both DFS (HR 1.39, 95% CI 1.10-1.77, p = 0.007) and OS (HR 1.54, 95% CI 1.61-2.05, p = 0.003) in the multivariate analysis.Conclusions: We showed that high OPN mRNA expression is associated with decreased DFS and OS in a large cohort of BC patients treated with adjuvant chemotherapy in a clinical trial setting. Our results suggest that OPN may serve as a prognostic factor and a potential target for therapy. Trial registration Australian New Zealand Clinical Trials Registry; HE10/97 ACTRN12611000506998; HE10/00 ACTRN12609001036202. [ABSTRACT FROM AUTHOR]

Background-Aim: Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. In the present study, we sought to develop a risk for recurrence score (RRS) based on mRNA expression of three proliferation markers in high-risk early breast cancer patients and evaluate its ability to predict risk for relapse and death. In addition the Adjuvant! Online score (AOS) was also determined for each patient, providing a 10-year estimate of relapse and mortality risk. We then evaluated whether RRS or AOS might possibly improve the prognostic information of the clinical treatment score (CTS), a model derived from clinicopathological variables. Methods: A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Sufficient RNA was extracted from 875 samples followed by multiplex quantitative reverse transcription-polymerase chain reaction for assessing RACGAP1, TOP2A and Ki67 mRNA expression. The CTS, slightly modified to fit our cohort, integrated the prognostic information from age, nodal status, tumor size, histological grade and treatment. Patients were also classified to breast cancer subtypes defined by immunohistochemistry. Likelihood ratio (LR) tests and concordance indices were used to estimate the relative increase in the amount of information provided when either RRS or AOS is added to CTS. Results: The optimal RRS, in terms of disease-free survival (DFS) and overall survival (OS), was based on the co-expression of two of the three evaluated genes (RACGAP1 and TOP2A). CTS was prognostic for DFS (p<0.001), while CTS, AOS and RRS were all prognostic for OS (p<0.001, p<0.001 and p = 0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ2 8.7, p = 0.003), however the use of RRS in addition to CTS did not. For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs. CTS alone (LR-Δχ2 20.8, p<0.001), as well as the use of CTS and RRS vs. CTS alone (LR-Δχ2 4.8, p = 0.028). Additionally, more patients were scored as high-risk by AOS than CTS. According to immunohistochemical subtypes, prognosis was improved in the Luminal A (LR-Δχ2 7.2, p = 0.007) and Luminal B (LR-Δχ2 8.3, p = 0.004) subtypes, in HER2-negative patients (LR-Δχ2 23.4, p<0.001) and in patients with >3 positive nodes (LR-Δχ2 23.9, p<0.001) when AOS was added to CTS. Conclusions: The current study has shown a clear benefit in predicting overall survival of high-risk early breast cancer patients when combining CTS with either AOS or RRS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS has better prognostic value than CTS alone for OS. These findings could possibly add on the information needed for the best risk prediction strategy in high-risk early breast cancer patients in a rather simple and inexpensive way, especially in Luminal A and B subtypes, HER2-negative patients and those with >3 positive nodes. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher ( p < 0.001) and PIK3CA with lower ( p = 0.004) TILs in an ER /PgR-specific manner ( p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials. [ABSTRACT FROM AUTHOR]

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Background: Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study. Patients and Methods: Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa. Results: Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC. Conclusions: In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression. Trial Registration: ANZCTR.org.au [ABSTRACT FROM AUTHOR]

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Characterized by an aggressive clinical course and relatively poor prognosis, triple-negative breast cancer (TNBC) refers to a diverse group of tumors with distinct molecular characteristics rather than to a single entity. The recognition of distinct gene expression subtypes within the group of TNBC and the description of an ever-expanding set of genetic events has led to improved understanding of the underlying biology. However, the improvement of clinical results has been incremental despite undergoing efforts to evaluate the role of molecularly targeted agents in the treatment of TNBC. The relative rarity of each one of these genetic events increases the difficulty of conducting large clinical trials, further hindering our ability to identify meaningful, personalized treatment approaches. Herein, we summarize current knowledge on TNBC, focusing on molecular pathology and emerging treatment approaches. [ABSTRACT FROM AUTHOR]

A new hipparion species,Hipparion phlegrae, sp. nov., is described on the basis of both morphological characters and metrical data as a member ofHipparions.s. It is compared withH. dietrichi,H. prostylum, and similar forms of the Greco-Iranian province. The age of the Kryopigi fauna is discussed as Turolian on the basis of the hipparion assemblage, whereas the coexistence of a smallCremohipparionreferred here asC. matthewi/nikosiindicates thatH. phlegrae, sp. nov., is probably a derived species in respect toH. prostylum. The decreased size of theH. phlegraeand the short and wide muzzle are discussed forHipparions.s. during the Turolian period. Phylogenetic relationships of the new species and related taxa are reconstructed and also considered. SUPPLEMENTAL DATA—Supplemental materials are available for this article for free atwww.tandfonline.com/UJVP [ABSTRACT FROM AUTHOR]