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Over 50% of breast tumors harbor alterations in one or more genes of the phosphatidylinositol 3-kinase (PI3K) pathway including PIK3CA mutations (31%), PTEN loss (34%), PTEN mutations (5%) and AKT1 mutations (3%). While PI3K and mTOR inhibitors are already approved in advanced breast cancer, AKT inhibitors have been recently developed as a new therapeutic approach. Capivasertib (AZD5363) is a novel, selective ATP-competitive pan-AKT kinase inhibitor that exerts similar activity against the three AKT isoforms, AKT1, AKT2, and AKT3. Preclinical studies demonstrated efficacy of capivasertib in breast cancer cell lines as a single agent or in combination with anti-HER2 agents and endocrine treatment, especially in tumors with PIK3CA or MTOR alterations. Phase I/II studies demonstrated greater efficacy when capivasertib was co-administered with paclitaxel, fulvestrant in hormone receptor (HR)-positive, HER2-negative breast cancer or olaparib. The recommended phase II dose of capivasertib as monotherapy was 480 mg bid on a 4-days-on, 3-days-off dosing schedule. Toxicity profile proved to be manageable with hyperglycemia (20–24%), diarrhea (14–17%) and maculopapular rash (11–16%) being the most common grade ≥3 adverse events. Ongoing Phase III trials of capivasertib in combination with fulvestrant (CAPItello-291), CDK4/6 inhibitor palbociclib (CAPItello-292) and paclitaxel (CAPItello- 290) will better clarify the therapeutic role of capivasertib in breast cancer. © 2022

Background: Joint manifestations are ill-defined adverse events that were frequently reported of bevacizumab in ovarian cancer patients. The aim of this study is to describe the incidence and severity of joint manifestations among bevacizumab treated patients as well as their relation to clinical outcomes. Methods: Medical charts of all ovarian cancer patients that received bevacizumab from 2012 through 2017 were reviewed. Joint manifestations were staged. Kaplan-Meier Survival curves were generated; survival differences were estimated. Results: 76 Patients diagnosed with stage III or IV ovarian cancer were included. 23 patients (30.3%) developed joint manifestations, 12 of them had Grade I, 4 Grade II and 7 Grade III. Only 3 patients developed arthritis. In 8 cases (34.8%) one joint was affected and in the remaining 15, multiple sites. Median number of bevacizumab cycles to arthralgia development was 7. 3 patients were managed with corticosteroids or methotrexate, all had grade 3 AEs. The remaining received common analgesics. Median duration of the AE was 4.8 months. 7 patients discontinued bevacizumab due to AE. In all but 3 patients AE was finally resolved. Median number of bevacizumab cycles received, frequency of treatment completion or treatment discontinuation due to disease progression did not differ significantly among patients that developed joint manifestations or not. Median PFS and median OS did not differ statistical significantly. Conclusion: Joint manifestations are common AEs in bevacizumab treated ovarian cancer patients and led to treatment discontinuation in 9% of the patients. However, this has not adversely affected the clinical outcome of the patients. Further research is needed for the appropriate management of these patients. © 2022 The Author(s)

Background: Breast cancer remains the most common cancer in women and a leading cause of death. Elderly people have a higher incidence of breast cancer since it increases with age. Furthermore, the extended life expectancy and advances in imaging techniques have led to an increased number of cases. Guidelines concerning the management of this specific age group are rare, mainly due to underrepresentation of seniors in clinical trials. Moreover, increased frailty, comorbidities, and a poor performance status make it complex to determine the best therapeutic approach. Summary: In this review, we attempt to summarize the current literature and aim to provide specific approaches and recommendations for prompt diagnosis, treatment, and management of breast cancer in the elderly. Key Messages: The establishment of applicable protocols is imperative and efforts are being made in this direction. A careful geriatric assessment and adequate consultation should be the standard of care and patient's preferences should always be considered. © 2021 S. Karger AG, Basel. Copyright: All rights reserved.

BackgroundAround 5%-7% of breast cancer cases are diagnosed in women younger than 40, making it the leading cause of female cancer in the 25- to 39-year-old age group. Unfortunately, young age at diagnosis is linked to a more aggressive tumor biology and a worse clinical outcome. The identification of the mutational landscape of breast cancer in this age group could optimize the management. MethodsWe performed NGS analysis in paraffin blocks and blood samples of 32 young patients with breast cancer [

Background: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. Methods: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. Results: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

OBJECTIVE: Vancomycin use for intrapartum GBS prophylaxis is not well characterized. The objective of this study was to describe trends in the use of vancomycin among women undergoing vaginal delivery with group B Streptococcus (GBS) colonization. METHODS: An administrative inpatient database that includes medications was analyzed to evaluate antibiotic use in women undergoing vaginal delivery hospitalizations complicated by GBS colonization from January 2006 to March 2015. Patients with other obstetric or infectious indications for antibiotics were excluded. Frequency of use of individual antibiotic agents was determined. The Cochran-Armitage test was used to assess temporal trends. An adjusted log-linear regression model accounting for demographic and hospital factors with vancomycin receipt as the outcome was performed with adjusted risk ratios (aRR) and 95% confidence intervals (CI) as the measure of effect. Hospital level variation in administration of vancomycin was also evaluated. RESULTS: 469,717 deliveries met inclusion criteria and were included in this analysis. Use of vancomycin increased from 0.8% of patients in 2006 to 3.8% of patients in the first quarter of 2015. Comparing 2015 to 2006 both the unadjusted (relative risk 4.89 95% CI 4.26–5.60) and adjusted (aRR 4.52 95% 3.94–5.19) models demonstrated significantly increased likelihood of vancomycin administration. In evaluating hospital level vancomycin use, variation was noted with 8.0% of centers administering vancomycin to ≥6.0% of patients. CONCLUSIONS: Vancomycin is becoming increasingly commonly used for intrapartum GBS prophylaxis. Further research and quality improvements initiatives are indicated to optimize intrapartum GBS antibiotic prophylaxis.

OBJECTIVE: To describe risk of Clostridium difficile infection associated with clindamycin and acute kidney injury associated with gentamicin during delivery hospitalizations. METHODS: Women admitted for delivery from January 2006 to March 2015 were analyzed using an inpatient administrative database. Primary outcomes were C. difficile infection and acute kidney injury. Clostridium difficile infection was compared between women receiving clindamycin (with or without other antibiotics) and women receiving antibiotics other than clindamycin. Acute kidney injury was compared between women receiving gentamicin (with or without other antibiotics), women receiving antibiotics other than gentamicin, and women receiving no antibiotics. Unadjusted and adjusted log linear models analyzing the role of patient demographics, mode of delivery, and hospital-level characteristics were created evaluating risk for C. difficile infection and acute kidney injury with risk ratios (RR) and adjusted risk ratios with 95% confidence intervals (CI) as measures of association. A sensitivity analysis for gentamicin and acute kidney injury was performed restricted to women with preeclampsia. RESULTS: Of 5,657,523 women admitted for delivery hospitalization, 266,402 (4.7%) received clindamycin and 165,726 (2.9%) received gentamicin. Clostridium difficile infection was diagnosed in 0.04% of women receiving clindamycin. Compared to women receiving other antibiotics, clindamycin was associated with a nearly three-fold increased risk of C. difficile infection (RR 2.93, 95% CI 2.36, 3.65). Acute kidney injury was diagnosed in 0.24% of women receiving gentamicin. Gentamicin was associated with a three-fold risk of acute kidney injury (RR 3.01, 95% CI 2.71, 3.34) compared to women receiving other antibiotics, while receipt of no antibiotics was associated with significantly lower risk (RR 0.18, 95% CI 0.15, 0.20). In adjusted analyses, these associations retained significance. Significantly increased risk for acute kidney injury was noted with women with preeclampsia receiving gentamicin (RR 2.04, 95% CI 1.64, 2.53). CONCLUSION: Receipt of clindamycin was associated with significantly increased likelihood for C. difficile infection and receipt of gentamicin with significantly increased likelihood of acute kidney injury, although the absolute risk for these complications was low.

Objective Trends in use of antibiotics during delivery hospitalizations complicated by (1) 3rd/4th degree vaginal lacerations, (2) manual placenta extraction, and (3) uterine tamponade are not well characterized. The objective of this study was to analyze trends in antibiotic use during vaginal delivery hospitalizations complicated by these three clinical scenarios. Study Design An administrative inpatient database was used to perform a serial cross-sectional analysis of antibiotic administration during delivery hospitalizations in the United States from January 2006 to March 2015. The primary outcome was receipt of antibiotics during vaginal delivery hospitalizations complicated by (1) 3rd and 4th degree vaginal lacerations, (2) manual placenta extraction, and (3) uterine tamponade. Patients with other indications for antibiotics were excluded. The Cochran–Armitage test was used to assess trends. Adjusted log linear regression analyses including demographic, hospital, and obstetric factors were performed to analyze factors associated with antibiotic receipt for each of these three clinical scenarios in both primary and sensitivity analyses. Results From 2006 to 2015 the rate of antibiotic administration during delivery hospitalizations decreased from 43.1% in 2006 to 25.5% for 3rd and 4th degree lacerations and from 59.6% to 49.2% for manual extraction (p Conclusion Antibiotics are not used consistently during vaginal deliveries complicated by 3rd/4th degree lacerations, manual placenta extraction, and uterine tamponade. These findings support that a significant opportunity exists for comparative effectiveness research to assist in characterizing best practices.

OBJECTIVE: To analyze trends in unindicated antibiotic use during vaginal delivery hospitalization. METHODS: This study used an administrative database to analyze antibiotic use during delivery hospitalizations from January 2006 to March 2015. Women were classified by mode of delivery and whether they had an evidence based indication for antibiotics. Indications for antibiotics included preterm premature rupture of membranes, cesarean delivery, group B streptococcus colonization, chorioamnionitis, endometritis, urinary tract infections, and other infections. The Cochran-Armitage test was used to assess trends of antibiotic administration. Unadjusted and adjusted analyses for antibiotic receipt including demographic, hospital, and obstetric and medical factors with unadjusted and adjusted risk ratios (RR, aRR respectively) with 95% confidence intervals (CI) as measures of association were performed. RESULTS: 5,536,756 delivery hospitalizations including 2,872,286 vaginal deliveries with use of antibiotics without indication were analyzed. The most common indication for antibiotics was cesarean delivery (33.6% of the entire cohort), followed by GBS colonization (15.8%), chorioamnionitis (1.7%), PPROM (1.6%), endometritis (1.2%), urinary tract infections (0.6%), and other infections (total

Background: Tricuspid regurgitation (TR) is linked to poor outcomes and its progression is associated with higher mortality. Left heart disease, age and sex are factors related to TR progression. We assessed echocardiographic (Echo) and demographic predictors of moderate TR progression using Machine Learning Natural Language Processing (ML NLP). Methods: 54,315 patients were retrospectively assessed for moderate TR with an Echo between May 2017 to October 2020 and a follow-up Echo 30 days to 113 months. Exclusion criteria included prior pacemaker/ICD, tricuspid prosthesis or band/ring, history of Ebstein, tetralogy of Fallot and tricuspid endocarditis. Cardiac Intelligence TM (Mpirik, Milwaukee, WI) identified moderate TR, demographic and Echo indices using ML NLP of the Echo report. Our endpoint was progression from moderate to severe TR within 1 or 2 years. Univariate Cox proportional hazard model was used with univariate analysis. Results: Of 3,489 moderate TR patients, 1,564 had a subsequent Echo and 771 met study criteria. Table 1 shows baseline demographic and Echo data. 15% and 24% of moderate TR patients progressed to severe TR within 1 and 2 years, respectively. Black race, left ventricular size, moderate/severe right ventricular (RV) dysfunction and Doppler-based RV systolic pressure were found to be univariate predictors of progression (Figure 1). Conclusion: ML NLP based on input from Echo-derived parameters using a real-world sample can offer insights into risk stratification of moderate TR regarding risk of progression to severe disease. Including further clinical and demographic variables will allow to improve performance of a disease prediction ML model.

Recently, immunotherapy has shown promising results in solid tumors. To the best of our knowledge, this is the first systematic review of published literature synthesizing all the available data and evaluating both the efficacy and safety of pembrolizumab in endometrial cancer. The present study was performed in accordance with the PRISMA guidelines. Eligible articles were identified by searching the MEDLINE and ClinicalTrials.gov databases, using a predefined combination of the terms 'endometrial cancer' and 'pembrolizumab'. Overall, nine articles incorporating data from 712 patients were eligible. Pembrolizumab was demonstrated to be an effective and safe therapeutic option for the management of advanced/metastatic endometrial cancer. Results of ongoing trials evaluating either pembrolizumab alone or in combination with other antineoplastic regimens are expected to confirm its efficacy in this setting of patients. Pembrolizumab appears to be both durable and robust in endometrial cancer. However, there is an emerging need for novel predictive biomarkers to guide clinical practice.

Στις μέρες μας θεωρείται επιτακτική η ανάγκη για την προώθηση της Περιβαλλοντικής Εκπαίδευσης των μαθητών, με στόχο την δημιουργία αυριανών πολιτών με αίσθηση περιβαλλοντικής ευθύνης, περιβαλλοντικό ήθος, και οικολογική συνείδηση. Το εκπαιδευτικό σύστημα θέλοντας να ακολουθήσει και – ακόμα καλύτερα – να ενισχύσει αυτή την επιταγή θα πρέπει να στραφεί σε ριζικές αλλαγές και επικαιροποιήσεις των εκπαιδευτικών μεθόδων και διδακτικών εργαλείων που χρησιμοποιούνται από τους εκπαιδευτικούς και να προταθούν εναλλακτικές μέθοδοι διδασκαλίας που βασίζονται στην βιωματική μάθηση και την αλληλεπίδραση. Μια από αυτές τις μεθόδους είναι και η χρήση θεατρικών τεχνικών, ένα εκπαιδευτικό εργαλείο το οποίο εμπιστεύονται ολοένα και περισσότερο οι εκπαιδευτικοί σε μια ποικιλία γνωστικών αντικειμένων. Σύμφωνα με την βιβλιογραφική μελέτη, έρευνες στο εξωτερικό με μαθητές Πρωτοβάθμιας Εκπαίδευσης έχουν καταλήξει στο συμπέρασμα ότι η χρήση θεατρικών τεχνικών στην εκπαίδευση συμβάλλει σημαντικά στο ενδιαφέρον των μαθητών για συμμετοχή και δράση αναφορικά με το περιβάλλον και τον κόσμο γύρω τους. Το νέο θεατρικό είδος που συνδυάζει τις τέχνες του θεάτρου με τις περιβαλλοντικές ανησυχίες και ευαισθησίες ονομάζεται «οικολογικό θέατρο» (eco theatre), και τα θεατρικά έργα ή δρώμενα που επιμορφώνουν για τα περιβαλλοντικά θέματα και προάγουν την οικολογία, χαρακτηρίζονται ως «οικολογικά θεατρικά έργα» (ecodramas), είτε πρόκειται για συγγραφή θεατρικών κειμένων από θεατρικούς συγγραφείς, είτε για αυτοσχέδια θεατρικά δρώμενα που δημιουργούνται από μαθητές μέσα στην τάξη κατά την εκπαιδευτική διαδικασία. Στην Ελλάδα δεν έχει διερευνηθεί η σύνδεση του αυτοσχέδιου οικολογικού θεάτρου με την Περιβαλλοντική Εκπαίδευση και τα όποια αποτελέσματα από την εισαγωγή στη διδασκαλία για το περιβάλλον μιας διδακτικής μεθόδου που έχει ως βασικό της εργαλείο θεατρικές δραστηριότητες με οικολογικό περιεχόμενο.BΣκοπός της συγκεκριμένης έρευνας είναι να διερευνήσει κατά πόσο η εφαρμογή του αυτοσχέδιου οικολογικού θεάτρου ως εκπαιδευτικού εργαλείου μπορεί να συμβάλλει στην ευαισθητοποίηση της περιβαλλοντικής συνείδησης των μαθητών του δημοτικού. Τα ερευνητικά ερωτήματα της έρευνας είναι αν η εφαρμογή του αυτοσχέδιου οικολογικού θεάτρου στο πλαίσιο της Περιβαλλοντικής Εκπαίδευσης μαθητών δημοτικού : (1) ενισχύει την ικανότητα κατανόησης βασικών αρχών και ιδεών της οικολογίας, περισσότερο από ότι ο παραδοσιακός τρόπος διδασκαλίας, (2) συμβάλλει στην υιοθέτηση στάσεων και αξιών φιλικών προς το περιβάλλον και (3) ποιες είναι οι απόψεις των εκπαιδευτικών που εφαρμόζουν περιβαλλοντικά προγράμματα για το διδακτικό μοντέλο κατά το οποίο γίνεται χρήση θεατρικών τεχνικών στο πλαίσιο της Περιβαλλοντικής Εκπαίδευσης μαθητών δημοτικού. Προκειμένου να δοθούν απαντήσεις στα παραπάνω ερευνητικά ερωτήματα σχεδιάστηκαν δυο στάδια υλοποίησης της έρευνας, από τις αρχές του 2015 μέχρι το καλοκαίρι του 2017. Κατά το πρώτο στάδιο της έρευνας πραγματοποιήθηκε διδακτική παρέμβαση (τεσσάρων (04) μηνών), κατά το σχολικό έτος 2014-15, με τη μέθοδο της έρευνας – δράσης σε είκοσι οκτώ (28) μαθητές της Ε΄ τάξης του δημοτικού (ηλικίας 10-11 ετών). Καθώς η περιβαλλοντική συνείδηση αποτελεί μια συνένωση γνώσεων, στάσεων και συμπεριφορών, στο τέλος της παρέμβασης ερευνήθηκαν, μέσω ειδικά διαμορφωμένων ερωτηματολογίων που συμπληρώθηκαν από τους μαθητές πριν και μετά την παρέμβαση, μετρήσιμες αλλαγές σχετικά με τις γνώσεις, τα συναισθήματα και τις συμπεριφορές τους, αφού εξοικειώθηκαν με τις εναλλακτικές διδακτικές τεχνικές που περιλάμβαναν την υλοποίηση θεατρικών δραστηριοτήτων με οικολογικό περιεχόμενο κατά την Περιβαλλοντική Εκπαίδευση. Το δεύτερο στάδιο της έρευνας πραγματοποιήθηκε κατά το σχολικό έτος 2016-17, με τη συμμετοχή τριακοσίων τριάντα (330) εκπαιδευτικών Πρωτοβάθμιας Εκπαίδευσης που εφαρμόζουν Περιβαλλοντικά Προγράμματα στις σχολικές μονάδες που υπηρετούν και έχουν εφαρμόσει θεατρικές τεχνικές έστω μια φορά στο πλαίσιο των προγραμμάτων αυτών. Οι εκπαιδευτικοί συμπλήρωσαν ένα ερωτηματολόγιο σαράντα εννέα (49) ερωτήσεων σχετικά με τη χρήση θεατρικών τεχνικών ως διδακτικό εργαλείο μέσα στην τάξη προκειμένου να προωθηθούν οι αρχές της Περιβαλλοντικής Εκπαίδευσης. Τα αποτελέσματα της έρευνας δείχνουν ότι, όταν η Περιβαλλοντική Εκπαίδευση βασίζεται σε δραματικές δραστηριότητες, έχει σημαντικό αντίκτυπο και στους τρεις βασικούς τομείς της ανθρώπινης συμπεριφοράς (Γνωστικός τομέας, Συναισθηματικός τομέας, Ψυχοκινητικός τομέας) των μαθητών. Ενισχύει την επινοητικότητα, τη βαθιά κατα-νόηση, την ενσυναίσθηση, την προθυμία για συμμετοχή σε κοινωνικές ενέργειες, την κατανομή των ευθυνών και της δέσμευσης, την ευαισθησία. Επιπλέον, η έρευνα δείχνει ότι οι Έλληνες εκπαιδευτικοί, όπως και οι ομόλογοι τους σε όλο τον κόσμο, είναι πρόθυμοι να εφαρμόσουν εναλλακτικές διδακτικές στρατηγικές, όπως θεατρικές τεχνικές, στις αίθουσες διδασκαλίας τους και επίσης μέσω αυτών να εξυπηρετήσουν και να διαδώσουν σημαντικές ανθρωπιστικές και περιβαλλοντικές αξίες. Αρκεί να είναι καλά εκπαιδευμένοι, επαρκώς παρακινημένοι, εμπνευσμένοι και υποστηριγμένοι προκειμένου οι δραματικές δραστηριότητες στην Περιβαλλοντική Εκπαίδευση να έχουν τον προαναφερθέντα αντίκτυπο.

Archäologische Informationen, Bd. 21 Nr. 2 (1998): Archäologische Informationen