Εφαρμογή Επιθεμάτων με Αντιφλεγμονώδεις Ιδιότητες στην Ακτινοθεραπεία Δερματικών Καρκίνων

Ο συχνότερος καρκίνος του ανθρώπινου σώματος είναι ο μη μελανοκυτταρικός καρκίνος του δέρματος, με το βασικοκυτταρικό και το ακανθοκυτταρικό επιθηλίωμα, να αποτελούν το 95% περίπου των πρωτοπαθών νεοπλασμάτων του δέρματος. Αποτελεσματική θεραπευτική επιλογή αποτελεί η ακτινοθεραπεία, ιδιαίτερα σε περιπτώσεις όπου η χειρουργική αφαίρεση δεν μπορεί να εφαρμοσθεί, λόγω ιδιαίτερου ανατομικού σημείου του όγκου ή συννοσηρότητας του ασθενή. Κυρίαρχη και πιο συχνή ανεπιθύμητη ενέργεια της ακτινοθεραπείας είναι η οξεία ακτινοδερματίτιδα, η οποία επηρεάζει την ποιότητα ζωής των ασθενών και τη συμμόρφωσή τους στη θεραπεία. Αναντίστοιχο με το πλήθος των κλινικών μελετών, που έχουν διεξαχθεί παγκοσμίως, αποτελεί το γεγονός, ότι μέχρι σήμερα δεν υπάρχει κατάλληλο θεραπευτικό μέσο για την πρόληψη και την αντιμετώπιση της επικείμενης σοβαρής ανεπιθύμητης ενέργειας. Η συγκεκριμένη κλινική μελέτη σχεδιάστηκε βασιζόμενη στα ενθαρρυντικά φαρμακολογικά και τοξικολογικά αποτελέσματα, που προέκυψαν από προγενέστερη προκλινική και κλινική έρευνα, σχετικά με την ευεργετική δράση του εκχυλίσματος από τον φλοιό του φυτού Pinus halepensis (PHBE) στη φλεγμονή και στη διατήρηση των φυσιολογικών ιδιοτήτων του δέρματος. Η μακροχρόνια προκλινική έρευνα διεξήχθη στο εργαστήριο μικρών πειραματοζώων του Τομέα Φαρμακευτικής Τεχνολογίας του Εθνικού και Καποδιστριακού Πανεπιστημίου Αθηνών, ενώ οι προηγούμενες κλινικές μελέτες, όπως και η παρούσα, διεξήχθησαν στο Ακτινοθεραπευτικό Ογκολογικό τμήμα του Νοσοκομείου Αφροδίσιων και Δερματικών Νόσων «Ανδρέας Συγγρός». Βάσει προηγούμενης μελέτης, παρασκευάστηκε πολυμερικό επίθεμα νανοϊνών PHBE μέσω ηλεκτροστατικής ινοποίησης, αποτελούμενο από Αλγινικό Νάτριο (SA), Οξική Κυτταρίνη (CA), Πολυαιθυλενοξείδιο (PEO) και δραστικό συστατικό το εκχύλισμα από τον φλοιό του φυτού Pinus halepensis σε ποσοστό 26,2% w/w. Σκοπός ήταν η κατάλληλη μορφοποίηση του επιθέματος PHBE για χορήγηση σε ακτινοθεραπευόμενους ασθενείς με μη μελανοκυτταρικό καρκίνο του δέρματος, και η εξέταση της αποτελεσματικότητας και της ασφάλειας του, ως προς την πρόληψη και την αντιμετώπιση της προκαλούμενης από την ακτινοθεραπεία οξείας ακτινοδερματίτιδας. Η δράση του επιθέματος PHBE αξιολογήθηκε σε σύγκριση με ιατροτεχνολογικό προϊόν του εμπορίου. Σύμφωνα με τα κριτήρια ένταξης, επιλέχθηκαν και συμμετείχαν στη μελέτη, δώδεκα εθελοντές ασθενείς, οι οποίοι διαχωρίστηκαν, κατόπιν τυχαιοποίησης και με ισοκατανομή, σε δύο ομάδες. Οι ασθενείς εφάρμοζαν καθημερινά για το χρονικό διάστημα της ακτινοθεραπείας, καθώς και για ένα μήνα μετά το πέρας αυτής, το υπό εξέταση επίθεμα PHBE και το σκεύασμα αναφοράς, αντίστοιχα. Η αξιολόγηση του ακτινοεπαγόμενου ερεθισμού έγινε συνδυάζοντας κλινικά ιατρικά κριτήρια (RTOG), εκβάσεις αναφερόμενες από τον ασθενή (κλίμακα VAS), μη επεμβατικές μετρήσεις των βιοφυσικών παραμέτρων του δέρματος και απεικονιστική εξέταση της ακτινοθεραπευόμενης περιοχής (φωτοτεκμηρίωση, Antera 3D), στη διάρκεια της θεραπείας, καθώς και στον επανέλεγχο, ένα μήνα μετά το πέρας αυτής. Από τον στατιστικό έλεγχο προέκυψε η συντριπτική υπεροχή του επιθέματος PHBE, έναντι του σκευάσματος αναφοράς, ως προς την πρόληψη και την αντιμετώπιση της προκαλούμενης από την ακτινοθεραπεία ακτινικής δερματίτιδας, σε όλο το διάστημα της θεραπείας, όπως και ένα μήνα μετά το πέρας αυτής. Ειδικότερα, στους ασθενείς που εφάρμοσαν το επίθεμα PHBE, παρατηρήθηκε άμεση βελτίωση της κλινικής εικόνας, πρόληψη των υποκειμενικών ενοχλήσεων, καθώς και επίτευξη καλύτερων αποτελεσμάτων στις εμβιομηχανικές μετρήσεις. Εξετάζοντας περαιτέρω την άμεση ανταπόκριση της ομάδας των ασθενών που εφάρμοζε το επίθεμα PHBE, παρατηρήθηκαν και διατυπώθηκαν δύο πιθανά μοντέλα εξέλιξης της ακτινικής δερματίτιδας. Το πρώτο μοντέλο εξέλιξης της οξείας ακτινοδερματίτιδας στους ασθενείς με επίθεμα PHBE χαρακτηρίζεται από επιβράδυνση της εμφάνισης της οξείας ακτινοδερματίτιδας και εν συνεχεία αντιμετώπιση των κλινικών συμπτωμάτων, ενώ το δεύτερο μοντέλο χαρακτηρίζεται από πρόληψη της εμφάνισης της οξείας ακτινοδερματίτιδας και απουσία κλινικών εκδηλώσεων. Η έλλειψη ανεπιθύμητων ενεργειών καθιστά το υπό δοκιμή επίθεμα PHBE μια ασφαλή τοπική αγωγή. Ως εκ τούτου, για την ισχυροποίηση των αποτελεσμάτων κρίνεται σκόπιμη η περαιτέρω διερεύνηση της συμβολής του επιθέματος PHBE στην πρόληψη της οξείας ακτινοδερματίτιδας σε μεγαλύτερο δείγμα πληθυσμού.The most common cancer of the human body is non-melanoma skin cancer (NMSC), with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) accounting for 95% of primary skin tumors. Radiation therapy is an effective treatment option, especially in cases where surgical removal cannot be applied, due to a particular anatomical point of the tumor or comorbidity of the patient. The main side effect of radiotherapy is acute radiodermatitis, which affects the quality of life of patients and their compliance to therapy. Despite the growing number of clinical trials, that have been conducted worldwide, there is still no regimen fulfilling our needs and expectations, in order to prevent such a disturbing side effect. This clinical study was designed based on encouraging pharmacological and toxicological results, which emerged from previous preclinical and clinical research, during the application of Pinus halepensis bark extract (PHBE) in skin inflammation. The long-term preclinical research was conducted in Small Animal Laboratory of Pharmaceutical Technology Department of National and Kapodistrian University of Athens, while the previous clinical studies, same as the present study, were conducted in the Radiotherapy Oncology Department of Andreas Syggros Hospital of Cutaneous and Venereal Diseases. Based on a previous study, PHBE nanofiber polymeric patch was produced by electrospinning, composed of Sodium Alginate (SA), Cellulose Acetate (CA), Polyethylene Oxide (PEO) and the active ingredient, bark extract of the plant Pinus halepensis (26,2% w/w). Purpose of this study was to formulate the PHBE patch, as well as, examine its efficacy and safety, in order to prevent acute radiodermatitis in patients with non-melanoma skin cancer undergoing radiotherapy. The action of PHBE patch was evaluated in comparison to a commercially available medical device. According to the inclusion criteria, twelve volunteer patients were selected and randomly assigned to two groups, applying daily either PHBE patch or reference product. Evaluation of radiation-induced skin reactions was made according to RTOG grading scale, patients reported outcomes (VAS scale), biophysical measurements and image analysis (Antera 3D), during radiotherapy time and one month afterwards. Statistical analysis showed PHBE patch to be more effective at ameliorating skin condition during radiotherapy time, as well as, one month afterwards preventing inflammation, reducing subjective discomfort and achieving better scores in biophysical measurements. PHBE patch showed significant anti-inflammatory activity and maintenance of the normal skin properties. Examining further these results, two possible models of acute radiodermatitis progression were observed in intervention group. The first model is characterized by slowing acute radiodermatitis progression and finally symptom reduction, while the second one by acute radiodermatitis prevention. No adverse event was reported in intervention group, indicating that PHBE patch is a safe topical prophylactic treatment for radiodermatitis. Future studies on greater sample size should be executed, in order to confirm these results

Ulvan-Based Nanofibrous Patches Enhance Wound Healing of Skin Trauma Resulting from Cryosurgical Treatment of Keloids

Keloids are skin fibroproliferative disorders, resulting from abnormal healing of deep cutaneous injuries. Cryosurgery, the most common treatment for keloids, causes skin traumas. Even though the clinical practice of cryosurgery has increased, effective wound healing therapy is still lacking. In this investigation, nonwoven nanofibrous patches composed of ulvan, a marine sulfated polysaccharide exhibiting anti-inflammatory and antioxidant activities, and polyethylene oxide (PEO) were fabricated through electrospinning and characterized. Their wound healing efficacy on skin traumas resulting from cryosurgical treatment of keloids was clinically tested and evaluated in comparison to a reference product. Twenty-four volunteer patients undergoing cryosurgery as a treatment of keloids were selected to apply either the ulvan/PEO patch or the reference product for 21 days. The ulvan/PEO patch, 21 days after cryosurgery, showed significant wound healing, elimination of skin inflammation, restoration of biophysical parameters similar to normal values and significant decrease in haemoglobin concentration, skin texture and volume, while no discomfort or adverse reaction was observed. In contrast, the reference product showed inferior performance in all evaluated parameters. The designed ulvan/PEO patch represents the first wound dressing to effectively heal skin trauma after cryosurgical treatment of keloids

Management of Acute Radiodermatitis in Non-Melanoma Skin Cancer Patients Using Electrospun Nanofibrous Patches Loaded with Pinus halepensis Bark Extract

Acute radiodermatitis is the most common side effect in non-melanoma skin cancer patients undergoing radiotherapy. Nonetheless, despite the ongoing progress of clinical trials, no effective regimen has been found yet. In this study, a non-woven patch, comprised of electrospun polymeric micro/nanofibers loaded with an aqueous extract of Pinus halepensis bark (PHBE), was fabricated and clinically tested for its efficacy to prevent radiodermatitis. The bioactivity of the PHBE patch was evaluated in comparison with a medical cream indicated for acute radiodermatitis. Twelve volunteer patients were selected and randomly assigned to two groups, applying either the PHBE patch or the reference cream daily. Evaluation of radiation-induced skin reactions was performed during the radiotherapy period and 1 month afterwards according to the Radiation Therapy Oncology Group (RTOG) grading scale, photo-documentation, patient-reported outcomes (Visual Analog Scale, questionnaire), biophysical measurements (hydration, transepidermal water loss, erythema, melanin), and image analysis. In contrast with the reference product, the PHBE patch showed significant anti-inflammatory activity and restored most skin parameters to normal levels 1 month after completion of radiation therapy. No adverse event was reported, indicating that the application of the PHBE patch can be considered as a safe medical device for prophylactic radiodermatitis treatment

Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis

Purpose: To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods: Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results: The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value ≤ 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion: 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome

Epidemiology of intra-abdominal infection and sepsis in critically ill patients: "AbSeS", a multinational observational cohort study and ESICM Trials Group Project

Purpose To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). Methods We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. Results The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. Conclusion This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection

Antimicrobial Lessons From a Large Observational Cohort on Intra-abdominal Infections in Intensive Care Units

evere intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by disease-specific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed.Severe intra-abdominal infection commonly requires intensive care. Mortality is high and is mainly determined by diseasespecific characteristics, i.e. setting of infection onset, anatomical barrier disruption, and severity of disease expression. Recent observations revealed that antimicrobial resistance appears equally common in community-acquired and late-onset hospital-acquired infection. This challenges basic principles in anti-infective therapy guidelines, including the paradigm that pathogens involved in community-acquired infection are covered by standard empiric antimicrobial regimens, and second, the concept of nosocomial acquisition as the main driver for resistance involvement. In this study, we report on resistance profiles of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Enterococcus faecalis and Enterococcus faecium in distinct European geographic regions based on an observational cohort study on intra-abdominal infections in intensive care unit (ICU) patients. Resistance against aminopenicillins, fluoroquinolones, and third-generation cephalosporins in E. coli, K. pneumoniae and P. aeruginosa is problematic, as is carbapenem-resistance in the latter pathogen. For E. coli and K. pneumoniae, resistance is mainly an issue in Central Europe, Eastern and South-East Europe, and Southern Europe, while resistance in P. aeruginosa is additionally problematic in Western Europe. Vancomycin-resistance in E. faecalis is of lesser concern but requires vigilance in E. faecium in Central and Eastern and South-East Europe. In the subcohort of patients with secondary peritonitis presenting with either sepsis or septic shock, the appropriateness of empiric antimicrobial therapy was not associated with mortality. In contrast, failure of source control was strongly associated with mortality. The relevance of these new insights for future recommendations regarding empiric antimicrobial therapy in intra-abdominal infections is discussed