Αναδρομική μελέτη κοόρτης για τη χρήση φαρμάκων εκτός ενδείξεων στην παιδιατρική αιματολογία-ογκολογία

Εισαγωγή / Σκοπός: Η επιλογή θεραπείας εκτός ενδείξεων αποτελεί κοινή πρακτική στους παιδιατρικούς ασθενείς, ωστόσο η συχνότητα της χρήσης της και η αποτελεσματικότητά της στην παιδιατρική αιματολογία – ογκολογία δεν έχουν σαφώς καθοριστεί. Σκοπός της παρούσας εργασίας είναι η συμβολή στην καταγραφή και αξιολόγηση της επιλογής θεραπείας εκτός ενδείξεων, ως κίνητρο για περαιτέρω διεξαγωγή κλινικών δοκιμών σε μεγαλύτερα δείγματα ασθενών. Υλικό και Μέθοδος: Πραγματοποιήθηκε μια αναδρομική μελέτη κοόρτης των 989 ασθενών ηλικίας 0-18 ετών που νοσηλεύτηκαν στην Πανεπιστημιακή Μονάδα Αιματολογίας – Ογκολογίας (Π.Ο.ΑΙ.Μ.) του Νοσοκομείου Παίδων «Η Αγία Σοφία» από 1 Ιανουαρίου 2013 έως και 31 Δεκεμβρίου 2022, εκ των οποίων οι 240 έλαβαν θεραπεία εκτός ένδειξης, από δεξαμενή 70 φαρμάκων (σύνολο αιτήσεων: 589). Η εκτός ένδειξης χορήγηση θεραπείας, συνίσταται στη χορήγηση φαρμάκων εγκεκριμένων για το νόσημα, αλλά όχι στην ηλικία του ασθενούς, ή φαρμάκων μη εγκεκριμένων για το νόσημα, αλλά ειδικών για γενετική μετάλλαξη του συγκεκριμένου ασθενή ή με επαρκή βιβλιογραφικά στοιχεία για τη χρήση στην εκάστοτε περίπτωση. Διενεργήθηκε στατιστική επεξεργασία και αξιολόγηση των δεδομένων που αφορούν τα χαρακτηριστικά των ασθενών και της θεραπείας εκτός ένδειξης και επακόλουθη συσχέτιση της επιλογής θεραπείας με την κλινική πορεία των ασθενών. Αποτελέσματα: Ο επιπολασμός της χρήσης φαρμάκων εκτός ενδείξεων είναι συνολικά 24,27%, και αυξήθηκε σημαντικά μετά την εισαγωγή του Εθνικού Συστήματος Ηλεκτρονικής Προέγκρισης Φαρμάκων (πριν: 8,54% και 81 αιτήσεις, μετά: 39,83% και 508 αιτήσεις). Η διάμεση ηλικία των ασθενών είναι 7 κατά τη διάγνωση και 9,5 κατά τη χορήγηση του φαρμάκου και η διάμεση χρονική διάρκεια θεραπείας είναι 0,5 έτη. Το 76,67% των υπό εκτός ένδειξης θεραπεία συμμετεχόντων είναι ογκολογικοί ασθενείς, ενώ επικρατέστερη διάγνωση (23,75%) είναι τα κακοήθη νεοπλάσματα εγκεφάλου. Από τα 70 φάρμακα, 53 (75,71%) χρησιμοποιήθηκαν σε τουλάχιστον 1 ασθενή και 36 (51,43%) είναι παράγοντες στοχευμένης θεραπείας η χρήση της οποίας αφορά το 75% των ασθενών. Το συχνότερα χρησιμοποιούμενο εκτός ένδειξης φάρμακο (14,17% των ασθενών) είναι το Bevacizumab. Το 15% των ασθενών στους οποίους χορηγήθηκαν φάρμακα εκτός ενδείξεων κατέληξε, ενώ το 2,5% εμφάνισε σοβαρή τοξικότητα στη θεραπεία. Συμπεράσματα: Η φαρμακευτική θεραπεία εκτός ένδειξης είναι συχνή στην παιδιατρική αιματολογία – ογκολογία και η χρήση της έχει διευκολυνθεί με την εισαγωγή ηλεκτρονικού τρόπου αιτήσεων.Introduction / Aim: Off-label therapy is a common practice in pediatric patients, however the prevalence of its use in pediatric hematology-oncology has not been established yet. The aim of our study is to contribute to the global recording of off-label treatment and to highlight the need of further evaluation in larger cohorts. Methods and materials: We completed a retrospective single-institution cohort study of 989 patients, aged 0-18 years, who were treated at the University Pediatric Hematology-Oncology Unit of “Aghia Sophia” Children’s Hospital, between 2013 and 2022. 240 patients received off-label therapy, from a pool of 70 drugs (total requests: 589). The term “off-label” refers to the application of EMA-approved drugs beyond the approved label and include alternative indications (usually after tumor molecular profiling) or unapproved patient’s age. The present analysis consists of evaluating the prevalence, the characteristics and clinical outcomes of off-label treatment in our cohort. Results: The prevalence of off-label use is 24.27% and increased significantly after the introduction of the National Electronic Drug Pre-Authorization System (before: 8.54% /81 requests and after: 39.83% /508 requests). The patients’ median age is 7 at diagnosis and 9.5 at off-label drug administration, while the median off-label treatment duration is 0.5 years. 76.67% of all patients treated off-label are oncology patients and the most common diagnosis (23.75% of all) is malignant brain neoplasm. 53 drugs (75,71%) were used off-label by at least 1 patient. 36 drugs (51,43%) are targeted agents and 75% of the patients were off-label treated with targeted therapy. The most commonly off-label used drug is Bevacizumab, which was used by 14.17% of the patients. 15% of the patients treated off-label died and 2.5% presented serious toxicity to therapy. Conclusions: Off-label therapy is common in pediatric hematology-oncology and has been facilitated after the introduction of the National Electronic Drug Pre-Authorization System

Pneumococcal Immunization Strategies for High-Risk Pediatric Populations Worldwide: One Size Does Not Fit All

Despite the significant reduction in pneumococcal disease due to pneumococcal vaccines, protection of vulnerable high-risk individuals, especially pediatric populations, remains a great challenge. In an effort to maximize the protection of high-risk children against pneumococcal disease, a combined schedule that includes both conjugate and polysaccharide vaccines is recommended by several countries in the developed world. On the other hand, middle- and low-income countries do not have in place established policies for pneumococcal immunization of children at risk. Pneumococcal conjugate vaccines, despite their benefits, have several limitations, mainly associated with serotype replacement and the wide range of serotype coverage worldwide. In addition, PPV23-impaired immunogenicity and the hyporesponsiveness effect among populations at risk have been well-documented. Therefore, the added value of continuing to include PPV23 in vaccination schedules for high-risk individuals in the years to come remains to be determined by monitoring whether the replacing/remaining serotypes causing IPD are covered by PPV23 to determine whether its benefits outweigh its limitations. In this review, we aim to describe serotype distribution and vaccine efficacy data on pneumococcal disease in the pre- and post-PCV implementation era among high-risk children in both developed and developing countries, assessing the optimization of current recommendations for their vaccination against pneumococcal disease

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential