Eftichia Stiakaki

Antibiotics are among the transformative advances in medicine, but many interact with mammalian cellular targets and pathways beyond their antimicrobial activity. A clinically important expression of these off-target effects is hematologic toxicity, including immune-mediated cytopenias and direct bone marrow suppression. This narrative review examines whether the same biology that injures normal hematopoietic cells can, in selected contexts, reveal therapeutically exploitable vulnerabilities in leukemia. We synthesize molecular, clinical, and preclinical evidence and organize it into an integrative framework linking mitochondrial translation inhibition, mitonuclear imbalance, oxidative phosphorylation failure, reactive oxygen species generation, DNA/topoisomerase stress, autophagy and lysosomal-flux blockade, and apoptosis modulation with both hematotoxicity and antileukemic activity. The strongest preclinical evidence supports selected tetracyclines, macrolides, and oxazolidinones, whereas evidence for beta-lactams, glycopeptides, polymyxins, rifamycins, fluoroquinolones, and folate-pathway agents remains more limited or largely hypothesis-generating. Importantly, antibiotic-induced cytopenia should not be interpreted as proof of leukemia selectivity: immune-mediated toxicity, supratherapeutic in vitro exposure, normal progenitor injury, pharmacokinetic constraints, microbiome effects, and resistance mechanisms all narrow the translational window. Overall, antibiotic hematotoxicity is best viewed as a biologically informative signal that can guide mechanism-based repurposing and combination strategies, but clinical development requires rigorous pharmacokinetic/pharmacodynamic validation, normal hematopoietic comparators, and biomarker-driven patient selection.

Background/Objectives: Inherited variants in IKZF1 and CDKN2A/2B are among the most consistently reported germline susceptibility markers for childhood acute lymphoblastic leukemia (ALL). Nonetheless, effect sizes differ across ancestry groups, age ranges, and immunophenotypic subtypes, making well-characterized population-specific replication studies valuable for refining ancestry-specific evidence. This study examined two sentinel variants with historical relevance, IKZF1 rs4132601 and CDKN2A rs3731217, within a pediatric Greek cohort. Methods: A case–control study with retrospective case ascertainment and control recruitment through routine pediatric visits was conducted, comprising 50 children and adolescents with ALL and 91 healthy controls from Crete, Greece. Constitutional DNA was isolated from peripheral blood samples collected during remission in cases, while controls provided peripheral blood for targeted germline genotyping. Genotyping was performed using PCR-restriction fragment length polymorphism analysis. We evaluated Hardy–Weinberg equilibrium and genotype and allele distributions and analyzed the data using logistic regression models. Results: Control minor allele frequencies were broadly compatible with public European reference data. Neither IKZF1 rs4132601 nor CDKN2A rs3731217 showed a significant association with susceptibility to childhood ALL under either genotype-based or additive models. Results remained consistent after excluding T-cell ALL cases. Exploratory genotype-phenotype analyses did not reveal robust associations with clinical or molecular features. Conclusions: In this first Greek pediatric assessment of IKZF1 rs4132601 and CDKN2A rs3731217, no significant association with ALL susceptibility was observed. Within the constraints of limited statistical power, these negative findings provide population-specific evidence, refine regional allele-frequency and effect-size estimates, highlight the limitations of relying on single historical sentinel single-nucleotide polymorphisms (SNPs), and support future ancestry-informed and polygenic approaches in southeastern European cohorts.

With each replication cycle, telomeres shorten. Telomerase can slow or reverse the rate of telomere shortening. In the era of cancer immunotherapy, telomerase is a promising tumor-associated antigen due to its widespread and specific expression in cancer cells and its strong immunogenicity. Interestingly, telomerase-based vaccines eradicate telomerase-expressing cancer cells by increasing antigen-specific T-cell responses rather than by directly inhibiting telomerase enzymatic activity as telomerase inhibitors function. To support this, telomerase-based vaccines, including DNA, mRNA, peptide-, and cell-based vaccines, have been evaluated in clinical settings to elucidate their molecular mechanisms of action. The aim of this review is to present the clinical effectiveness of telomerase vaccines alone or in combination with immunotherapy. In particular, the therapeutic effectiveness of telomerase vaccines is influenced by the tumor microenvironment and can be substantially increased by combining them with immune checkpoint inhibitors. To further optimize telomerase-based vaccines, we discuss translational challenges and highlight the need for further optimization.

Aims/Background: Myosin heavy chain 9-related disease (MYH9-RD) is a rare inherited disorder characterised by macrothrombocytopenia, often misdiagnosed as immune thrombocytopenia (ITP). Early identification is crucial to prevent unnecessary treatments and to ensure appropriate monitoring. The present case aims to highlight the diagnostic challenges and clinical management of MYH9-RD in a toddler, emphasising the importance of early genetic testing. Case Presentation: We discuss a 13.5-month-old girl with macrothrombocytopenia lacking Döhle bodies, who initially received intravenous immunoglobulin (IVIg) and corticosteroids without any response. Within two months, whole-exome sequencing identified a pathogenic MYH9 mutation (c.287C>T; p.Ser96Leu). Results: One year later, the patient remains clinically stable without significant bleeding. The occurrence of petechial rash exhibited a more pronounced correlation with platelet mass index (PMI) values compared to platelet count (PLT), underscoring its significance in clinical evaluation. Conclusion: MYH9-RD should be considered in cases of IVIg-resistant thrombocytopenia accompanied by macrothrombocytes. Timely genetic testing can facilitate accurate diagnosis and may help avoid unnecessary procedures, while routine renal and auditory monitoring is important for managing the S96L variant.

Background and Clinical significance: Cowden syndrome is an autosomal dominant disorder caused by germline loss-of-function mutations in the PTEN tumor suppressor gene. It is characterized by multiple hamartomas and an increased lifetime risk of malignancies affecting the breast, thyroid, endometrium, and gastrointestinal (GI) tract. Pediatric presentations may include macrocephaly, scrotal tongue, and intellectual disability. Gastrointestinal involvement is frequent, with juvenile-like hamartomatous polyps occurring in at least half of patients and distributed throughout the GI tract, posing a risk for malignant transformation. Early diagnosis and surveillance are crucial for improving patient outcomes. Case Presentation: We report a case of a 10-year-old Caucasian female with Cowden syndrome, with a history of a malignant germ cell tumor of the ovary consisting of a yolk sac tumor and low-grade immature teratoma diagnosed at age six, and thyroidectomy at age nine. The patient has mild intellectual disability. Routine radiological surveillance revealed a right colon intraluminal mass, prompting referral for pediatric gastroenterology evaluation. Endoscopy identified multiple polyps throughout the colon, stomach, and small intestine. Polypectomy of larger lesions was performed, and histopathology confirmed juvenile-like hamartomatous polyps without dysplasia or malignancy. This case highlights the necessity of comprehensive gastrointestinal evaluation in pediatric Cowden syndrome patients. Endoscopic surveillance is essential for early detection and management of polyps. Conclusions: Given the multisystem involvement and elevated cancer risk associated with PTEN mutations, a multidisciplinary approach that includes genetic counseling, dermatologic evaluation, and ongoing oncologic monitoring is recommended. Increased awareness of gastrointestinal manifestations enables timely intervention and may reduce morbidity and mortality in this high-risk population.

Despite significant advancements in overall survival rates for childhood acute lymphoblastic leukemia (ALL), relapse continues to pose a major challenge. MicroRNAs have proven valuable for improving diagnosis, treatment, and survival outcomes, establishing themselves as key biomarkers. Using RNA-seq data from 123 ALL patients and employing predictive modeling via automated machine learning (AutoML) alongside causal-inspired biomarker discovery, we identified highly predictive microRNA signatures linked to high-risk strata and clinical features in unfavorable cases. We further identified predictive signatures for each genetic subtype of childhood ALL, highlighting shared miRNAs throughout the study. A thorough literature review of the relationships between miRNA differential expression and key high-risk features in childhood ALL [immunophenotype, elevated white blood cell counts at diagnosis, central nervous system involvement, measurable residual disease (MRD), and chemoresistance] confirmed the signatures generated in this study. Our results revealed a highly predictive signature distinguishing B- and T-ALL, associated with apoptosis, confirming the reported difference between the two immunophenotypes. Additionally, miR-223 emerged as crucial for high-risk stratification and chemoresistant MRD-positive cases. These findings demonstrate the potential of AutoML tools to reveal novel biological insights in pediatric ALL, driving future advancements.

Background: Recent advances in childhood cancer treatment and increased survival rates have led to a growing number of adolescents and young adults (AYAs) who are survivors of childhood cancer (CCSs). This study aimed to examine health status, health-related quality of life (HRQoL), and social outcomes in AYA CCSs. Methods: Sixty-two AYAs who were CCSs (treated within the same tertiary Pediatric Hematology–Oncology Department in Crete, Greece) were enrolled in the study. Self-reported HRQoL was assessed using the Short-Form Health Survey (SF-36). Sixty-five never-ill peers constituted the control group. Results: CCSs reach adolescence and young adulthood without significant deviations in HRQoL from their healthy peers. The presence and severity of late effects were significantly correlated with lower scores in physical health. The cancer type seems to play a pivotal role: Langerhans cell histiocytosis survivors displayed significantly lower scores in mental health, and brain tumor survivors scored substantially lower scores in physical functioning. Acute lymphoblastic leukemia survivors reported the highest scores in mental health. Age at diagnosis of neoplasia was negatively correlated with physical functioning. No significant sex differences were identified. Adherence to multiple healthy lifestyle behaviors (regular exercise, abstaining from alcohol consumption and smoking, and using sun protection) and active employment were correlated with significantly higher scores in mental health. Conclusions: Appropriate therapy and regular follow-up after treatment have led to improved clinical and social outcomes, as assessed by CCSs. More efforts are needed to increase awareness of avoiding harmful behaviors that raise the risk of late effects in this specific group.

Background: Although telomere length maintenance is a common characteristic of hematological malignancies, the role of telomere length as a prognostic factor to stratify acute lymphoblastic leukemia (ALL) patients depending on their risk of relapse remains elusive. Methods: This knowledge gap motivated us to examine telomere length values in children with ALL at the time of diagnosis and after treatment using quantitative polymerase chain reaction (qPCR) (n = 35). To achieve high-resolution precision and cell specificity, a quantitative fluorescence in situ hybridization (qFISH) technique was developed (n = 5). Results: The results demonstrated statistically significant evidence of telomere shortening in the lymphoblasts of children with ALL but not in the lymphocytes of children after remission following treatment. Our findings also suggested a significant association between telomere shortening and a high risk of relapse disease. Last but not least, our preliminary results showed a trend that telomere shortening was more pronounced in children with B-ALL compared to those with T-ALL in a non-significant manner. Conclusions: Consequently, the current study provides preliminary insights into the potentially substantial prognostic value of telomere length in the progression of pediatric ALL, with the possibility of predicting treatment response. To clarify the application of telomere length as a possible biomarker for disease progression and treatment response in children with ALL, the telomere length values of additional participants need to be examined in further studies.

MicroRNAs are key regulators of lymphoid differentiation, exhibiting a pivotal role in acute lymphoblastic leukemia (ALL) biology and prognosis. The initial steps of canonical miRNA biogenesis involve the microprocessor complex processing the primary miRNA transcripts into precursor miRNAs via Drosha. DROSHA polymorphisms have been implicated in pediatric ALL and linked with cancer risk. This study investigated the role of rs642321, rs3805500, and rs10035440 DROSHA polymorphisms in ALL susceptibility, relapse, and outcomes in children and adolescents of Greek descent. The study included 252 children and adolescents (115 ALL cases and 137 controls). Genotyping was performed using RT-qPCR and the TaqMan Genotyping Assay. Homozygotes for the minor allele in DROSHA rs642321 were nominally associated with ALL susceptibility (TT vs. CC+CT; OR 4.5; 95% CI: 1.2–21.2; p_adj = 0.034). Likewise, homozygotes for the minor allele in rs3805500 were linked with ALL risk (GG vs. AA+AG; OR 2.7; 95% CI: 1.3–6.1; p_adj = 0.012). A suggestive association was observed between the rs3805500 AG genotype and both relapsed (OR 5.8; 95% CI: 1.6–24.3; p_adj = 0.011) and deceased cases (OR 5; 95% CI: 1.1–26.3; p_adj = 0.038). Patients with the rs3805500 AG and GG genotypes showed a trend toward poorer overall survival rates. In summary, certain haplotypes of DROSHA polymorphisms may be modestly associated with the occurrence of childhood ALL and its outcomes, although these findings require validation in larger, independent cohorts.