Effect of apolipoprotein E (APOE) gene polymorphisms on the lipid profile of children being treated for acute lymphoblastic leukemia.

BACKGROUND: Medications used to treat acute lymphoblastic leukemia (ALL), such as L-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. PROCEDURE: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. RESULTS: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). CONCLUSIONS: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings.

Prognostic factors in high-grade pediatric osteosarcoma among children and young adults: Greek Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data along with a systematic review and meta-analysis.

The 5-year overall survival of children and adolescents with osteosarcoma has been in plateau during the last 30 years. The present systematic review (1976-2023) and meta-analysis aimed to explore factors implicated in the prognosis of children and young adults with high-grade osteosarcoma. Original studies including patients ≤30 years and the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data (2010-2021) referred to children ≤14 years were analysed. Individual participant data (IPD) and summary estimates were used to assess the n-year survival rates, as well as the association of risk factors with overall survival (OS) and event-free survival (EFS). IPD and the n-year survival rates were pooled using Kaplan-Meier and Cox regression models, and random effects models, respectively. Data from 8412 patients, including 46 publications, NARECHEM-ST data, and 277 IPD from 10 studies were analysed. The summary 5-year OS rate was 64% [95% confidence interval (95%CI): 62%-66%, 37 studies, 6661 patients] and the EFS was 52% (95%CI: 49%-56%, 30 studies, 5010 patients). The survival rates generally differed in the pre-specified subgroups. Limb-salvage surgery showed a higher 5-year OS rate (69%) versus amputation (47%). Good responders had higher OS rates at 3 years (94%) and 5 years (81%), compared to poor responders at 3 years (66%), and 5 years (56%). Patients with metastatic disease had a higher risk of death [Hazard Ratio (HR): 3.60, 95%CI: 2.52, 5.15, 11 studies]. Sex did not have an impact on EFS (HR females/males: 0.90, 95%CI: 0.54, 1.48, 3 studies), whereas age>18 years seems to adversely affect EFS (HR 18+/<10 years: 1.36, 95%CI: 1.09, 1.86, 3 studies). Our results summarize the collective experience on prognostic factors of high-grade osteosarcoma among children and young adults. Poor response to neoadjuvant chemotherapy and metastatic disease at diagnosis were confirmed as primary risk factors of poor outcome. International collaboration of osteosarcoma study groups is essential to improve survival.

The inter-familiar issues of Greek parents facing childhood cancer.

Cancer as a whole, but especially childhood cancer, creates a number of psychological, social, and family problems as well as practical and financial issues, which every parent is called upon to solve. This study focuses on childhood cancer and aims at a thorough analysis of the physical/organic, psychological, and social problems associated with the parents and relatives of a child with cancer. The special element in pediatric neoplasms is not only the vulnerable population target group, but also the set of secondary effects it has on the environment of the sick child. The research was conducted on a sample of 133 families of children with cancer, and the results were displayed after statistical processing and data analysis with R statistical software. The results of the study confirm with statistically significant data the effect of childhood cancer on the physical, mental, and social health and behavior of the parent. Thus, 53.8% of the respondents stated 5 and above on the 7-point Likert scale for fatigue issues, 55.6% for sleep disorders, 78.1% for stress, and 82.7% for fear. The key findings are characterized by high specificity as it is a unique study that reveals particular aspects of the Greek parent's behavior, mind, and body during the period of their child's illness.   Conclusion: The effects of childhood illnesses, particularly when they are severe, such as neoplasms, present a looming threat, ushering in a multitude of adverse alterations in the daily lives of the affected child's family. What is Known - What is New: • We know the effects that a childhood illness brings not only to the sick child, but also to the entire family circle. The new element in the present research is that these data reflect the situation in Greece, for which the research data in this area is quite limited. Our research is one of the few studies that demonstrate with statistical data the change in the psychosomatic health of the parent who has a child with cancer.

Smoking during pregnancy and gestational diabetes mellitus: a systematic review and meta-analysis.

PURPOSE: To investigate whether maternal cigarette smoking during pregnancy is a risk factor for developing GDM. METHODS: MEDLINE, Scopus, CENTRAL and Google Scholar databases were searched from inception to December 2022 to identify eligible original articles. A systematic review and meta-analysis (weighted data, random-effects model) were performed. The primary outcome was the development of GDM in pregnant women. The results were expressed as odds ratios (OR) with 95% confidence interval (CI) (inverse variance method). Subgroup analysis was planned according to the maternal smoking status and GDM diagnostic criteria. Statistical heterogeneity was checked with the Chi-squared (Chi2) test and the I2 index was used to quantify it. The studies were evaluated for publication bias. RESULTS: Thirty-five studies, including 23,849,696 pregnant women, met the inclusion criteria. The pooled OR of smoking during pregnancy compared with non-smoking (never smokers and former smokers) was 1.06 (95% CI 0.95-1.19), p = 0.30; I2 = 90%; Chi2 = 344; df=34; p < 0.001. Subgroup analysis was performed according to the two-step Carpenter-Coustan diagnostic criteria, due to the high heterogeneity among the other applied methods. The pooled OR for the Carpenter-Coustan subgroup was 1.19 (95% CI 0.95-1.49), p = 0.12; I2 = 63%; Chi2 = 27; df=10; p < 0.002. Further subgroup analysis according to maternal smoking status was not performed due to missing data. CONCLUSION: There is no evidence to support an association between maternal cigarette smoking during pregnancy and the risk for GDM. Universally accepted diagnostic criteria for GDM must be adopted to reduce heterogeneity and clarify the association between smoking and GDM.

A national study of antibiotic use in Greek pediatric hematology oncology and bone marrow transplant units.

Objective: We surveyed antimicrobials used in Greek pediatric hematology-oncology (PHO) and bone marrow transplant (BMT) units before and after an intervention involving education regarding the 2017 clinical practice guidelines (CPG) for the management of febrile neutropenia in children with cancer and hematopoietic stem-cell transplant recipients. Design: Antibiotic prescribing practices were prospectively recorded between June 2016 and November 2017. Intervention: In December 2017, baseline data feedback was provided, and CPG education was provided. Prescribing practices were followed for one more year. For antibiotic stewardship, days of therapy, and length of therapy were calculated. Setting: Five of the 6 PHO units in Greece and the single pediatric BMT unit participated. Participants: Admitted children in each unit who received the first 15 new antibiotic courses each month. Results: Administration of ≥4 antibiotics simultaneously and administration of antibiotics with overlapping activity for ≥2 days were significantly more common in PHO units in general hospitals compared to children's hospitals. Use of at least 1 antifungal was recorded in ∼47% of the patients before and after the intervention. De-escalation and/or discontinuation of antibiotics on day 6 of initial treatment increased significantly from 43% to 53.5% (P = .032). Although the number of patients requiring intensive care support for sepsis did not change, a significant drop was noted in all-cause mortality (P = .008). Conclusions: We recorded the antibiotic prescribing practices in Greek PHO and BMT units, we achieved improved prescribing with a simple intervention, and we identified areas in need of improvement.

Safety and efficacy of insulin detemir versus NPH in the treatment of diabetes during pregnancy: Systematic review and meta-analysis of randomized controlled trials.

AIMS: To compare the safety and efficacy of insulin detemir versus neutral protamine Hagedorn (NPH) in pregnant women with diabetes. METHODS: MEDLINE, CENTRAL, Google Scholar databases, and ClinicalTrials.gov registry were searched from inception to December 2021 to identify randomized controlled trials (RCTs) concerning adult women with singleton pregnancies, gestational or pregestational diabetes, and the need for insulin therapy. A systematic review and a meta-analysis (weighted data, random-effects model) were performed. Continuous outcomes were expressed as mean difference (MD) with 95% confidence interval (CI) (inverse variance method); dichotomous outcomes were expressed as risk ratio (RR) with 95% CI (Mantel-Haenszel method). Heterogeneity was quantified using the I2 index. RESULTS: Five RCTs involving 1450 participants met the inclusion criteria. Outcomes that showed significant results in favor of insulin detemir over NPH were maternal hypoglycemic events (RR 0.64, 95% CI 0.48-0.86, p = 0.003; I2 = 0%) and gestational age at delivery (MD 0.48, 95% CI 0.16-0.81, p = 0.003; I2 = 0%). CONCLUSIONS: Insulin detemir was associated with less maternal hypoglycemic events and decreased risk for prematurity compared with NPH insulin. More research should be conducted to reach a safe conclusion about the optimal insulin regimen for women with diabetes in pregnancy.

Pediatric Leukemia From an Orthopedic Perspective: A Case of Acute Lymphoblastic Leukemia Initially Managed as Septic Hip With Osteomyelitis.

Acute lymphoblastic leukemia (ALL) represents the most common pediatric cancer accounting for about one-third of all malignancies in childhood. The differential diagnosis for a pediatric patient manifesting with joint pain and refusal to bear weight is wide and includes trauma, transient synovitis, septic arthritis, rheumatologic disorders, and malignancy. Overt complaints from the musculoskeletal system as the initial manifestation of ALL may present in up to 30% of cases with normal laboratory tests and without hepatosplenomegaly or lymphadenopathy, perplexing the establishment of a definite diagnosis. Herein, we report the case of a three-year-old male who presented with recurrent hip pain and fever masquerading as septic arthritis recalcitrant to intravenous (IV) antibiotics, irrigation, and debridement of the hip joint with a final diagnosis of acute lymphoblastic leukemia confirmed by bone marrow biopsy.

G6PD deficiency and Harilaou variant in a newborn: Intrauterine haemolysis and meconium aspiration syndrome.

G6PD deficiency is one of the most commonly inherited enzymopathies with a hallmark of an X-linked pattern. G6PD has more than 300 unique variants with different enzyme activity. The G6PD Mediterranean variant is prevalent in Greece and associated with asymptomatic patients who may experience haemolysis under specific circumstances. G6PD Harilaou is a new variant that was first described in Greece in an eight-year-old boy who suffered chronic haemolysis demanding multiple transfusions. We present a new case of the G6PD Harilaou variant in a Greek male neonate who suffered severe intrauterine haemolysis and passed away 39 hours after birth. To our knowledge, it is the second reported G6PD Harilaou case.

Limb-salvage surgery offers better five-year survival rate than amputation in patients with limb osteosarcoma treated with neoadjuvant chemotherapy. A systematic review and meta-analysis.

BACKGROUND: Osteosarcoma is the most common primary bone sarcoma. Currently, the main treatment option for high-grade osteosarcomas is neoadjuvant chemotherapy, followed by surgical resection of the lesion and adjuvant chemotherapy. Limb salvage surgery (LSS) and amputation are the main surgical techniques; however, controversy still exists concerning the best surgical method. Our meta-analysis compared the effectiveness of LSS and amputation combined with neoadjuvant chemotherapy in patients with limb osteosarcoma, in terms of 5-year overall survival (OS), 5-year disease-free survival (DFS) and local recurrence rate. METHODS: Following the established methodology of PRISMA guidelines, a literature search was conducted in PubMed, Cochrane, Google Scholar from 1975 until January 2020. Two independent reviewers evaluated the study quality based on the Newcastle-Ottawa scale. Odds ratio and 95% confidence interval of the OS, DFS and local recurrence rate were calculated. RESULTS: Thirteen studies were finally included with a total of 2884 patients; 1986 patients undergone LSS and 898 amputations. Five-year overall survival was almost 2-fold in patients treated with LSS than those treated with amputation (OR: 1.99; 95% CI: 1.35-2.93; I2 = 74%, p < 0.001). No difference was found in 5-year DFS between LSS patients and amputees (OR: 1.24; 95% CI: 0.55-2.79; I2 = 67%, p = 0.01). The odds of local recurrence was numerically higher in LSS compared to amputation but not statistically significant (OR: 2.29; 95% CI: 0.95-5.53; I2 = 47%, p = 0.05). However, the included studies did not clearly define differences in the stages of patients of the two groups. CONCLUSION: Our study demonstrated that in patients with limb osteosarcoma treated with neoadjuvant chemotherapy, LSS is associated with a higher 5-year overall survival and the odds of local recurrence may be increased but these results should be interpreted with caution due to high heterogeneity.

Pulmonary Infectious Complications in Children with Hematologic Malignancies and Chemotherapy-Induced Neutropenia.

Infections frequently complicate the treatment course in children with hematologic malignancies undergoing chemotherapy. Febrile neutropenia (FN) remains a major cause of hospital admissions in this population, and respiratory tract is often proven to be the site of infection even without respiratory signs and symptoms. Clinical presentation may be subtle due to impaired inflammatory response. Common respiratory viruses and bacteria are widely identified in these patients, while fungi and, less commonly, bacteria are the causative agents in more severe cases. A detailed history, thorough clinical and basic laboratory examination along with a chest radiograph are the first steps in the evaluation of a child presenting signs of a pulmonary infection. After stratifying patient's risk, prompt initiation of the appropriate empirical antimicrobial treatment is crucial and efficient for the majority of the patients. High-risk children should be treated with an intravenous antipseudomonal beta lactam agent, unless there is suspicion of multi-drug resistance when an antibiotic combination should be used. In unresponsive cases, more invasive procedures, including bronchoalveolar lavage (BAL), computed tomography (CT)-guided fine-needle aspiration or open lung biopsy (OLB), are recommended. Overall mortality rate can reach 20% with higher rates seen in cases unresponsive to initial therapy and those under mechanical ventilation.

Maternal lifestyle characteristics and Wilms tumor risk in the offspring: A systematic review and meta-analysis.

BACKGROUND: Little is known about the etiology of childhood Wilms tumor (WT) and potentially modifiable maternal risk factors, in particular. METHODS: Unpublished data derived from the hospital-based, case-control study of the Greek Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) were included in an ad hoc conducted systematic literature review and meta-analyses examining the association between modifiable maternal lifestyle risk factors and WT. Eligible data were meta-analysed in separate strands regarding the associations of WT with (a) maternal folic acid and/or vitamins supplementation, (b) alcohol consumption and (c) smoking during pregnancy. The quality of eligible studies was evaluated using the Newcastle-Ottawa Scale. RESULTS: Effect estimates from 72 cases and 72 age- and sex-matched controls contributed by NARECHEM-ST were meta-analysed together with those of another 17, mainly medium size, studies of ecological, case-control and cohort design. Maternal intake of folic acid and/or other vitamins supplements during pregnancy was inversely associated with WT risk (6 studies, OR: 0.78; 95 %CI: 0.69-0.89, I2 = 5.4 %); of similar size was the association for folic acid intake alone (4 studies, OR: 0.79; 95 %CI: 0.69-0.91, I2 = 0.0 %), derived mainly from ecological studies. In the Greek study a positive association (OR: 5.31; 95 %CI: 2.00-14.10) was found for mothers who consumed alcohol only before pregnancy vs. never drinkers whereas in the meta-analysis of the four homogeneous studies examining the effect of alcohol consumption during pregnancy the respective overall result showed an OR: 1.60 (4 studies, 95 %CI: 1.28-2.01, I2 = 0.0 %). Lastly, no association was seen with maternal smoking during pregnancy (14 studies, OR: 0.93; 95 %CI: 0.80-1.09, I2 = 0.0 %). CONCLUSIONS: In the largest to-date meta-analysis, there was an inverse association of maternal folic acid or vitamins supplementation with WT risk in the offspring, derived mainly from ecological studies. The association with maternal alcohol consumption found in our study needs to be further explored whereas no association with maternal smoking was detected. Given the proven benefits for other health conditions, recommendations regarding folic acid supplementation as well as smoking and alcohol cessation should apply. The maternal alcohol consumption associations, however, should be further explored given the inherent limitations in the assessment of exposures of the published studies.

Successful treatment of rhinoorbital mucormycosis due to Rhizopus arrhizus with liposomal amphotericin B, posaconazole and surgical debridement in a child with neuroblastoma.

Mucormycosis is a rare but potentially mortal opportunistic infection caused by Mucorales. We present a case of rhinoorbital mucormycosis in an 11-year old male with neuroblastoma successfully treated with aggressive surgical debridement and antifungal combination of liposomal amphotericin B and posaconazole. Our patient developed signs of paranasal sinus infection and culture of fine needle biopsy grew Rhizopus arrhizus. Prompt treatment and drastic surgical resection led to complete clinical and radiological recovery without evidence of mucormycosis relapse.

Perinatal and early life risk factors for childhood brain tumors: Is instrument-assisted delivery associated with higher risk?

BACKGROUND: The childhood peak of brain tumors suggests that early-life exposures might have a role in their etiology. Hence, we examined in the Greek National Registry for Childhood Hematological Malignancies and Solid tumors (NARECHEM-ST) whether perinatal and early-life risk factors influence the risk of childhood brain tumors. METHODS: In a nationwide case-control study, we included 203 cases (0-14 years) with a diagnosis of brain tumor in NARECHEM-ST (2010-2016) and 406 age-, sex-, and center-matched hospital controls. Information was collected via interviews with the guardians and we analyzed the variables of interest in multivariable conditional logistic regression models. RESULTS: Instrument-assisted delivery was associated with higher (OR: 7.82, 95%CI: 2.18-28.03), whereas caesarean delivery with lower (OR: 0.67, 95%CI: 0.45-0.99) risk of childhood brain tumors, as compared to spontaneous vaginal delivery. Maternal alcohol consumption during pregnancy (OR: 2.35, 95%CI: 1.45-3.81) and history of living in a farm (OR: 4.98, 2.40-10.32) increased the odds of childhood brain tumors. Conversely, higher birth order was associated with lower risk (OR for 2nd vs. 1st child: 0.60, 95%CI: 0.40-0.89 and OR for 3rd vs. 1st: 0.34, 95%CI: 0.18-0.63). Birth weight, gestational age, parental age, history of infertility, smoking during pregnancy, allergic diseases, and maternal diseases during pregnancy showed no significant associations. CONCLUSIONS: Perinatal and early-life risk factors, and specifically indicators of brain trauma, exposure to toxic agents and immune system maturation, might be involved in the pathogenesis of childhood brain tumors. Larger studies should aim to replicate our findings and examine associations with tumor subtypes.

Incidence, time trends and survival patterns of childhood pilocytic astrocytomas in Southern-Eastern Europe and SEER, US.

Pilocytic astrocytomas (PA) comprise the most common childhood central nervous system (CNS) tumor. Exploiting registry-based data from Southern and Eastern Europe (SEE) and SEER, US, we opted to examine incidence, time trends, survival and tentative outcome disparities of childhood PA by sociodemographic and clinical features. Childhood PA were retrieved from 12 SEE registries (N = 552; 1983-2014) and SEER (N = 2723; 1973-2012). Age-standardized incidence rates (ASR) were estimated and survival was examined via Kaplan-Meier and Cox regression analysis. ASR of childhood PA during 1990-2012 in SEE was 4.2/106, doubling in the USA (8.2/106). Increasing trends, more prominent during earlier registration years, were recorded in both areas (SEE: +4.1 %, USA: +4.6 %, annually). Cerebellum comprised the most common location, apart from infants in whom supratentorial locations prevailed. Age at diagnosis was 1 year earlier in SEE, whereas 10-year survival was 87 % in SEE and 96 % in SEER, improving over time. Significant outcome predictors were age <1 year at diagnosis diagnosis (hazard ratio, HR [95% confidence intervals]: 3.96, [2.28-6.90]), female gender (HR: 1.38, [1.01-1.88]), residence in SEE (HR: 4.07, [2.95-5.61]) and rural areas (HR: 2.23, [1.53-3.27]), whereas non-cerebellar locations were associated with a 9- to 12-fold increase in risk of death. The first comprehensive overview of childhood PA epidemiology showed survival gains but also outcome discrepancies by geographical region and urbanization pointing to healthcare inequalities. The worse prognosis of infants and, possibly, females merits further consideration, as it might point to treatment adjustment needs, whereas expansion of systematic registration will allow interpretation of incidence variations.

Childhood central nervous system tumour mortality and survival in Southern and Eastern Europe (1983-2014): Gaps persist across 14 cancer registries.

AIM: Childhood central nervous system (CNS) tumour registration and control programs in Southern and Eastern Europe remain thin, despite the lethal nature of the disease. Mortality/survival data were assembled to estimate the burden of malignant CNS tumours, as well as the potential role of sociodemographic survival determinants across 14 cancer registries of this region. METHODS: Average age-adjusted mortality rates were calculated, whereas time trends were quantified through Poisson and Joinpoint regressions. Kaplan-Meier curves were derived for the maximum and the more recent (10 and 5 year) registration periods. Multivariate Cox regression models were used to assess demographic and disease-related determinants. RESULTS: Variations in mortality (8-16 per million) and survival (5-year: 35-69%) were substantial among the participating registries; in most registries mortality trend was stable, whereas Bulgaria, having the highest starting rate, experienced decreasing annual mortality (-2.4%, p=0.001). A steep decrease in survival rates was evident before the second year of follow-up. After controlling for diagnostic subgroup, age, gender and diagnostic year, Greece seemed to present higher survival compared with the other contributing registries, although the follow-up period was short. Irrespective of country, however, rural residence was found to impose substantial adverse repercussions on survival (hazard ratio (HR): 1.2, 95% confidence interval (CI): 1.1-1.4). CONCLUSION: Cross-country mortality and survival variations possibly reflect suboptimal levels of health care delivery and cancer control in some regions of Southern and Eastern Europe, notwithstanding questionable death certification patterns or follow-up procedures. Continuous childhood cancer registration and linkage with clinical data are prerequisite for the reduction of survival inequalities across Europe.

Childhood central nervous system tumours: Incidence and time trends in 13 Southern and Eastern European cancer registries.

AIM: Following completion of the first 5-year nationwide childhood (0-14 years) registration in Greece, central nervous system (CNS) tumour incidence rates are compared with those of 12 registries operating in 10 Southern-Eastern European countries. METHODS: All CNS tumours, as defined by the International Classification of Childhood Cancer (ICCC-3) and registered in any period between 1983 and 2014 were collected from the collaborating cancer registries. Data were evaluated using standard International Agency for Research on Cancer (IARC) criteria. Crude and age-adjusted incidence rates (AIR) by age/gender/diagnostic subgroup were calculated, whereas time trends were assessed through Poisson and Joinpoint regression models. RESULTS: 6062 CNS tumours were retrieved with non-malignant CNS tumours recorded in eight registries; therefore, the analyses were performed on 5191 malignant tumours. Proportion of death certificate only cases was low and morphologic verification overall high; yet five registries presented >10% unspecified neoplasms. The male/female ratio was 1.3 and incidence decreased gradually with age, apart from Turkey and Ukraine. Overall AIR for malignant tumours was 23/10(6) children, with the highest rates noted in Croatia and Serbia. A statistically significant AIR increase was noted in Bulgaria, whereas significant decreases were noted in Belarus, Croatia, Cyprus and Serbia. Although astrocytomas were overall the most common subgroup (30%) followed by embryonal tumours (26%), the latter was the predominant subgroup in six registries. CONCLUSION: Childhood cancer registration is expanding in Southern-Eastern Europe. The heterogeneity in registration practices and incidence patterns of CNS tumours necessitates further investigation aiming to provide clues in aetiology and direct investments into surveillance and early tumour detection.