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Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 non-transplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome.

Bannayan–Riley–Ruvalcaba syndrome (BRRS) is a rare overgrowth condition caused by a pathogenic variant in the phosphatase and tensin homolog ( PTEN ) gene and belongs to a group of disorders called PTEN hamartoma tumor syndrome (PHTS). The diagnosis is often complicated by great phenotypic diversity. Furthermore, to this date treatment options are limited. Here we performed a systematic review using PubMed, Cochrane, and Scopus databases to identify cases of pediatric patients diagnosed with BRRS and summarized information about the clinical presentation, treatment, and long-term patient care. A total of 83 pediatric patients with BRRS were identified. The most common clinical findings were macrocephaly (77%) and developmental disorders (63%). Surgical interventions were the treatment of choice, described in 19 articles. Patient surveillance was proposed in 15 case reports and mostly aimed at periodic cancer screening. Recognition of BRRS clinical symptoms and early referral to a geneticist is important for better disease control and overall prognosis. As targeted treatment is still lacking, symptom relief and long-term surveillance remain the main management strategies.

Intestinal damage (ID) leads to bacterial translocation and bloodstream infections—the common cause of non-relapse mortality in childhood acute lymphoblastic leukemia (ALL). This study evaluated ID over ALL induction and the significance of body mass index (BMI) for its development and identified biomarkers reflecting chemotherapy-induced ID. The composite biomarker panel included 37 plasma amino acids, urea, ammonia, fecal calprotectin (fCLP), absolute neutrophil count (ANC), C-reactive protein, and albumin. We prospectively assessed 45 children treated according to the ALLTogether protocol in 2020–2024. Analysis and sample collection were performed on days 1, 8, 15, 22, and 29 of the protocol. The obtained values were compared between the ID and non-ID groups. 40% of patients (18/45) had grade I–III ID which was more pronounced on day 22 of induction when the ANC increased from its lowest point. Age younger than 5.5 years at a diagnosis was a significant prognostic factor for ID. Decreasing BMI and concentrations of citrulline, taurine, cystine, phosphoethanolamine, A-aminobutyric acid, B-alanine, and albumin suggest progressive ID in children treated due to ALL. No difference in ANC and fCLP was found between patients with and without ID, but fCLP levels start to rise simultaneously as the most intense ID is observed. In conclusion, assessing nutritional status and prospective evaluation of biomarkers may provide valuable information on treatment-related ID.

Pediatric very rare tumors (VRTs) represent a heterogeneous subset of childhood cancers, with reliable survival estimates depending dramatically on each (un)registered case. The current study aimed to evaluate the number of VRTs among Lithuanian children, to assess the impact of the registration status on survival rates and to track changes in treatment outcomes over the 16-year study period. We performed a population-based retrospective study across children below 18 years old diagnosed with VRTs in Lithuania between the years 2000 and 2015. The identified cases were cross-checked with the Lithuanian Cancer Registry—a population-based epidemiology cancer registry—for the fact of registration and survival status. The overall survival was calculated in relation to the registration status and treatment period. Thirty-seven children with VRTs were identified within the defined time frame. Six of them (16.2%) were not reported to the Lithuanian Cancer Registry at diagnosis. The probability of overall survival at 5 years (OS 5y ) differed significantly between the registered (n = 31) and unregistered (n = 6) cohorts: 51.6% versus 100%, respectively ( p  = 0.049). A 5-year survival estimate for children diagnosed with a VRT at the age of 0–14 years differed by 10 percentage points according to the registration completeness: 52.1% calculated for the entire cohort versus 42.1% for registered patients only. The OS 5y has not improved over the analyzed period: 61.1% in 2000–2007 versus 57.9% in 2008–2015 ( p  = 0.805). The survival continued to decline beyond 5 years post-diagnosis due to late cancer-related adverse events: 59.5% of patients were alive at 5 years as compared to 44.3% at 10 years. The OS 5y of children affected by VRT was lower than in more common childhood cancers. The survival rate of the unregistered patients may lead to misinterpretation of treatment outcomes. Meticulous registration of VRTs is crucial for correct evaluation of treatment outcomes, especially across small countries with few cases.

Although most children with acute lymphoblastic leukemia (ALL) receive fractionated total body irradiation (FTBI) as myeloablative conditioning (MAC) for allogeneic hematopoietic stem cell transplantation (allo-HSCT), it is an important matter of debate if chemotherapy can effectively replace FTBI. To compare outcomes after FTBI versus chemotherapy-based conditioning (CC), we performed a retrospective EBMT registry study. Children aged 2–18 years after MAC for first allo-HSCT of bone marrow (BM) or peripheral blood stem cells (PBSC) from matched-related (MRD) or unrelated donors (UD) in first (CR1) or second remission (CR2) between 2000 and 2012 were included. Propensity score weighting was used to control pretreatment imbalances of the observed variables. 3.054 patients were analyzed. CR1 (1.498): median follow-up (FU) after FTBI (1.285) and CC (213) was 6.8 and 6.1 years. Survivals were not significantly different. CR2 (1.556): median FU after FTBI (1.345) and CC (211) was 6.2 years. Outcomes after FTBI were superior as compared with CC with regard to overall survival (OS), leukemia-free survival (LFS), relapse incidence (RI), and nonrelapse mortality (NRM). However, we must emphasize the preliminary character of the results of this retrospective “real-world-practice” study. These findings will be prospectively assessed in the ALL SCTped 2012 FORUM trial.

Background ABL-class and JAK-STAT signaling pathway activating alterations have been associated with both a poor post-induction minimal residual disease (MRD) response and an inferior outcome in B-cell acute lymphoblastic leukemia (B-ALL). However, in most of the studies patients received non-uniform treatment. Methods We performed a population-based analysis of 160 (122 pediatric and 38 adult) Lithuanian BCR - ABL1 -negative B-ALL patients who had been uniformly treated according to MRD-directed NOPHO ALL-2008 protocol. Targeted RNA sequencing and FISH analysis were performed in cases without canonical B-ALL genomic alterations (high hyperdiploids and low hypodiploids included). Results We identified ABL-class fusions in 3/160 (1.9%) B-ALL patients, and exclusively in adults ( p  = 0.003). JAK-STAT pathway fusions were present in 4/160 (2.5%) cases. Of note, P2RY8-CRLF2 fusion was absent in both pediatric and adult B-ALL cases. Patients with ABL-class or JAK-STAT pathway fusions had a poor MRD response and were assigned to the higher risk groups, and had an inferior event-free survival (EFS) / overall survival (OS) compared to patients without these fusions. In a multivariate analysis, positivity for ABL-class and JAK-STAT fusions was a risk factor for worse EFS ( p  = 0.046) but not for OS ( p  = 0.278) in adults. Conclusions We report a low overall frequency of ABL-class and JAK-STAT fusions and the absence of P2RY8-CRLF2 gene fusion in the Lithuanian BCR-ABL1 negative B-ALL cohort. Future (larger) studies are warranted to confirm an inferior event-free survival of ABL-class/JAK-STAT fusion-positive adult patients in MRD-directed protocols.

Background Optimal long-term follow-up (LTFU) care for survivors of childhood, adolescent and young adult (CAYA) cancer can improve or maintain their quality of life by prevention and early treatment of late effects. However, optimal LTFU care is not provided to all CAYA cancer survivors. This systematic review sought to identify associated barriers, facilitators and other factors of LTFU care for CAYA cancer survivors worldwide. Methods We included barriers and facilitators from a previously published guideline in 2017, and performed a systematic search using PubMed/Medline to identify studies between 1-1-2017 and 5-6-2025 examining barriers, facilitators and other factors associated with LTFU care from the perspectives of CAYA cancer survivors, diagnosed with cancer ≤25 years of age, healthcare providers (HCPs), and hospital managers involved in the provision of LTFU care for CAYA cancer survivors. Qualitative and (semi)quantitative (survey) studies with multivariable analyses were eligible for inclusion. Standardised evidence tables were made independently by one author and checked by another author to extract relevant information. Results The search yielded 4,677 unique records, of which 230 were selected for full-text screening and 51 articles were included in this systematic review. Twenty-two studies were qualitative, twenty-two were quantitative and seven used a mixed methods design. The previous published guideline provided 19 barriers and 5 facilitators until 2017. Within the current review, 85 barriers, 63 facilitators, and 23 other factors were reported. Main barriers included lack of knowledge, information and awareness of LTFU care, lack of resources, poor transition from paediatric to adult care, and the lack of national/regional LTFU care programmes or clinics. Main facilitators included a treatment summary/survivorship care plan, involvement of multidisciplinary specialists, education to improve late effects knowledge, a clear contact/information point, and improved communication. Regarding other factors, treatment with radiation only, older attained age, age at diagnosis, and non-white descent were most frequently associated with less LTFU care. The main factor associated with more LTFU care by survivors was the number of late effects. Conclusions We encourage raising awareness, provision of appropriate information, treatment summaries and survivorship care plans, and advocacy for supportive policies and funding in order to optimise LTFU care and facilitate engagement for CAYA cancer survivors.

Background and objectives: Acute lymphoblastic leukaemia (ALL) is associated with a cytokine imbalance and oxidative stress, which can be aggravated by malnutrition. Malnutrition, defined by the World Health Organisation (WHO) as obesity or undernutrition, can affect treatment complications and outcomes. Therefore, we aimed to analyse the change in the body mass index (BMI) z-score during induction, as well as evaluate the impact of childhood malnutrition on fevers at an ALL presentation and early response to therapy. Methods: An observational cohort study of 50 consecutive children with ALL, diagnosed in 2019–2022, was performed. Patients were divided into age groups of 0–5, 6–11, and 12–17 years. BMI-for-age z-scores were used to define undernutrition and overnutrition according to WHO growth standards. Results: The number of patients with an abnormal BMI increased from 3 (6%) at diagnosis to 10 (20%) at the end of induction (from 2 (4%) to 6 (12%) in overweight/obese, and from 1 (2%) to 4 (8%) in underweight patients). At the end of induction, all overweight/obese patients were 0–5 years old. On the other hand, a statistically significant decrease in the mean BMI z-score among patients aged 12–17 was observed (p = 0.005). The mean BMI z-score differed statistically significantly among children aged 0–5 presenting with and without fever (p = 0.001). The minimal residual disease (MRD) level at the end of induction was not related to BMI at diagnosis. Conclusions: Despite the use of steroids, adolescents are prone to losing weight during an ALL induction, in contrast to preschool children, who tend to gain weight under the same treatment. BMI at diagnosis was related to a fever of ≥38 °C (at ALL presentation) in the 0–5 age group. The results emphasise the importance of careful nutritional status monitoring, with younger and older children as important target groups for weight gain and weight loss interventions, respectively.

Background Currently the five-year survival of childhood cancer is up to 80% due to improved treatment modalities. However, the majority of childhood cancer survivors develop late effects including infertility. Survivors describe infertility as an important and life-altering late effect. Fertility preservation options are becoming available to pre- and postpubertal patients diagnosed with childhood cancer and fertility care is now an important aspect in cancer treatment. The use of fertility preservation options depends on the quality of counseling on this important and delicate issue. The aim of this manuscript is to present a questionnaire to determine the impact of fertility counseling in patients suffering from childhood cancer, to improve fertility care and evaluate what patients and their parents or guardians consider good fertility care. Methods Within the framework of the EU-Horizon 2020 TREL project, a fertility care evaluation questionnaire used in the Netherlands was made applicable for international multi-center use. The questionnaire to be used at least also in Lithuania, incorporates patients’ views on fertility care to further improve the quality of fertility care and counseling. Results evaluate fertility care and will be used to improve current fertility care in a national specialized pediatric oncology center in the Netherlands and a pediatric oncology center in Lithuania. Conclusion An oncofertility-care-evaluation questionnaire has been developed for pediatric oncology patients and their families specifically. Results of this questionnaire may contribute to enhancement of fertility care in pediatric oncology in wider settings and thus improve quality of life of childhood cancer patients and survivors.