Long-term Survival Of Children Research Articles

The prognostic role of 18F-FDG PET/CT-based response evaluation in children with stage 4 neuroblastoma.

To evaluate the association between metabolic response on 18F-FDG PET/CT and long-term survival in children with neuroblastoma (NB). A total of 39 consecutive children with newly diagnosed stage 4 NB undergoing both 18F-FDG PET/CT imaging at baseline and after chemotherapy were retrospectively analyzed. The associations between metabolic parameters, including SUVmax of the lesion with the most intense 18F-FDG uptake at baseline (SUVb), after chemotherapy (SUVe), and the percentage change between SUVb and SUVe, and long-term survival were evaluated. With a median follow-up of 56 months, 22 patients who had achieved complete resolution on PET (no residual 18F-FDG uptake higher than the surrounding backgrounds) after chemotherapy had superior 5-year overall survival (OS) (73.6% vs. 39.0%, p = 0.044). SUVb > 6.9 indicated significantly poorer 5-year event-free survival (EFS) (12.5% vs. 59.3%, p = 0.005), as did SUVe > 1.2 (18.8% vs. 41.7%, p = 0.041). Children with SUVe > 1.2 had shorter 5-year OS (33.9% vs. 75.0%, p = 0.018). Multivariate analysis identified SUVe > 1.2 as an independent predictor for both EFS [hazard ratio (HR), 3.479, 95% CI, 1.381-8.761, p = 0.008] and OS (HR, 6.948, 95% CI, 1.663-29.025, p = 0.008), while SUVb > 6.9 was a predictor for EFS (HR, 2.889, 95% CI, 1.064-7.842, p = 0.037). Among 11 children with both SUVb > 6.9 and SUVe > 1.2, all experienced disease progression or relapse within 2 years since diagnosis. 18F-FDG PET/CT could be of useful to evaluate treatment response in children with stage 4 NB. 18F-FDG PET/CT after chemotherapy exhibits prognostic significance in neuroblastoma and holds potential as an alternative imaging modality for response evaluation, especially in cases with metaiodobenzylguanidine-nonavid or persistent avid disease. The prognostic value of chemotherapy response on 18F-FDG PET/CT in advanced neuroblastoma is unknown. Higher 18F-FDG uptake after chemotherapy was associated with worse long-term event-free survival and overall survival. 18F-FDG PET/CT after chemotherapy holds prognostic significance in children with stage 4 neuroblastoma.

Preservation of Pancreatic Function Should Not Be Disregarded When Performing Pancreatectomies for Pancreatoblastoma in Children.

Complete surgical resection in the context of a multimodal approach has been associated with excellent long-term survival in children diagnosed with pancreatoblastoma (PB). Traditionally, curative intent surgery for PB implies standard pancreatic resections such as pancreaticoduodenectomies and distal pancreatectomies with splenectomies, surgical procedures that may lead to significant long-term pancreatic functional deficiencies. Postoperative pancreatic functional deficiencies are particularly interesting to children because they may interfere with their development, considering their long life expectancy and the significant role of pancreatic functions in their nutritional status and growth. Thus, organ-sparing pancreatectomies, such as spleen-preserving distal pancreatectomies and central pancreatectomies, are emerging in specific tumoral pathologies in children. However, data about organ-sparing pancreatectomies' potential role in curative-intent PB surgery in children are scarce. Based on the literature data, the current review aims to present the early and late outcomes of pancreatectomies in children (including long-term deficiencies and their potential impact on the development and quality of life), particularly for PB, and further explore the potential role of organ-sparing pancreatectomies for PB. Organ-sparing pancreatectomies are associated with better long-term pancreatic functional outcomes, particularly central pancreatectomies, and have a reduced impact on children's development and quality of life without jeopardizing their oncological safety. The long-term preservation of pancreatic functions should not be disregarded when performing pancreatectomies for PB in children. A subset of patients with PB might benefit from organ-sparing pancreatectomies, particularly from central pancreatectomies, with the same oncological results as standard pancreatectomies but with significantly less impact on long-term functional outcomes.

Factors Associated With Long-term Survival in Children With Bronchial and Lung Carcinoid Tumors

Background and aimsBronchial carcinoids are rare in children and the treatment is based on tumor behavior in adults. The purpose of this study was to determine factors and management strategies associated with long-term survival in the pediatric population using a national cohort. MethodsPatients aged ≤20 years with bronchial carcinoid tumors were identified in the 2004–2020 National Cancer Database using ICD-O-3 codes. Tumor characteristics and management were compared among typical (TC) and atypical (AC) histological subtypes using Chi-square and Fisher's exact tests. Kaplan–Meier and univariate Cox proportional hazards analyses were used to assess survival. ResultsOf 273 patients, 251 (92%) had TCs, and 22(8%) had ACs. The median (IQR) age was 18 (16,19) years. Most patients underwent lobectomy or bilobectomy (67%), followed by sublobar resection (17%), no resection or bronchoscopic excision or ablation (8%), and pneumonectomy (7.7%). Margins were negative in 96%. Lymph node (LN) assessment was performed in 216 patients (84%) with a median (IQR) of 7(3,13) LNs, and 50 (23%) had ≥1 positive LN. There was no difference in age, resection, margin status, LN assessment, or positivity between TC and AC (all p > 00.05). Detection of nodal metastasis did not increase beyond the resection of 1–3 LNs (p = 0.72). Ten-year survival was worse for AC than TC (79% (41, 100) vs 98% (95, 100), HR = 6.9 (95% CI: 1.2–38.3, p = 0.03). Ten-year survival among those with and without LN assessment was 97% (94, 100) vs 91% (81, 100), HR = 4.0, 95% CI: 0.8–19.9, p = 0.09). There were no deaths in those with negative LN while 10-year survival was 89% (72, 100) in those with ≥1 positive LN. ConclusionAmong children with bronchial carcinoids, survival is excellent with TC or negative LN. Atypical histology and positive LN have poor survival and should prompt close monitoring. These risk factors may be missed in the absence of surgical resection and lymph node sampling. Level of EvidenceIII. Type of StudyRetrospective Study.

The relationship between the intestinal microbiome and body mass index in children with cystic fibrosis

BackgroundThe nutritional status of children with cystic fibrosis (CF), as assessed by their body mass index percentile (BMIp), is a critical determinant of long-term health outcomes. While the intestinal microbiome plays an important role in nutrition, little is known regarding the relationship of the microbiome and BMIp in children with CF. MethodsPediatric patients (< 18 years old) with CF and healthy comparison patients (HCs) were enrolled in the study and stool samples obtained. BMIp was categorized as Green Zone (BMIp > 50th), Yellow Zone (BMIp 25th–49th) and Red Zone (BMIp < 25th). Intestinal microbiome assessment was performed via 16S rRNA gene sequencing; microbial richness, diversity, and differential species abundance were assessed. ResultsStool samples were collected from 107 children with CF and 50 age-matched HCs. Compared to HCs, children with CF were found to have lower bacterial richness, alpha-diversity, and a different microbial composition. When evaluating them by their BMIp color zone, richness and alpha-diversity were lowest in those in the Red Zone. In addition, an unclassified amplicon sequence variant (ASV) of Blautia, a known butyrate-producing anaerobe, was of lowest abundance in children in the Red Zone. ConclusionChildren with CF have a dysbiotic intestinal microbiome with specific changes that accompany changes in BMIp. Longitudinal assessments of the microbiome and its metabolic activities over time are needed to better understand how improvements in the microbiome may improve nutrition and enhance long-term survival in children with CF.

Safe and Effective Escalation of Evidence-Based Chemotherapy for Mature B Cell Non-Hodgkin's Lymphoma in a Low Resource Setting

BACKGROUND Although high intensity chemotherapy regimens result in &amp;gt;90% long term survival of children with Mature B-cell Non-Hodgkin Lymphoma (MB-NHL), low intensity chemotherapy regimens are used in most Sub-Sahara African (SSA) setting resulting in decades of less than 20% long term survival. This is in part because dose-intense chemotherapy strategies that are standard of care in high income countries (HIC) have not been widely or effectively implemented in low- and middle income countries (LMIC). We investigated the toxicity and outcomes of children with MB-NHL who were treated with a treatment regimen that includes 1g/M2 of methotrexate per dose (mini COPADM) at Mulago National Referral Hospital in Uganda. The objective of this study was to evaluate the safety and effectiveness of an incremental chemotherapy escalation strategy to control treatment-related toxicities and increase response and survival of children treated for MB-NHL at a pediatric oncology center in the SSA setting. METHODS We prospectively collected clinical outcomes on children under 18 years with MB-NHL at Mulago National Referral Hospital (MNRH) in Uganda between January 2020 and July 2023. Overall (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method. Events in the EFS analysis were: 1) Death; 2) Relapse; or 3) Persistent or progressive disease at the end of Cycle 3. Patients were censored at the earlier of two years from presentation or their last day of follow-up. Descriptive statistics were presented. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5. RESULTS We identified 77 patients, among whom 16 (21%) died prior to commencement of the first cycle of chemotherapy and 6 (8%) treated with alternative therapies. The 55 patients who were treated with mini COPADM with 1g/M 2 of methotrexate and are included in this analysis had similar demographics and clinical phenotypes to the 22 that were excluded. The median age was 9.6 years (interquartile range ((IQR) 6.6 - 11.7 years) with 38 (69%) males. Patients were Stage III (53%, 29/55), stage IV (38%, 21/55); and 55%, (30/55) were high-risk. The most common presentations were abdominal mass 43 (78%) and jaw mass 14 (25%). With a median follow-up time of 9 months (IQR 6 - 24 months), the 1-year overall survival (OS) and event free survival (EFS) were 56%; 95% CI (41 - 76) and 41%; 95%CI (27 - 61) respectively. For children with high-risk disease, 1-year OS was 44%; 95%CI (28 - 72) and EFS 25%; 95% CI (12 - 51). Toxicities included febrile neutropenia (83%) and CTCAE grade ≥3 mucositis (44%). For the 12 patients whose cause of mortality was recorded, 1 case (8.3%) was treatment-related and 11 (91.7%) were due to cancer. CONCLUSION: This study establishes baseline response rates, survival, and toxicity for patients with pediatric MB-NHL in Uganda treated with 1g/M2 of methotrexate. Toxicities were consistent with treatment received, perhaps exacerbated by synergy of anthracycline (50 mg/m2) along with intermediate dose MTX. These findings suggest that mini-COPADM with 1g/M 2 of methotrexate can be safely supported with the current clinical resources at MNRH and this low dose regimen accounts for the poor survival of children with MB-NHL in our center. We plan to escalate our therapy to mini-COAPDM with 3g/M2 and addition of Rituximab, with contingent intensification of supportive care to curb treatment-related toxicities.

Impact of tracheostomies on the long-term survival of patients with trisomy 13 syndrome.

In this retrospective cohort study, we investigated the impact of tracheostomies on the long-term survival of children with trisomy 13 syndrome at a Japanese tertiary pediatric center. We compared survival and survival to discharge rates between patients who underwent tracheostomies during their NICU stays (T group, n = 8) and those who did not (non-T group, n = 11). A total of 19 patients enrolled. Median survival in all patients was 673 (266-1535) days. Significant differences in the 1-, 2-, and 3-year survival rates were found between the T and the non-T groups (100% vs. 46%, p = 0.018; 88% vs. 18%, p = 0.006; 63% vs. 9%, p = 0.041, respectively). The survival to discharge rate was higher in the T versus non-T group (75% vs. 45%, p = 0.352). This study highlights a significantly higher long-term survival of patients with trisomy 13 syndrome who underwent tracheostomies during their NICU stays.

Long-Term Results of the Treatment of Adolescents and Adults with Acute Lymphoblastic Leukemia with a Pediatric-Inspired Regimen Delivered on an Outpatient Basis: A Single Institution Experience

INTRODUCTION Long-term survival in children with acute lymphoblastic leukemia (ALL) is achieved in around 80%; however, cure rates for adolescents and young adults (AYA) and older adults remain relatively low, at only 40% to 50%. The regimens used in adults are usually less intense than the ones used in their pediatric counterparts, mainly since adults do not tolerate the intensity as well as children do. Different studies have found that adolescents with ALL have a better outcome when treated with pediatric-inspired regimens compared to adult protocols, and other reports suggest improved outcomes for adult patients when treated with ALL pediatric-inspired combination chemotherapy (PICC) regimens. To this effect, we have designed a modification of the St. Jude's TOTAL XI combined chemotherapy program with the goal of delivering it on an outpatient basis. We report here the long-term results of a group of 126 non-pediatric patients with ALL treated with an asparaginase-containing PICC. MATERIAL AND METHODS All consecutive adolescents (12 - 17.9 years), young adults (18 - 24.9 years) and adult (>25 years) patients with ALL diagnosed and treated in the Centro de Hematología y Medicina Interna de Puebla since June 1983 were prospectively included in the study. At diagnosis, the immunophenotype of the malignant cells and the desoxyrribonucleic acid (DNA) content was analyzed by flow cytometry, and cytogenetic markers were also obtained. Patients were treated with a modification of the St. Jude's TOTAL XI PICC regimen, delivered in an outpatient setting. RESULTS A total of 126 patients with ALL (69 AYAs and 57 adults were prospectively enrolled in the study. Median age was 22.5 years (range 12 - 80 years). B-cell lineage was identified in 117 (93%) and T-cell in 9 (7%). At diagnosis, 13 cases (11%) displayed more than 20 x 109/L white blood cells (WBC), 20 (16%) more than 50 x 109/L WBC, while 93 (74%) had less than 20 x 109/L WBC. DNA content was diploid in 69% of cases, hyperploid in 20% and hypodiploid in 11%. Twenty patients (21% of 94 tested) had a BCR::ABL1 rearrangement. The median follow-up was 20 months (range 3 to 326 months). Of the 126 patients enrolled, 5 did not complete the first course of chemotherapy and were lost to follow up. Of the remaining 121 patients, early discontinuation occurred in 5 patients that had complications upon initial therapy and died 3 - 15 days after the diagnosis. Among the remaining 116 patients, 90 (77%) achieved a complete remission (CR) (71% on intention to treat analysis). Chemotherapy was initiated on an outpatient basis in all patients and 24 (20%) had to be admitted in the hospital during the initial 7-week period of the induction / consolidation. Relapses were observed in 38 of the 90 patients who achieved a CR (43%); 13 relapses presented in the CNS and 25 in the BM; two persons had both relapses. The median remission duration for the total cohort was 48 months, while the median overall survival (OS) for the total population was 30 months. CONCLUSION The use of an asparaginase-containing PICC in AYAs and adult patients with ALL renders acceptable results, which are better than those obtained in similar socioeconomic circumstances using adult-oriented treatments, such as Hyper-CVAD. The toxicity of this regimen is acceptable and since it can be delivered on an outpatient basis, it results in diminished costs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cranial Irradiation for Childhood Cancers and Adult Risk of Meningioma

Introduction: Following cranial irradiation, there is an increased risk of developing secondary neoplasms, especially meningiomas. Despite childhood cancer survivors who have undergone cranial irradiation having an increased risk of acquiring radiation-induced meningioma (RIM), there is no widely used standard guideline for meningioma screening. Methods: At a single institution, we reviewed three adult survivors of childhood cancer who were treated for RIM between 2010 and 2020. We recorded age at diagnosis for the primary lesion, the radiation dose, age at RIM diagnosis, and tumor characteristics including treatment, pathology, and outcome. Two had had T-cell acute lymphocytic leukemia and one a rhabdomyosarcoma. The age of diagnosis of the RIM ranged from 20 to 40 years, with latencies ranging from 18 to 33 years. All lesions were classified as WHO Grade I meningiomas, and only 1 patient had a subsequent recurrence. A literature search identified articles that address RIM: a total of 684 cases were identified in 36 publications. Results: Mean radiation doses ranged from 1.4 gray to 70 gray. Mean age of diagnosis for secondary meningioma ranged from 8 to 53.4 years old, with latency periods ranging from 2.8 to 44 years. Given variability in the way that investigators have published their results, it is difficult to make a single recommendation for RIM screening. Using our experience and the literature, we devised two different screening protocols and calculated their expense. Conclusions: We recommend that data be standardized in a registry to provide greater insight into the clinical and resource allocation questions, especially as long-term survival of children with pediatric cancer into full adulthood becomes more commonplace worldwide.

Long‐term prognostic value of cardiac catheterization and acute vasodilator testing with inhaled iloprost in pediatric idiopathic pulmonary arterial hypertension

To assess the long-term prognostic value of cardiac catheterization and acute vasodilator testing (AVT) with inhaled iloprost in children with idiopathic pulmonary arterial hypertension (IPAH).Data on 81 consecutive children with IPAH referred to our center who underwent cardiac catheterization and AVT between June 2008 and August 2019 were collected. The correlation between the invasive hemodynamic data and transplant-free survival was analyzed. Twenty-four patients died and 1 underwent lung transplantation during a median follow-up of 3.8 years, with a 5-year transplant-free survival rate of 64.9%. Univariate analysis showed that predictors associated with improved survival included a lower pulmonary vascular resistance index (PVRI), PVRI/systemic vascular resistance index (SVRI), mean pulmonary arterial pressure (mPAP)/mean systemic arterial pressure, mean right atrial pressure, and a higher cardiac index (CI), mixed systemic venous oxygen saturations (SvO2), and acute vasodilator response (AVR) according to the Barst criteria (decrease in mPAP and PVRI/SVRI ratio of >20% without a decrease in CI). In multivariate Cox regression analysis, Barst AVR and SvO2 were independently related to transplant-free survival. Multiple hemodynamic variables from cardiac catheterization and AVT with inhaled iloprost have important prognostic value for long-term survival in children with IPAH, of which pulmonary vasoreactivity defined by the Barst criteria and SvO2 are independent prognostic factors.

Pulmonary complications in children and adolescents after allogeneic hematopoietic stem cell transplantation

Relevance. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) makes it possible to treat severe malignant and non-malignant hematopoietic disorders system. Pulmonary complications (PC) occur in 40–60 % of patients after allo-HSCT. However to date, the effect of HSCT on functional and morphological pulmonary changes in recipients remains insufficiently studied.The objective of current study was to evaluate risk factors affecting long-term survival in children and adolescents after allo-HSCT.Methods and materials. The current study was both retrospective and prospective. The analysis included 362 patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), aged 5 months to 18 years, who received allo-HSCT at Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation in 2000–2018. All the patients underwent chest computed tomography (CT). When detecting CT changes, we performed fibrobronchoscopy (FBS) with microbiological examination of bronchoalveolar lavage (BAL).Results. PC were diagnosed in 124 patients (64 %) who received allo-HSCT in 2014–2018. Decrease of overall survival (OS) is associated with PC development during the first year after allo-HSCT(р&lt;0,001).The development of early PC in remission of the underlying disease significantly affected OS (p=0.001).The probability of PC development is 2.26 times higher in patients older than 9 years (p=0.006). When comparing the intensity of conditioning regimens (MACvsRIC) in remission of the underlying disease, we did not get significant differences in the incidence of PC (p&gt;0.05). Graft source, donor type, HLA-compatibility, recipient gender did not affect the incidence of PC (p&gt;0.05). When using graft-versus-host disease (GVHD) prophylaxis (ptCYvsATG), the 5-year OS in patients without PC was 78.8 % and 62.8 %respectively. The 5-year OS in patients with PC was 51.8 % and 42.4 % respectively (р=0.007). Decrease of OS in patients with PC is associated with chGVHD(58.3 %,) (р=0.03).Conclusion. Pulmonary complications (infectious and non-infectious) in allo-HSCT recipients are more likely to occur in the first year after transplantation. Among bacterial pathogens, the predominance of Gr(-) flora remains. The incidence of pulmonary complications was significantly lower when using ptCY as a prevention of GVHD.

Autologous hematopoietic stem cell transplantation in children with relapsed or refractory Hodgkin lymphoma

The majority of patients with Hodgkin lymphoma (HL) are cured, which represents one of the best cure rates in oncology. However, the prognosis is not as favorable in case of relapsed or refractory (RR) disease. Autologous hematopoietic stem cell transplantation (auto-HSCT) is an effective way to consolidate remission in patients with RR HL. Despite the many years of experience and the availability of results of randomized trials confirming the efficacy of high-dose chemotherapy in adults, the role of auto-HSCT in children with HL has not been studied as extensively, and there are only a limited number of publications on the subject. As is the case with the majority of other pediatric tumors, RR HL is a rare entity, which is why it is so difficult to study it. Here we share the experience of the R. M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation in auto-HSCT in children and adolescents with HL. The study was approved by an Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint-Petersburg State Medical University. We included 54 patients with RR HL who had undergone auto-HSCT during the period from 2007 to 2021. Refractory disease (n = 29; 54 %) was diagnosed in case of HL progression either during first-line therapy or in the first 3 months after the completion of the treatment. Relapsed disease was diagnosed in 25 (46 %) children. Early HL relapse (&lt; 12 months since the start of therapy) was evident in 18 (72 %) patients, while late HL relapse (≥ 12 months since the start of therapy) occurred in 7 (28 %) children. The median number of lines of therapy before auto-HSCT was 3 (1–6). The first line of treatment was chemotherapy in accordance with the GPOH-HD (n = 27; 50 %), BEACOPP (n = 19; 35 %), or other protocols (n = 8; 15 %); the second line involved the use of IEP/ABVD (n = 14; 27 %), DHAP (n = 12; 23%), ICE (n = 13; 25 %), or other combinations (n = 13; 25%); and third-line treatment consisted of DHAP (n = 9; 29 %), a combination of brentuximab vedotin and bendamustine (n = 8; 26%), immune checkpoint inhibitors (ICIs) (n = 7; 22.5 %) or other regimens (n = 7; 22.5 %). ICIs were used for remission induction prior to auto-HSCT in 14 (26 %) patients. Response was assessed using the Lugano classification. Status before transplantation: complete remission (CR) – 21 (39 %) patients, partial remission (PR) – 30 (56 %), disease stabilization – 2 (3.5 %), disease progression – 1 (1.5 %). The BEAM conditioning regimen was used in 17 (31 %) patients, and the BeEAM regimen – in 32 (59 %) patients. The 3-, 5- and 10-year overall survival (OS) was 88% (95 % confidence interval (CI) 74–95), 80% (95 % CI 62–90) and 63% (95 % CI 34–81) respectively. The 10-year progression-free survival (PFS) was 46% (95 % CI 24–65). The median follow-up was 3.3 (0.1–12.3) years. The long-term PFS in children with CR and PR was 72% (95 % CI 41–89) and 33 % (95 % CI 8–61) respectively (p = 0.067). A total of 9 (16.7 %) patients died during follow-up. The main cause of death was progressive HL (n = 6), while some patients died in the early post-transplant period due to infections (n = 3; 5.6 %). The median time to relapse or progression after auto-HSCT was 6 (1–77) months. Out of 17 (31 %) patients with relapsed or progressive HL after auto-HSCT, 9 (53 %) children are alive at a median follow-up of 2.3 (0.7–9) years. Considering that our study included patients who had been more extensively pre-treated (the median number of lines of therapy – 3) than patients in the majority of other studies (the median number of lines of therapy – 2), it can be assumed that our results are superior to historical data. The improvement of transplantation outcomes observed over time can be attributed to better supportive treatment and probably, to the use of immunotherapy. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), it is crucially important that long-term survival in children with RR HL be monitored closely since it can be drastically different from results obtained during the first years of follow-up - due to late relapses and complications of the received treatment. The 10-year survival rates show that the RR HL problem is yet to be resolved. With the help of auto-HSCT, approximately half of children and adolescents with RR HL can be cured. One of the most important favorable prognostic factors in these patients is the achievement of CR before transplantation. The use of immunotherapy for remission induction before auto-HSCT is also promising.

Interdisciplinary Radical "En-Bloc" Resection of Ewing Sarcoma of the Chest Wall and Simultaneous Chest Wall Repair Achieves Excellent Long-Term Survival in Children and Adolescents.

Introduction: Ewing sarcomas of the chest wall, historically known as “Askin tumors” represent highly aggressive pediatric malignancies with a reported 5-year survival ranging only between 40 and 60% in most studies. Multimodal oncological treatment according to specific Ewing sarcoma protocols and radical “en-bloc” resection with simultaneous chest wall repair are key factors for long-term survival. However, the surgical complexity depends on tumor location and volume and potential infiltrations into lung, pericardium, diaphragm, esophagus, spine and major vessels. Thus, the question arises, which surgical specialties should join their comprehensive skills when approaching a child with Ewing sarcoma of the chest wall.Patients and Methods: All pediatric patients with Ewing sarcomas of the chest wall treated between 1990 and 2020 were analyzed focusing on complete resection, chest wall reconstruction, surgical complications according to Clavien-Dindo (CD) and survival. Patients received neo-adjuvant chemotherapy according to the respective Ewing sarcoma protocols. Depending on tumor location and organ infiltration, a multi-disciplinary surgical team was orchestrated to perform radical en-bloc resection and simultaneous chest wall repair.Results: Thirteen consecutive patients (seven boys and six girls) were included. Median age at presentation was 10.9 years (range 2.2–21 years). Neo-adjuvant chemotherapy (n = 13) and irradiation (n = 3) achieved significant reduction of the median tumor volume (305.6 vs. 44 ml, p < 0.05). En-bloc resection and simultaneous chest wall reconstruction was achieved without major complications despite multi-organ involvement. Postoperatively, one patient with infiltration of the costovertebral joint and laminectomy required surgical re-intervention (CD IIIb). 11/13 patients were treated with clear resections margins (R1 resection in one patient with infiltration of the costovertebral joint and marginal resection <1 mm in one child with multiple pulmonary metastases). All patients underwent postoperative chemotherapy; irradiation was performed in four children. Two deaths occurred 18 months and 7.5 years after diagnosis, respectively. Median follow-up for the remaining patients was 8.8 years (range: 0.9–30.7 years). The 5-year survival rate was 89% and the overall survival 85%.Conclusion: EWING specific oncological treatment and multi-disciplinary surgery performing radical en-bloc resections and simultaneous chest wall repair contribute to an improved survival of children with Ewing sarcoma of the chest wall.

Potential Importance of Early Focal Radiotherapy Following Gross Total Resection for Long-Term Survival in Children With Embryonal Tumors With Multilayered Rosettes.

Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on nine consecutive patients and review the role of initiation/timing of radiotherapy on survival. Between 2006 and 2018, nine patients were diagnosed with ETMR. Diagnosis was confirmed histopathologically, immunohistochemically and molecularly. Median age was 25 months (5–38). Location was supratentorial in five, pineal in three, and brainstem in one. Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis. Chemotherapy augmented with intrathecal therapy started a median of 10 days (7–20) after surgery. Only two patients who after gross total resection received radiotherapy very early on (six weeks after diagnosis) are alive and in complete remission 56 and 50 months after diagnosis. All remaining patients for whom radiotherapy was deferred until the end of chemotherapy recurred, albeit none with leptomeningeal disease. A literature research identified 228 patients with ETMR. Including our patients only 26 (11%) of 237 patients survived >36 months with no evidence of disease at last follow-up. All but two long-term (>36 months) survivors received radiotherapy, ten of whom early on following gross total resection (GTR). GTR followed by early focal radiotherapy and intrathecal therapy to prevent leptomeningeal disease are potentially important to improve survival of ETMR in the absence of effective targeted therapies.

MBRS-31. COMBINING IRRADIATION AND ANTI-CD47 TO ENHANCE THE TREATMENT OF GROUP 3 MEDULLOBLASTOMA

Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. The Group 3 molecular subgroup of Medulloblastoma (Group 3 MB) is the deadliest with only 30% long term survival. Irradiation for Group 3 Medulloblastoma is required for long term survival of children. Methods to enhance the effect of irradiation against Group 3 MB are an active area of investigation. Immunotherapy using the anti-CD47 treatment has shown promise in treating Group 3 MB. We recently demonstrated that irradiation significantly enhanced anti-CD47-mediated phagocytosis of high-grade glioma cells in vitro. Furthermore, mice engrafted with human high-grade glioma that received anti-CD47 combined with irradiation showed a significant increase in the survival rate and a significant decrease in tumor growth than those that received a single treatment. We have now extended these studies to demonstrate the enhancement of anti-CD47-dependent phagocytosis of human Group 3 MB with irradiation. We also analyzed normal human neural stem cells exposed to the same treatments to assess for the potential toxicity that uniquely exists with this treatment combination.

Congenital short bowel syndrome: a case report and review of the literature

Congenital short bowel syndrome is a rare condition of the newborn, with several reports demonstrating high mortality. For the first time in Russia, we report a case of treatment of a newborn girl with genetically confirmed congenital short bowel syndrome, and also provide a review of the literature on this syndrome. After birth, the child experienced constant vomiting of bile with a progressive decrease in body weight. The laparotomy for congenital adhesions between the loops of the small intestine with severe violations of the evacuation function revealed that the small bowel was 50 cm in length, confirming the diagnosis of congenital short bowel syndrome. The genetic test, using whole exome sequencing, identified a homozygous mutation in the CLMP gene in this patient. A positive result in the postoperative period was achieved using the protocol for the management of patients with short bowel syndrome. Currently, the girl is 11 months old, body weight is 9 kg, development is harmonious. Long-term survival of children with congenital short bowel syndrome is now possible if enteral feeds are introduced early to promote intestinal adaptation, with subsequent weaning off parenteral nutrition.

Long-term survival of children following acute peritoneal dialysis in a resource-limited setting.

BackgroundThere is a paucity of data on long term-outcomes of children who undergo acute peritoneal dialysis (PD) in resource-limited settings. We reviewed the outcomes of children who underwent PD after 18 months of follow-up.MethodsWe conducted a prospective cohort study in children with acute kidney injury (AKI) who underwent PD. Diagnosis of AKI was based on the 2012 Kidney Disease Improving Global Outcomes definition. We assessed outcomes of in-hospital mortality, 18-month post-dialysis survival, factors associated with survival, and progression to chronic kidney disease (CKD).ResultsTwenty-nine children with a median age of 6 (3 to 11) years underwent acute PD. In-hospital mortality was 3/29 (10.3%) and rose to 27.6% during follow-up. Seven (24.1%) children were lost to follow-up. Of the 14 remaining children, six (42.9%) experienced full recovery of renal function, while eight (57.1%) progressed to CKD. Among those who experienced full recovery, median (interquartile range) estimated glomerular filtration rate (eGFR) rose from 12.67 (7.05, 22.85) mL/min/1.73 m2 to 95.56 (64.50, 198.00) mL/min/1.73 m2, P = 0.031. No significant changes in median eGFR from baseline were observed among those who progressed to CKD (P = 0.383) or in non-survivors (P = 0.838). According to Kaplan-Meier curve analyses, 18-month survival during follow-up was 66.0% (95% CI, 45.0% to 86.5%). Age < 5 was associated with greater likelihood of survival (OR, 3.217; 95% CI, 1.240 to 8.342).ConclusionProgression of post-PD AKI to CKD occurred in more than half of survivors. Age < 5 was associated with greater likelihood of survival.

Cisplatin-induced nephrotoxicity in children: what is the best protective strategy?

Platinum compounds, which are considerably effective for the treatment of childhood malignancies, have significantly contributed to the increase in long-term survival of children with cancer. Unfortunately, children receiving cisplatin-based chemotherapy have been known to be at risk for severe disabling adverse effects, such as nephrotoxicity. A literature research of the MEDLINE PubMed database was conducted to identify articles published between 1980 and 2019 reviewing "Cisplatin AND mannitol." The primary pharmacodynamics and clinical characteristics of cisplatin were described, focusing on its renal toxic effects and potential preventive strategies, in order to improve clinical outcomes among children with cancer aged 1 to 14 years. Currently, selecting either hydration alone or hydration plus mannitol for preventing nephrotoxicity has been controversial considering the lack of guidelines to provide treatment recommendations both among adults and children. Appropriate knowledge regarding the pharmacokinetics and toxicological profile of cisplatin may help physicians prevent renal toxicity. Unfortunately, published data regarding the nephroprotective utility of adding mannitol appear to be inconclusive. As such, appropriate hydration remains the main fundamental strategy for reducing the risk of cisplatin-induced nephrotoxicity. Considering the increasing number of children safely cured of their tumours, it is imperative that those treated with cisplatin receive the most appropriate nephroprotective strategy for reducing the negative impact of platinum compounds on quality of life.

Short- and Long-Term Outcome in Critically Ill Children After Acute Interhospital Transport to a PICU in Sweden.

Data on long-term survival in children after interhospital transport to a PICU are scarce. The main objective was to investigate short- and long-term outcome after acute interhospital transport to a PICU for different age and risk stratification groups. Secondary aims were to investigate whether neonatal patients would have higher mortality and be more resource demanding than older patients. Single-center, retrospective cohort study. Specialist pediatric transport team and a tertiary PICU in Sweden. Critically ill children 0-18 years old, acutely transported by a specialist pediatric transport team to a PICU in Sweden (January 1, 2008, to December 31, 2016). None. A total of 401 acute transport events were included. Overall mortality was 15.7% with a median follow-up time of 3.4 years (range, 0-10.2 yr). Median predicted death rate was 4.9%. There was no mortality during transport. Cumulative mortality almost doubled within the first 6 months after PICU discharge, from 6.5% to 12.0%. Of late deaths, 66.7% occurred in the risk stratification group predicted death rate 0-10%, and 95% suffered from severe comorbidity. There were no deaths after PICU discharge in the neonatal group. Cumulative mortality in multiple transported patients was 36.4%. This is the first report on long-term survival after acute pediatric interhospital transport. For the entire cohort, there was significant mortality after PICU discharge, especially in multiple transported patients. In contrast, survival in the subgroup of neonatal patients was high after PICU discharge.

Phase 1 Study of Decitabine and Vorinostat Followed By Fludarabine, Cytarabine and G-CSF (FLAG) in Children, Adolescents and Young Adults with Relapsed/Refractory AML: Report from the Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium

Introduction: Despite progress in the treatment of acute myeloid leukemia (AML) over the past few decades, long-term survival of children, adolescents and young adults remains poor. Most treatment failure is secondary to the development of chemotherapy resistance resulting in relapsed or refractory disease. Epigenetic changes in leukemia cells, such as DNA methylation and/or histone acetylation, can lead to alterations in gene expression thereby causing resistance to chemotherapeutic agents. These epigenetic changes are potentially reversible with agents that demethylate DNA and/or inhibit histone deacetylation which ultimately leads to restoration of normal gene expression and chemosensitivity. We are reporting an ongoing phase I trial of decitabine and vorinostat, two epigenetic modifying agents, followed by chemotherapy in children, adolescents and young adults with relapsed or refractory AML. Methods: T2016-003 is a phase I study that was developed and activated in the TACL consortium in July 2017 for patients 1 to 25 years of age with relapsed or refractory AML. The study followed a standard 3 + 3 phase I cohort escalation design. Three dose levels of decitabine were investigated: dose level 1 (7.5 mg/m2); dose level 2 (10 mg/m2); and dose level 3 (15 mg/m2). Patients received decitabine (at assigned dose level) and vorinostat (age &amp;lt;18 years, 180 mg/m2 once daily; &amp;gt;18 years, 200 mg twice daily) days 1 to 5 followed by fludarabine (30 mg/m2, days 6 to 10), cytarabine (2000 mg/m2, days 6 to 10) and granulocyte colony stimulating factor (G-CSF) (5 μ/kg/dose, days 5 until neutrophil recovery) (FLAG). Intrathecal therapy was given up to 72 hours prior to the initial doses of decitabine/vorinostat, with additional intrathecal therapy for central nervous system disease. Patients could receive up to two cycles of therapy. End of course evaluation by bone marrow minimal residual disease (MRD) testing using flow cytometry was performed between days 35 and 42 or upon adequate blood count recovery. Results: Twenty-five patients have enrolled to date with 24 evaluable for dose limiting toxicity (DLT) and response. Median age was 7 (range, 1 to 20) years. Fourteen patients (58.3%) had relapsed after a prior bone marrow transplant and 7 (29.2%) had refractory disease at time of enrollment. There were no dose limiting toxicities at dose level 1 (n=3, 7.5 mg/m2) or 2 (n=3, 10 mg/m2) of decitabine. However, at dose level 3 (n=12, 15 mg/m2), 3 subjects reported Grade 4 invasive fungal infection (Aspergillus terreus, Candida parapsilosis and Rhizomucor pusillus) leading to de-escalation of decitabine to dose level 2. The study continued dose expansion at dose level 2 without DLT, enrolling 7 additional patients. Twenty-two subjects have completed the study and are evaluable for response. Responses were noted at all dose levels. Eight subjects (36.4%) achieved a complete response (CR) or complete response with incomplete hematologic recovery (CRi). Five of the 8 subjects who achieved a CR/CRi were also negative for MRD. Eight subjects had known epigenetic lesions (i.e. KMT2Ar, CEBPα, IDH2) with 6 (75%) achieving a CR, 4 of whom (66.7%) were also MRD negative. Conclusion: Overall, we identified decitabine (10 mg/m2) in combination with vorinostat and followed by FLAG chemotherapy to be well-tolerated and an effective regimen in pediatric patients with relapsed AML, particularly in subjects with known epigenetic lesions. The study continues to enroll at dose level 2 of decitabine for a total accrual goal of 33 subjects. Correlative analysis of peripheral blood and bone marrow investigating methylation, histone acetylation and gene expression is ongoing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau.

Outcome of children with T cell acute lymphoblastic leukemia treated with Chinese Children Leukemia Group acute lymphoblastic leukemia (CCLG-ALL) 2008 protocol

Objective: To evaluate the efficacy of the Chinese Children's Leukemia Group (CCLG) acute lymphoblastic leukemia (ALL) 2008 protocol (CCLG-ALL 2008) in the treatment of children's T-cell acute lymphoblastic leukemia (T-ALL). Methods: Clinical characteristics and outcomes of 84 newly diagnosed T-ALL children (63 males and 21 females) treated with CCLG-ALL 2008 protocol from April 2008 to April 2015 in the Department of Pediatric Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences were analyzed retrospectively. Kaplan-Meier analysis was used to evaluate the overall survival (OS) and event free survival (EFS), and COX regression was used to evaluate the influencing factors of OS and EFS. Results: (1) Baseline data: 84 children were included, 56 cases (67%) of children were younger than 10 years old. Patients whose white blood cell count≥50×10(9)/L ranked 70% (59/84). Karyotype: 58% (49/84) with normal karyotype, 10% (8/84) with abnormality of chromosome 11, 8%(7/84) with abnormality of chromosome 9, 2%(2/84) with abnormality in both chromosome 11 and chromosome 9, 8% (7/84) with other complex karyotypes. Fusion gene: 33%(28/84) were SIL-TAL1 positive. The patients were grouped by CCLG-ALL 2008 risk score, 40% (34/84) were in the intermediate risk group and 60% (50/84) in the high risk group. (2) Treatment efficacy: 84 cases were followed up until May 30, 2018. The follow-up time was 42.0 (0.3-120.0) months. The sensitivity rate of prednisone treatment was 56% (47/84); the complete response (CR) rate after the induction therapy of vincristine+daunoblastina+L-asparaginase+dexamethasone (VDLD)(d 33) was 88% (74/84); the total CR rate after VDLD induction combined with cyclophosphamide+cytarabine+6-mercaptopurine (CAM) treatment (d80) was 94% (79/84); the recurrence rate was 24% (20/84). Among the 20 recurrent cases, there were 13 cases (65%) with ultra-early recurrence (within 18 months after diagnosis), 6 cases (30%) with early recurrence (18 to 36 months after diagnosis); 1 patient (5%) with late recurrence (over 36 months after diagnosis). During the follow-up period, twenty-eight children (33%) died (22 cases with recurrence or suspending treatment without remission, 2 cases with infection, 1 case of sudden death in chemotherapy, 1 patient failed in transplantation, 1 patient with severe cirrhosis, and 1 patient with unknown cause). (3) Kaplan-Meier analysis: the 5-year OS and EFS of the 84 children were (63±6)% and (60±6)% respectively. (4) Efficacy in different risk groups: prednisone sensitivity rates in the two different risk groups were 100% (34/34) and 26% (13/50), respectively (χ(2)=3.237, P<0.05). The CR rates at the end of VDLD induction therapy (d 33) were 100% (34/34) and 80% (40/50), respectively (χ(2)=2.767, P<0.05). The recurrence rate of children in the two groups was 12% (4/34) and 32% (16/50), respectively (χ(2)=4.245, P<0.05).The mortality rates of the two groups were 21% (7/34) and 42% (21/50), respectively (χ(2)=3.198, P<0.05). Kaplan-Meier analysis showed that the 5-year OS of the two groups were (77±7)% and (53±8)%; and the 5-year EFS of the two groups were (75±8)% and (49±8)% (χ(2)=4.235, 3.875, both P<0.05) . (5) COX multivariate regression analysis showed that the classification of risk according to CCLG-ALL 2008 was an important factor influencing the prognosis of children with T-ALL (OR=3.313, 95% CI 1.165-9.422, P=0.025). Conclusions: The results of the risk group treatment according to the CCLG-ALL 2008 protocol showed that the long-term survival of children with middle risk was significantly better than that of children at high risk.