Dual roles of HK3 in regulating the network between tumor cells and tumor-associated macrophages in neuroblastoma.

Neuroblastoma (NB) is the most common and deadliest extracranial solid tumor in children. Targeting tumor-associated macrophages (TAMs) is a strategy for attenuating tumor-promoting states. The crosstalk between cancer cells and TAMs plays a pivotal role in mediating tumor progression in NB. The overexpression of Hexokinase-3 (HK3), a pivotal enzyme in glucose metabolism, has been associated with poor prognosis in NB patients. Furthermore, it correlates with the infiltration of M2-like macrophages within NB tumors, indicating its significant involvement in tumor progression. Therefore, HK3 not only directly regulates the malignant biological behaviors of tumor cells, such as proliferation, migration, and invasion, but also recruits and polarizes M2-like macrophages through the PI3K/AKT-CXCL14 axis in neuroblastoma. The secretion of lactate and histone lactylation alterations within tumor cells accompanies this interaction. Additionally, elevated expression of HK3 in M2-TAMs was found at the same time. Modulating HK3 within M2-TAMs alters the biological behavior of tumor cells, as demonstrated by our in vitro studies. This study highlights the pivotal role of HK3 in the progression of NB malignancy and its intricate regulatory network with M2-TAMs. It establishes HK3 as a promising dual-functional biomarker and therapeutic target in combating neuroblastoma.

Pediatric Solid Cancers: Dissecting the Tumor Microenvironment to Improve the Results of Clinical Immunotherapy.

Despite advances in their diagnosis and treatment, pediatric cancers remain among the leading causes of death in childhood. The development of immunotherapies and other forms of targeted therapies has significantly changed the prognosis of some previously incurable cancers in the adult population. However, so far, the results in pediatric cohorts are disappointing, which is mainly due to differences in tumor biology, including extreme heterogeneity and a generally low tumor mutational burden. A central role in the limited efficacy of immunotherapeutic approaches is played by the peculiar characteristics of the tumor microenvironment (TME) in pediatric cancer, with the scarcity of tumor infiltration by T cells and the abundance of stromal cells endowed with lymphocyte suppressor and tumor-growth-promoting activity. Thus, progress in the treatment of pediatric solid tumors will likely be influenced by the ability to modify the TME while delivering novel, more effective therapeutic agents. In this review, we will describe the TME composition in pediatric solid tumors and illustrate recent advances in treatment for the modulation of immune cells belonging to the TME.

A Retrospective Analysis of the Therapeutic Outcomes of 117 Neuroblastoma Patients Treated at a Single Pediatric Oncology Center in China.

OBJECTIVE: Recent therapeutic advances have greatly enhanced the survival rates of patients with neuroblastoma (NB). However, the outcomes of neuroblastoma patients in China, particularly those with high-risk (HR) NB, remain limited. METHOD: We retrospectively analyzed the clinical data and outcomes of NB patients who were treated at a tertiary pediatric cancer facility in China between January 2013 and October 2021. RESULTS: A total of 117 NB patients were recruited. Patients with very low-risk (VLR), low-risk (LR), intermediate-risk (IR), and HR-NB patients made up 4%, 27%, 15%, and 54% of total patient population, respectively. Patients diagnosed between 2013 and 2018 were treated according to the protocol of Sun Yat-Sen University Cancer Center and those diagnosed between 2019 and 2021 were treated according to the COG ANBL0531 or ANBL0532 protocol with or without autologous stem cell transplantation (ASCT). The 5-year EFS and OS of all risk groups of patients were 67.29% and 77.90%, respectively. EFS and OS were significantly decreased in patients with higher risk classifications (EFS: VLR/LR vs IR vs HR: 97.22% vs 67.28% vs 51.83%; ***P = .001; OS: VLR/LR vs IR vs HR: 97.06% vs 94.12% vs 64.38%; *P = .046). In HR-NB patients treated according to the COG protocol between 2019 and 2021, the 3-year OS of patients who received tandem ASCT was significantly greater than those who did not receive ASCT (93.33% % vs 47.41%; *P = .046; log-rank test). EFS was not significantly different between patients with and without ASCT (72.16% vs 60.32%). CONCLUSION: Our findings show that patients with lower risk classification have a positive prognosis for survival. The prognosis of patients with HR-NB remains in need of improvement. ASCT may enhance OS in HR-NB patients; however, protocol adjustment may be necessary to increase EFS in these patients.

Microsatellite instability-high is rare events in refractory pediatric solid tumors.

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

Association Between Arg72Pro Polymorphism in TP53 and Malignant Abdominal Solid Tumor Risk in Hunan Children.

Pediatric solid tumors are heterogeneous and comprise various histological subtypes. TP53, a tumor suppressor, orchestrates the transcriptional activation of anti-cancer genes. The gene coding for this protein is highly polymorphic, and its mutations are associated with cancer development. The Arg72Pro polymorphism in TP53 has been associated with susceptibility to various types of cancer. Here, in this hospital-based study, we evaluated the association of this polymorphism with susceptibility toward malignant abdominal solid tumors in children in the Hunan province of China. We enrolled 162 patients with neuroblastoma, 60 patients with Wilms' tumor, and 28 patients with hepatoblastoma as well as 270 controls. Genotypes were determined using a TaqMan assay, and the strength of the association was assessed using an odds ratio, within a 95% confidence interval identified using logistic regression models. Our results showed that the Arg72Pro polymorphism did not exhibit significant association with susceptibility toward pediatric malignant abdominal solid tumors. Stratification analysis revealed that this polymorphism exerts weak sex- and age-specific effects on Wilms' tumor and hepatoblastoma susceptibility, respectively. Overall, our results indicate that the Arg72Pro polymorphism may have a marginal effect on susceptibility toward pediatric malignant abdominal solid tumors in Hunan, and this finding warrants further confirmation.

Prophylactic piperacillin administration in pediatric patients with solid tumors following different intensities of chemotherapy.

BACKGROUND: Prophylactic antibiotics decrease mortality and morbidity in patients with hematological malignancies following intensive chemotherapy. However, the efficacy of prophylactic antibiotics for pediatric patients with solid tumors remains unclear. METHODS: We retrospectively assessed 103 neutropenic periods from 26 patients with neuroblastoma or brain tumors following three different intensity chemotherapy regimens (05A3, A, and B). While piperacillin was intravenously administered as prophylaxis (PIPC prophylaxis group), the historical control group received no prophylaxis. As patients exhibited a variable degree of myelosuppression based on the intensity of the chemotherapy regimen, we separately evaluated the frequency and severity of febrile neutropenia (FN) in each regimen. RESULTS: Following intensive chemotherapy, we observed a significantly lower frequency of FN in the PIPC prophylaxis group compared with the historical control group in both regimen 05A3 (20% vs 65%; P = 0.01) and regimen A (56% vs 93%; P = 0.02). We also observed a shorter duration of fever, lower maximum fever, and lower C-reactive protein levels in the PIPC prophylaxis group compared with the historical control group after regimens 05A3 and A. Conversely, the frequency and severity of FN were not different between the two groups after moderate-intensity chemotherapy (regimen B). However, a longitudinal routine surveillance study of Pseudomonas aeruginosa also indicated a reduction in the susceptibility to PIPC throughout the study period. CONCLUSIONS: Although PIPC prophylaxis might provide an advantage for severe neutropenia in pediatric patients with solid tumors, there is concern regarding bacterial resistance to antibiotics. Therefore, further careful examination is necessary for adaptation.

Double-conditioning regimen consisting of high-dose thiotepa and melphalan with autologous stem cell rescue for high-risk pediatric solid tumors: A second report.

BACKGROUND: Pediatric patients with high-risk, relapsed, or refractory solid tumors have a poor prognosis. We have previously reported a dose-finding experience of high-dose chemotherapy consisting of thiotepa and melphalan ("double-conditioning regimen"). Using doses derived from that study, we have treated patients since 2005. We now report a retrospective review of patients treated by this fixed dose. PROCEDURE: We reviewed 50 patients (median 4 years; range 0-15 years) with high-risk or relapsed/refractory solid tumors treated by this dose-fixed, double-conditioning regimen from April 2005 to May 2014. Doses were thiotepa 800 mg/m2 and melphalan 280 mg/m2 for children ≥2 years of age, and 32 mg/kg and 6 mg/kg, respectively, for children <2 years of age. Further, doses were reduced according to creatinine clearance with poor renal function. RESULTS: Nonhematological toxicity was mainly gastrointestinal-grade 3 mucositis (n = 41) and grade 3-4 diarrhea (n = 10). Neurological, renal, and endothelial cell toxicity and sinusoidal obstruction syndrome were not observed. There were two toxic deaths (interstitial viral pneumonia). This regimen demonstrated antitumor activity against several types of tumors. Although the frequency of gastrointestinal toxicity was high, other severe toxicity was not observed. CONCLUSIONS: Our double-conditioning regimen was very well tolerated and demonstrated antitumor activity. We are moving forward with multi-institutional trials now.

Vincristine, irinotecan, and temozolomide treatment for refractory/relapsed pediatric solid tumors: A single center experience.

BACKGROUND: Although the survival of pediatric cancer has increased dramatically in the last decades, the survival of refractory, relapsed, and metastatic cases is still dismal. The combination of irinotecan and temozolomide has shown activity against refractory/relapsed pediatric solid tumors. METHOD: Thirty-four children with refractory/relapsed solid tumors who had previously been heavily pretreated and who were given vincristine, irinotecan, and temozolomide as third- or further line chemotherapy during 2004-2015 were evaluated. RESULTS: Patients were diagnosed with Ewing sarcoma (n = 15), rhabdomyosarcoma (n = 8), neuroblastoma (n = 8), osteosarcoma (n = 2), and Wilms' tumor (n = 1). Thirty patients presented with disease progression on therapy and the other four presented with relapsing. A total of 141 cycles were administered. Radiotherapy was used in 17 patients and surgery in 4 as local therapy. Among all patients, 6 had complete response, 3 had partial response, 14 had stable disease, and 11 had progressive disease. The objective response was 26.4% (complete response + partial response) and median survival duration was six months. The first and second year overall survival rates were 22.3% and 16.8%. The objective response in Ewing sarcoma patients was 40%. Diarrhea was the most common toxicity and 14 (10%) courses were associated with grade 3-4 diarrhea. CONCLUSIONS: In heavily pretreated patients with refractory/relapsed solid tumors, the vincristine, irinotecan, and temozolomide regimen seemed promising in Ewing sarcoma patients and was well tolerated.

Various checkpoint molecules, and tumor-infiltrating lymphocytes in common pediatric solid tumors: Possibilities for novel immunotherapy.

Long-term survival rates for pediatric patients with cancer have significantly improved, but novel approaches are desired for those with refractory/relapsed solid tumors. Recently, programed cell death-1/programed cell death-ligand-1 blockade has emerged as an effective option for many intractable cancers. However, not all patients show objective response to such therapy. On the other hand, several other checkpoint pathways, including Herpes virus entry mediator (HVEM)/B- and T-lymphocyte attenuator (BTLA), galectin-9 (GAL9)/T-cell immunoglobulin and mucin domain-3 (TIM3), and major histocompatibility complex class II (MHC-II)/lymphocyte activation gene-3 (LAG3), also regulate immune responses in the tumor microenvironment and may be alternative targets for novel immune therapies. In this study, we examined 65 common pediatric solid tumors and characterized the expression of Herpes virus entry mediator, GAL9, and MHC-II on tumor cells and their corresponding receptors B- and T-lymphocyte attenuator, TIM3, and LAG3, respectively, on tumor-infiltrating lymphocytes (TILs) with immunohistochemistry. Whereas the expression of GAL9 and MHC-II was limited, 73% of rhabdomyosarcomas and 100% of osteosarcomas expressed moderate to high levels of Herpes virus entry mediator on the tumor. TILs were detected in all tumor samples except one osteosarcoma. Interestingly, 45% of rhabdomyosarcomas, and 45% of osteosarcomas expressed moderate to high levels of both Herpes virus entry mediator on the tumor cells and B- and T-lymphocyte attenuator on the TILs. Results showed that a subset of pediatric solid tumors expressed tumor-associated checkpoint molecules, and TILs expressed corresponding receptors for these checkpoint molecules. Thus, immunogenic environments may be created, and checkpoint blockade may induce favorable immune responses.

A study of axitinib, a VEGF receptor tyrosine kinase inhibitor, in children and adolescents with recurrent or refractory solid tumors: A Children's Oncology Group phase 1 and pilot consortium trial (ADVL1315).

BACKGROUND: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors. METHODS: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m2 /dose and 3.2 mg/m2 /dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed. RESULTS: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≤6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified. CONCLUSIONS: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m2 /dose, which provides PK exposures similar to those of adults.

Cellular immunotherapy for pediatric solid tumors.

Substantial progress has been made in the treatment of pediatric solid tumors over the past 4 decades. However, children with metastatic and or recurrent disease continue to do poorly despite the aggressive multi-modality conventional therapies. The increasing understanding of the tumor biology and the interaction between the tumor and the immune system over the recent years have led to the development of novel immune-based therapies as alternative options for some of these high-risk malignancies. The safety and anti-tumor efficacy of various tumor vaccines and tumor-antigen specific immune cells are currently being investigated for various solid tumors. In early clinical trials, most of these cellular therapies have been well tolerated and have shown promising clinical responses. Although substantial work is being done in this field, the available knowledge for pediatric tumors remains limited. We review the contemporary early phase cell-based immunotherapy efforts for pediatric solid tumors and discuss the rationale and the challenges thereof.

Nonurological malignancies in children.

CONTEXT: Nonurological malignancies in children include a wide variety of tumors. These tumors include primary tumors of the liver, thyroid, lung, gastrointestinal tract (GIT), and adrenals; soft tissue sarcomas (STSs) like rhabdomyosarcoma (RMS) and non-RMS; and finally extragonadal germ cell tumors (GCT). AIMS: This article aims at describing the current thinking in the management of these childhood solid tumors. This is critical in view of the recent advances in the elucidation of the molecular, genetic, and biologic behavior of these tumors and how these factors are getting integrated not only in the staging but also in developing a risk-based approach towards the management of these tumors. MATERIALS AND METHODS: Reference was made to recently published literature from the leading pediatric cancer centers of the world to make a sense of things of the most current thinking in this rapidly expanding field. This will provide surgeons and physicians taking care of these children with a working knowledge in this somewhat challenging field. CONCLUSIONS: Treatment results vary from center to center depending on access to resources and following different management protocols. Results have improved for these tumors with the advent of newer chemotherapeutic agents, novel delivery methods of radiation therapy (RT), and improvement in surgical technique. Due to the limited number of patients presenting with these tumors, national and international collaboration of data is critical for all and beneficial to individual treatment centers. This has resulted in better results in the past and will definitely result in still better results in the future.

Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors.

PURPOSE: This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT). MATERIALS AND METHODS: Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk. RESULTS: A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively. CONCLUSION: The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma.

Introduction: The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2. Methods: We compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 versus IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines. Results: The IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h. Conclusion: CB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

Characteristics of gut microbiome in patients with pediatric solid tumor.

Background: Pediatric solid tumors are a common malignant disease in children, and more and more studies have proved that there is an inseparable relationship between adult tumors and intestinal microbiome, but the changes in the intestinal microbiota of pediatric solid tumor (PST) patients have been scarcely examined. This study aims to examine the differences in the intestinal microbiota features between patients diagnosed with PST and healthy controls (HCs). Methods: To elucidate the unique characteristics of the gut microbiota in pediatric patients with solid tumors, we recruited 23 PST patients and 20 HCs. A total of 43 stool samples were gathered, and then 16S rRNA sequencing was performed. Results: We noticed a noticeable pattern of elevated diversity in the gut microbiota within the PST groups. The differences in microbial communities among two groups were remarkable, regarding the analysis at the class level, the abundance of Bacilli was markedly increased in PST patients compared to HCs (P < 0.05), regarding the analysis at the genus level, The presence of Enterococcus was significantly higher in PST cases compared to HCs (P < 0.01), while Lachnospiraceae unclassified, Lachnospira, Haemophilus and Colidextribacter in PST cases, the abundance was significantly reduced. (P < 0.05), 6 genera, including Bacilli, Lactobacillales, Enterococcaceae and Morganella, showed a significant enrichment compared to healthy controls, while 10 genera, including Bilophila, Colidextribacter, Pasteurellales, Haemophilus, Lachnospiraceae unclassified, Lachnospira and Fusobacteriales, were significant reduction in the PST groups. Conclusion: Our research conducted the characterization analysis of the gut microbiota in PST patients for the first time. More importantly, there are some notable differences in the gut microbiota between PST patients and healthy controls, which we believe is an interesting finding.

Genomics-Driven Precision Medicine in Pediatric Solid Tumors.

Over the past decades, several study programs have conducted genetic testing in cancer patients to identify potential genetic targets for the development of precision therapeutic strategies. These biomarker-driven trials have demonstrated improved clinical outcomes and progression-free survival rates in various types of cancers, especially for adult malignancies. However, similar progress in pediatric cancers has been slow due to their distinguished mutation profiles compared to adults and the low frequency of recurrent genomic alterations. Recently, increased efforts to develop precision medicine for childhood malignancies have led to the identification of genomic alterations and transcriptomic profiles of pediatric patients which presents promising opportunities to study rare and difficult-to-access neoplasms. This review summarizes the current state of known and potential genetic markers for pediatric solid tumors and provides perspectives on precise therapeutic strategies that warrant further investigations.

Lymphatic Embolization for the Management of Post-operative Chyle Leaks Following Solid Tumor Resection in Pediatric Patients.

BACKGROUND: Chyle leaks are a common post-operative complication following solid-tumor resection in pediatric patients. Current treatments for persistent chyle leaks are limited, leading many patients to experience prolonged hospitalization, nutritional deficits and/or delays in cancer therapies. Lymphatic embolization is an emerging treatment option for chyle leaks, however, limited reports exist of its use in pediatric populations. METHODS: We conducted a retrospective review of pediatric patients (<18) who underwent lymphangiogram with intent for lymphatic embolization for the management of chyle leaks following solid-tumor resection between 2017 and 2022. RESULTS: Seven patients underwent a total of 11 attempted lymphatic embolization procedures after current standard of care treatments failed to resolve the leak. Lymphangiograms identified a chyle leak in 6 of 7 patients and embolization had a technical success rate of 73%. The complication rate was 9% and complications were limited to one episode of inadvertent gastric wall perforation that did not result in a gastric leak. Lymphatic embolization was ultimately associated with chyle leak resolution in 100% of patients within a median of 24 days, however, repeat embolization was required in 5 of 7 patients (83%). CONCLUSION: Lymphatic embolization appears to be a safe and effective treatment for persistent chyle leaks in pediatric patients, leads to a direction reduction in chyle output, and has high rates of technical and clinical success. Complete resolution of the chyle leak may require multiple embolization procedures. Further work is needed to determine whether earlier intervention may offer benefit for the management of pediatric chyle leaks. LEVEL OF EVIDENCE: IV.

A phase 1, first-in-child, multicenter study to evaluate the safety and efficacy of the oncolytic herpes virus talimogene laherparepvec in pediatric patients with advanced solid tumors.

Background: The survival rates for pediatric patients with relapsed and refractory tumors are poor. Successful treatment strategies are currently lacking and there remains an unmet need for novel therapies for these patients. We report here the results of a phase 1 study of talimogene laherparepvec (T-VEC) and explore the safety of this oncolytic immunotherapy for the treatment of pediatric patients with advanced non-central nervous system tumors. Methods: T-VEC was delivered by intralesional injection at 106 plaque-forming units (PFU)/ml on the first day, followed by 108 PFU/ml on the first day of week 4 and every 2 weeks thereafter. The primary objective was to evaluate the safety and tolerability as assessed by the incidence of dose-limiting toxicities (DLTs). Secondary objectives included efficacy indicated by response and survival per modified immune-related response criteria simulating the Response Evaluation Criteria in Solid Tumors (irRC-RECIST). Results: Fifteen patients were enrolled into two cohorts based on age: cohort A1 (n = 13) 12 to ≤21 years old (soft-tissue sarcoma, n = 7; bone sarcoma, n = 3; neuroblastoma, n = 1; nasopharyngeal carcinoma, n = 1; and melanoma, n = 1) and cohort B1 (n = 2) 2 to <12 years old (melanoma, n = 2). Overall, patients received treatment for a median (range) of 5.1 (0.1, 39.4) weeks. No DLTs were observed during the evaluation period. All patients experienced at least one treatment-emergent adverse event (TEAE), and 53.3% of patients reported grade ≥3 TEAEs. Overall, 86.7% of patients reported treatment-related TEAEs. No complete or partial responses were observed, and three patients (20%) overall exhibited stable disease as the best response. Conclusions: T-VEC was tolerable as assessed by the observation of no DLTs. The safety data were consistent with the patients' underlying cancer and the known safety profile of T-VEC from studies in the adult population. No objective responses were observed. Trial Registration: ClinicalTrials.gov: NCT02756845. https://clinicaltrials.gov/ct2/show/NCT02756845.

Management and Outcomes of Children with Stage 4S (MS) Neuroblastoma: A Single-Center Experience from a Resource-Challenged Nation.

OBJECTIVES: To demonstrate the clinical profile, management options, and outcomes of children with stage 4S neuroblastoma (NB 4S) diagnosed at a tertiary care center in a resource-challenged nation. The authors also intend to highlight the factors associated with an unfavorable prognosis in this series of patients. METHODS: The archives for children with NB 4S, diagnosed over a 24-y period (January 1996-December 2019), were retrospectively retrieved. Data on patient characteristics, management protocols, oncologic outcomes, and overall survival (OS) were reviewed. Multivariate logistic- regression analysis was performed to identify the factors independently predicting unfavorable outcomes. RESULTS: A total of 22 children (59% males) were included. Adrenal was the most common (82%) primary site. Liver involvement (100%), bone marrow infiltration (23%), and subcutaneous nodules (9%) were observed upon evaluation. Management involved supportive treatment (22%), chemotherapy only (41%), chemotherapy and tumor excision (28%). Ventral hernia was created in two children (9%) due to abdominal compartment syndrome (ACS). Four children died (4/22; 18%) due to ACS (n = 2) and refractory coagulopathy (n = 2). There were no recurrences and all survivors were disease-free. The 5-y OS was 81.8% with a median follow-up duration of 31 mo (range 9 mo-22 y). Age < 2 mo (p = 0.002), respiratory distress at presentation (p < 0.001), and chemotherapy nonresponsiveness (p < 0.001) were significantly associated with mortality. All three factors were independent predictors of mortality. CONCLUSION: Children with NB 4S have a favorable outcome with 5-y OS of 81.8%. Age < 2 mo, respiratory distress at presentation, and chemotherapy nonresponsiveness are independent predictors of a poor outcome.

Oral microbiome characteristics in patients with pediatric solid tumor.

Background: Pediatric solid tumor, the abnormal proliferation of solid tissues in children resulting in the formation of tumors, represent a prevailing malignant ailment among the younger population. Extensive literature highlights the inseparable association linking oral microbiome and adult tumors, but due to differences in age of onset, characteristics of onset, etc., there are many differences between Pediatric solid tumors and adult tumors, and therefore, studying the relationship between Pediatric solid tumor and the oral microbiota is also essential. Methods: To unravel the distinct characteristics of the oral microbiota within Pediatric solid tumor patients, 43 saliva samples, encompassing 23 Pediatric solid tumor patients and 20 healthy controls, were diligently procured. A meticulous screening process ensued, and conducted microbial MiSeq sequencing after screening. Results: We documented the oral microbiome attributes among pediatric diagnosed with solid tumors (PST), and meanwhile, we observed a significant trend of decreased oral microbiota diversity in the pediatric solid tumor group. There were notable disparities in microbial communities observed between the two groups, 18 genera including Veillonellaceae, Firmicutes unclassified, Coriobacteriia, Atopobiaceae, Negativicutes, were significantly enriched in PST patients, while 29 genera, including Gammaproteobacteria, Proteobacteria, Burkholderiales, Neisseriaceae, were dominant in the HCs group. It was found that PST group had 16 gene functions, including Amino acid metabolism, Cysteine and methionine metabolism, Photosynthesis antenna proteins, Arginine and proline metabolism, and Aminoacyl tRNA biosynthesi, were significantly dominant, while 29 gene functions that prevailed in HCs. Conclusion: This study characterized the oral microbiota of Pediatric solid tumor patients for the first time, and importantly, targeted biomarkers of oral microbiota may serve as powerful and non-invasive diagnostic tools for pediatric solid tumor patients.