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Children with rare, relapsed or refractory cancers often face limited treatment options, and few predictive biomarkers are available that can enable personalized treatment recommendations. The implementation of functional precision medicine (FPM), which combines genomic profiling with drug sensitivity testing (DST) of patient-derived tumor cells, has potential to identify treatment options when standard-of-care is exhausted. The goal of this prospective observational study was to generate FPM data for pediatric patients with relapsed or refractory cancer. The primary objective was to determine the feasibility of returning FPM-based treatment recommendations in real time to the FPM tumor board (FPMTB) within a clinically actionable timeframe (<4 weeks). The secondary objective was to assess clinical outcomes from patients enrolled in the study. Twenty-five patients with relapsed or refractory solid and hematological cancers were enrolled; 21 patients underwent DST and 20 also completed genomic profiling. Median turnaround times for DST and genomics were within 10 days and 27 days, respectively. Treatment recommendations were made for 19 patients (76%), of whom 14 received therapeutic interventions. Six patients received subsequent FPM-guided treatments. Among these patients, five (83%) experienced a greater than 1.3-fold improvement in progression-free survival associated with their FPM-guided therapy relative to their previous therapy, and demonstrated a significant increase in progression-free survival and objective response rate compared to those of eight non-guided patients. The findings from our proof-of-principle study illustrate the potential for FPM to positively impact clinical care for pediatric and adolescent patients with relapsed or refractory cancers and warrant further validation in large prospective studies. ClinicalTrials.gov registration: NCT03860376.

The generalized form of UDP-galactose-4′-epimerase (GALE) deficiency causes hypotonia, failure to thrive, cataracts, and liver failure. Individuals with non-generalized forms may remain asymptomatic with uncertain long-term outcomes. We report a 2-year-old child compound heterozygous for GALE p.R51W/p.G237D who never developed symptoms of classic galactosemia but has a history of congenital combined mitral and tricuspid valve malformation and pyloric stenosis, and presented with pancytopenia. Variant pathogenicity was supported by predictive computational tools and decreased GALE activity measured in erythrocytes. GALE function extends to the biosynthesis of glycans by epimerization of UDP-N-acetyl-galactosamine and -glucosamine. Interrogation of the Gene Ontology consortium database revealed several putative proteins involved in normal hematopoiesis and atrioventricular valve morphogenesis, requiring N-glycosylation for adequate functionality. We hypothesize that by limiting substrate supply due to GALE deficiency, alterations in N-linked protein glycosylation can explain the patient’s phenotype.

Deep venous thrombosis (DVT) has been previously reported in children with methicillin-resistant Staphylococcus aureus(MRSA). This study reviews our institutional experience by evaluating characteristics and outcomes of children with DVT and staphylococcal infections. Retrospective clinical data from 16 pediatric patients with DVT and staphylococcal infections over a 5-year period was obtained via medical record abstraction. Sixteen patients with a median age at diagnosis of 8 years were included. The most common infection encountered was osteomyelitis (56%). The most common isolated organism was MRSA (63%). Central venous catheters were present in 50% of cases. All patients received anticoagulation with low molecular weight heparin except 1 patient with superficial venous thrombosis who was managed conservatively. Fifty percent of patients had complete resolution of DVT by the end of treatment, 25% of the patients had early disappearance of the thrombus at 7 to 10 days. Only 2 patients (12.5%) had persistent thrombus at 6 months. Staphylococcal infections may increase the risk of DVT in children. Therefore, a high index of suspicion for DVT is warranted in children with Staphylococcal infections (particularly MRSA) to promptly diagnose, treat and minimize complications. Prophylactic anticoagulation in presence of staphylococcal infection, particularly MRSA, may be considered in future studies.

Angiomatoid fibrous histiocytoma (AFH) is a soft-tissue tumor of low-grade malignancy and uncommon metastatic behavior. In this study, we describe the clinical findings of a metastatic case of AFH in the pelvis. In addition, we characterize 16 patients in the literature with AFH who metastasized over the last 4 decades. The time of appearance of metastases varied substantially and was reported 5 months to 16 years after primary tumor resection. Nine patients metastasized to lymph nodes. Excision of metastatic lymph nodes was usually curative. Pulmonary metastases were associated with fatal outcome. Long-term monitoring should be considered in patients with AFH.

Background: Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n= 15) / atypical teratoid/rhabdoid tumor (AT/RT, n= 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose. Results: In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM. Conclusion: Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.

No relevant conflicts of interest to declare.

Introduction

No relevant conflicts of interest to declare.

Introduction: Acute lymphoblastic Leukemia (ALL) is associated with distinctive biologic and clinical features. The diagnoses and treatments have encountered several challenges in rural area of developing countries populations.

T cell lymphoid malignancies are associated with distinctive clinical and biologic features; however, true lineage-specific treatments have yet to be identified. Recent trials have shown promising results for patients with advanced T-cell malignancies given novel treatment regimens of rotating myelosuppressive agents.To evaluate the response of children with advanced stage lymphoblastic lymphoma (T-NHL) and T-cell acute lymphoblastic lymphoma (T-ALL) to high dose methotrexate (HDMTX) (5gm/m2) and cranial radiation (1800 cGy). Estimates of complete response rate (CRR), disease free survival (DFS), event-free survival (EFS), and overall survival (OS) will be analyzed. The administered protocol was modeled after the POG 9404 study, Arm IV, to assess its effectiveness in a developing country's patient population.The regimen included 4 doses of HDMTX (5gm/m2) plus leucovorin rescue, given at weeks 4,7, 10, and 13 of therapy. An intensive anthracycline based multidrug regimen (vincristine, doxorubicin, prednisone, methotrexate, and mercaptopurine) combined with high dose asparginase consolidation (25.000 IU/m2) was added by intramuscular injection weekly for 20 weeks starting at week 7. Extended intrathecal chemotherapy (methotrexate and cytarabine) was given as CNS prophylaxis throughout different phases of treatment in addition to central nervous system (CNS) irradiation (1800 cGy) to the brain and meninges given to all patients beginning at week 22.105 patients with newly diagnosed T-Cell lymphoid malignancy presenting to the department of Pediatric Oncology at the National Cancer Institute, Cairo University between November 1st 2004 and August 1st 2008, were considered eligible for the study and enrolled. Sample population had a mean age of 9.75 years (2–18 years) comprised of 72 (68.6%) T-ALL and 33 (31.4%) T-NHL (stage III & IV) subtypes. All patients were started on the novel regimen as described. 94 cases (89.5%) achieved complete remission post induction therapy. At the conclusion of our follow-up period (6–48 months, median 24 months), 58/105 cases (55.2%) maintained complete remission (CR). Three year disease free survival (DFS) was 47.1±8.6% and 93.3±6.4% for T-Cell ALL and NHL groups, respectively (Fig 1). Three year estimated free survival (EFS) was 48.5±6.2% and 59.2 ±9.2% in T- ALL and T-NHL groups, respectively (Fig 2). 22/105 (20.9%) cases relapsed with classification including nodal relapse in 4 cases, hematological relapse (HR) in 3 cases, CNS relapse in 12 cases, both CNS and HR relapse in 2 cases and both hematological and testicular relapse in 1 case. CNS relapse was the most frequent occurrence, recorded in 14 cases (13.3%), 13 cases for T-ALL and 1 case for T-NHL. Time to relapse ranged between 3 months and 24 months, with 12 cases occurring early in the maintenance phase after cranial irradiation and 2 cases occurring early in consolidation phase before cranial prophylaxis. 6/105 (5.7%) cases failed induction, incorrect diagnoses was found in 2 (1.9%) of those cases.12/105 (11.4%) patients died during active treatment with mortality equally distributed amongst each phase of therapy. Most common cause of death was sepsis in febrile neutropenic patients 8/105 (7.6%). 6/105 (5.7%) cases were lost to follow up. Toxicities were tolerable in most cases; however, 1 case (1.1%) developed toxicity not amenable to HDMTX. No secondary malignancies were found and no patients underwent bone marrow transplantation (BMT) during the follow up period. Isolated relapse in sanctuary sites was not effectively prevented in this study. Both CNS prophylaxis and CNS directed therapy were administered through extended intrathecal chemotherapy, high dose methotrexate and cranial irradiation.Superior response to extended intrathecal chemotherapy, high dose methotrexate and cranial irradiation was achieved in the T-NHL group compared to the T-ALL group, without significant P value. T-ALL has more significant risk of induction failure (3 of 4 resistant cases), early relapse (<18 months from diagnosis), and isolated CNS relapse when compared to T-NHL. Further studies must be done to delineate the role of CNS directed therapy in improving outcomes for T-cell lymphoid malignancies.No relevant conflicts of interest to declare.

Abstract 4310