Case Report: Recurrence of Testicular Myofibroblastic Tumor After Surgery

Inflammatory myofibroblastic tumour (IMT), also known as plasma cell granuloma (PCG) or inflammatory pseudotumour (IPT), is a distinctive, rarely metastasizing neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory infiltration of plasma cells, lymphocytes and/or eosinophils. IMT predominantly affects children and young adults, and the age at presentation ranges from 3 to 89 years. We present a very rare case of recurrent testicular IMT without ALK rearrangement. This case highlights the clinical characteristics and diagnostic factors associated with primary and recurrent foci of this rare tumour, along with key therapeutic approaches.

Effect of Previous Alkylating Agent Exposure on Follicle Numbers in Cryopreserved Prepubertal and Young Adult Ovarian Tissue after Long-Term Xenografting

Purpose and methods: To elucidate whether previous cancer treatment affects graft recovery and follicle numbers, morphology, and development in grafts, cryopreserved ovarian biopsies obtained from 18 cancer patients aged 1–24 years with and without exposure to chemotherapy were xenografted as 1 mm3 fragments to immunodeficient mice for 22 weeks with exogenous stimulation. Results: Graft recovery showed no association with chemotherapy exposure, pubertal stage, or leukemia contamination. Total follicle number per recovered graft varied between 0 and 1031 in the chemotherapy-exposed and between 0 and 502 in the non-chemotherapy-exposed group. Atretic follicles formed the largest proportion of the follicle pool in chemotherapy-exposed grafts. Increased atresia correlated with exposure to alkylating agents (mean ± SD 8866.2 ± 9316.3 mg/m2) but not with anthracyclines, pubertal stage, or leukemia contamination. Conclusion: The observation confirms the harmful effects of alkylating agents on ovarian tissue. Therapy at the median cumulative dose of 8866 mg/m2 leads to the decreased quality of cryopreserved ovarian follicles in children and young adults.

Neonatal osteofibrous dysplasia: Synchronous tibial and fibular involvement is common

Osteofibrous dysplasia is a rare non-malignant fibro-osseous bone tumour, first described and characterised under this name by Campanacci (1976). It is most commonly encountered in the tibia of children and young adults, but less frequently seen in the neonate with only few prior reports in the literature. We report a case of neonatal congenital osteofibrous dysplasia, presenting with unilateral limb deformity at birth. Radiographs demonstrated well-defined mixed lytic-sclerotic lesions, in a previously unreported distribution in this age-group, confined to the distal metadiaphysis of the affected tibia and fibula. Open surgery was performed for deformity correction, with tissue biopsy confirming the radiographically-suspected diagnosis. We present the up-to-date clinical, radiological, and pathological findings in this case of a rare pathology with some novel features, within this age group, in disease distribution and consequent radiographic appearances. OFD should be considered in the differential of similar congenital deforming bone lesions of the lower limb. We also review the small number of previously published cases of congenital OFD in the neonate, noting in particular that the frequency of ipsilateral fibular involvement appears to be higher than that observed in older patients.

Clofarabine with topotecan, vinorelbine, and thiotepa reinduction regimen for children and young adults with relapsed AML

Effective reinduction regimens are needed for children with relapsed and refractory acute myeloid leukemia (AML) as outcomes remain poor. Therapeutic options are limited in this heavily pre-treated patient population, many of whom have reached lifetime recommended doses of anthracycline chemotherapy. The development of effective non-anthracycline based salvage regimens is crucial to these patients who are at significant risk of life-threatening cardiotoxicity. We previously reported results of a phase 2 trial of a clofarabine-based regimen with topotecan, vinorelbine, and thiotepa (TVTC) in patients with relapsed acute leukemias. Here we report on an expanded bicenter cohort of 33 patients, <25 years of age, with relapsed/refractory (R/R) AML treated with up to 2 cycles of the TVTC reinduction regimen from 2007 to 2018. The overall response rate (ORR), defined as complete remission (CR) or CR with partial recovery of platelet count (CRp), was 71.4% (95%CI: 41.9 to 91.6%) for those patients in first relapse (n=14) and 47.4% ( 95%CI: 24.4 to 71.1%) for patients in 2nd or greater relapse or refractory disease. Responses were seen across multiple high risk cytogenetic and molecular subtypes, with 84% of responders successfully bridged to allogeneic stem cell transplantation. The 5-year OS for patients in first relapse was 46.2% (95%CI: 19.1 to 73.3%) and 50.0% (95%CI: 26.9 to 73.1%) for patients who responded to TVTC. For pediatric and young adult patients with R/R AML, TVTC reinduction compares favorably with currently used salvage regimens and warrants further exploration.

Eculizumab precision dosing algorithm for thrombotic microangiopathy in children and young adults undergoing HSCT

Transplant-associated thrombotic microangiopathy (TA-TMA) is a fatal post-transplant complication of hematopoietic stem cell transplantation (HSCT). We recently reported that survival for TA-TMA has been improved by early intervention with eculizumab, a complement C5 inhibitor, guided by pharmacokinetic/pharmacodynamic (PK/PD) model-informed precision dosing. However, patients with gastrointestinal (GI) bleeding showed poor survival even when treated with more frequent dosing. Our objective was to develop separate models in bleeding and non-bleeding TA-TMA patients and propose precision dosing algorithms. Eculizumab PK/PD were analyzed in 19 bleeding and 38 non-bleeding patients (0.5-29.9 years). A complement activation biomarker (sC5b-9) and bodyweight were identified as significant determinants of eculizumab clearance regardless of bleeding. Eculizumab clearance after the first dose was higher in bleeding patients than in non-bleeding patients (83.8 vs. 61.3 mL/h/70kg, p=0.07). The high clearance was maintained over treatment doses in bleeding patients, whereas non-bleeding patients showed a time-dependent decrease in clearance. sC5b-9 levels were highest before the first dose and decreased over time regardless of bleeding complications. A Monte Carlo Simulation analysis showed that the current dosing protocols recommended for aHUS had less than 15% probability of eculizumab target concentration attainment of >100 g/mL in non-bleeding patients. This study identified an intensified loading protocol to reach 80% target attainment. Our data clearly showed the need for individualized dosing for patients with significant bleeding, and for ongoing dose adjustments to optimize outcomes. The developed models will be incorporated into a clinical decision support for precision dosing to improve outcomes in children and young adults with TA-TMA.