Desmoid tumor (DT) is a rare, soft tissue neoplasm associated with an unpredictable clinical course. Although lacking metastatic potential, DT is often locally aggressive and invasive, causing significant morbidity. Both sporadic DT and familial adenomatous polyposis (FAP)-associated DT are linked to constitutive activation of the Wnt signaling pathway with mutations in the β-catenin oncogene CTNNB1 or the tumor suppressor gene APC, respectively. Cross-talk between the Notch and Wnt pathways, as well as activation of the Notch pathway resulting from dysregulation of the Wnt pathway, suggest a possible therapeutic target for DT. Due to the role γ-secretase plays in Notch signaling through cleavage of the Notch intracellular domain (with subsequent translocation to the nucleus to activate gene transcription), γ-secretase inhibitors (GSIs) have emerged as a potential treatment for DT. Two GSIs, nirogacestat (PF-03084014) and AL102 are in later-stage clinical development; nirogacestat is being evaluated in a phase 3, randomized, placebo-controlled trial while AL102 is being evaluated in a phase 2/3, dose-finding (part A) and placebo-controlled (part B) trial. This review summarizes current understanding of the molecular pathogenesis of DT focusing on dysregulation of the Wnt signaling pathway, crosstalk with the Notch pathway, and the potential therapeutic role for GSIs in DT.

Patients with suspected or confirmed osteosarcoma should be evaluated and treated at a comprehensive cancer center within a multidisciplinary sarcoma program that includes pediatric, medical and radiation oncologists, orthopedic and surgical oncologists, musculoskeletal pathologists, and radiologists. Successful treatment involves proper diagnosis, neoadjuvant and adjuvant multi-agent chemotherapy, and aggressive surgery with an emphasis toward limb-preserving procedures. Treatment of osteosarcoma should be undertaken within the framework of large cooperative group clinical trials for children, adolescents, and adults. Patients treated with osteosarcoma should be followed closely both for recurrence of disease and for development of late effects of the treatment of their cancer. The treatment of metastatic, recurrent and/or refractory disease is more controversial. Despite advances in systemic treatment, surgical technique, and supportive care, the overall outcome is still poor.

Soft tissue sarcoma is a rare neoplasm of mesenchymal origin, accounting for only ~1% of all adult cancers and consisting of 75 histological subtypes. In the present report, the unique case of a 14 year-old female with metastatic malignant peripheral nerve sheath tumor (formerly, malignant melanotic schwannoma) of the parotid gland, who experienced a durable response and sustained tumor control with Rexin-G^®, a tumor-targeted retroviral expression vector encoding an anti-cyclin G1 construct, is described. Post-parotidectomy, and prior to the administration of Rexin-G^®, the patient received various chemotherapy regimens, including doxorubicin, ifosfamide, temozolomide, sorafenib, and an immunological therapy with interleukin-2, which only resulted in the further progression of lung metastases. The patient subsequently participated in a Phase 1/2 gene therapy study, during which she received intravenous Rexin-G^® as monotherapy for two years with minimal drug-associated adverse events. Currently, the patient has no evidence of active disease 9 years after commencing the Rexin-G^® treatment, and with no additional anti-cancer therapy. In conclusion, Rexin-G^® may be a viable therapeutic option for malignant peripheral nerve sheath tumors, and should be further investigated in prospective histology-specific clinical trials for this type, and possibly other types, of chemotherapy-resistant sarcoma.

This review aims to summarize the putative role of histone deacetylases (HDACs) in rhabdomyosarcoma (RMS) and the effects of HDAC inhibitors (HDACi) on RMS by elucidating and highlighting known oncogenic pathways, mechanisms of resistance, and the synergistic potential of histone deacetylase inhibitors. We searched two databases (PubMed and Google Scholar) for the keywords "Rhabdomyosarcoma, histone deacetylase, histone deacetylase inhibitors." We excluded three publications that did not permit access to the full text to review and those that focus exclusively on pleiomorphic RMS in adults. Forty-seven papers met the inclusion criteria. This review highlights that HDACi induce cytotoxicity, cell-cycle arrest, and oxidative stress in RMS cells. Ultimately, HDACi have been shown to increase apoptosis and the cessation of embryonal and alveolar RMS proliferation in vivo and in vitro, both synergistically and on its own. HDACi contain potent therapeutic potential against RMS. This review discusses the significant findings and the biological mechanisms behind the anti-cancer effects of HDACi. Additionally, this review highlights important clinical trials assessing the efficacy of HDACi in sarcomas.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and its corresponding ligand PD-L1 are being increasingly used for a wide variety of cancers, including refractory sarcomas. Autoimmune hepatitis is a known side effect of ICIs, and is typically managed with broad, non-specific immunosuppression. Here, we report a case of severe autoimmune hepatitis occurring after anti-PD-1 therapy with nivolumab in a patient with osteosarcoma. Following prolonged unsuccessful treatment with intravenous immunoglobulin, steroids, everolimus, tacrolimus, mycophenolate, and anti-thymoglobulin, the patient was eventually treated with the anti-CD25 monoclonal antibody basiliximab. This resulted in prompt, sustained resolution of her hepatitis without significant side effects. Our case demonstrates that basiliximab may be an effective therapy for steroid-refractory severe ICI-associated hepatitis.

Immune checkpoint inhibitor (ICI) therapies are now first-line therapy for many advanced malignancies in adults, with emerging use in children. With increasing ICI use, prompt recognition and optimal management of ICI-associated immune-related adverse events (IRAEs) are critical. Nearly 60% of ICI-treated adults develop IRAEs, which commonly manifest as autoimmune skin, gastrointestinal, and endocrine disease and can be life-threatening. The incidence, presentation, and disease course of spontaneous autoimmune diseases differ between adults and children, but the pattern of pediatric IRAEs is currently unclear. We report a case of a pediatric patient presenting with new onset autoimmune diabetes mellitus and diabetic ketoacidosis during ICI treatment of fibrolamellar hepatocellular carcinoma (FLC). Distinct from spontaneous type 1 diabetes mellitus (T1DM), this patient progressed rapidly and was negative for known β cell autoantibodies. Additionally, the patient was positive for 21-hydroxylase autoantibodies, suggesting development of concomitant adrenal autoimmunity. Current guidelines for the management of IRAEs in adults may not be appropriate for the management of pediatric patients, who may have different autoimmune risks in a developmental context.

Background

The "fetal programming" hypothesis has been evaluated in many adult diseases including cancer, but not for Wilms tumor. Wilms tumor has been related to high birthweight, but little is known about other growth metrics such as a baby's birth length, ponderal index, or placenta size, which can shed additional light on growth patterns.

Methods

Cases of Wilms tumor (N = 217) were taken from the Danish Cancer Registry, and controls (N = 4340) were randomly selected from the Population Register and matched to cases by sex and age. Linkage to the Medical Births Registry provided information on gestational factors and fetal growth measurements, while linkage to the Patient Register provided information on maternal and child health conditions.

Results

Despite having typically normal to higher birthweights, Wilms tumor cases had smaller placentas (≤540 g; odds ratio (OR) = 4.24; 95% confidence interval (CI), 1.84-9.78) and a lower placenta-to-birthweight ratio (OR = 1.81; 95% CI, 1.17-2.82, per 1 SD decrease). Small placentas were more common among Wilms cases without congenital anomalies (OR = 6.43; 95% CI, 1.95-21.21). Wilms tumor cases had a higher prevalence of high birthweight (>4000 g; OR = 1.57; 95% CI, 1.11-2.22), birth length 55 cm or longer (OR = 1.74; 95% CI, 1.09-2.78), and being large for gestational age (OR = 1.79; 95% CI, 1.08-2.96).

Conclusions

Our study corroborates earlier studies showing associations with high birthweight and suggests associations between Wilms tumor and decreased placental size and low placenta-to-birthweight ratio.

This is the case of a previously healthy 15-month-old girl who initially presented to her primary pediatrician with a 2-week history of intermittent periorbital edema. The edema had improved by the time of the visit, and a urine specimen was unable to be obtained in the clinic. A routine fingerstick demonstrated anemia to 8.8 mg/dL, so the patient was started on ferrous sulfate. She then returned to the emergency department 1 month later with severe periorbital edema and pallor but no other significant symptoms. On physical examination, she was tachycardic with striking periorbital edema and an otherwise normal physical examination. She was noted to have a severe microcytic anemia (hemoglobin of 3.9 mg/dL and mean corpuscular volume of 53.1 fL) and hypoalbuminemia (albumin of 1.9 g/dL and total protein of 3.3 g/dL). The remainder of her electrolytes and liver function test results were within normal limits. A urinalysis was sent, which was negative for protein. Our panel of experts reviews her case to determine a unifying diagnosis for both her severe anemia and her hypoalbuminemia.

The use of image-guided percutaneous core needle biopsy (PCNB) to obtain tissue diagnosis of musculoskeletal lesions has become the standard of care in adult patients with a success rate of over 80%. Previous reports indicate a similar success rate in diagnosing pediatric solid tumors. In this large study, we analyzed >10 years of data in which PCNB was used for tissue diagnosis of musculoskeletal lesions in children; we evaluated the histopathologic accuracy, anesthetic requirements, and complications of these procedures. In 122 children, tissue diagnosis was successfully obtained in 82% of cases, and there were 0 complications associated with the procedure. There was a significantly higher PCNB diagnostic success rate in malignant lesions (93%). These data suggest that the use of PCNB is a safe and effective means of diagnosing musculoskeletal lesions in children.

The increasing use of serial PET/CT scans in the management of pediatric malignancies raises the important consideration of radiation exposure in children. To estimate the cumulative radiation dose from PET/CT studies to children with malignancy and to compare with the data in literature. Two hundred forty-eight clinical PET/CT studies performed on 78 patients (50 boys/28 girls, 1.3 to 18 years old from December 2002 to October 2007) were retrospectively reviewed under IRB approval. The whole-body effective dose (ED) estimates for each child were obtained by estimating the effective dose from each PET/CT exam performed using the ImPACT Patient Dosimetry Calculator for CT and OLINDA for PET. The average number of PET/CT studies was 3.2 per child (range: 1 to 14 studies). The average ED of an individual CT study was 20.3 mSv (range: 2.7 to 54.2), of PET study was 4.6 mSv (range: 0.4 to 7.7) and of PET/CT study was 24.8 mSv (range: 6.2 to 60.7). The average cumulative radiation dose per patient from CT studies was 64.4 mSv (range: 2.7 to 326), from PET studies was 14.5 mSv (range: 2.8 to 73) and from PET/CT studies was 78.9 mSv (range: 6.2 to 399). The radiation exposure from serial PET/CT studies performed in pediatric malignancies was considerable; however, lower doses can be used for both PET and CT studies. The ALARA principle must be applied without sacrificing diagnostic information.