Clinicopathological and treatment response characteristics of updated rhabdomyosarcoma histomolecular subtypes: An Asian population-based study.

AIM: New histomolecular subtypes of rhabdomyosarcoma have recently been defined but their corresponding clinical characteristics are not well described. Also, these clinical phenotypes vary greatly by age and ethnicity but have not been profiled in Asian populations. Thus, we sought to determine the landscape of rhabdomyosarcoma subtypes in a national Asian cohort and compare clinical characteristics among age groups and molecular subtypes. METHODS: We performed a retrospective population-based study of all rhabdomyosarcoma patients in Singapore public hospitals from 2004 to 2014 (n = 67), and assigned histomolecular subtypes according to the updated 2020 WHO classification of soft tissue tumors following central pathology review and molecular profiling. RESULTS: Age-specific prevalence followed a tri-modal peak. There were significantly more embryonal and alveolar (p = 0.032) and genitourinary (non-bladder/prostate) tumors (p = 0.033) among children. Older age was associated with complete resection among spindle cell/sclerosing tumors (p = 0.027), with the omission of chemotherapy among embryonal tumors (p = 0.001), and with poorer survival among embryonal and alveolar tumors (p = 0.026, p = 0.022, respectively). Overall survival differed with stage, group, and surgical resection, adjusted for age group (p = 0.004, p = 0.001, p = 0.004, respectively). Spindle-cell/sclerosing tumors showed an indolent phenotype with a significantly lower incidence of nodal metastasis (p = 0.002), but two of 15 patients with MYOD1 mutations had a contrastingly aggressive disease. CONCLUSION: Disease and treatment response profiles of rhabdomyosarcoma subtypes vary significantly between adults and children, especially surgical resectability. In our Asian population, poorer outcomes were observed in adults with embryonal and alveolar tumors, while activating mutations influence the behavior of otherwise favorable spindle cell/sclerosing tumors.

Denosumab: a potential treatment option for aneurysmal bone cyst of the atlas.

PURPOSE: Aneurysmal bone cysts (ABCs) of spine are conventionally treated with en-bloc resection or intralesional excision/curettage and reconstruction or filling of defects with bone cement. For the treatment of upper cervical ABCs, en-bloc resections are often not desirable considering the risk/benefit ratio while the risk of recurrence after intralesional excision is high. Hence, alternative management options are often necessary. We describe our clinical experience with one such treatment alternative-denosumab for the treatment of ABC of Atlas. METHODS AND RESULTS: We present a case of 16-year-old boy who presented with neck pain and restriction of neck movements. A large lytic lesion with multiple fluid-fluid interfaces involving vertebral arch of atlas was identified on further imaging. There was destruction of right lateral mass and the lesion was found encasing the right vertebral artery. Core needle biopsy confirmed the diagnosis of ABC. With no visible CT response after first session of intra-lesional injection of Calcitonin and Methylprednisolone, the patient was treated with denosumab (120 mg SC once-a-month) for a period of 12 months. His symptoms resolved within 7 months of onset of treatment and serial CT scans over 12-month treatment period showed complete ossification of the lesion. Further there was no evidence of recurrence at 12 months after completion of treatment. CONCLUSION: Our case report contributes to the accruing evidence on the effectiveness of denosumab for the treatment of spinal ABCs. However, long-term safety, risk of recurrence, optimal duration of treatment and consistency of denosumab are yet to be determined.

P/CAF mediates PAX3-FOXO1-dependent oncogenesis in alveolar rhabdomyosarcoma.

Alveolar rhabdomyosarcoma (ARMS) is an aggressive paediatric cancer of skeletal muscle with poor prognosis. A PAX3-FOXO1 fusion protein acts as a driver of malignancy in ARMS by disrupting tightly coupled but mutually exclusive pathways of proliferation and differentiation. While PAX3-FOXO1 is an attractive therapeutic target, no current treatments are designed to block its oncogenic activity. The present work shows that the histone acetyltransferase P/CAF (KAT2B) is overexpressed in primary tumours from ARMS patients. Interestingly, in fusion-positive ARMS cell lines, P/CAF acetylates and stabilizes PAX3-FOXO1 rather than MyoD, a master regulator of muscle differentiation. Silencing P/CAF, or pharmacological inhibition of its acetyltransferase activity, down-regulates PAX3-FOXO1 levels concomitant with reduced proliferation and tumour burden in xenograft mouse models. Our studies identify a P/CAF-PAX3-FOXO1 signalling node that promotes oncogenesis and may contribute to MyoD dysfunction in ARMS. This work exemplifies the therapeutic potential of targeting chromatin-modifying enzymes to inhibit fusion oncoproteins that are a frequent event in sarcomas. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.