A familial deletion of 10p12.1 associated with thrombocytopenia.

Thrombocytopenia can be inherited or acquired from a variety of causes. While hereditary causes of thrombocytopenia are rare, several genes have been associated with the condition. In this report, we describe an 18-year-old man and his mother, both of whom have congenital thrombocytopenia. Exome sequencing in the man revealed a 1006 kb maternally inherited deletion in the 10p12.1 region (arr[GRCh37] 10p12.1(27378928_28384564)x1) of uncertain clinical significance. This deletion in the THC2 locus includes genes ANKRD26, known to be involved in normal megakaryocyte differentiation, and MASTL, which some studies suggest is linked to autosomal dominant thrombocytopenia. In the family presented here, the deletion segregated with the congenital thrombocytopenia phenotype, suggesting that haploinsufficiency of one or both genes may be the cause. To our knowledge, this is the first report of a deletion of the THC2 locus associated with thrombocytopenia. Future functional studies of deletions of the THC2 locus may elucidate the mechanism for this phenotype observed clinically.

The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

Management of Sickle Cell Disease Complications Beyond Acute Chest Syndrome.

Sickle cell disease results in numerous complications that can lead to significant morbidity and mortality. Amongst them, acute chest syndrome is the leading cause of mortality. As a result, most providers are in tune with this complication and well versed with management. As sickle cell patients now live longer, they face a multitude of other complications that if left unattended, can lead to significant morbidity and mortality as well. It is critical to look beyond acute chest syndrome and adopt a more comprehensive approach to the management of the sickle cell patient.

Multimodality Treatment of Desmoplastic Small Round Cell Tumor: Chemotherapy and Complete Cytoreductive Surgery Improve Patient Survival.

Purpose: Desmoplastic small round cell tumor (DSRCT), which harbors EWSR1-WT1 t(11;22)(p13:q12) chromosomal translocation, is an aggressive malignancy that typically presents as intra-abdominal sarcomatosis in young males. Given its rarity, optimal treatment has not been defined.Experimental Design: We conducted a retrospective study of 187 patients with DSRCT treated at MD Anderson Cancer Center over 2 decades. Univariate and multivariate regression analyses were performed. We determined whether chemotherapy, complete cytoreductive surgery (CCS), hyperthermic intraperitoneal cisplatin (HIPEC), and/or whole abdominal radiation (WART) improve overall survival (OS) in patients with DSRCT. Critically, because our institutional practice limits HIPEC and WART to patients with less extensive, potentially resectable disease that had benefited from neoadjuvant chemotherapy, a time-variant analysis was performed to evaluate those adjunct treatment modalities.Results: The pre-2003 5-year OS rate of 5% has substantially improved to 25% with the advent of newer chemotherapies and better surgical and radiotherapy techniques (HR, 0.47; 95% CI, 0.29-0.75). Chemotherapy response (log rank P = 0.004) and CCS (log rank P < 0.0001) were associated with improved survival. Although WART and HIPEC lacked statistical significance, our study was not powered to detect their potential impact upon OS.Conclusions: Improved 3- and 5-year OS were observed following multidisciplinary treatment that includes Ewing sarcoma (ES)-based chemotherapy and complete tumor cytoreductive surgery, but few if any patients are cured. Prospective randomized studies will be required to prove whether HIPEC or WART are important. In the meantime, chemotherapy and CCS remain the cornerstone of treatment and provide a solid foundation to evaluate new biologically targeted therapies. Clin Cancer Res; 24(19); 4865-73. ©2018 AACR.

Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor.

Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4) within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell-based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT.

Clinical Activity of Pazopanib in Patients with Advanced Desmoplastic Small Round Cell Tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive, often fatal soft tissue sarcoma that lacks an optimal salvage regimen. We retrospectively reviewed data from 29 pretreated DSRCT patients who received pazopanib at MD Anderson Cancer Center after failure of standard chemotherapies. SUBJECTS, MATERIALS, AND METHODS: Medical records of patients treated from January 2012 to December 2016 were reviewed and regression analyses were performed. Median progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and differences in survival were assessed by a log-rank test. A landmark statistical analysis was used to assess OS at a predefined 12-week time point following pazopanib initiation. RESULTS: The mean age at pazopanib treatment was 27.5 years (range, 6.3-50.1 years). According to RECIST 1.1 criteria, 16 patients (55%) had stable disease, 1 patient (3%) had partial response, 1 patient (3%) had complete response, and 11 patients (38%) had progressive disease. Estimated median PFS was 5.63 months (95% confidence interval [CI]: 3.23-7.47). Median OS was 15.7 months (95% CI: 10.3-32.4). As of December 2016, 11 patients (38%) were still alive, with a median follow-up time of 16.8 (range 3.8-30.1) months. Doses between 400 and 800 mg were included. Pazopanib was well tolerated and 23 (79%) of the patients continued it until progression or death, 4 discontinued because of side effects, and 2 were still on pazopanib at the time of data analysis. CONCLUSION: In the largest study conducted to date in DSRCT, pazopanib was well tolerated and clinically active in heavily pretreated patients who otherwise lack good treatment options. IMPLICATIONS FOR PRACTICE: Desmoplastic small round cell tumor (DSRCT) is a rare, extremely aggressive soft tissue sarcoma subtype that most commonly occurs in adolescent and young adult males. No DSRCT-specific therapies exist, and for lack of a better treatment approach, current therapies have relied upon U.S. Food and Drug Administration-approved drugs like pazopanib that exhibit clinical activity in other sarcoma subtypes. This article describes the largest experience to date using pazopanib as salvage treatment in heavily pretreated DSRCT patients. Pazopanib was well tolerated and clinically active, surpassing predefined metrics proposed by the European Organization for Research and Treatment of Cancer indicative of "active" sarcoma drugs (5.63 months progression-free survival [PSF], with 62% of the study population achieving progression-free survival at 12 weeks).