Sclerosing rhabdomyosarcoma (ScRMS) and spindle cell rhabdomyosarcoma (SRMS) have been recently reclassified as a stand-alone pathologic entity, separate from embryonal RMS. Genetically, a subset of ...the congenital cases display NCOA2 gene rearrangements, whereas tumors occurring in older children or adults harbor MYOD1 gene mutations with or without coexisting PIK3CA mutations. Despite these recent advances, a significant number of tumors lack known genetic alterations. In this study we sought to investigate a large group of pediatric SRMS/ScRMS, spanning a diverse clinical and pathologic spectrum, by using a combined fluorescence in situ hybridization, targeted DNA, and whole-transcriptome sequencing methodology for a more definitive molecular classification. A total of 26 SRMS and ScRMS cases were selected from the 2 participating institutions for the molecular analysis. Ten of the 11 congenital/infantile SRMS showed recurrent fusion geneswith novel VGLL2 rearrangements seen in 7 (63%), including VGLL2-CITED2 fusion in 4 and VGLL2-NCOA2 in 2 cases. Three (27%) cases harbored the previously described NCOA2 gene fusions, including TEAD1-NCOA2 in 2 and SRF-NCOA2 in 1. All fusion-positive congenital/infantile SRMS patients with available long-term follow-up were alive and well, none developing distant metastases. Among the remaining 15 SRMS patients older than 1 year, 10 (67%) showed MYOD1 L122R mutations, most of them following a fatal outcome despite an aggressive multimodality treatment. All 4 cases harboring coexisting MYOD1/PIK3CA mutations shared sclerosing morphology. All 5 fusion/mutation-negative SRMS cases presented as intra-abdominal or paratesticular lesions.
Purpose/objectives
To examine the late effects of intensity‐modulated radiation therapy (IMRT) in pediatric patients with rhabdomyosarcoma of the head and neck.
Materials/methods
All 1‐year survivors ...of pediatric head and neck rhabdomyosarcoma treated with IMRT at a single institution from 1999 to 2014 were assessed for long‐term complications. Late toxicities were graded according to CTCAE version 4.03.
Results
Among 30 patients, median age at IMRT was 7.4 (1.5–20.8) years, median follow‐up was 7.7 (1.2–14.4) years, and median IMRT dose was 50.4 (36–50.4) Gy. Tumor subsites included parameningeal (80%), orbit (13%), and other (7%). Common late toxicities were facial disfigurement (n = 23, 77%), growth hormone deficiency (n = 11, 37%), cataract (n = 10, 34%), and dental problems (n = 10, 33%). Twenty‐two patients (73%) had ≥2 late toxicities and 14 patients (47%) had ≥3 late toxicities. Seventeen patients (57%) experienced grade 2 toxicity and 10 patients (33%) had grade 3 toxicity. Grade 3 toxicities included visual disturbance, cataract, facial disfigurement, chronic sinusitis/otitis, and hearing loss. Severe facial deformity was noted in nine patients (30%), and three patients underwent cosmetic surgery. Patients with severe facial deformity were treated at younger ages (median 6.0 years vs. 8.1 years for patients with no/nonsevere facial deformity) and more likely to have infratemporal fossa tumors. There were no secondary solid malignancies.
Conclusions
Late radiation toxicities are common in survivors of pediatric head and neck rhabdomyosarcoma treated with IMRT. While the majority of late effects are mild–moderate, they can significantly impact quality of life, particularly facial disfigurement.
Identifying large expansions of short tandem repeats (STRs), such as those that cause amyotrophic lateral sclerosis (ALS) and fragile X syndrome, is challenging for short-read whole-genome sequencing ...(WGS) data. A solution to this problem is an important step toward integrating WGS into precision medicine. We developed a software tool called ExpansionHunter that, using PCR-free WGS short-read data, can genotype repeats at the locus of interest, even if the expanded repeat is larger than the read length. We applied our algorithm to WGS data from 3001 ALS patients who have been tested for the presence of the
repeat expansion with repeat-primed PCR (RP-PCR). Compared against this truth data, ExpansionHunter correctly classified all (212/212, 95% CI 0.98, 1.00) of the expanded samples as either expansions (208) or potential expansions (4). Additionally, 99.9% (2786/2789, 95% CI 0.997, 1.00) of the wild-type samples were correctly classified as wild type by this method with the remaining three samples identified as possible expansions. We further applied our algorithm to a set of 152 samples in which every sample had one of eight different pathogenic repeat expansions, including those associated with fragile X syndrome, Friedreich's ataxia, and Huntington's disease, and correctly flagged all but one of the known repeat expansions. Thus, ExpansionHunter can be used to accurately detect known pathogenic repeat expansions and provides researchers with a tool that can be used to identify new pathogenic repeat expansions.
Glypican 3 (GPC3) is a heparan sulfate proteoglycan and cell surface oncofetal protein which is highly expressed on a variety of pediatric solid embryonal tumors including the majority of ...hepatoblastomas, Wilms tumors, rhabdoid tumors, certain germ cell tumor subtypes, and a minority of rhabdomyosarcomas. Via both its core protein and heparan sulfate side chains, GPC3 activates the canonical Wnt/β-catenin pathway, which is frequently overexpressed in these malignancies. Loss of function mutations in
lead to Simpson-Golabi-Behmel Syndrome, an X-linked overgrowth condition with a predisposition to GPC3-expressing cancers including hepatoblastoma and Wilms tumor. There are several immunotherapeutic approaches to targeting GPC3, including vaccines, monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, cytolytic T lymphocytes, and CAR T cells. These therapies offer a potentially novel means to target these pediatric solid embryonal tumors. A key pediatric-specific consideration of GPC3-targeted immunotherapeutics is that GPC3 can be physiologically expressed in normal tissues during the first year of life, particularly in the liver and kidney. In summary, this article reviews the current evidence for targeting childhood cancers with GPC3-directed immunotherapies.
p53 plays a key role in the DNA repair process and response to ionising radiation. We sought to determine the clinical phenotype of TP53 mutations and p53 pathway alterations in patients with ...rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) treated with radiation.
Of patients with available genomic sequencing, we identified 109 patients with RMS and ES treated to a total of 286 radiation sites. We compared irradiated tumour control among tumours with TP53 mutations (n = 40) to those that were TP53 wild-type (n = 246). We additionally compared irradiated tumour control among tumours with any p53 pathway alteration (defined as tumours with TP53 mutations or TP53 wild-type tumours identified to have MDM2/4 amplification and/or CDKN2A/B deletion, n = 78) to those without such alterations (n = 208).
The median follow-up was 26 months from radiation. TP53 mutations were associated with worse irradiated tumour control among the entire cohort (hazard ratio, HR = 2.8, P < 0.0001). Tumours with any p53 pathway alteration also had inferior irradiated tumour control (HR = 2.0, P = 0.003). On multivariable analysis, after controlling for tumour histology, intent of radiation, presence of gross disease, and biologically effective dose, TP53 mutations continued to be associated with a radioresistant phenotype (HR = 7.1, P < 0.0001).
Our results show that TP53 mutations are associated with increased radioresistance in RMS and ES. Novel strategies to overcome this radioresistance are important for improved outcomes in p53 disruptive RMS and ES.
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle‐aged adults and showing a variable degree of skeletal muscle ...differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well‐characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA‐targeted Next generation sequencing (NGS) panels (MSK‐IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31–76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm‐level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression‐free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.
Purpose
The optimal management of central nervous system (CNS) relapse of rhabdomyosarcoma (RMS) is unclear. We examined diagnosis, management, and outcomes of patients with RMS developing CNS ...relapse.
Methods
Records of 23 patients diagnosed with CNS relapse between 1999 and 2016 were reviewed. Median age at presentation of CNS relapse was 15 years (range, 1–34 years). High‐risk features at initial presentation were as follows: 16 alveolar patients, 13 Stage IV, and 13 with primary tumor in parameningeal locations.
Results
CNS relapse occurred at a median 12 months (range, 1–23 months) from diagnosis and most common presenting symptoms were headache (n = 9), nausea/vomiting (n = 8), visual difficulty (n = 5), and none (n = 5). Leptomeningeal metastases were detected in 21 patients while only 2 developed parenchymal metastases without leptomeningeal involvement. Fifteen patients received CNS‐directed radiation therapy (RT), including craniospinal irradiation to a median 36 Gy (range, 18–36 Gy) and/or whole brain radiotherapy to a median 30 Gy (range, 6–41.4 Gy). Three patients received concurrent chemotherapy. Follow‐up magnetic resonance imaging was conducted in 13 patients after RT initiation with 8 demonstrating improvement, 2 with stable disease, and 3 with progression. Twelve patients were tested for reactivity to I‐131‐labeled monoclonal antibody 8H9, and three tested positive and received at least one intra‐Ommaya dose; all three lived >12 months post‐CNS relapse. Twenty‐one patients died of CNS disease and two of metastatic disease at other sites. Median survival post‐CNS relapse was 5 months (range, 0.1–49 months).
Conclusions
The prognosis for patients with RMS developing CNS relapse remains poor. Treatment including CNS‐directed RT should be considered and investigation into preventative therapies is warranted.
Recent trends, including the use of proton therapy and administration of reduced doses of cyclophosphamide, have been adapted in head and neck (HN) rhabdomyosarcoma (RMS) to reduce late morbidity. ...Our primary goal was to analyze local control and survival outcomes after photon versus proton irradiation in pediatric patients with HN-RMS, with the secondary goal of analyzing the effect of cyclophosphamide dose on disease outcomes.
This single-institution cohort study comprised 76 pediatric HN-RMS patients treated with definitive chemoradiation from 2000 to 2018. Fifty-one patients (67%) received intensity modulated photon radiation therapy, and 25 (33%) received proton therapy.
Local failure (LF) at 2 years was 12.5% for parameningeal RMS and 0% for orbital RMS and other head and neck sites (P = .24). Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (P < .0001). The 2-year LF was 7.9% in the intensity modulated photon radiation therapy cohort versus 14.6% in the proton cohort (P = .07), with no difference in survival outcomes. Cumulative cyclophosphamide dose was significantly associated with 2-year LF: 0% for cumulative dose of >20 g/m
versus 15.3% for ≤20 g/m
(P = .04). In parameningeal RMS patients (n = 59), both cumulative cyclophosphamide dose and dose intensity were associated with LF (P = .01). There was a trend toward worse event-free survival for parameningeal RMS patients who received reduced-dose-intensity cyclophosphamide (59.2% vs 70.6%, P = .11).
Both dose-intensity and cumulative cyclophosphamide dose seem to play an important role in achieving local control for HN-RMS patients treated with either protons or photons. Longer follow-up is needed to further assess disease outcomes with proton therapy.
The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 ...sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor-related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid ...tumors.
This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age≤21 years with recurrent or progressive solid tumors.
Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response.
Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects.
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