DICER1-associated central nervous system sarcoma in children: comprehensive clinicopathologic and genetic analysis of a newly described rare tumor.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.

Intrathyroidal Parathyroid Cyst in a Middle-aged Woman.

Parathyroid cyst is a rare entity that can closely mimic thyroid and brachial cleft cysts, particularly when located within the thyroid gland. Most commonly, the cysts are non-functional but can produce compressive symptoms. The cyst contains watery content with elevated PTH levels, specifying parathyroid origin1. Parathyroid cysts should be considered in the differential in patients with a neck mass. This study describes a rare case of a middle-aged woman with a history of a symptomatic intrathyroidal parathyroid cyst discovered intraoperatively.

Model-supported decision-making at a contaminated sediment site: Post-audit and site closure.

Computer simulation models have been used to support decision-making at contaminated sediment sites for decades. Nonetheless, their reliability in remedial decision-making has been questioned, and there is a need for retrospective studies of the accuracy of model predictions, that is, post-audits. The Neal's Landfill site near Bloomington, Indiana, provides an example of the successful use of a mathematical simulation model in the selection of a remedy for a site that includes streams with polychlorinated biphenyl (PCB)-affected sediment, water, and fish. A chemical fate and transport and bioaccumulation computer simulation model was developed to compare the effectiveness of alternative remediation plans in reducing fish total PCB concentrations. A post-audit of the model, using several years of data collected after remediation, demonstrates that the model successfully predicted declines in surface water and fish tissue PCB concentrations over a decade, including those associated with longer term natural recovery processes as well as the response to remedial actions. The model predicted, and the post-audit bore out, that risk-based goals would be met using an alternative less extensive than others under consideration. An uncertainty analysis, based on bounding model calculations, provided important support for decision-making, as did the inclusion of a statistical Remedy Confirmation Clause in the Consent Decree for the site. This study demonstrates the utility of a computer simulation model to guide remedial decision-making at a contaminated sediment site. Integr Environ Assess Manag 2022;18:1233-1245. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer.

To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors.

The impact of precursors on aquatic exposure assessment for PFAS: Insights from bioaccumulation modeling.

Risk assessment for per- and polyfluoroalkyl substances (PFAS) is complicated by the fact that PFAS include several thousand compounds. Although new analytical methods have increased the number that can be identified in environmental samples, a significant fraction of them remain uncharacterized. Perfluorooctane sulfonate (PFOS) is the PFAS compound of primary interest when evaluating risks to humans and wildlife owing to the consumption of aquatic organisms. The exposure assessment for PFOS is complicated by the presence of PFOS precursors and their transformation, which can occur both in the environment and within organisms. Thus, the PFOS to which wildlife or people are exposed may consist of PFOS that was discharged directly into the environment and/or other PFOS precursors that were transformed into PFOS. This means that exposure assessment and the development of remedial strategies may depend on the relative concentrations and properties not only of PFOS but also of other PFAS that are transformed into PFOS. A bioaccumulation model was developed to explore these issues. The model embeds toxicokinetic and bioenergetic components within a larger food web calculation that accounts for uptake from both food and water, as well as predator-prey interactions. Multiple chemicals are modeled, including parent-daughter reactions. A series of illustrative simulations explores how chemical properties can influence exposure assessment and remedial decision making. Integr Environ Assess Manag 2021;17:705-715. © 2021 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Germline Sequencing Improves Tumor-Only Sequencing Interpretation in a Precision Genomic Study of Patients With Pediatric Solid Tumor.

PURPOSE: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND METHODS: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation. RESULTS: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events. CONCLUSION: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition.