Aggressive embryonal rhabdomyosarcoma in a 3-month-old boy: A clinical and molecular analysis.

Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy. Cytogenetic analysis of the brain metastases at the time of autopsy as well as next-generation sequencing analysis revealed a reciprocal translocation involving the SH3 domain containing ring finger 3 gene (SH3RF3, on chromosome 2q13) and the Lipase C gene (LIPC, on chromosome 15q21.3). Due to the poor quality of the pretreatment and postresection samples, cytogenetics and NGS analysis looking for the presence of this balanced translocation in these specimens could not be performed. To the authors' knowledge, this translocation has never been described in RMS. Further studies are needed to determine the biological and clinical implications of this novel translocation.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset. Therapeutically targetable variants (54% of patients) were of unanticipated timing and type, with over 20% derived from the germline. Corroborating mutational signatures (SBS3/BRCAness) in patients with germline homologous recombination defects demonstrates the potential utility of PARP inhibitors. Mutational burden was significantly elevated in 9% of patients. Sequential sampling identified changes in therapeutically targetable drivers in over one-third of patients, suggesting benefit from rebiopsy for genomic analysis at the time of relapse. Comprehensive cancer genomic profiling is useful at multiple points in the care trajectory for children and adolescents/young adults with cancer, supporting its integration into early clinical management.

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

Evolving patterns of reactive arthritis.

OBJECTIVE: To characterize rheumatologists' perspectives on evolving trends of reactive arthritis (ReA). METHODS: After ethics approval, 548 members of the Canadian Rheumatology Association were surveyed with 37 questions covering their demographic information, subspecialty, level of experience, practice setting and opinions on prevalence, treatment, and causes of ReA. Results were analyzed with descriptive statistics. RESULTS: Ninety-seven responded to the survey (18% response rate); 66 fully completed it. Nearly half of respondents believed that the incidence of ReA is declining and causes of ReA may be changing. Physicians reported that most of the ReA cases in their practices were caused by an unknown organism, sexually transmitted, or gastrointestinal infection. Full triad ReA increased the chance of recurrence according to their impressions. Common investigations in ReA included inflammatory markers, HLA-B27, chlamydia and gonorrhea testing, stool cultures, synovial fluid analyses, SI joint imaging. ReA treatment included NSAIDs, intra-articular corticosteroid injections, and DMARDs. Two-thirds said they used TNF alpha inhibitors in chronic ReA occasionally or more frequently. CONCLUSION: ReA may be decreasing in frequency and severity in Canada. Changes could be due to less food borne illness, cleaner water, or more rapid treatment of sexually transmitted infections. The cause is often unknown in clinical practice.Key Points• Reactive arthritis (ReA) is likely decreasing in prevalence and severity.• Patients with classic trial of arthritis, urethritis, and conjunctivitis are more likely to have recurrent and/or chronic ReA.• The causal organisms are often not detected and seem to be changing over time.

Effect of Copper and Zinc on the Single Molecule Self-Affinity of Alzheimer's Amyloid-ß Peptides.

The presence of trace concentrations of metallic ions, such as copper and zinc, has previously been shown to drastically increase the aggregation rate and neurotoxicity of amyloid-ß (Aß), the peptide implicated in Alzheimer's disease (AD). The mechanism of why copper and zinc accelerate Aß aggregation is poorly understood. In this work, we use single molecule force spectroscopy (SMFS) to probe the kinetic and thermodynamic parameters (dissociation constant, Kd, kinetic dissociation rate, koff, and free energy, ΔG) of the dissociation of an Aß dimer, the amyloid species which initiates the amyloid cascade. Our results show that nanomolar concentrations of copper do not change the single molecule affinity of Aß to another Aß peptide in a statistically significant way, while nanomolar concentrations of zinc decrease the affinity of Aß-Aß by an order of magnitude. This suggests that the binding of zinc ion to Aß may interfere with the binding of Aß-Aß, leading to a lower self-affinity.