The Clinical Utility of a Tiered Approach to Pediatric Glioma Molecular Characterization for Resource-Limited Settings.

PURPOSE: Molecular characterization is key to optimally diagnose and manage cancer. The complexity and cost of routine genomic analysis have unfortunately limited its use and denied many patients access to precision medicine. A possible solution is to rationalize use-creating a tiered approach to testing which uses inexpensive techniques for most patients and limits expensive testing to patients with the highest needs. Here, we tested the utility of this approach to molecularly characterize pediatric glioma in a cost- and time-sensitive manner. METHODS: We used a tiered testing pipeline of immunohistochemistry (IHC), customized fusion panels or fluorescence in situ hybridization (FISH), and targeted RNA sequencing in pediatric gliomas. Two distinct diagnostic algorithms were used for low- and high-grade gliomas (LGGs and HGGs). The percentage of driver alterations identified, associated testing costs, and turnaround time (TAT) are reported. RESULTS: The tiered approach successfully characterized 96% (95 of 99) of gliomas. For 82 LGGs, IHC, targeted fusion panel or FISH, and targeted RNA sequencing solved 35% (29 of 82), 29% (24 of 82), and 30% (25 of 82) of cases, respectively. A total of 64% (53 of 82) of samples were characterized without targeted RNA sequencing. Of 17 HGG samples, 13 were characterized by IHC and four were characterized by targeted RNA sequencing. The average cost per sample was more affordable when using the tiered approach as compared with up-front targeted RNA sequencing in LGG ($405 US dollars [USD] v $745 USD) and HGGs ($282 USD v $745 USD). The average TAT per sample was also shorter using the tiered approach (10 days for LGG, 5 days for HGG v 14 days for targeted RNA sequencing). CONCLUSION: Our tiered approach molecularly characterized 96% of samples in a cost- and time-sensitive manner. Such an approach may be feasible in neuro-oncology centers worldwide, particularly in resource-limited settings.

Malignant Melanotic Nerve Sheath Tumors: A Review of Clinicopathologic and Molecular Characteristics.

Malignant melanotic nerve sheath tumor (MMNST) which was formerly known as melanocytic schwannoma, is an uncommon aggressive type of nerve sheath tumor. It originates from nerve roots with clonal Schwann cell proliferation and melanin pigment production. MMNST which was once thought to be a benign tumor is now considered a malignant disease based on the latest 2020 World Health Organization classification of soft tissue tumors. Interestingly, despite the histologic features appearing benign with a low proliferation index, the clinical course of this tumor is malignant, which was demonstrated in case series with high rate of recurrences and metastasis. This tumor can occur sporadically or in patients with an underlying familial predisposition syndrome called, Carney's complex. Affected patients will often harbor a germline mutation in the PRKAR1A gene. MMNST can be histologically difficult to distinguish from malignant melanoma, other melanocytic tumors, and Schwannoma. Having a better understanding of its clinic pathologic characteristics and associated conditions is essential in properly diagnosing and managing affected individuals. This includes the possible need for genetic testing to detect germline mutations, genetic counseling, and surveillance according to published recommendations. In this article, we summarize the clinic pathologic and molecular features of MMNST and discuss what is known about its molecular biology and its associations with predisposing conditions. The review was conducted through an extensive PubMed search using keywords then relevant publications were selected.

Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes.

BACKGROUND: Cancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety of clinical screening guidelines are used in healthcare settings to help clinicians detect patients who have a higher likelihood of having a CPS. The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) is an electronic health decision support tool that uses algorithms to help clinicians determine if a child/adolescent diagnosed with cancer should be referred to genetics for a CPS evaluation. METHODS: This study assessed MIPOGG's performance in identifying Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin (nevoid basal cell carcinoma) syndromes in a retrospective series of 84 children diagnosed with cancer and one of these four CPSs in Canadian hospitals over an 18-year period. RESULTS: MIPOGG detected 82 of 83 (98.8%) evaluable patients with any one of these four genetic conditions and demonstrated an appropriate rationale for suggesting CPS evaluation. When compared with syndrome-specific clinical screening criteria, MIPOGG's ability to correctly identify children with any of the four CPSs was equivalent to, or outperformed, existing clinical criteria respective to each CPS. CONCLUSION: This study adds evidence that MIPOGG is an appropriate tool for CPS screening in clinical practice. MIPOGG's strength is that it starts with a specific cancer diagnosis and incorporates criteria relevant for associated CPSs, making MIPOGG a more universally accessible diagnostic adjunct that does not require in-depth knowledge of each CPS.

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.

Congenital midline spinal hamartoma in an infant with DICER1 syndrome: A case report.

Congenital spinal hamartomas are rare benign tumors. They are mostly seen in infants and are typically asymptomatic at presentation. Spinal hamartomas have not been associated with any known cancer predisposition syndrome. DICER1 syndrome is a well-characterized cancer predisposition syndrome caused by a germline mutation in the DICER1 gene, which shows variable expressivity. To our knowledge, spinal hamartoma has never been described in individuals with DICER1 syndrome. Here, we describe a rare association of congenital spinal hamartoma and DICER1 syndrome in a 5-week-old infant, with molecular findings suggestive of the implication of DICER1 in the pathogenesis of this tumor.

Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes.

IMPORTANCE: Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. OBJECTIVE: To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. DESIGN, SETTING, AND PARTICIPANTS: In this international, multicenter diagnostic accuracy study, 1071 pediatric (<19 years of age) oncology patients who had a confirmed CPS (12 oncology referral centers) or who underwent germline DNA sequencing through precision medicine programs (6 centers) from January 1, 2000, to July 31, 2020, were studied. EXPOSURES: Exposures were MIPOGG application in patients with cancer and a confirmed CPS (diagnosed through routine clinical care; n = 413) in phase 1 and MIPOGG application in patients with cancer who underwent germline DNA sequencing (n = 658) in phase 2. Study phases did not overlap. Data analysts were blinded to genetic test results. MAIN OUTCOMES AND MEASURES: The performance of MIPOGG in CPS recognition was compared with that of routine clinical care, including identifying a CPS earlier than practitioners. The tool's test characteristics were calculated using next-generation germline DNA sequencing as the comparator. RESULTS: In phase 1, a total of 413 patients with cancer (median age, 3.0 years; range, 0-18 years) and a confirmed CPS were identified. MIPOGG correctly recognized 410 of 412 patients (99.5%) as requiring referral for CPS evaluation at the time of primary cancer diagnosis. Nine patients diagnosed with a CPS by a practitioner after their second malignant tumor were detected by MIPOGG using information available at the time of the first cancer. In phase 2, of 658 children with cancer (median age, 6.6 years; range, 0-18.8 years) who underwent comprehensive germline DNA sequencing, 636 had sufficient information for MIPOGG application. When compared with germline DNA sequencing for CPS detection, the MIPOGG test characteristics for pediatric-onset CPSs were as follows: sensitivity, 90.7%; specificity, 60.5%; positive predictive value, 17.6%; and negative predictive value, 98.6%. Tumor DNA sequencing data confirmed the MIPOGG recommendation for CPS evaluation in 20 of 22 patients with established cancer-CPS associations. CONCLUSIONS AND RELEVANCE: In this diagnostic study, MIPOGG exhibited a favorable accuracy profile for CPS screening and reduced time to CPS recognition. These findings suggest that MIPOGG implementation could standardize and rationalize recommendations for CPS evaluation in children with cancer.

Acquired thrombotic thrombocytopenic purpura with isolated CFHR3/1 deletion-rapid remission following complement blockade.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is caused by the abundance of uncleaved ultralarge von Willebrand factor multimers (ULvWF) due to acquired (autoantibody-mediated) or congenital vWF protease ADAMTS13 deficiency. Current treatment recommendations include plasma exchange therapy and immunosuppression for the acquired form and (fresh) frozen plasma for congenital TTP. CASE-DIAGNOSIS/TREATMENT: A previously healthy, 3-year-old boy presented with acute microangiopathic hemolytic anemia, thrombocytopenia, erythrocyturia and mild proteinuria, but normal renal function, and elevated circulating sC5b-9 levels indicating complement activation. He was diagnosed with atypical hemolytic uremic syndrome and treated with a single dose of eculizumab, followed by prompt resolution of all hematological parameters. However, undetectably low plasma ADAMTS13 activity in the pre-treatment sample, associated with inhibitory ADAMTS13 antibodies, subsequently changed the diagnosis to acquired TTP. vWF protease activity normalized within 15 months without further treatment, and the patient remained in long-term clinical and laboratory remission. Extensive laboratory workup revealed a homozygous deletion of CFHR3/1 negative for anti-CFH antibodies, but no mutations of ADAMTS13, (other) alternative pathway of complement regulators or coagulation factors. CONCLUSIONS: This case, together with a previous report of a boy with congenital TTP (Pecoraro et al. Am J Kidney Dis 66:1067, 2015), strengthens evolving in-vitro and ex-vivo evidence that ULvWF interferes with complement regulation and contributes to the TTP phenotype. Comprehensive, prospective complement studies in patients with TTP may lead to a better pathophysiological understanding and novel treatment approaches for acquired or congenital forms.

Success importance and urge magnitude as determinants of cardiovascular response to a behavioral restraint challenge.

Decades of research have investigated a conceptual analysis concerned with determinants and cardiovascular correlates of effort in people confronted with performance challenges, that is, opportunities to alter some course of events by acting. One suggestion is that effort and associated cardiovascular responses should be determined jointly by the difficulty of meeting a challenge and the importance of doing so. The present experiment tested this in a context involving behavioral restraint, that is, effortful resistance against a behavioral impulse or urge. Participants were presented a mildly evocative violent film clip (restraint difficulty low) or a strongly evocative violent film clip (restraint difficulty high) with instructions to refrain from showing any facial response. Success was made more or less important through coordinated manipulations of outcome expectancy, ego-involvement and social evaluation. As expected, SBP responses assessed during the work period were proportional to clip evocativeness - i.e., the difficulty of the restraint challenge - when importance was high, but low regardless of clip evocativeness when importance was low. Findings conceptually replicate previous cardiovascular results and support extension of the guiding analysis to the behavioral restraint realm.