Citations

AbstractPurpose:Fumarate hydratase–deficient renal cell carcinoma (FH-deficient RCC) is a rare but lethal subtype of RCC. Little is known about the genomic profile of FH-deficient RCC, and the therapeutic options for advanced disease are limited. To this end, we performed a comprehensive genomics study to characterize the genomic and epigenomic features of FH-deficient RCC.Experimental Design:Integrated genomic, epigenomic, and molecular analyses were performed on 25 untreated primary FH-deficient RCCs. Complete clinicopathologic and follow-up data of these patients were recorded.Results:We identified that FH-deficient RCC manifested low somatic mutation burden (median 0.58 mutations per megabase), but with frequent somatic copy-number alterations. The majority of FH-deficient RCCs were characterized by a CpG sites island methylator phenotype, displaying concerted hypermethylation at numerous CpG sites in genes of transcription factors, tumor suppressors, and tumor hallmark pathways. However, a few cases (20%) with low metastatic potential showed relatively low DNA methylation levels, indicating the heterogeneity of methylation pattern in FH-deficient RCC. Moreover, FH-deficient RCC is potentially highly immunogenic, characterized by increased tumor T-cell infiltration but high expression of immune checkpoint molecules in tumors. Clinical data further demonstrated that patients receiving immune checkpoint blockade–based treatment achieved improved progression-free survival over those treated with antiangiogenic monotherapy (median, 13.3 vs. 5.1 months; P = 0.03).Conclusions:These results reveal the genomic features and provide new insight into potential therapeutic strategies for FH-deficient RCC.

PURPOSE SJMB03 (ClinicalTrials.gov identifier: NCT00085202 ) was a phase III risk-adapted trial that aimed to determine the frequency and clinical significance of biological variants and genetic alterations in medulloblastoma. PATIENTS AND METHODS Patients 3-21 years old were stratified into average-risk and high-risk treatment groups based on metastatic status and extent of resection. Medulloblastomas were molecularly classified into subgroups (Wingless [WNT], Sonic Hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing. Coprimary study end points were (1) to assess the relationship between ERBB2 protein expression in tumors and progression-free survival (PFS), and (2) to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were evaluated, and the most robust were used to model new risk-classification categories. RESULTS Three hundred thirty eligible patients with medulloblastoma were enrolled. Five-year PFS was 83.2% (95% CI, 78.4 to 88.2) for average-risk patients (n = 227) and 58.7% (95% CI, 49.8 to 69.1) for high-risk patients (n = 103). No association was found between ERBB2 status and PFS in the overall cohort ( P = .74) or when patients were stratified by clinical risk ( P = .71). Mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were most common in WNT tumors and PTCH1 (38%), TP53 (21%), and DDX3X (19%) in SHH tumors. Methylome profiling classified 53 WNT (17.4%), 48 SHH (15.7%), 65 group 3 (21.3%), and 139 group 4 (45.6%) tumors. A comprehensive clinicomolecular risk factor analysis identified three low-risk groups (WNT, low-risk SHH, and low-risk combined groups 3 and 4) with excellent (5-year PFS > 90%) and two very high-risk groups (high-risk SHH and high-risk combined groups 3 and 4) with poor survival (5-year PFS < 60%). CONCLUSION These results establish a new risk stratification for future medulloblastoma trials.

Objective Young-onset colorectal cancer (YCRC) incidence is rising. Scant data exist on YCRC risk after presentation with concerning symptoms such as iron-deficiency anaemia (IDA) or haematochezia. We examined the association between IDA and YCRC, and haematochezia and YCRC. Design Cohort study of US Veterans aged 18–49 years receiving Veterans Health Administration (VHA) care 1999–2016. IDA analytic cohort was created matching individuals without incident IDA to those with IDA 4:1 based on sex, birth year and first VHA visit date (n=239 000). We used this approach to also create a distinct haematochezia analytic cohort (n=653 740). Incident YCRC was ascertained via linkage to cancer registry and/or cause-specific mortality data. We computed cumulative incidence, risk difference (RD) and HRs using Cox models in each cohort. Results Five-year YCRC cumulative incidence was 0.45% among individuals with IDA versus 0.05% without IDA (RD: 0.39%, 95% CI: 0.33%–0.46%), corresponding to an HR of 10.81 (95% CI: 8.15–14.33). Comparing IDA versus no IDA, RD was 0.78% for men (95% CI: 0.64%–0.92%) and 0.08% for women (95% CI: 0.03%–0.13%), and RD increased by age from 0.14% for <30 years to 0.53% for 40–49 years. YCRC cumulative incidence was 0.33% among individuals with haematochezia versus 0.03% without haematochezia (RD: 0.30%, 95% CI: 0.26%–0.33%), corresponding to an HR of 10.66 (95% CI: 8.76–12.97). Comparing haematochezia versus no haematochezia, RD increased by age from 0.04% for <30 years to 0.43% for 40–49 years. Conclusion Colonoscopy should be strongly considered in adults aged <50 years with IDA or haematochezia without a clinically confirmed alternate source.

Background and Purpose: To describe the neurological and cerebrovascular findings in patients who tested positive for SARS-CoV-2 and underwent head imaging in ambulatory and inpatient settings. Methods: Consecutive patients aged ≥18 years with SARS-CoV-2 infection diagnosed or treated at Mayo Clinic sites from 3/11/2020 to 7/23/2020 with head CT or brain MRI within 30 days of SARS-CoV-2 diagnosis were included. Demographics, medical history, indication for SARS-CoV-2 testing, neurologic symptoms, indication for brain imaging, neuroimaging findings, etiology of cerebrovascular events, and hospital course were abstracted from medical records. Results: Of 8,675 patients with SARS-CoV-2, 180 (2.07%) had head imaging. Mean age of the entire cohort was 42 ± 18 years, whereas mean age of those with head imaging was 62 ± 19 years. Common indications for imaging were headache (34.4%), encephalopathy (33.4%), focal neurologic symptom (16.7%), and trauma (13.9%). While 86.1% of patients who underwent head imaging had normal exams, cerebrovascular events occurred in 18 patients (0.21% of the total cohort). Of patients with cerebrovascular events, 8 (44.5%) had acute infarct; 6 (33.3%), acute intracranial hemorrhage; 5 (2.8%), subacute infarct; and 1 (0.6%) posterior reversible encephalopathy syndrome. In the thirteen patients with ischemic stroke, 6 (46.2%) had cryptogenic stroke; 3 (23.1%), other defined causes; 2 (15.4%), small vessel stroke; 1 (7.7%), large vessel stroke; and 1 (7.7%) cardioembolic stroke. Conclusion: In ambulatory and hospitalized patients with SARS-CoV-2 infection, the rate of head imaging is low, with common indications of encephalopathy and headache. Cerebrovascular events occurred rarely, and cryptogenic stroke was the most common stroke mechanism.