PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum.

Large-scale molecular profiling studies in recent years have shown that central nervous system (CNS) tumors display a much greater heterogeneity in terms of molecularly distinct entities, cellular origins and genetic drivers than anticipated from histological assessment. DNA methylation profiling has emerged as a useful tool for robust tumor classification, providing new insights into these heterogeneous molecular classes. This is particularly true for rare CNS tumors with a broad morphological spectrum, which are not possible to assign as separate entities based on histological similarity alone. Here, we describe a molecularly distinct subset of predominantly pediatric CNS neoplasms (n = 60) that harbor PATZ1 fusions. The original histological diagnoses of these tumors covered a wide spectrum of tumor types and malignancy grades. While the single most common diagnosis was glioblastoma (GBM), clinical data of the PATZ1-fused tumors showed a better prognosis than typical GBM, despite frequent relapses. RNA sequencing revealed recurrent MN1:PATZ1 or EWSR1:PATZ1 fusions related to (often extensive) copy number variations on chromosome 22, where PATZ1 and the two fusion partners are located. These fusions have individually been reported in a number of glial/glioneuronal tumors, as well as extracranial sarcomas. We show here that they are more common than previously acknowledged, and together define a biologically distinct CNS tumor type with high expression of neural development markers such as PAX2, GATA2 and IGF2. Drug screening performed on the MN1:PATZ1 fusion-bearing KS-1 brain tumor cell line revealed preliminary candidates for further study. In summary, PATZ1 fusions define a molecular class of histologically polyphenotypic neuroepithelial tumors, which show an intermediate prognosis under current treatment regimens.

Epigenetic and genomic profiling of chordoid meningioma: implications for clinical management.

Chordoid meningioma is a morphological variant of meningioma designated as WHO grade 2. However, the recurrence rates varied widely in different case series, and to date, a unifying molecular genetic signature has not been identified. Among 1897 meningiomas resected at our institution, we identified 12 primary chordoid meningiomas from 12 patients. Histologically, all 12 cases had predominant (> 50%) chordoid morphology. Ten were otherwise grade 1, and two were also atypical. We performed DNA global methylation profile, copy number variation analysis, and targeted next-generation sequencing on 11 chordoid meningiomas, and compared to those of 51 non-chordoid, mostly high grade meningiomas. The chordoid meningiomas demonstrated a unique methylation profile in tSNE, UMAP, and hierarchical heatmap clustering analyses of the most differentially methylated CpGs. The most common copy number variation in chordoid meningioma was loss of 1p (7/11, 64%). Three chordoid meningiomas had 2p loss, which was significantly higher than the non-chordoid control cohort (27% vs 7.2%, p = 0.035). 22q loss was only seen in the two cases with additional atypical histological features. Chordoid meningiomas were enriched in mutations in chromatin remodeling genes EP400 (8/11,73%) KMT2C (4/11, 36%) and KMT2D (4/11, 36%), and showed low or absent NF2, TERT, SMO, and AKT1 mutations. Prognosis wise, only one case recurred. This case had atypical histology and high-grade molecular features including truncating NF2 mutation, 1p, 8p, 10, 14, 22q loss, and homozygous deletion of CDKN2A/B. Progression free survival of chordoid, otherwise grade 1 meningioma was comparable to non-chordoid WHO grade 1 meningioma (p = 0.75), and significantly better than chordoid WHO grade 2 meningioma (p = 0.019). Conclusion: the chordoid histology alone may not justify a universal WHO grade 2 designation. Screening for additional atypical histological or molecular genetic features is recommended.

DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome.

PURPOSE: Lung adenocarcinoma (LUAD) is a clinically heterogeneous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation-based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. EXPERIMENTAL DESIGN: We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. RESULTS: Deconvolution of DNA methylation data identified immunologically hot and cold subsets of LUADs. In addition, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified six molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. CONCLUSIONS: Our results demonstrate that DNA methylation signatures can stratify LUAD into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.

Mitigation of SARS-CoV-2 transmission at a large public university.

In Fall 2020, universities saw extensive transmission of SARS-CoV-2 among their populations, threatening health of the university and surrounding communities, and viability of in-person instruction. Here we report a case study at the University of Illinois at Urbana-Champaign, where a multimodal "SHIELD: Target, Test, and Tell" program, with other non-pharmaceutical interventions, was employed to keep classrooms and laboratories open. The program included epidemiological modeling and surveillance, fast/frequent testing using a novel low-cost and scalable saliva-based RT-qPCR assay for SARS-CoV-2 that bypasses RNA extraction, called covidSHIELD, and digital tools for communication and compliance. In Fall 2020, we performed >1,000,000 covidSHIELD tests, positivity rates remained low, we had zero COVID-19-related hospitalizations or deaths amongst our university community, and mortality in the surrounding Champaign County was reduced more than 4-fold relative to expected. This case study shows that fast/frequent testing and other interventions mitigated transmission of SARS-CoV-2 at a large public university.

Anaplastic Transformation in Myxopapillary Ependymoma: A Report of 2 Cases and Review of the Literature.

Myxopapillary ependymoma (MPE) is a relatively common neoplasm arising primarily in the filum terminale/lumbosacral region of the spinal cord. It is designated as a grade I tumor in the most recent WHO Classification of Tumours of the CNS, although aggressive clinical behavior can be observed, especially in cases arising in an extradural location. Anaplastic transformation in MPE is exceedingly rare with <20 examples reported in the English literature, and consensus on diagnostic features and definitive grading remain to be determined. Here, we present 2 cases of recurrent MPE with anaplastic features, both of which had histology consistent with conventional MPE as well as areas with significant atypia, frequent mitotic figures, elevated Ki-67 proliferation indices (>10%-50%), necrosis, and focal vascular proliferation. Targeted next-generation sequencing panels revealed no definitive pathogenic mutations or fusion proteins in either case. Copy number profiling, methylation profiling, and t-Distributed Stochastic Neighbor Embedding were performed to investigate the molecular characteristics of these tumors. To the best of our knowledge, these are the first reported cases of MPE with anaplastic features with methylation profiling data. In addition, we review the literature and discuss common histologic and molecular findings associated with anaplastic features in MPE.

Exploring DNA Methylation for Prognosis and Analyzing the Tumor Microenvironment in Pleomorphic Xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare type of brain tumor that affects children and young adults. Molecular prognostic markers of PXAs remain poorly established. Similar to gangliogliomas, PXAs show prominent immune cell infiltrate, but its composition also remains unknown. In this study, we correlated DNA methylation and BRAF status with clinical outcome and explored the tumor microenvironment. We performed DNA methylation in 21 tumor samples from 18 subjects with a histological diagnosis of PXA. MethylCIBERSORT was used to deconvolute the PXA microenvironment by analyzing the associated immune cell-types. Median age at diagnosis was 16 years (range 7-32). At median follow-up of 30 months, 3-year and 5-year overall survival was 73% and 71%, respectively. Overall survival ranged from 1 to 139 months. Eleven out of 18 subjects (61%) showed disease progression. Progression-free survival ranged from 1 to 89 months. Trisomy 7 and CDKN2A/B (p16) homozygous deletion did not show any association with overall survival (p = 0.67 and p = 0.74, respectively). Decreased overall survival was observed for subjects with tumors lacking the BRAF V600E mutation (p = 0.02). PXAs had significantly increased CD8 T-cell epigenetic signatures compared with previously profiled gangliogliomas (p = 0.0019). The characterization of immune cell-types in PXAs may have implications for future development of immunotherapy.

Dissecting the immunosuppressive tumor microenvironments in Glioblastoma-on-a-Chip for optimized PD-1 immunotherapy.

Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-ß1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.

Molecular and clinicopathologic features of gliomas harboring NTRK fusions.

Fusions involving neurotrophic tyrosine receptor kinase (NTRK) genes are detected in ≤2% of gliomas and can promote gliomagenesis. The remarkable therapeutic efficacy of TRK inhibitors, which are among the first Food and Drug Administration-approved targeted therapies for NTRK-fused gliomas, has generated significant clinical interest in characterizing these tumors. In this multi-institutional retrospective study of 42 gliomas with NTRK fusions, next generation DNA sequencing (n = 41), next generation RNA sequencing (n = 1), RNA-sequencing fusion panel (n = 16), methylation profile analysis (n = 18), and histologic evaluation (n = 42) were performed. All infantile NTRK-fused gliomas (n = 7) had high-grade histology and, with one exception, no other significant genetic alterations. Pediatric NTRK-fused gliomas (n = 13) typically involved NTRK2, ranged from low- to high-histologic grade, and demonstrated histologic overlap with desmoplastic infantile ganglioglioma, pilocytic astrocytoma, ganglioglioma, and glioblastoma, among other entities, but they rarely matched with high confidence to known methylation class families or with each other; alterations involving ATRX, PTEN, and CDKN2A/2B were present in a subset of cases. Adult NTRK-fused gliomas (n = 22) typically involved NTRK1 and had predominantly high-grade histology; genetic alterations involving IDH1, ATRX, TP53, PTEN, TERT promoter, RB1, CDKN2A/2B, NF1, and polysomy 7 were common. Unsupervised principal component analysis of methylation profiles demonstrated no obvious grouping by histologic grade, NTRK gene involved, or age group. KEGG pathway analysis detected methylation differences in genes involved in PI3K/AKT, MAPK, and other pathways. In summary, the study highlights the clinical, histologic, and molecular heterogeneity of NTRK-fused gliomas, particularly when stratified by age group.

Temporal trends in the utilization of diagnostic testing and treatments for cardiovascular disease in the United States, 1993-2001.

BACKGROUND: Rates of invasive testing and treatment for coronary artery disease have increased over time. Less is known about trends in the utilization of noninvasive cardiac testing for coronary artery disease. The objective of this study was 2-fold: to explore temporal trends in the utilization of noninvasive and invasive cardiac services in relation to changes in the prevalence of cardiac disease, and to examine whether temporal increases have been targeted to potentially underserved populations. METHODS AND RESULTS: We performed an annual cross-sectional population-based study of Medicare patients from 1993 to 2001. We identified stress testing, cardiac catheterization, and revascularization procedures, as well as hospitalizations for acute myocardial infarction, during each year and calculated population-based rates for each using the total fee-for-service Medicare population as the denominator and adjusting for age, gender, and race. We observed marked growth in the utilization rates of cardiac services over time, with relative rates nearly doubling for most services. Acute myocardial infarction hospitalization rates have remained stable over the study period. Although rates of all procedures except coronary artery bypass increased in all subgroups, differences in rates of cardiac testing and treatment between nonblack men and other subgroups persisted over time. CONCLUSIONS: Temporal increases in the use of noninvasive and invasive cardiac services are not explained by changes in disease prevalence and have not succeeded in narrowing preexisting treatment differences by gender and race. Such increases, although conferring benefit for some, may expose others to risk and cost without benefit.

Differences in cardiac stress testing by sex and race among Medicare beneficiaries.

BACKGROUND: Although there is a wide literature demonstrating sex and race differences in the receipt of invasive cardiac tests and treatments, much less is known about the influence of such characteristics on receipt of a stress test, the first event in the diagnostic/treatment cascade for many patients. We explored the influence of patient characteristics on receipt of a stress test, with special attention to sex and race. METHODS: We performed a nested case-control study of Medicare beneficiaries who were aged 66 years and older during 1999-2001 and were free of cardiac diagnoses and procedures for at least 1 year. Cases were recipients of a stress test. RESULTS: Cases were younger, less likely to be female or black, but more likely to live in high-income, highly educated, and urban areas than controls. Nonblack men were more likely to receive a stress test than women and black men, controlling for age, area characteristics, and clinical characteristics (odds ratio for nonblack men compared with black women 1.71). These results were not explained by physician visit frequency. CONCLUSIONS: Efforts at minimizing disparities in cardiac care must attend to what is, for many patients, the entry into the cardiac care system: the stress test. Our findings suggest that simple "access," as measured by physician visit frequency, is not a rate-limiting factor.

Epidemiology and short-term outcomes of injured medicare patients.

OBJECTIVES: To describe characteristics and short-term outcomes of Medicare patients hospitalized after injuries in 1999. DESIGN: Analysis of national population-based case series. SETTING: Hospitalized Medicare patients. PARTICIPANTS: All fee-for-service Medicare patients aged 65 and older admitted for the first time in 1999 with principal injury diagnoses (International Classification of Diseases, Ninth Revision, codes 800-904, 910-929, 940-957, 959). MEASUREMENTS: Incidence rates, stratified by anatomic location (hip, other extremity, spine, head, chest, other), sex, and age group (65-74, 75-84, >or=85). For each category, Charlson comorbidity scores, Abbreviated Injury Scores, hospital length of stay, discharge disposition, hospital mortality, 30-day mortality, and readmissions within 30 days of discharge. RESULTS: A total of 439,605 persons were admitted at least once (crude rate 1,654/100,000). Rates of hospitalization increased with age and were generally higher in women (except head injuries). Comorbidities were more common in men. Hip fractures constituted 46.6% of cases and other extremity injuries another 30.7%. Hospital mortality (3.7% overall) increased with age, was greater in men, and was highest in patients with head injuries. The proportion discharged to skilled nursing facilities (43.8% overall, range 10.0-61.9% by age/sex/anatomic category) also increased with age, was higher in women, and was highest in patients with hip fractures. Slightly more than one-tenth (12.3%) of patients were readmitted within 30 days. Thirty-day mortality was 2.0 times hospital mortality (range 1.2-3.4 by category). CONCLUSION: Most injuries resulting in hospitalization for the Medicare population involve the extremities, but other injuries have higher mortality. Many injured patients are not discharged home but receive additional institutional care. Thirty-day survival is much lower than observed hospital survival. Further studies of injuries using Medicare data are warranted.

Regional variation in hospital mortality and 30-day mortality for injured Medicare patients.

BACKGROUND: We sought to evaluate how survival of older patients with injuries differs by geographic region within the United States. METHODS: We analyzed Medicare fee-for-service records for patients aged 65 years and older with principal injury diagnoses (ICD-9 800-959, excluding 905, 930-939, 958). Cases were classified by Maximum Abbreviated Injury Score (AISmax) and Charlson Comorbidity score (0, 1, 2, >or=3). Hospital mortality and 30-day mortality were modeled as functions of age, sex, AISmax, comorbidity, and geographic region (northeast, midwest, south, west). RESULTS: Hospital and 30-day mortality were both higher with male sex and increased age, AISmax, or Charlson score. Adjusted hospital mortality was highest in the northeast and south, but 30-day adjusted mortality was lowest in the same two regions. CONCLUSIONS: Regional differences in risk-adjusted hospital survival for older patients with injuries are different from regional differences in 30-day survival. Hospital mortality as an outcome for older injured patients should be interpreted cautiously.

Long-term survival of Medicare patients with head injury.

BACKGROUND: An increasing number of older patients are being hospitalized with traumatic brain injury (TBI). Knowledge of their expected long-term survival may be useful in making clinical decisions. METHODS: Patients age 65 or older admitted for the first time with head injury (ICD-9 800-804 or 850-854) during 1999 were identified in a complete national sample of fee-for-service Medicare hospitalization and denominator data. Cases were categorized by age, sex, maximum Abbreviated Injury Score (AISmax), and Charlson comorbidity score. Survival was determined at hospital discharge, and (using the denominator file) at 1, 6, 12, and 24 months after the initial hospital admission. RESULTS: For all cases (n = 30,684), the hospital mortality was 14.3%, but was cumulatively 19.75%, 30.5%, 36.1%, and 44.9% at successive times up to 24 months. Long-term mortality was higher with increased age, comorbidity, or AISmax, and higher in men. These effects persisted with multivariate logistic regression analysis and were used to construct a simplified prediction score for clinical use. CONCLUSIONS: The mortality for older patients with TBI is much higher than for an uninjured control population. The relative risk for death remains elevated after hospital discharge and for at least 2 years. Awareness of the expected prognosis may help family members and health care providers make appropriate clinical decisions during acute hospitalization.

Initial presentation of older injured patients to high-volume hospitals is not associated with lower 30-day mortality in Medicare data.

OBJECTIVE: To evaluate whether survival of older patients with severe injuries is positively associated with initial presentation to high-volume trauma hospitals. DESIGN: Historical cohort study. SETTING: We analyzed Medicare fee-for-service records. Cases were classified by maximum Abbreviated Injury Score (AISmax); those with isolated hip fractures or AISmax <3 were excluded. The initial hospital (emergency department or inpatient) for each case was classified by its number of included inpatient cases. PATIENTS: Patients aged >or=65 with principal injury diagnoses (ICD-9 800-959, excluding 905, 930-939, 958) admitted to hospitals or who died in emergency departments during 1999. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirty-day mortality was determined using Medicare denominator data and modeled as a function of hospital volume, AISmax, age, gender, and comorbidity. We found that 95,867 patients (74,894 AISmax = 3; 17,932 AISmax = 4; 3,041 AISmax = 5) were managed in 4,391 hospitals. More than 90% of the interhospital transfers were from emergency departments, mostly from low-volume to high-volume hospitals, and were more frequent with greater severity. Regression models showed no difference in 30-day survival between patients taken first to low-volume hospitals (and possibly transferred) vs. patients taken directly to high-volume hospitals. Prior studies showing a positive or negative effect of hospital volume on survival of older patients could be replicated but their findings could not be generalized. CONCLUSIONS: Existing systems of trauma care result in similar survival for older patients with serious injuries seen first at low-volume or high-volume hospitals.

The rising prevalence of androgen deprivation among older American men since the advent of prostate-specific antigen testing: a population-based cohort study.

OBJECTIVE: To investigate the effect of efforts in the early detection of prostate cancer using prostate-specific antigen (PSA) testing in the USA, by estimating the regional prevalence of androgen deprivation therapy (ADT) among older men in 1993-2000, and correlating the prevalence with early detection and aggressive treatment rates in 1987-91, as some authors predicted that ADT, a treatment traditionally reserved for advanced prostate cancer, would become less common over time as a result of such efforts. PATIENTS AND METHODS: A sample of 5% of men who were Medicare beneficiaries was used in this prospective population-based cohort study. The main outcome measures were the overall prevalence of ADT (medical and surgical) in the cohort from 1993 to 2000, and correlations between rates of prostate procedures in the 306 USA hospital referral regions in 1987-91 and prevalence of ADT in those regions from 1993 to 2000. RESULTS: The prevalence of ADT among these men in the USA increased steadily from 1.8% in 1993 to 2.9% in 2000 (P < 0.001). Regions with higher rates of prostate biopsy in 1987-91 had a higher prevalence of ADT in 1993, 1995 and 1997 (P < 0.05). Regions with higher rates of transurethral prostatectomy in 1987-91 had a higher prevalence of ADT in 1993-2000 (P < 0.01). Regions with higher rates of radical prostatectomy in 1987-91 had higher rates of ADT in 1993-99 (P < 0.05). CONCLUSIONS: Widespread early detection and aggressive treatment for prostate cancer in the USA has been associated with more, not less, ADT among older men over time.

Injuries among older Americans with and without Medicare.

OBJECTIVES: We evaluated the generalizability of Medicare fee-for-service data for patients hospitalized with injuries. METHODS: We used 1998-2000 Medicare hospitalization data and National Hospital Discharge Survey (NHDS) data to analyze patients aged 65 years and older with principal injury diagnoses. RESULTS: Demographics and injury patterns were similar in Medicare data and NHDS Medicare data. Injured patients without Medicare or health maintenance organization coverage were younger, less likely to have hip fractures, and more likely to have head or chest injuries. Mortality and discharge to long-term care were not significantly affected by insurance coverage, after we controlled for injury type and severity, age, gender, and comorbidity. Medicare patients had slightly longer hospital lengths of stay. CONCLUSIONS: Hospital outcomes are generally similar among older patients with a given anatomic injury, regardless of insurance coverage.