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-β1, 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.
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.
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.
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.
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.
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.
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.
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, ≥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.
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, ≥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.
To evaluate whether survival of older patients with severe injuries is positively associated with initial presentation to high-volume trauma hospitals.
Historical cohort study.
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 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.
None.
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.
Existing systems of trauma care result in similar survival for older patients with serious injuries seen first at low-volume or high-volume hospitals.
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.
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.
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.
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.
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.
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