Differences in Patient-Reported Outcome Measures in Patients With Cancer Six Months Before Death.

PURPOSE: Patient-reported outcome measures (PROMs) provide a direct report of the patient's perspective, complementary to clinician assessment. Currently, understanding the real-time changes in PROM scores near the end of life remains limited. This study evaluated differences in mean PROM scores between patients with cancer within 6 months before death compared with surviving patients with cancer. METHODS: This retrospective case-control study uses the National Institutes of Health's Patient-Reported Outcomes Measurement Information System computer adaptive testing instruments to assess pain interference, physical function, fatigue, and depression. Patients dying within 6 months of PROM completion were selected as cases and matched to controls 1:3 by age at PROM completion, sex, cancer disease site, and cancer stage at diagnosis. Generalized estimating equation models assessed the difference in mean PROM score in cases compared with controls. RESULTS: A total of 461 cases and 1,270 controls from September 2020 to January 2023 were included. After adjustment for ethnicity, Charlson Comorbidity Index, and census tract median household income, significant differences in mean scores were demonstrated. Physical function domain showed the largest difference, with cases averaging 6.52 points lower than controls (95% CI, -8.25 to -4.80). Fatigue and pain interference domains showed a rise in PROMs scores by 4.83 points (95% CI, 2.94 to 6.72) and 4.33 points (95% CI, 2.53 to 6.12), respectively. CONCLUSION: Compared with controls, patients dying within 6 months of PROM completion demonstrated worse PROM scores in the four domains assessed. These findings suggest the utility of routinely collected PROMs as a real-time indicator of the terminal stage of life among patients with cancer to allow for earlier intervention with supportive oncology services.

Sex-Specific Differences in Patients with IDH1-Wild-Type Grade 4 Glioma in the ReSPOND Consortium.

BACKGROUND AND PURPOSE: Understanding sex-based differences in patients with glioblastoma is necessary for accurate personalized treatment planning to improve patient outcomes. Our purpose was to investigate sex-specific differences in molecular, clinical, and radiologic tumor parameters, as well as survival outcomes in patients with glioblastoma, isocitrate dehydrogenase-1 wild-type (IDH1-WT), grade 4. MATERIALS AND METHODS: Retrospective data of 1832 patients with glioblastoma, IDH1-WT with comprehensive information on tumor parameters was acquired from the Radiomics Signatures for Precision Oncology in Glioblastoma consortium. Data imputation was performed for missing values. Sex-based differences in tumor parameters, such as age, molecular parameters, preoperative Karnofsky performance score (KPS), tumor volumes, epicenter, and laterality were assessed through nonparametric tests. Spatial atlases were generated by using preoperative MRI maps to visualize tumor characteristics. Survival time analysis was performed through log-rank tests and Cox proportional hazard analyses. RESULTS: Glioblastoma was diagnosed at a median age of 64 years in women compared with 61.9 years in men (false discovery rate [FDR] = 0.003). Men had a higher KPS (above 80) as compared with women (60.4% women versus 69.7% men, FDR = 0.044). Women had lower tumor volumes in enhancing (16.7 cm3 versus 20.6 cm3 in men, FDR = 0.001), necrotic core (6.18 cm3 versus 7.76 cm3 in men, FDR = 0.001), and edema regions (46.9 cm3 versus 59.2 cm3 in men, FDR = 0.0001). The right temporal region was the most common tumor epicenter in the overall population. Right as well as left temporal lobes were more frequently involved in men. There were no sex-specific differences in survival outcomes and mortality ratios. Higher age, unmethylated O6-methylguanine-DNA-methyltransferase promoter and undergoing subtotal resection increased the mortality risk in both men and women. CONCLUSIONS: Our study demonstrates significant sex-based differences in clinical and radiologic tumor parameters of patients with glioblastoma. Sex is not an independent prognostic factor for survival outcomes and the tumor parameters influencing patient outcomes are identical for men and women.

The Epigenetic Evolution of Glioma Is Determined by the IDH1 Mutation Status and Treatment Regimen.

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype. SIGNIFICANCE: Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

Detection of diagnostic and prognostic methylation-based signatures in liquid biopsy specimens from patients with meningiomas.

Recurrence of meningiomas is unpredictable by current invasive methods based on surgically removed specimens. Identification of patients likely to recur using noninvasive approaches could inform treatment strategy, whether intervention or monitoring. In this study, we analyze the DNA methylation levels in blood (serum and plasma) and tissue samples from 155 meningioma patients, compared to other central nervous system tumor and non-tumor entities. We discover DNA methylation markers unique to meningiomas and use artificial intelligence to create accurate and universal models for identifying and predicting meningioma recurrence, using either blood or tissue samples. Here we show that liquid biopsy is a potential noninvasive and reliable tool for diagnosing and predicting outcomes in meningioma patients. This approach can improve personalized management strategies for these patients.

Association of partial T2-FLAIR mismatch sign and isocitrate dehydrogenase mutation in WHO grade 4 gliomas: results from the ReSPOND consortium.

PURPOSE: While the T2-FLAIR mismatch sign is highly specific for isocitrate dehydrogenase (IDH)-mutant, 1p/19q-noncodeleted astrocytomas among lower-grade gliomas, its utility in WHO grade 4 gliomas is not well-studied. We derived the partial T2-FLAIR mismatch sign as an imaging biomarker for IDH mutation in WHO grade 4 gliomas. METHODS: Preoperative MRI scans of adult WHO grade 4 glioma patients (n = 2165) from the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium were analyzed. Diagnostic performance of the partial T2-FLAIR mismatch sign was evaluated. Subset analyses were performed to assess associations of imaging markers with overall survival (OS). RESULTS: One hundred twenty-one (5.6%) of 2165 grade 4 gliomas were IDH-mutant. Partial T2-FLAIR mismatch was present in 40 (1.8%) cases, 32 of which were IDH-mutant, yielding 26.4% sensitivity, 99.6% specificity, 80.0% positive predictive value, and 95.8% negative predictive value. Multivariate logistic regression demonstrated IDH mutation was significantly associated with partial T2-FLAIR mismatch (odds ratio [OR] 5.715, 95% CI [1.896, 17.221], p = 0.002), younger age (OR 0.911 [0.895, 0.927], p < 0.001), tumor centered in frontal lobe (OR 3.842, [2.361, 6.251], p < 0.001), absence of multicentricity (OR 0.173, [0.049, 0.612], p = 0.007), and presence of cystic (OR 6.596, [3.023, 14.391], p < 0.001) or non-enhancing solid components (OR 6.069, [3.371, 10.928], p < 0.001). Multivariate Cox analysis demonstrated cystic components (p = 0.024) and non-enhancing solid components (p = 0.003) were associated with longer OS, while older age (p < 0.001), frontal lobe center (p = 0.008), multifocality (p < 0.001), and multicentricity (p < 0.001) were associated with shorter OS. CONCLUSION: Partial T2-FLAIR mismatch sign is highly specific for IDH mutation in WHO grade 4 gliomas.

Glioma progression is shaped by genetic evolution and microenvironment interactions.

The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo.

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin's antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers.

Detection of tumor-specific DNA methylation markers in the blood of patients with pituitary neuroendocrine tumors.

BACKGROUND: DNA methylation abnormalities are pervasive in pituitary neuroendocrine tumors (PitNETs). The feasibility to detect methylome alterations in circulating cell-free DNA (cfDNA) has been reported for several central nervous system (CNS) tumors but not across PitNETs. The aim of the study was to use the liquid biopsy (LB) approach to detect PitNET-specific methylation signatures to differentiate these tumors from other sellar diseases. METHODS: We profiled the cfDNA methylome (EPIC array) of 59 serum and 41 plasma LB specimens from patients with PitNETs and other CNS diseases (sellar tumors and other pituitary non-neoplastic diseases, lower-grade gliomas, and skull-base meningiomas) or nontumor conditions, grouped as non-PitNET. RESULTS: Our results indicated that despite quantitative and qualitative differences between serum and plasma cfDNA composition, both sources of LB showed that patients with PitNETs presented a distinct methylome landscape compared to non-PitNETs. In addition, LB methylomes captured epigenetic features reported in PitNET tissue and provided information about cell-type composition. Using LB-derived PitNETs-specific signatures as input to develop machine-learning predictive models, we generated scores that distinguished PitNETs from non-PitNETs conditions, including sellar tumor and non-neoplastic pituitary diseases, with accuracies above ~93% in independent cohort sets. CONCLUSIONS: Our results underpin the potential application of methylation-based LB profiling as a noninvasive approach to identify clinically relevant epigenetic markers to diagnose and potentially impact the prognostication and management of patients with PitNETs.

Correction: The novel long non-coding RNA TALNEC2, regulates tumor cell growth and the stemness and radiation response of glioma stem cells.

[This corrects the article DOI: 10.18632/oncotarget.15991.].

Expression and regulatory roles of lncRNAs in G-CIMP-low vs G-CIMP-high Glioma: an in-silico analysis.

BACKGROUND: Clinically relevant glioma subtypes, such as the glioma-CpG island methylator phenotype (G-CIMP), have been defined by epigenetics. In this study, the role of long non-coding RNAs in association with the poor-prognosis G-CMIP-low phenotype and the good-prognosis G-CMIP-high phenotype was investigated. Functional associations of lncRNAs with mRNAs and miRNAs were examined to hypothesize influencing factors of the aggressive phenotype. METHODS: RNA-seq data on 250 samples from TCGA's Pan-Glioma study, quantified for lncRNA and mRNAs (GENCODE v28), were analyzed for differential expression between G-CIMP-low and G-CIMP-high phenotypes. Functional interpretation of the differential lncRNAs was performed by Ingenuity Pathway Analysis. Spearman rank order correlation estimates between lncRNA, miRNA, and mRNA nominated differential lncRNA with a likely miRNA sponge function. RESULTS: We identified 4371 differentially expressed features (mRNA = 3705; lncRNA = 666; FDR ≤ 5%). From these, the protein-coding gene TP53 was identified as an upstream regulator of differential lncRNAs PANDAR and PVT1 (p = 0.0237) and enrichment was detected in the "development of carcinoma" (p = 0.0176). Two lncRNAs (HCG11, PART1) were positively correlated with 342 mRNAs, and their correlation estimates diminish after adjusting for either of the target miRNAs: hsa-miR-490-3p, hsa-miR-129-5p. This suggests a likely sponge function for HCG11 and PART1. CONCLUSIONS: These findings identify differential lncRNAs with oncogenic features that are associated with G-CIMP phenotypes. Further investigation with controlled experiments is needed to confirm the molecular relationships.

A serum-based DNA methylation assay provides accurate detection of glioma.

BACKGROUND: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches. METHODS: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients. RESULTS: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment). CONCLUSIONS: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma.

DNA methylation-based signatures classify sporadic pituitary tumors according to clinicopathological features.

BACKGROUND: Distinct genome-wide methylation patterns cluster pituitary neuroendocrine tumors (PitNETs) into molecular groups associated with specific clinicopathological features. Here we aim to identify, characterize, and validate methylation signatures that objectively classify PitNET into clinicopathological groups. METHODS: Combining in-house and publicly available data, we conducted an analysis of the methylome profile of a comprehensive cohort of 177 tumors (Panpit cohort) and 20 nontumor specimens from the pituitary gland. We also retrieved methylome data from an independent PitNET cohort (N = 86) to validate our findings. RESULTS: We identified three methylation clusters associated with adenohypophyseal cell lineages and functional status using an unsupervised approach. Differentially methylated probes (DMP) significantly distinguished the Panpit clusters and accurately assigned the samples of the validation cohort to their corresponding lineage and functional subtypes memberships. The DMPs were annotated in regulatory regions enriched with enhancer elements, associated with pathways and genes involved in pituitary cell identity, function, tumorigenesis, and invasiveness. Some DMPs correlated with genes with prognostic and therapeutic values in other intra- or extracranial tumors. CONCLUSIONS: We identified and validated methylation signatures, mainly annotated in enhancer regions that distinguished PitNETs by distinct adenohypophyseal cell lineages and functional status. These signatures provide the groundwork to develop an unbiased approach to classifying PitNETs according to the most recent classification recommended by the 2017 WHO and to explore their biological and clinical relevance in these tumors.

miR-504 modulates the stemness and mesenchymal transition of glioma stem cells and their interaction with microglia via delivery by extracellular vesicles.

Glioblastoma (GBM) is a highly aggressive tumor with poor prognosis. A small subpopulation of glioma stem cells (GSCs) has been implicated in radiation resistance and tumor recurrence. In this study we analyzed the expression of miRNAs associated with the functions of GSCs using miRNA microarray analysis of these cells compared with human neural stem cells. These analyses identified gene clusters associated with glioma cell invasiveness, axonal guidance, and TGF-ß signaling. miR-504 was significantly downregulated in GSCs compared with NSCs, its expression was lower in GBM compared with normal brain specimens and further decreased in the mesenchymal glioma subtype. Overexpression of miR-504 in GSCs inhibited their self-renewal, migration and the expression of mesenchymal markers. The inhibitory effect of miR-504 was mediated by targeting Grb10 expression which acts as an oncogene in GSCs and GBM. Overexpression of exogenous miR-504 resulted also in its delivery to cocultured microglia by GSC-secreted extracellular vesicles (EVs) and in the abrogation of the GSC-induced polarization of microglia to M2 subtype. Finally, miR-504 overexpression prolonged the survival of mice harboring GSC-derived xenografts and decreased tumor growth. In summary, we identified miRNAs and potential target networks that play a role in the stemness and mesenchymal transition of GSCs and the miR-504/Grb10 pathway as an important regulator of this process. Overexpression of miR-504 exerted antitumor effects in GSCs as well as bystander effects on the polarization of microglia via delivery by EVs.

COVID-19 and Cancer: Lessons Learnt from a Michigan Hotspot.

(1) Background: Outcomes with coronavirus disease 2019 (COVID-19) have been worse in those with comorbidities and amongst minorities. In our study, we describe outcomes amongst cancer patients in Detroit, a major COVID-19 hotspot with a predominant inner-city population. (2) Methods: We retrospectively analyzed 85 patients with active invasive cancers who were infected with COVID-19. The primary outcome was death or transition to hospice. (3) Results: The majority were males (55.3%, n = 47), ≤70 years old (58.5%, n = 50), and African Americans (65.5%, n = 55). The most common primary site was prostate (18.8%, n = 16). Inpatient admission was documented in 85.5% (n = 73), ICU admission in 35.3% (n = 30), and primary outcome in 43.8% (n = 32) of hospitalized patients. On a multivariate analysis, factors associated with increased odds of a primary outcome included an age of >70 years versus ≤70 years (OR 4.7, p = 0.012) and of male gender (OR 4.8, p = 0.008). Recent cancer-directed therapy was administered in 66.7% (n = 20) of ICU admissions versus 39.5% (n = 17) of general floor admissions (Chi-square p-value of 0.023). (4) Conclusions: High rates of mortality/transition to hospice and ICU utilization were noted amongst our patients with active invasive cancer, following a COVID-19 infection. Men and those of >70 years of age had a greater than four-fold increase in odds of death or transition to hospice.

Developing Real-world Evidence-Ready Datasets: Time for Clinician Engagement.

PURPOSE OF REVIEW: Real-world data (RWD) applications in healthcare that support learning health systems and pragmatic clinical trials are gaining momentum, largely due to legislation supporting real-world evidence (RWE) for drug approvals. Clinical notes are thought to be the cornerstone of RWD applications, particularly for conditions with limited effective treatments, extrapolation of treatments from other conditions, or heterogenous disease biology and clinical phenotypes. RECENT FINDINGS: Here, we discuss current issues in applying RWD captured at the point-of-care and provide a framework for clinicians to engage in RWD collection. To achieve clinically meaningful results, RWD must be reliably captured using consistent terminology in the description of our patients. RWD complements traditional clinical trials and research by informing the generalizability of results, generating new hypotheses, and creating a large data network for scientific discovery. Effective clinician engagement in the development of RWD applications is necessary for continued progress in the field.

Factors associated with employment discontinuation among older and working age survivors of oropharyngeal cancer.

BACKGROUND: Oropharyngeal cancer survivors experience difficulty returning to work after treatment. To better understand specific barriers to returning to work, we investigated factors associated with discontinuing employment among older and working-age survivors. METHODS: The sample included 675 oropharyngeal cancer survivors (median: 6 years posttreatment) diagnosed from 2000 to 2013 and employed at diagnosis. Relative risk models were constructed to examine the independent associations of demographic and health factors, and symptom experiences per the MD Anderson Symptom Inventory - Head and Neck Module (MDASI-HN) with posttreatment employment, overall and by age (<60 years vs ≥60 years at survey). RESULTS: Symptom interference was not statistically significantly associated with posttreatment employment status among respondents ≥60 years. Among working-age respondents <60 years, symptom interference was strongly associated with posttreatment employment. CONCLUSIONS: Efforts to assess and lessen symptom burden in working-age survivors should be evaluated as approaches to support regaining core functions needed for continued employment.

MR imaging phenotype correlates with extent of genome-wide copy number abundance in IDH mutant gliomas.

PURPOSE: There is variability in survival within IDH mutant gliomas determined by chromosomal events. Copy number variation (CNV) abundance associated with survival in low-grade and IDH mutant astrocytoma has been reported. Our purpose was to correlate the extent of genome-wide CNV abundance in IDH mutant astrocytomas with MRI features. METHODS: Presurgical MRI and CNV plots derived from Illumina 850k EPIC DNA methylation arrays of 18 cases of WHO grade II-IV IDH mutant astrocytomas were reviewed. IDH mutant astrocytomas were divided into CNV stable group (CNV-S) with ≤ 3 chromosomal gains or losses and lack of focal gene amplifications and CNV unstable group (CNV-U) with > 3 large chromosomal gains/losses and/or focal amplifications. The associations between MR features, relative cerebral blood volume (rCBV), CNV abundance, and time to progression were assessed. Tumor rCBV estimates were obtained using DSC T2* perfusion analysis. RESULTS: There were nine (50%) CNV-S and nine (50%) CNV-U IDH mutant astrocytomas. CNV-U tumors showed larger mean tumor size (P = 0.004) and maximum diameter on FLAIR (P = 0.004) and also demonstrated significantly higher median rCBV than CNV-S tumors (2.62 vs 0.78, P = 0.019). CNV-U tumors tended to have shorter time to progression although without statistical significance (P = 0.393). CONCLUSIONS: Larger size/diameter and higher rCBVs were seen associated CNV-U astrocytomas, suggesting a correlation of aggressive imaging phenotype with unstable and aggressive genotype in IDH mutant astrocytomas.

Clinical and research applications of a brain tumor tissue bank in the age of precision medicine.

Marked progress has been made recently in the treatment of patients with central nervous system (CNS) tumors, especially gliomas. However, because of the relative rarity of these tumors compared with other malignancies, advances in the molecular/genetic analysis leading to future targeted treatments rely on systematic, organized tissue banking. Several large multi-institutional efforts have utilized major tissue banks that have yielded valuable information that may lead to a better understanding of the pathogenesis of CNS tumors. This manuscript portrays best practices for the establishment and maintenance of a well-organized CNS tumor bank. In addition, annotation for clinical and research needs is explained. The potential benefits to clinical care, as well as basic science and translational research are also described.