Exploring the interconnectedness between health-related quality of life factors among long-term adolescent and young adult cancer survivors (AYAs):a network analysis

Purpose: Adolescent and young adult cancer survivors (AYAs) are at increased risk of long-term and late effects, and experience unmet needs, impacting their health-related quality of life (HRQoL). In order to provide and optimize supportive care and targeted interventions for this unique population, it is important to study HRQoL factors’ interconnectedness on a population level. Therefore, this network analysis was performed with the aim to explore the interconnectedness between HRQoL factors, in the analysis described as nodes, among long-term AYAs. Methods: This population-based cohort study used cross-sectional survey data of long-term AYAs, who were identified by the Netherlands Cancer Registry (NCR). Participants completed a one-time survey (SURVAYA study), including the EORTC survivorship questionnaire (QLQ-SURV111) to assess their long-term HRQoL outcomes and sociodemographic characteristics. The NCR provided the clinical data. Descriptive statistics and a network analysis, including network clustering, were performed. Results: In total, 3596 AYAs (on average 12.4 years post diagnosis) were included in our network analysis. The network was proven stable and reliable and, in total, four clusters were identified, including a worriment, daily functioning, psychological, and sexual cluster. Negative health outlook, part of the worriment cluster, was the node with the highest strength and its partial correlation with health distress was significantly different from all other partial correlations. Conclusion: This study shows the results of a stable and reliable network analysis based on HRQoL data of long-term AYAs, and identified nodes, correlations, and clusters that could be intervened on to improve the HRQoL outcomes of AYAs.</p

Longitudinal characteristics of T2-FLAIR mismatch in IDH-mutant astrocytomas: Relation to grade, histopathology, and overall survival in the GLASS-NL cohort.

BACKGROUND: The T2-FLAIR mismatch sign is defined by signal loss of the T2-weighted hyperintense area with Fluid-Attenuated Inversion Recovery (FLAIR) on magnetic resonance imaging, causing a hypointense region on FLAIR. It is a highly specific diagnostic marker for IDH-mutant astrocytoma and is postulated to be caused by intercellular microcystic change in the tumor tissue. However, not all IDH-mutant astrocytomas show this mismatch sign and some show the phenomenon in only part of the lesion. The aim of the study is to determine whether the T2-FLAIR mismatch phenomenon has any prognostic value beyond initial noninvasive molecular diagnosis. METHODS: Patients initially diagnosed with histologically lower-grade (2 or 3) IDH-mutant astrocytoma and with at least 2 surgical resections were included in the GLASS-NL cohort. T2-FLAIR mismatch was determined, and the growth pattern of the recurrent tumor immediately before the second resection was annotated as invasive or expansive. The relation between the T2-FLAIR mismatch sign and tumor grade, microcystic change, overall survival (OS), and other clinical parameters was investigated both at first and second resection. RESULTS: The T2-FLAIR mismatch sign was significantly related to Grade 2 (80% vs 51%), longer post-resection median OS (8.3 vs 5.2 years), expansive growth, and lower age at second resection. At first resection, no relation was found between the mismatch sign and OS. Microcystic change was associated with areas of T2-FLAIR mismatch. CONCLUSIONS: T2-FLAIR mismatch in IDH-mutant astrocytomas is correlated with microcystic change in the tumor tissue, favorable prognosis, and Grade 2 tumors at the time of second resection

Genomic aberrations associated with outcome in anaplastic oligodendroglial tumors treated within the EORTC phase III trial 26951

Despite similar morphological aspects, anaplastic oligodendroglial tumors (AOTs) form a heterogeneous clinical subgroup of gliomas. The chromosome arms 1p/19q codeletion has been shown to be a relevant biomarker in AOTs and to be perfectly exclusive from EGFR amplification in gliomas. To identify new genomic regions associated with prognosis, 60 AOTs from the EORTC trial 26951 were analyzed retrospectively using BAC-array-based comparative genomic hybridization. The data were processed using a binary tree method. Thirty-three BACs with prognostic value were identified distinguishing four genomic subgroups of AOTs with different prognosis (p < 0.0001). Type I tumors (25%) were characterized by: (1) an EGFR amplification, (2) a poor prognosis, (3) a higher rate of necrosis, and (4) an older age of patients. Type II tumors (21.7%) had: (1) loss of prognostic BACs located on 1p tightly associated with 19q deletion, (2) a longer survival, (3) an oligodendroglioma phenotype, and (4) a frontal location in brain. Type III AOTs (11.7%) exhibited: (1) a deletion of prognostic BACs located on 21q, and (2) a short survival. Finally, type IV tumors (41.7%) had different genomic patterns and prognosis than type I, II and III AOTs. Multivariate analysis showed that genomic type provides additional prognostic data to clinical, imaging and pathological features. Similar results were obtained in the cohort of 45 centrally reviewed–validated cases of AOTs. Whole genome analysis appears useful to screen the numerous genomic abnormalities observed in AOTs and to propose new biomarkers particularly in the non-1p/19q codeleted AOTs

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 histological 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 neo-angiogenesis 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 towards an IDHwt-like phenotype

Health-related quality of life of Adolescent and Young Adult Cancer Survivors before and during the COVID-19 pandemic: longitudinal improvements on social functioning and fatigue

The health-related quality of life (HRQoL) among long-term Adolescent and Young Adult Cancer Survivors (AYACS) and an age- and sex-matched normative population was examined. Although the HRQoL of AYACS was worse compared to the normative population before and during the COVID-19 pandemic, the scores of AYACS improved over time in contrast to the normative population. Presumably, AYACS are used to adjusting their lives to stressful life events. Furthermore, the lockdown may have been beneficial for AYACS who face difficulties fully participating in society due to the impact of cancer. AYACS who encounter HRQoL issues could benefit from support interventions to empower them and build resilience

MGMT promoter hypermethylation is a frequent, early, and consistent event in astrocytoma progression, and not correlated with TP53 mutation

Hypermethylation of the MGMT gene promoter and mutation of the TP53 tumor-suppressor gene are frequently present in diffuse astrocytomas. However, there is only anecdotal information about MGMT methylation status and TP53 mutations during progression of low-grade diffuse astrocytoma (AII) to anaplastic astrocytoma (AIII) and secondary glioblastoma (sGB). In this study biopsy specimens from 51 patients with astrocytic tumors with radiologically proved progression from low to high-grade malignancy were investigated for the presence and consistency of MGMT promoter hypermethylation and TP53 mutations. For 27 patients biopsy samples both of primary tumors and their recurrences were available. For the other 24 patients histology of either the low-grade lesion or the high-grade recurrence was available. It was found that MGMT promoter hypermethylation and TP53 mutations are both frequent and early events in the progression of astrocytomas and that their status is consistent over time. No correlation was found between MGMT methylation status and the presence of TP53 mutations. In addition, no correlation was found between MGMT promoter hypermethylation and the type of TP53 mutations. These results argue against the putative TP53 G:C>A:T transition mutations suggested to occur preferentially in MGMT hypermethylated tumors

Patient-Reported Outcomes of Accelerated Aging: A Novel Approach to Investigate Second Cancer Risk in Adolescent and Young Adult (18-39 Years) Cancer Survivors

BACKGROUND: Adolescent and young adult cancer survivors (AYAs, aged 18-39 years at first diagnosis) have a higher second cancer risk. Accelerated aging is hypothesized as underlying mechanism and has been described clinically by 6 indicators; fatigue, low quality of sleep, low mood, lack of motivation, subjective memory complaints, and poor exercise tolerance. Using patient-reported outcomes, we aimed to identify clusters of accelerated aging among AYA cancer survivors and to investigate their association with second cancer development. PATIENTS AND METHODS: Patient, tumor, and treatment data were obtained from the Netherlands Cancer Registry. Patient-reported clinical indicators and second cancer data were obtained from the SURVivors (5-20 years) of cancer in AYAs (SURVAYA) questionnaire study between 1999 and 2015. Latent class and multivariable logistic regression analyses were performed. RESULTS: In total, n = 3734 AYA survivors with known second cancer status (n = 278 [7.4%] second cancers) were included. Four latent clusters were identified and named based on their clinical indicator features; (1) high accelerated aging (31.3%), (2) intermediate accelerated aging without poor exercise tolerance (15.1%), (3) intermediate accelerated aging without lack of motivation (27.4%), and (4) low accelerated aging (26.2%). AYAs in the high accelerated aging cluster were more likely to have second cancer (odds ratio: 1.6; 95% CI, 1.1-2.3) compared to the low accelerated aging cluster. CONCLUSION: AYAs with a higher burden of accelerated aging were more likely to develop a second cancer. Validation of the clinical indicators and how to best capture them is needed to improve (early) detection of AYAs at high risk of developing second cancer

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

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.</p

Exploring the interconnectedness between health-related quality of life factors among long-term adolescent and young adult cancer survivors (AYAs): a network analysis

Purpose: Adolescent and young adult cancer survivors (AYAs) are at increased risk of long-term and late effects, and experience unmet needs, impacting their health-related quality of life (HRQoL). In order to provide and optimize supportive care and targeted interventions for this unique population, it is important to study HRQoL factors’ interconnectedness on a population level. Therefore, this network analysis was performed with the aim to explore the interconnectedness between HRQoL factors, in the analysis described as nodes, among long-term AYAs. Methods: This population-based cohort study used cross-sectional survey data of long-term AYAs, who were identified by the Netherlands Cancer Registry (NCR). Participants completed a one-time survey (SURVAYA study), including the EORTC survivorship questionnaire (QLQ-SURV111) to assess their long-term HRQoL outcomes and sociodemographic characteristics. The NCR provided the clinical data. Descriptive statistics and a network analysis, including network clustering, were performed. Results: In total, 3596 AYAs (on average 12.4 years post diagnosis) were included in our network analysis. The network was proven stable and reliable and, in total, four clusters were identified, including a worriment, daily functioning, psychological, and sexual cluster. Negative health outlook, part of the worriment cluster, was the node with the highest strength and its partial correlation with health distress was significantly different from all other partial correlations. Conclusion: This study shows the results of a stable and reliable network analysis based on HRQoL data of long-term AYAs, and identified nodes, correlations, and clusters that could be intervened on to improve the HRQoL outcomes of AYAs