Age-Specific Signatures of Glioblastoma at the Genomic, Genetic, and Epigenetic Levels

Age is a powerful predictor of survival in glioblastoma multiforme (GBM) yet the biological basis for the difference in clinical outcome is mostly unknown. Discovering genes and pathways that would explain age-specific survival difference could generate opportunities for novel therapeutics for GBM. Here we have integrated gene expression, exon expression, microRNA expression, copy number alteration, SNP, whole exome sequence, and DNA methylation data sets of a cohort of GBM patients in The Cancer Genome Atlas (TCGA) project to discover age-specific signatures at the transcriptional, genetic, and epigenetic levels and validated our findings on the REMBRANDT data set. We found major age-specific signatures at all levels including age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes in older GBMs. These age-specific differences in GBM, which are independent of molecular subtypes, may in part explain the preferential effects of anti-angiogenic agents in older GBM and pave the way to a better understanding of the unique biology and clinical behavior of older versus younger GBMs

Виживаність після гіпофракційної променевої терапії пацієнтів похилого віку з гліобластомою

Background. Glioblastoma (GB) is the most common primary brain tumor that is malignant, and its incidence increases with age. The prognosis for elderly patients with GB (GBe) is significantly worse than that of younger patients. Due to the global trend of aging population and age-related features of the GB cohort, the number of GBe patients is expected to increase. Although there is no full consensus regarding the clinical management of GBe, hypofractionated radiation therapy (RT) has become a common therapeutic option for elderly and/or poor prognosis GB patients. Purpose. To analyze the survival of patients with glioblastoma in the age group ≥60 years old after standard and hypofractionated regimens   of   adjuvant radiation therapy. Materials and methods. A retrospective single-center non-randomized study based on a total cohort of 53 patients (≥60 years old) with histogically verified diagnosis of GB was performed at the State Institution «Romodanov Neurosurgery Institute of the National Academy of Medical Sciences of Ukraine» over the period of 6 years, from 2014 to 2020. According to the RT regimen, patients were stratified into 2 groups: standard RT (SRT group) – 16 (30.2%) patients (30 fractions, 2.0 Gy per fraction, total radiation dose – 60.0 Gy) and hypofractionated RT (HRT group) – 37 (69.8%) patients (15 fractions, 3.5 Gy per fraction, total dose – 52.5 Gy). Cancer-specific survival (CSS) and progression-free survival (PFS) were analyzed in the total cohort and both groups separately. Results. With a median follow-up of 21.9 months (95% CI (confidence interval) 20.7 – 32.3), the median CSS in the total cohort was 15.0 (95% CI 13.3 – 17.3) months; the median PFS – 9.0 (95% CI 8.0 – 10.6) months. In the HRT group, the median CSS was 14.7 (95% CI 10.5 – 18.5) months; in the SRT group – 15.0 (95% CI 12.4 – 19.3) months. In the HRT group, the median PFS was 9.0 (95% CI 7.0 – 11.9) months; in the SRT group – 9.0 (95% CI 8.0 – 11.0) months. Before and after the stratification point of 15 months, the HRT and SRT groups did not differ significantly in CSS (Log-rank test p = 0.0588 and p = 0.2009, respectively). There was no significant difference in PFS between the HRT and SRT groups before and after the stratification point of 9 months (Log-rank test p = 0.0653 and p = 0.0722, respectively). Conclusions. Improving survival of GBe pts is an urgent issue, especially taking into account global trends in population aging and age-specific features of GB. The proposed hypofractionated RT regime can be considered as an optional approach in the complex treatment of GBe pts.Актуальність. Гліобластома (ГБ) є найбільш поширенішою злоякісною первинною пухлиною головного мозку, частота якої зростає з віком. Пацієнти похилого віку з ГБ (ГБп) мають значно гірший прогноз порівняно з молодшою віковою групою. Вікова особливість ГБ у вигляді зростання захворюваності серед осіб похилого віку при загально світовій тенденції старіння населення є об’єктивною передумовою збільшення в клінічній практиці частки ГБп пацієнтів. Водночас на сьогодні консенсус щодо оптимальної тактики лікування ГБп пацієнтів залишається предметом дискусії. При цьому гіпофракційна променева терапія (ПТ) набуває поширеності як терапевтична альтернатива для лікування літніх та/або ослаблених пацієнтів з ГБ. Мета роботи. Проаналізувати виживаність пацієнтів з гліобластомою вікової групи 60 і старше років при застосуванні стандартного та гіпофракційного режимів ад’ювантної ПТ. Матеріали та методи. Ретроспективне одноцентрове нерандомізоване дослідження вибірки 53 пацієнтів з патогістологічно верифікованим діагнозом ГБ, вікової групи ≥60 років проведено в Державній установі «Інститут нейрохірургії ім. акад. А.П. Ромоданова НАМН України» (2014–2020 рр.). За режимом опромінення пацієнти розподілені на   2   групи:   стандартна   ПТ   (група   СПТ)   – 16 (30,2%) пацієнтів (30 фракцій, разова вогнищева доза (РВД) 2,0 Гр, сумарна вогнищева доза (СВД) 60,0 Гр) і гіпофракційна ПТ (група ГПТ ) – 37 (69,8%) пацієнтів (15 фракцій, РВД 3,5 Гр, СВД 52,5 Гр). Проаналізовано канцерспецифічну виживаність (КСВ) та виживаність без прогресування (БПВ) в загальній вибірці, окремо в групах СПТ і ГПТ. Результати та їх обговорення. При медіані спостереження 21,9 місяців (95% ДІ (довірчі інтервали) 20,7–32,3) медіана КСВ в загальній вибірці склала 15,0 (95% ДІ 13,3–17,3) місяців; медіана БПВ 9,0 (95% ДІ 8,0–10,6) місяців. У групі ГПТ медіана КСВ склала 14,7 (95% ДІ 10,5–18,5) місяців; в групі СПТ 15,0 (95% ДІ 12,4–19,3) місяців. У групі ГПТ медіана БПВ склала 9,0 (95% ДІ 7,00– 11,9) місяців; у групі СПТ 9,0 (95% ДІ 8,0–11,0) місяців. За КСВ до і після точки стратифікації 15 місяців групи ГПТ та СПТ статистично не розрізняються (Logrank test р = 0,0588 і р = 0,2009 відповідно). Не зареєстровано значущої різниці за БПВ між групами ГПТ та СПТ до і після точки стратифікації 9 місяців (Logrank test р = 0,0653 і р = 0,0722 відповідно). Висновки. Підвищення ефективності лікування пацієнтів з ГБп є нагальною проблемою в нейроонкології, враховуючи загальносвітові тенденції щодо старіння населення та епідеміологічні особливості вікової структури ГБ. Запропонований нами гіпофракційний режим опромінення може розглядатись як прийнятний в комплексному лікуванні пацієнтів з ГБп

Radiotherapy for elderly patients with glioblastoma: An assessment of hypofractionation and modern treatment techniques

Glioblastoma (GBM) is a disease with a poor prognosis. For decades, radiotherapy has played a critical role in the management of GBM. The standard of care radiation prescription is 60 Gy in 30 fractions, but landmark trials have historically excluded patients older than 70 years. Currently, there is considerable variation in the management of elderly patients with GBM. Shortened radiation treatment (hypofractionated) regimens have been explored since conventional treatment schedules are lengthy and many elderly patients have functional, cognitive, and social limitations. Clinical trials have demonstrated the effectiveness of hypofractionated radiotherapy (40 Gy in 15 fractions) to treat elderly or frail patients with GBM. Although previous studies have suggested these unique hypofractionation prescriptions effectively treat these patients, there are many avenues for improvement in this patient population. Herein, we describe the unique tumor biology of glioblastoma, key hypofractionated radiotherapy studies, and health-related quality of life (HRQOL) studies for elderly patients with GBM. Hypofractionated radiation has emerged as a shortened alternative and retrospective studies have suggested survival outcomes are similar for elderly patients with GBM. Prospective studies comparing hypofractionation with conventional treatment regiments are warranted. In addition to evaluating survival outcomes, HRQOL endpoints should be incorporated into future studies

Identifying the miRNA Signature Association with Aging-Related Senescence in Glioblastoma.

Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein-protein, protein-ncRNA, and protein-peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from 574 samples to explore the role of non-coding RNAs in the disease progression and unique signaling communication in GBM. A series of computational methods involving miRNA expression, gene ontology (GO) based gene enrichment, pathway mapping, and annotation from metabolic pathways databases, and network analysis were used for the analysis. Our study revealed the physiological roles of many known and novel miRNAs in cancer signaling, especially concerning signaling in cancer progression and proliferation. Overall, the results revealed a strong connection with stress induced senescence, significant miRNA targets for cell cycle arrest, and many common signaling pathways to GBM in the network

MicroRNA-based linkage between aging and cancer: From epigenetics view point

Ageing is a complex process and a broad spectrum of physical, psychological, and social changes over time. Accompanying diseases and disabilities, which can interfere with cancer treatment and recovery, occur in old ages. MicroRNAs (miRNAs) are a set of small non-coding RNAs, which have considerable roles in post-transcriptional regulation at gene expression level. In this review, we attempted to summarize the current knowledge of miRNAs functions in ageing, with mainly focuses on malignancies and all underlying genetic, molecular and epigenetics mechanisms. The evidences indicated the complex and dynamic nature of miRNA-based linkage of ageing and cancer at genomics and epigenomics levels which might be generally crucial for understanding the mechanisms of age-related cancer and ageing. Recently in the field of cancer and ageing, scientists claimed that uric acid can be used to regulate reactive oxygen species (ROS), leading to cancer and ageing prevention; these findings highlight the role of miRNA-based inhibition of the SLC2A9 antioxidant pathway in cancer, as a novel way to kill malignant cells, while a patient is fighting with cancer

Glioblastoma in Elderly Population

Glioblastoma (GBM) is the third most common primary intracranial tumor and the commonest primary malignant brain tumor in adults. The peak incidence is between 65 and 84 years old. The incidence of GBM increases starkly with age—from 1.3/100,000 between the ages of 35–44 to 15.3/100,000 between the ages of 75–84 years. Elderly patients with GBM have increased comorbidities, lower functional status, aggressive tumor biology, and an overall worse outcome as compared with their younger counterparts. Age is an independent and powerful prognosticator of GBM outcomes, even if the performance status is controlled. Elderly patients with GBM represent a vulnerable heterogeneous cohort. Surgical resection in elderly patients offers a better outcome and improved quality of life as compared with biopsy alone and nowadays can be safely tolerated by elderly patients in specialized centers. The standard of care treatment of glioblastoma based on the Stupp’s protocol excluded patients over the age of 70. Thus, the standard of care treatment in elderly patients with GBM remains controversial. Selected elderly patients with excellent performance status may be treated with Stupp’s protocol. Elderly patients with lower functional status may be treated with a hypofractionated treatment regimen with concomitant and adjuvant temozolomide. Frail patients with MGMT methylated tumor can be treated with temozolomide monotherapy alone. It is also not unreasonable to treat elderly frail patients with MGMT unmethylated GBM with hypofractionated RT alone. Thus, treatment of elderly patients with GBM needs a multidisciplinary approach based on the extent of the tumor, MGMT methylation status, performance status, and even the social situation unique to the elderly patient. This chapter seeks to bring a comprehensive and updated review on the treatment of glioblastoma in the elderly population

Neurosurgery in the elderly patient

Objective. For government officials and health providers, elderly population - aged 65 and over, especially neurosurgical patient, represent a larger concern, an increasing problem not only for socio-economic reasons related to the medical act, but also for additional care requirements which should be done by the family and society, including rehabilitation facilities, occupational & physical therapy, speech therapists, visiting nurses, to insure an effective recuperation after hospital discharge. A retrospective study with 325 "elderly" patients cohort, aged 65 and over, admitted in the Neurosurgery Department undergoing common neurosurgical procedures, in the last five years offer an evaluation for neurosurgical procedures, outcomes, comorbidities, anaesthetic and analgesic requirements, outcome. Material and method. This study was performed on patients aged 65 years or older, with neurosurgical diseases, admitted to the Neurosurgery or the Intensive Care Unit of our hospital, between 2014-2019. An analysis was made on variables such as age, pathology, comorbidities, length of hospital stay especially in the ICU unit, type of cranio-cerebral or spinal procedures performed, anaesthesia protocols, complications, performance status, re-admissions and mortality. Results. Patients age were divided into three categories: between 65-70 years old there were 152 patients (46,76%), between 70-85 years old 93 patients (28.61%) and over 85 years old 80 patients (24,61%). 173 patients were females (53,23%), 152 were males (46.76 %). The admission Glasgow Coma Scale (GCS) score to those over 85 years old was between 3-12 in 29 cases (8.02%) with early death in 13 patients. Several comorbidities were noticed in 294 patients (90.15%): cardiac, pulmonary, hematologic especially coumarinic overdose, hepatic and renal failures, psychiatric illnesses, concomitant systemic disease or immunosuppressed patients by decompensated diabetes, primitive cancers affecting various organs, infectious diseases, also severe osteoporosis, chronic ethylic intoxication, limiting surgical attitude, also obtaining the informed consent for surgery. There were 154 (47,38%) patients with cerebral pathology and 171 (52,61%) patients with spinal pathology. Most common surgical procedures performed were: craniotomies for tumours and hematoma removal, minimal invasive procedures for spine, endovascular and vertebroplasty. The median length of stay for emergency patients was significantly longer than that of elective patients (13 vs. 8 days). For 215 (66.15%) patients general anaesthesia was performed, local anaesthesia in 97 (29.84%) patients, 13 patients (4%) were not operated. Good quality of life results appreciated by patients and relatives were recorded in 236 cases (72.61%) in the first and second category; less better results to those over 85 years old; same symptoms especially pain 63 patients (19.38%), complications to 47 patients (14,46%) especially cardiac, renal and respiratory failures, also motor deficits, seizures, CSF fistula, mortality in 26 cases (8%), re-admissions in 45 cases (13.84%) less than 1 month after discharge. Conclusions. Old prejudices that old age is a contraindication for surgery have to be removed. Clinical and surgical decisions for neurosurgical procedures in the elderly are decisive for limiting reported morbidity and mortality rates. For life quality, realistic family and society expectations, several aspects should be considered for safe and effective results: careful patient selection on patient status, comorbidities and physiological reserve; neurosurgical pathology, urgency of the surgical procedure, the strategy of neurosurgical management based on advances in imaging and interventional radiology, minimal invasive neurosurgical procedures with significant preoperative and postoperative care. Good results could be obtained even in elderly people for chronic subdural hematoma, simple brain or spinal tumour, good grade aneurysm, trigeminal pain, vertebroplasty in spinal vertebral fractures, etc