Comparison of glioma stem cells to neural stem cells from the adult human brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome

AbstractGlioblastoma is the most common brain tumor. Median survival in unselected patients is <10 months. The tumor harbors stem-like cells that self-renew and propagate upon serial transplantation in mice, although the clinical relevance of these cells has not been well documented. We have performed the first genome-wide analysis that directly relates the gene expression profile of nine enriched populations of glioblastoma stem cells (GSCs) to five identically isolated and cultivated populations of stem cells from the normal adult human brain. Although the two cell types share common stem- and lineage-related markers, GSCs show a more heterogeneous gene expression. We identified a number of pathways that are dysregulated in GSCs. A subset of these pathways has previously been identified in leukemic stem cells, suggesting that cancer stem cells of different origin may have common features. Genes upregulated in GSCs were also highly expressed in embryonic and induced pluripotent stem cells. We found that canonical Wnt-signaling plays an important role in GSCs, but not in adult human neural stem cells. As well we identified a 30-gene signature highly overexpressed in GSCs. The expression of these signature genes correlates with clinical outcome and demonstrates the clinical relevance of GSCs

Surgery for brain metastases – real-world prognostic factors’ association with survival

Background Surgical resection of brain metastases (BM) improves overall survival (OS) in selected patients. Selecting those patients likely to benefit from surgery is challenging. The Graded Prognostic Assessment (GPA) and the diagnosis-specific Graded Prognostic Assessment (ds-GPA) were developed to predict survival in patients with BM, but not specifically to guide patient selection for surgery. Our aim was to evaluate the feasibility of preoperative GPA/ds-GPA scores and assess variables associated with OS. Methods We retrospectively reviewed first-time surgical resection of BM from solid tumors at a Norwegian regional referral center from 2011 to 2018. Results Of 590 patients, 51% were female and median age was 63 years. Median OS was 10.3 months and 74 patients (13%) died within three months after surgery. Preoperatively tumor origin was unknown in 20% of patients. A GPA score could be calculated for 92% of the patients preoperatively, but could not correctly predict survival. A ds-GPA score could be calculated for 46% of patients. Multivariable regression analysis revealed shorter OS in patients with higher age, worse functioning status, colorectal primary cancer compared to lung cancer, presence of extracranial metastases, and more than four BM. Patients with preoperative progressive extracranial disease or synchronous BM had shorter OS compared to patients with stable extracranial disease. Conclusion Ds-GPA could be calculated in less than half of patients preoperatively and GPA poorly identified patients which had minimal benefit of surgery. Including status of extracranial disease improve prognostication and therefore selection to surgery for brain metastases

Surgery for brain metastases – real-world prognostic factors’ association with survival

Background Surgical resection of brain metastases (BM) improves overall survival (OS) in selected patients. Selecting those patients likely to benefit from surgery is challenging. The Graded Prognostic Assessment (GPA) and the diagnosis-specific Graded Prognostic Assessment (ds-GPA) were developed to predict survival in patients with BM, but not specifically to guide patient selection for surgery. Our aim was to evaluate the feasibility of preoperative GPA/ds-GPA scores and assess variables associated with OS. Methods We retrospectively reviewed first-time surgical resection of BM from solid tumors at a Norwegian regional referral center from 2011 to 2018. Results Of 590 patients, 51% were female and median age was 63 years. Median OS was 10.3 months and 74 patients (13%) died within three months after surgery. Preoperatively tumor origin was unknown in 20% of patients. A GPA score could be calculated for 92% of the patients preoperatively, but could not correctly predict survival. A ds-GPA score could be calculated for 46% of patients. Multivariable regression analysis revealed shorter OS in patients with higher age, worse functioning status, colorectal primary cancer compared to lung cancer, presence of extracranial metastases, and more than four BM. Patients with preoperative progressive extracranial disease or synchronous BM had shorter OS compared to patients with stable extracranial disease. Conclusion Ds-GPA could be calculated in less than half of patients preoperatively and GPA poorly identified patients which had minimal benefit of surgery. Including status of extracranial disease improve prognostication and therefore selection to surgery for brain metastases

MR elastography identifies regions of extracellular matrix reorganization associated with shorter survival in glioblastoma patients

Abstract Background Biomechanical tissue properties of glioblastoma tumors are heterogeneous, but the molecular mechanisms involved and the biological implications are poorly understood. Here, we combine magnetic resonance elastography (MRE) measurement of tissue stiffness with RNA sequencing of tissue biopsies to explore the molecular characteristics of the stiffness signal. Methods MRE was performed preoperatively in 13 patients with glioblastoma. Navigated biopsies were harvested during surgery and classified as “stiff” or “soft” according to MRE stiffness measurements (|G*|norm). Twenty-two biopsies from eight patients were analyzed by RNA sequencing. Results The mean whole-tumor stiffness was lower than normal-appearing white matter. The surgeon’s stiffness evaluation did not correlate with the MRE measurements, which suggests that these measures assess different physiological properties. Pathway analysis of the differentially expressed genes between “stiff” and “soft” biopsies showed that genes involved in extracellular matrix reorganization and cellular adhesion were overexpressed in “stiff” biopsies. Supervised dimensionality reduction identified a gene expression signal separating “stiff” and “soft” biopsies. Using the NIH Genomic Data Portal, 265 glioblastoma patients were divided into those with (n = 63) and without (n = 202) this gene expression signal. The median survival time of patients with tumors expressing the gene signal associated with “stiff” biopsies was 100 days shorter than that of patients not expressing it (360 versus 460 days, hazard ratio: 1.45, P &lt; .05). Conclusion MRE imaging of glioblastoma can provide noninvasive information on intratumoral heterogeneity. Regions of increased stiffness were associated with extracellular matrix reorganization. An expression signal associated with “stiff” biopsies correlated with shorter survival of glioblastoma patients

Glioblastom hos voksne

Glioblastom er den vanligste formen for primær hjernekreft hos voksne, og sykdommen har en alvorlig prognose. Selv om det er gjort store fremskritt i molekylær karakteristikk, har det ikke vært større gjennombrudd i behandlingen på mange år. Vi presenterer her en klinisk oversikt over dagens diagnostikk og behandling samt hvilke utfordringer og muligheter som ligger i å utvikle bedre og mer persontilpasset behandling. Hvert år rammes over 200 mennesker i Norge av glioblastom (1). Median overlevelse for alle pasienter i Norge er kun 11 måneder (2). Med full onkologisk behandling er median overlevelse 15 måneder, og femårsoverlevelse er 6,8 % (3, 4). Glioblastomer antas å oppstå fra nevrogliale stamceller eller progenitorceller, og er preget av betydelig molekylær heterogenitet. De aller fleste glioblastomer er sporadisk forekommende og ses hyppigere ved økende alder og hos menn (4). Kun en liten andel kan tilskrives tidligere eksponering for ioniserende stråling eller arvelige faktorer (4).. Formålet med denne artikkelen er å gi norske klinikere en oppdatert oversikt over diagnostikk og behandling samt å belyse faktorer som har vesentlig betydning for behandling. Artikkelen er basert på gjennomgang av relevant norsk og internasjonal litteratur samt forfatternes egne erfaringer med pasientgruppen. Flere av forfatterne er medlemmer av Norsk hjernesvulstkonsortium (NBTC, Norwegian Brain Tumor Consortium)

Stable glioma incidence and increased patient survival over the past two decades in Norway: a nationwide registry-based cohort study

Background: Surveillance of incidence and survival of central nervous system tumors is essential to monitor disease burden and epidemiological changes, and to allocate health care resources. Here, we describe glioma incidence and survival trends by histopathology group, age, and sex in the Norwegian population. Material and methods: We included patients with a histologically verified glioma reported to the Cancer Registry of Norway from 2002 to 2021 (N = 7,048). Population size and expected mortality were obtained from Statistics Norway. Cases were followed from diagnosis until death, emigration, or 31 December 2022, whichever came first. We calculated age-standardized incidence rates (ASIR) per 100,000 person-years and age-standardized relative survival (RS). Results: The ASIR for histologically verified gliomas was 7.4 (95% CI: 7.3–7.6) and was higher for males (8.8; 95% CI: 8.5–9.1) than females (6.1; 95% CI: 5.9–6.4). Overall incidence was stable over time. Glioblastoma was the most frequent tumor entity (ASIR = 4.2; 95% CI: 4.1–4.4). Overall, glioma patients had a 1-year RS of 63.6% (95% CI: 62.5–64.8%), and a 5-year RS of 32.8% (95% CI: 31.6–33.9%). Females had slightly better survival than males. For most entities, 1- and 5-year RS improved over time (5-year RS for all gliomas 29.0% (2006) and 33.1% (2021), p Interpretation: The incidence of gliomas has been stable while patient survival has increased over the past 20 years in Norway. As gliomas represent a heterogeneous group of primary CNS tumors, regular reporting from cancer registries at the histopathology group level is important to monitor disease burden and allocate health care resources in a population