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Divyalakshmi Ramakrishna, MDS

Content writer – Clinical

A molecularly integrated grade for meningioma.

Published on: May 31, 2023

Original author: Joseph Driver, et al., 2022 (doi: 10.1093/neuonc/noab213)

Meningiomas are one of the most common primary intracranial tumors in adults. Ass there is presence of more number of cases worldwide, there is a need for a reliable, widely accessible and acceptable predictor of clinical outcome after a diagnosis. At present, the World Health Organization (WHO) places meningioma into 3 grades based on the histopathological features, and is the primary measure used to predict outcome and guide postsurgical treatment decision making. It is well recognized, however, that the behavior of a number of meningiomas does not conform to their assigned WHO grade, with some histologically benign meningiomas developing repeated recurrences despite aggressive treatment while other higher-grade meningiomas remain stable after surgical resection. The limitations of WHO grading is dependent on the interobserver variability in histological assessment, the potential for under-sampling of a tumor type with known histologic and molecular heterogeneity, and the possibility that malignant potential may not be uniformly reflected in assessment of the histological features. Hence, molecular based approaches were incorporated to develop a grading system for meningiomas. This grading system incorporates mitotic index and multiple high-risk copy-number alterations for identification of patients at risk for tumor recurrence, despite complete tumor resection, and in some cases, despite benign-appearing histopathology (WHO grade I). A critical aspect of this approach is that the features are transparent, and can be assessed by a number of genomic platforms that have proliferated across medical centers. Methodology A total number of 699 meningiomas with detailed clinical, imaging, histological, and molecular annotation, were evaluated inorder to formulate a molecularly integrated grade that is simple to apply, transparent, scalable, and accurate in long-term prediction of clinical behavior. Out of which, 527 meningiomas resected from unique patients evaluated at the Brigham and Women’s Hospital (BWH) from 2003 to 2019 as the discovery cohort. An additional 172 patients with surgically resected meningioma, including 117 from BWH and 55 from the University of Toronto, were examined as independent validation cohorts. The clinical history, tumor location, and radiographic recurrence were assessed. Preoperative and postoperative MRIs underwent volumetric contouring to define the extent of resection, with gross total resection (GTR) defined by no residual enhancing nodular tumor on imaging, and all others classified as subtotal resection. All follow-up MRIs were independently reviewed by 3 authors (W.L.B., J.D., and S.T.) to evaluate for recurrence. The histopathological review of all the tumors was performed by board-certified neuropathologists and tumor grade was abstracted from the pathology reports issued by the BWH Neuropathology division according to the WHO Classification of Tumors (2007 and 2016). The whole-genome microarray analysis for DNA copy-number profiling was available for 527 tumors from the discovery cohort and 83 samples from the BWH validation cohort. Targeted mutational profiling of 227-447 cancer-associated genes (OncoPanel, versions 1-3) was available for 118 samples from the discovery cohort and all 117 of the BWH validation set. Using all of the discovery cohort, which included tumors with varied treatment histories, the Integrated Grade was included along with extent of resection, tumor size, and tumor status (primary vs recurrent) into a Cox proportional hazards model to generate a nomogram for recurrence risk. A decision curve analysis was performed to evaluate the clinical utility of the nomogram. Results The results were subdivided into: 1) Development of a molecularly based Integrated grade An Integrated grade was devised, which accounts for mitotic count, focal hemizygous or homozygous loss of CDKN2A, and loss of 1p, 3p, 4p/q, 6p/q, 10p/q, 14q, 18p/q, and 19p/q. Several high-risk chromosomes, including 4, 6, 10, 18, and 19, exhibited synchronous loss of the short and long arms when altered, mitotic count exhibited less variance and all these features were assigned 1 point for the presence of any of the above chromosomal losses. Also, for CDKN2A loss and a mitotic count of 4-19; 2 points were assigned for mitotic count >20. Tumors were divided into three Integrated Grades based on their point score: Integrated Grade 1 (0-1 pt), Integrated Grade 2 (2-3 pts), and Integrated Grade 3 (>4 pts). 2) Association between WHO grade and Integrated grade The association of WHO grade and Integrated Grade for 527 meningiomas, showed 87% concordance between WHO grade I and Integrated Grade 1, 31% concordance between WHO grade II and Integrated Grade 2, and 72% concordance between WHO grade III and Integrated Grade 3. 3) Integrated Grade and Clinical Outcome The authors reported that in the subset of 338 primary non-irradiated meningiomas with gross total resection (GTR), tumors demonstrated distinct progression-free survival as stratified by either WHO grade or Integrated grade. The Integrated Grade was compared to WHO grade for predicting tumor recurrence using time-dependent receiver operator curves (ROC), time-dependent average precision (AP) curves, and Brier curves. Also, they found that the Integrated grading scheme significantly improved the ability to predict recurrence risk compared to the WHO grade, as evaluated by time-dependent (ROC) area under the curve and Brier score even when restricted to the prospectively collected cases. Notably, the predictive capacity of the Integrated grade compared to WHO grade strengthened with follow-up time. In each of these cohorts, the study reported that the Integrated grade was superior to WHO grade in predicting recurrence. In addition, the Integrated Grade was superior to WHO grade in assessing overall survival on long-term follow-up. Conclusion The present study shows that mitotic index and copy-number profile can appraise tumor behavior with satisfactory results. Taken together, the modular nature of the proposed risk stratified Integrated grading scheme lends itself to future refinement with incorporation of additional axes of genomic data as scientific discovery advances and has immediate relevance to management of meningioma patients. Also, the authors propose that the Integrated grading system can enhance the clinical care of meningioma patients and aid in the design of future prospective clinical trials. Impact of research 1. Improve clinical outcome and better patient management. 2. Help to identify recurrence of tumors and progression free survival rate. 3. Provide more effective grading of meningiomas, and genomically informed clinical trials.

Prognostic factors associated with survival in patients with diffuse astrocytoma.

Published on: February 08, 2023

Original author: Liu S, Liu X, and Zhuang W (2021) (DOI: 10.3389/fsurg.2021.712350)

Astrocytomas are the most common primary tumors in the central nervous system (CNS). These tumors arise from astrocytes—star-shaped cells that make up the “glue-like” or supportive tissue of the brain. The diagnosis is based primarily on histopathological criteria defined by the World Health Organisation (WHO) that grades astrocytomas as pilocytic astrocytoma (grade I), diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV).​ Diffuse astrocytomas (DA) are grade II astrocytomas also known as low-grade astrocytomas. DA consists of fibrillary astrocytoma, protoplasmic astrocytoma, and gemistocytic astrocytoma. Diffuse astrocytoma is a slow-growing brain tumor. They are infiltrating tumors with ill-defined borders. Although diffuse astrocytoma is a relatively slow-growing tumor with a median survival time of 5-8 years, they have a high recurrence rate due to diffuse infiltration of brain tissue and an inherent malignant potential to transform into high-grade astrocytomas. Clinical symptoms of DA vary depending on the location of the tumor. Seizures, headaches, and focal neurologic deficits are the most frequent presenting symptoms. The histopathological diagnosis of a diffuse astrocytoma can be challenging due to its pronounced heterogeneity. Hence, the tumor characteristics and the factors associated with the prognosis are inadequately understood. However, studies about the clinicopathological characteristics of DA are scarce in the literature at present. Factors influencing the prognosis of DA are also unclear. Thus, identifying the factors associated with prognosis and survival rate in DA patients is necessary. Methodology Given this, a population-based cohort study was conducted, utilizing prospectively extracted data from the Surveillance, Epidemiology, and End Results (SEER) database. The patients were collected from the SEER database, documented from 1973-2017. In this retrospective study, the patients diagnosed with primary tumor as DA, according to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), were identified. The demographic features as well as the clinicopathological characteristics of the patients were also collected. The age of the patient at diagnosis, race, sex, marital status, primary tumor site, histological type, tumor size, surgical treatment, survival duration in months, and survival status were collected in this study. Patients with unclear information on any of the collected variables were excluded.​ Kaplan–Meier analysis was used to assess the cancer-specific survival (CSS) stratified by each factor. The clinicopathological factors and CSS were analyzed using Cox proportional hazards model. Statistically significant variables in univariate Cox analysis were further included in multivariate Cox analysis. For each patient, significant prognostic factors were further utilized to prepare a nomogram and then put into the nomogram calculator to get a predicted survival rate at 5- and 10 years. The C-index and receiver operating characteristic (ROC) curve were utilized to evaluate the accuracy of the nomogram. R software (version 3.5.0) was utilized to perform the statistical analysis. Results A total of 799 participants with DA were included, consisting of 95.9% fibrillary astrocytoma and 4.1% protoplasmic variants. The average age of participants was 41.9 years, with 57.2% being male. The majority of the population was white (87.5%). More than half (53.9%) of the patients were married. DA arose mostly in the cerebrum (63.8%). Around 71.6% of the population had received surgical treatment. The overall 1-, 3-, 5-, and 10-year survival rates were 73.7, 55.2, 49.4, and 37.6%, respectively. Kaplan–Meier analysis showed that age at diagnosis, marital status, primary tumor site, tumor size, and surgery was possibly associated with cancer-specific survival (CSS) (p

Reassessing Diabetes and APOE Genotype as Potential Interacting Risk Factors for Alzheimer’s disease.

Published on: November 2, 2022

Original author: Ravipati K, Chen Y, Manns JR. et al. (2022) (DOI: 10.1177/15333175211070912)

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which the death of brain cells causes memory loss and cognitive decline. Alzheimer's disease is the most common cause of dementia — a continuous decline in thinking, behavioral and social skills that affect a person's ability to function independently. Out of the approximately 50 million people worldwide with dementia, between 60% and 70% are estimated to have Alzheimer's disease. Approximately 5.8 million people in the United States aged 65 years and older live with Alzheimer's disease. The early signs of the disease include forgetting recent events or conversations. As the disease progresses, a person with Alzheimer's disease will develop severe memory impairment and lose the ability to carry out everyday tasks along with difficulty concentrating and thinking, especially about abstract concepts such as numbers. Hence, there is a need for a better early diagnosis of AD.​ There are various/multiple risk factors associated with AD. Accurate assessment of risk factors is the key focus for early diagnosis of AD. Researchers believe that genetics play a major role in the development of Alzheimer's disease. One of the best-characterized genetic risk factors for AD is the Apolipoprotein E (APOE) ε4 allele, one of three polymorphisms of the apolipoprotein E gene. Diabetes has also been proposed to be another risk factor for AD, and several recent studies have attempted to characterize the physiological relationship between diabetes and AD. However, an important unanswered question is an extent to which diabetes alone or in combination with APOE ε4 carriage predicts AD diagnosis. Methodology The present study assessed the interaction between APOE ε4 and diabetes in the context of AD diagnosis by analyzing a large and diverse participant population. A retrospective cohort study was conducted on participants from the NIA-funded National Alzheimer’s Coordinating Center (NACC) database, which included data (n = 33456) collected (longitudinally for many participants) from 2005 to 2016 at 29 Alzheimer’s disease Centers (ADCs). A standardized clinical evaluation that included neuropsychological tests was used to diagnose participants into three categories: AD, cognitive impairment without AD, and cognitively unimpaired. Data were also collected regarding health, cognition, and demographics. Diagnosis of diabetes was based on patient self-reporting. No other confirmatory testing, including biomarkers or medication history, was available regarding diabetic status. APOE genotype was available for 24336 participants and was presented as 0, 1, or 2 APOE ε4 alleles in the NACC database. Of the 4204 who self-reported diabetes, 2803 (66.6%) had APOE genotype information. Results All the data collected were tabulated and multiple statistical analysis models were used to assess the relationship between APOE genotype, diabetes, and AD diagnosis. All statistical analyses were performed using R software, version 3.4.1. Multinomial Logistic Regression Models were used to assess the participant’s first and last Alzheimer’s disease center (ADC) visit, as well as the association between the APOE 4 genotype and AD along with the association of diabetes and AD. A mixed effects model, was used to assess the risk of being diagnosed with AD at any visit. Structural Equation Modelling (SEM) was used to model how various factors mediated the influence of APOE genotype and diabetes on conversion to AD diagnosis in individuals not diagnosed with AD on their first visit.​ In the present study, APOE 4 genotype showed a strong association with AD diagnosis and was significant whereas the association between diabetes and AD diagnosis was weak and non-significant. Conclusion In conclusion, the present study reported that the APOE ε4 genotype was strongly associated with AD risk and the finding that the APOE ε4 genotype correlates with impairment of long-term memory (LTM) loss provides clinicians with additional insight to make the most accurate diagnosis possible. Also, it was suggested that diabetes was not a potential risk factor for AD, and associating diabetes with working memory (WM) rather than LTM impairments will aid to distinguish AD from other types of dementia. Impact of the research 1. The identification of risk factors associated with AD may help in better and early diagnosis. 2. It helps to differentiate different types of dementia to a certain extent. 3. It also paves the way to unveil the pathophysiological link between APOE 4 genotype, diabetes, and AD pathology.

Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma.

Published on: July 29, 2022

Original author: Giulia Agliardi et al. (2021) (DOI: 10.1038/s41467-020-20599-x)

Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer in adults. It accounts for about 60-70% of gliomas. The standard treatment regimen for GBM is tumor resection followed by radiotherapy and concomitant chemotherapy with temozolomide. However, GBM has high recurrence attributed to the infiltrative nature of the tumor, and also a dismal prognosis with a poor median survival of around 14 months, hence there is a need for more effective therapies. In this arena, immunotherapy treatment directed towards T-cells with tumor specificity may be a promising therapeutic strategy. Research overview The treatment with chimeric antigenic receptor (CAR) T-cells is preferable to treat intracranial tumors due to the ability of T- cells to access the central nervous system (CNS), and penetrate the infiltrative sites of the tumor, and show antitumor activity. But the CAR-T cells efficacy may be impaired by various adaptive immune-suppressive responses. CAR – T cell therapy alone was not sufficient to eradicate GBM. However, an additional or a combinational therapeutic option was added to overcome tumor heterogeneity and the altered tumor microenvironment (TME). In this scenario, Interleukin 12 (IL – 12), a proinflammatory cytokine with potent tumor suppressor activity has been implemented as a combination agent with CAR T- cells in the present study. IL – 12 directly supports the cytotoxic activity of T- cells as well as plays a role in reshaping the TME to achieve antitumor immunity. Methodology In the present study, in the first phase, an immunocompetent orthotopic syngeneic mouse model of GBM was used to evaluate the anti-tumor activity of EGFRvIII-specific murine CAR-T cells as a single agent which was administered by intravenous injection. Also, the efficacy of EGFRvIII-directed CAR-T cells in vivo in mice was tested. The first phase consisted of an evaluation of recombinant single-chain IL-12 fused to the Fc portion of murine IgG3 (hereafter called IL-12:Fc) as a single agent in an orthotopic syngeneic mouse model with GBM. In the second phase, a combinatorial immunotherapy approach was designed where the local intratumoral delivery of a single dose of IL-12:Fc was administered along with systemic (intravenous) CAR – T cell therapy. Tumor growth was monitored using a magnetic resonance imaging (1T-MRI) system by measuring the tumor volumes.​ The results of the present study demonstrated that both the single therapies were only able to delay tumor growth to a certain extent, whereas the combination of systemic EGFRvIII-specific CAR infusion and local IL-12:Fc administration eliminated tumors in most treated mice and showed a synergistic effect on the overall survival. Moreover, combination treatment with IL-12:Fc and CAR-T cell therapy showed significantly improved survival as compared to either treatment alone. Also, local delivery of a single dose of IL-12 improves the efficacy of CAR-T cells. Therefore, the authors have reported that the data has demonstrated that combined IL-12 and CAR-T cell therapy promotes an effective and persistent anti-tumor response, even in the context of a poorly immunogenic model. Impact of the research The benefit of combined therapy of CAR - T cells and local IL – 12, is multifaceted as the administration of IL -12 at the tumor site improves the efficacy of CAR T – cells in aggressive and poorly immunogenic tumors and thus also affect the transferred CAR –T cells, T – cell compartment and the myeloid cells in TME in preclinical models which helps in reshaping the TME and achieving antitumor immunity. Hence, the present study showed that the local administration of IL – 12, overcomes the barriers which are encountered by the CAR-T cell therapy in GBM. Thus, the authors have suggested trials for clinical studies of the combinational approach of systemic CAR –T cell therapy along with intratumoral administration of IL-12 in patients with GBM.

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