Biomedical subjects

Gelareh Zadeh

Publications and source records attributed to Gelareh Zadeh.

17 recordsLinked to original sources

PubMed2026

DNA copy number patterns reveal prognostic markers and elucidate mechanisms of evolution in IDH-mutant astrocytoma.

BACKGROUND: Current literature suggestsisocitrate dehydrogenase (IDH)-mutant astrocytoma contains several molecular subgroups. In this study, we are interested in determining the connection between different molecular subgroups with grade and/or survival. METHODS: A cohort of 470 Mayo Clinic adult patients (≥18 years, 56.2% male) with primary IDH-mutant astrocytoma diagnosed by World Health Organization (WHO) 2021 criteria were examined. Results were validated in an independent cohort of 614 Mayo Clinic Neuropathology consult patients and 235 The Cancer Genome Atlas (TCGA) patients. RESULTS: The Mayo Clinic Practice cohort confirmed the association of CDKN2A/B deletion with overall survival (OS, homozygous vs hemizygous vs intact, 2.7 vs 9.6 vs 17.2 years, P < .001). Phosphatase and tensin homolog (PTEN) deletion was also associated with poor OS (7.3 vs 17.4 years, P < .001). Increased number of copy number alterations was associated with OS (continuous variable, HR = 1.027, P < .001). Carrying one or more copies of the germline risk allele at rs55705857 was associated with earlier age of onset (median age 33 vs 35 years, P = .01), and a shorter OS after adjusting for age, grade, sex and treatment (HR = 1.81, P = .007). The Mayo Clinic Neuropathology Consult cohort and TCGA were utilized to validate age of onset and survival, respectively. Unsupervised clustering of the copy number alterations identified several clinically significant groups that may define pathways to disease progression. Losses of chromosomes 11p, 13q, 1p, and 10q were all associated with reduced overall survival in the Mayo Clinic cohort. CONCLUSIONS: Patients with hemizygous loss of CDKN2A/B, loss of PTEN, increased number of copy number alterations, specific chromosomal arm losses or rs55705857 germline risk allele have reduced overall survival.

Humans↗

PubMed2025

Cross-Platform Methylation-Based Site of Origin Classification for Squamous Cell Carcinomas.

Squamous cell carcinomas (SCCs) are one of the most common cancer types and can arise at nearly any anatomic site. Because SCCs are one of the most common metastases, do not have reliable site-specific morphologic or genomic features, and have considerable morphologic and immunohistochemical overlap with urothelial carcinomas, distinguishing between primary and metastatic squamous-appearing tumors can be challenging. This distinction can be critical to clinical management. We present Squamous cell carcinoma Methylation for Origin Site (SquaMOS), a methylation-based classifier to predict site of origin of squamous-appearing carcinomas. Trained on publicly available array-based methylation data from 1062 primary SCCs (from lung, head and neck, cervix, and esophagus) and urothelial carcinomas, SquaMOS predicted site of origin in primary tumors with 96.1% accuracy in an internal test set (n = 458) and 97.4% accuracy in an external test set from 3 institutions (n = 78). On metastatic tumors (n = 51), SquaMOS predictions were 96.1% accurate. SquaMOS was directly applicable to shallow Nanopore sequencing data (CpG probe site coverage, 0.25-2.88×) with an accuracy of 91.7% (n = 36; 100% accurate for high-confidence predictions). When tested on SCCs outside the training set types (n = 15, including 3 metastases to lung), no cases were misclassified as of lung origin, supporting accuracy of lung vs nonlung origin classification for diverse SCC types. Overall, we demonstrate highly accurate performance of the SquaMOS classifier on primary and metastatic tumors from multiple data sources, robust to suboptimal tumor purity. We illustrate transferability of our array-based classifier to low-depth Nanopore sequencing data, a potentially rapid means of site of origin determination in a clinical setting.

Humans↗

PubMed2025

The effect of TERT promoter mutation on predicting meningioma outcomes: a multi-institutional cohort analysis.

BACKGROUND: Molecular aberrations have been incorporated into tumour classification guidelines of meningioma. TERT-promoter (TERTp) mutation is associated with worse prognosis and is designated a WHO grade 3 biomarker. However, it remains unclear whether TERTp mutation is context-dependent, with other co-occurring genetic alterations potentially driving its association with prognosis. We sought to characterise the role of TERTp mutation in meningioma and guide TERTp sequencing. METHODS: We identified 1492 patients of all ages who had previously received surgery for meningioma across 14 medical centres in the USA, Canada, and Germany. Patients were eligible if they had post-surgical clinical or radiographical assessment of the resection site, and TERTp status evaluated by Nov 1, 2024. Multi-modal profiling was used to assess TERTp mutation, focal gene alterations-including CDKN2A/B loss-and copy number alterations. An adjusted WHO grade was calculated for TERTp-mutant meningiomas, incorporating all WHO criteria except TERTp status. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to quantify the effect of TERTp mutation on the endpoints of overall survival and recurrence-free survival across adjusted WHO grade and co-occurring molecular alterations. FINDINGS: 64 (4·3%) of 1492 meningiomas were TERTp-mutant and 1428 (95·7%) were TERTp-wildtype. Of the TERTp-mutant meningiomas, 33 (51·6%) were from female patients and 31 (48·4%) were from male patients, and the overall median age was 67 years (IQR 60-75). Of the wildtype meningiomas, 965 (67·6%) were from female patients and 463 (32·4%) were from male patients, and the overall median age of the patients was 59 years (IQR 48-70). Data on race was inconsistently reported and thus excluded. The TERTp-mutant patients had a 5-year overall survival (49·4% [95% CI 33·7-72·4]) and 5-year recurrence-free survival (27·6% [95% CI 16·8-45·5]) resembling that of patients with WHO grade 3 TERTp-wildtype tumours (5-year overall survival 32·3% [95% CI 17·2-60·5], p=0·28, 5-year recurrence-free survival 14·3% [5·8-35·2], p=0·28). However, the TERTp-mutant group had heterogenous histological grading and was enriched for aggressive molecular features, with 1p loss present in 44 (77·2%) of 57 profiled tumours and CDKN2A/B loss in 24 (41·4%) of the 58 profiled tumours. Adjusting tumour grade revealed a subset of TERTp-mutant meningiomas that were more molecularly and clinically benign. Among TERTp-mutant tumours, CDKN2A/B loss played a defining role in stratifying tumour behaviour. Multivariable analysis confirmed this, with CDKN2A/B loss being significantly associated with shorter overall survival (HR 3·04 [95% CI 1·67-5·52], p=0·00026) and faster time to recurrence (HR 5·22 [95% CI 3·10-8·79], p<0·0001), while TERTp-mutation did not independently affect overall survival (HR 1·00 [95% CI 0·53-1·87], p=0·99) or recurrence-free survival (1·17 [95% CI 0·75-1·83], p=0·49). Sequencing for TERTp-mutation demonstrated clinical impact only among histologically WHO grade 2 meningiomas. INTERPRETATION: The indolent behaviour of certain TERTp-mutant meningiomas suggests that TERTp mutation is not sufficient to assign the most aggressive meningioma grade. Instead, TERT sequencing might offer prognostic utility in identifying high-risk cases among WHO grade 2 meningiomas. FUNDING: National Institutes of Health, National Institute of Neurological Disorders and Stroke, Friedberg Charitable Foundation, Courtney Meningioma Research Fund, Fleming Meningioma Research Fund, and the Gray Family Foundation.

Humans↗

PubMed2024

Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.

Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.

Meningioma↗

PubMed2007

Radiation induced peripheral nerve tumors: case series and review of the literature.

PURPOSE: Radiation induced peripheral nerve tumors (PNT) are a rare but known complication of radiotherapy. The clinical and pathologic features of six cases of post-radiation PNT's are reported here, more than doubling the number of known cases reported in the literature. METHODS: We reviewed six cases of radiation induced PNT and performed a review of the current literature on radiation induced neurofibromas. RESULTS: Patient's ranged in age from 18 months to 49 years at the time of their original diagnosis, with radiation doses to the primary tumor ranging from 24 to 40 Gy with post radiation intervals from 10 to 50 years. The majority of PNT's identified were neurofibromas (3) and schwannomas (3). Nuclear atypia, S100 positive staining and mild-moderate cellularity were common pathologic findings. CONCLUSIONS: There are only a handful of neurofibromas in the 60 cases of PNT's thus far reported. This case series broadens the post-radiation neurofibroma literature. While the pathology of PNT induced transformation is still poorly understood, experiments and pathology are congruent on the possibility of malignant transformation, especially for the "atypical neurofibroma". On the clinical level, this case series lends its support to some, but not all, of the risk factors thought to predispose to the formation of radiation induced neurofibromas. Though rare, the complication of radiation-induced neurofibroma cannot be ignored, especially with the increasing use of focused radiosurgical techniques.

Adult↗

PubMed2006

Pediatric arteriovenous malformation: University of Toronto experience using stereotactic radiosurgery.

INTRODUCTION AND BACKGROUND: Arteriovenous malformations (AVMs) are congenital vascular lesions of the brain, which behave differently in pediatric population compared to adults. Treatment of pediatric AVMs includes a combination of microsurgery, embolization and radiation therapies. However, the role of radiosurgery in the treatment of pediatric AVMs is not fully accepted because of concerns regarding the long-term effects of radiation on the pediatric brain. DISCUSSION: In this study, we review our experience at the University of Toronto with treating pediatric AVMs using linear accelerator-based (LINAC) radiosurgery over the past 15 years. We report our results, obliteration rates, and complications on a total of 40 patients. In addition, we provide a review of series published to date combined with our own results to determine whether radiosurgery is a safe and reasonable treatment modality for pediatric AVMs.

Adolescent↗

PubMed2006

Radiosurgical retreatment for brain arteriovenous malformation.

OBJECTIVE: To analyze our experience with a second radiosurgical treatment for brain arteriovenous malformations (BAVMs) after an unsuccessful first radiosurgical treatment. METHODS: Between 1993 and 2000, 242 patients were treated by the Toronto Sunnybrook Regional Cancer Center using a LINAC system. Fifteen of these patients required a second radiosurgical intervention due to the failure of the first procedure. Data was collected on baseline patient characteristics, BAVM features, radiosurgery treatment plan and outcomes. Brain arteriovenous malformation obliteration was determined by follow-up MRI and angiography and the obliteration prediction index (OPI) calculated according to a previously established formula. RESULTS: The median interval between the first and second treatment was 46 months (range 39-109). The median follow-up after the second procedure was 39 months (range 26 to 72). The mean BAVM volume before the first treatment was 8.9cm3 (range 0.3-21) and before the second treatment was 3.6cm3 (range 0.2-11.6). The mean marginal dose during the first treatment was 18Gy (range 12-25) and during the second treatment was 16Gy (range 12-20). After the second treatment, nine patients had obliteration of their BAVM confirmed by angiography and one patient had obliteration confirmed by MRI, resulting in an obliteration rate of 66.6%, which is very comparable to that predicted by the OPI (65%). After the second treatment two patients had a radiation-induced complication (13.3%). CONCLUSION: Retreatment of BAVM using a second radiosurgery procedure is a safe and effective option that offers the same rate of success as the initial radiosurgery and an acceptable risk of radiation-induced complication.

Adolescent↗

PubMed2005

Radiosurgery for basal ganglia, internal capsule, and thalamus arteriovenous malformation: clinical outcome.

OBJECTIVE: Radiosurgery is accepted as the first option for treating deep arteriovenous malformations (AVMs), although the clinical outcome in this subgroup of brain AVMs is not well studied. The objective of this study is to review our experience with radiosurgical treatment for these AVMs. METHODS: Between October 1989 and December 2000, 45 patients with deep AVMs (including basal ganglia, internal capsule, and thalamus) underwent stereotactic radiosurgery. Three patients were lost to follow-up and therefore were excluded from this study. Patient characteristics and outcomes were collected and analyzed. The obliteration prediction index and the radiosurgery-based AVM score were calculated and tested. RESULTS: Forty-two patients were followed up for a median of 39 months (range, 25-90 mo; mean, 45.8 mo). The median maximum AVM diameter during the radiosurgery was 1.8 cm (range, 0.9-4.0 cm; mean, 2.07 cm), and the median AVM volume was 2.8 cm(3) (range, 0.2-18.3 cm(3); mean, 4.74 cm(3)). The mean marginal dose was 16.2 Gy (median, 15 Gy), and the median maximum dose was 22.4 Gy (range, 16.6-30 Gy). The AVM cure rate after the first radiosurgical treatment, using angiography- and magnetic resonance imaging-confirmed obliteration, was 61.9%. The predicted obliteration using the obliteration prediction index was 60%. Eight patients developed radiation-induced complications (19%). The deficit was transient in three patients (7.1%) and permanent in five patients (11.9%). The risk of postradiosurgical hemorrhage in this cohort was 9.5% for the first year, 4.7% for the second year, and 0% thereafter. Excellent outcome (obliteration plus no new deficit) was achieved in 70% of the patients in the group with radiosurgery-based AVM score less than 1.5 compared with 40.9% in the group with radiosurgery-based AVM score greater than 1.5% (P = 0.059). CONCLUSION: Radiosurgery for deep AVMs has a satisfactory obliteration rate and acceptable morbidity, considering the risk of hemorrhage without treatment and the risk of morbidity associated with other treatment modalities.

Adolescent↗

PubMed2005

Regulation of the pathological vasculature of malignant astrocytomas by angiopoietin-1.

Malignant astrocytomas are the most common and highly vascularized of all primary adult brain tumors. The histopathological hallmarks of malignant astrocytomas are microvascular proliferation and formation of vascular entities, which are referred to as "glomeruloid bodies." The significance of glomeruloid bodies and the molecular mechanisms driving the abnormal vascular architecture in malignant astrocytomas are not understood. We have observed that overexpression of angiopoietin-1 (Ang1) in both subcutaneous and intracranial xenograft models of malignant astrocytomas reproduces many of the vascular features of these tumors, including glomeruloid bodies. To confirm that the formation of glomeruloid bodies was directly dependent on Ang1, we performed experiments where levels of Ang1 expression were regulated under tetracycline control, and we found a direct correlation between levels of Ang1 expression and the occurrence of glomeruloid bodies in xenografts. Additionally, we inhibited the action of Ang1 by blocking its cognate receptor Tie2, and we found that the formation of glomeruloid bodies was inhibited. Collectively, these results support our hypothesis that Ang1 is a key molecular regulator of pathological vascularization characteristic of malignant astrocytomas.

Angiogenesis Inducing Agents↗

PubMed2005

Testing the radiosurgery-based arteriovenous malformation score and the modified Spetzler-Martin grading system to predict radiosurgical outcome.

OBJECT: The aim of this study was to validate the radiosurgery-based arteriovenous malformation (AVM) score and the modified Spetzler-Martin grading system to predict radiosurgical outcome. METHODS: One hundred thirty-six patients with brain AVMs were randomly selected. These patients had undergone a linear accelerator radiosurgical procedure at a single center between 1989 and 2000. Patients were divided into four groups according to an AVM score, which was calculated from the lesion volume, lesion location, and patient age (Group 1, AVM score <1; Group 2, AVM score 1-1.49; Group 3, AVM score 1.5-2; and Group 4, AVM score >2). Patients with a Spetzler-Martin Grade III AVM were divided into Grades IIIA (lesion >3 cm) and IIIB (lesion <3 cm). Sixty-two female (45.6%) and 74 male (54.4%) patients with a median age of 37.5 years (mean 37.5 years, range 5-77 years) were followed up for a median of 40 months. The median tumor margin dose was 15 Gy (mean 17.23 Gy, range 15-25 Gy). The proportions of excellent outcomes according to the AVM score were as follows: 91.7% for Group 1, 74.1% for Group 2, 60% for Group 3, and 33.3% for Group 4 (chi-square test, degrees of freedom (df) = 3, p < 0.001). Based on the modified Spetzler-Martin system, Grade I lesions had 88.9% excellent results; Grade II, 69.6%; Grade IIIB, 61.5%; and Grades IIIA and IV, 44.8% (chi-square test, df = 3, p = 0.047). CONCLUSIONS: The radiosurgery-based AVM score can be used accurately to predict excellent results following a single radiosurgical treatment for AVM. The modified Spetzler-Martin system can also predict radiosurgical results for AVMs, thus making it possible to use this system while deciding between surgery and radiosurgery.

Adolescent↗

PubMed2004

Contrasting in vivo and in vitro fates of glioblastoma cell subpopulations with amplified EGFR.

Despite the high incidence of EGFR amplification in patient glioblastoma multiforme (GBM) tissues, only a single GBM cell line, of the many described in the literature, is known to contain and maintain amplified EGFR. Because EGFR mutations in GBM manifest primarily, if not exclusively, in amplified form, it follows that the availability of cell lines with mutation of endogenous EGFR would also be in short supply. In fact, there are no GBM cell lines harboring the common EGFR mutants described in patient GBMs. These observations suggest that in vivo environments select for EGFR amplification, whereas in vitro environments, specifically cell cultures, select against this gene alteration. To contrast directly the fates of EGFR amplification in vivo and in vitro, as well as to examine potential relationships between EGFR amplification and mutation, we have established and maintained GBM explants as xenografts by serial passaging in nude mice. Analysis of EGFR copy number and EGFR mutation status in 11 patient tumors and their corresponding xenografts, as well as the monitoring of EGFR copy number during the establishment of a GBM cell line from a xenograft with amplified EGFR, indicated that selection for EGFR amplification is an in vivo phenomenon. Furthermore, our data indicated that EGFR mutation occurs only in tumors with EGFR amplification and showed that the selection of amplified mutant EGFR over amplified wild-type EGFR as a xenograft occurred rapidly and completely during tumor propagation.

Animals↗

PubMed2004

Targeting the Tie2/Tek receptor in astrocytomas.

Tie2 is an endothelial cell-specific receptor tyrosine kinase, whose activation is positively and negatively modulated by angiopoietin-1 and angiopoietin-2, respectively. Angiopoietin-mediated modulation of Tie2 activation contributes to normal vessel development and stability, however, its role in tumor angiogenesis is not well known. We investigated the role of Tie2 activation in malignant astrocytomas, a common and highly vascularized primary human brain tumor. We found that Tie2 expression and activation increases with increasing malignancy grade of astrocytomas. Inhibition of Tie2, using a kinase-deficient Tie2 construct, decreases growth of malignant human astrocytoma subcutaneous and intracranial xenografts. Tie2 inactivation disrupted the tumor vascularity, with a decrease in microvascular density, increased presence of abnormally dilated vessels, and loss of interaction between endothelial cells and surrounding smooth muscle cells, all collectively resulting in increased tumor cell apoptosis. Overall, these findings strongly suggest that Tie2 activation contributes significantly to astrocytoma tumor angiogenesis and growth. We postulate that targeting Tie2 activation, either independently or in conjunction with other anti-angiogenic therapies, such as against vascular endothelial growth factor, is of potential clinical interest.

3T3 Cells↗

PubMed2004

Role of Ang1 and its interaction with VEGF-A in astrocytomas.

Angiopoietins (Ang1 and Ang2) modulate the activity of the endothelial cell (EC)-specific receptor tyrosine kinase Tie2, which together with vascular endothelial growth factor (VEGF-A) and its EC-specific receptors, VEGFR1 and VEGFR2, regulate normal physiological vessel development. The functional role of angiopoietins in tumor angiogenesis, in particular astrocytoma angiogenesis, remains unclear. In this study, we focus on the specific contribution of Ang1 to the vascular growth of glioblastoma multiforme (GBM) and its interactive role with VEGF-A. Subcutaneous and intracranial GBM xenografts were generated using 3 established astrocytoma cell lines (U87, U373, and U343) that were transfected to stably over-express Ang1. GBM xenografts were also generated to express low levels of VEGF-A and high Angl. We found that Ang1 increases the vascular growth of both subcutaneous and intracranial xenografts of GBM by approximately 3-fold. However, the increased vascular growth was only seen in xenografts with concurrent VEGF-A elevation, since decreasing VEGF-A expression resulted in a loss of the pro-angiogenic growth advantage seen with Ang1. Collectively, our data suggest that Ang1 regulates GBM vascularity in a VEGF-A dependent manner, synergizing the initial pro-angiogenic response that is triggered by VEGF-A and promoting the vascular growth of GBM.

Angiopoietin-1↗

PubMed2003

Neoangiogenesis in human astrocytomas: expression and functional role of angiopoietins and their cognate receptors.

Since the introduction of the concept of an "angiogenic switch" driving tumor growth and malignant progression by Judah Folkman in 1971, there have been numerous scientific reports confirming the central concept that tumor growth is angiogenesis dependent. Various angiogenic genes and gene products, from both neoplastic and normal tissues, have been isolated, purified, and cloned that contribute to the 'angiogenic switch'. Of these various molecules, two have been identified that act specifically on endothelial cells. First is Vascular Endothelial Growth Factor (VEGF), the cognate receptors of which are almost specifically expressed on endothelial cells. VEGF plays a crucial role in the development of the embryonic vasculature by providing differentiation and mitogenic signals to endothelial cells and their mesodermal precursors. Second are the Angiopoietins and their cognate receptor, Tie2. Angiopoietins are primarily involved in maturation of both embryonal and adult vasculature, with Angiopoietin 1 2 being naturally occurring agonists and antagonists of Tie2 respectively, indicating a very precise level of regulation in-vivo. In this review we summarize what is known of the biological role of Angiopoietins and Tie2, their interaction with VEGF in normal and tumor related angiogenesis, with emphasis on their functional consequence in the progression and growth of malignant human astrocytomas.

Angiopoietins↗

PubMed2003

Angiogenesis in nervous system disorders.

Angiogenesis is a crucial requirement for embryonal development and new vessel formation during adult life. Various disease processes such as cancer, ischemia, vascular malformations, and inflammatory processes also depend on pathological angiogenesis. A better understanding of the complex and coordinated interactions among various angiogenic pathways involved in pathological angiogenesis is necessary to improve our therapeutic approaches to the various disease processes observed in the central nervous system. This review summarizes the current understanding of the role of principal angiogenic factors relevant to neurosurgical abnormalities.

Angiogenesis Modulating Agents↗

PubMed2003

Molecular regulators of angiogenesis in the developing nervous system and adult brain tumors (review).

Angiogenesis involves a highly regulated and coordinated interaction of multiple angiogenic factors and is critical for both embryonal development and physiological vessel formation in adults. Angiogenesis is also proven to significantly contribute to the progression of various disease processes. Pathological angiogenesis is thought to recapitulate physiological angiogenesis, however the precise molecular mechanisms are not understood. Various angiogenic genes and gene products have been isolated, purified, and cloned from both neoplastic and normal tissues that contribute to the angiogenic process. In this review we summarize the role of the main angiogenic factors in both normal embryonal vascularization of the embryonal nervous system together with the main brain tumors seen in adults.

Angiogenesis Inducing Agents↗

PubMedDate not supplied

High-resolution longitudinal screening with magnetic resonance imaging in a murine brain cancer model.

One of the main limitations of intracranial models of diseases is our present inability to monitor and evaluate the intracranial compartment noninvasively over time. Therefore, there is a growing need for imaging modalities that provide thorough neuropathological evaluations of xenograft and transgenic models of intracranial pathology. In this study, we have established protocols for multiple-mouse magnetic resonance imaging (MRI) to follow the growth and behavior of intracranial xenografts of gliomas longitudinally. We successfully obtained weekly images on 16 mice for a total of 5 weeks on a 7-T multiple-mouse MRI. T2- and T1-weighted imaging with gadolinium enhancement of vascularity was used to detect tumor margins, tumor size, and growth. These experiments, using 3D whole brain images obtained in four mice at once, demonstrate the feasibility of obtaining repeat radiological images in intracranial tumor models and suggest that MRI should be incorporated as a research modality for the investigation of intracranial pathobiology.

Angiopoietin-1↗