Search Results

You are looking at 1 - 3 of 3 items for

  • Author or Editor: Elena I. Fomchenko x
Clear All Modify Search
Restricted access

Elena I. Fomchenko, E. Zeynep Erson-Omay, Adam J. Kundishora, Christopher S. Hong, Ava A. Daniel, August Allocco, Phan Q. Duy, Armine Darbinyan, Asher M. Marks, Michael L. DiLuna, Kristopher T. Kahle and Anita Huttner

Pediatric midline tumors are devastating high-grade lesions with a dismal prognosis and no curative surgical options. Here, the authors report the clinical presentation, surgical management, whole-exome sequencing (WES), and clonality analysis of a patient with a radically resected H3K27M-mutant pineal parenchymal tumor (PPT) and spine metastases consistent with PPT of intermediate differentiation (PPTID). They identified somatic mutations in H3F3A (H3K27M), FGFR1, and NF1 both in the original PPT and in the PPTID metastases. They also found 12q amplification containing CDK4/MDM2 and chromosome 17 loss of heterozygosity overlapping with NF1 that resulted in biallelic NF1 loss. They noted a hypermutated phenotype with increased C>T transitions within the PPTID metastases and 2p amplification overlapping with the MYCN locus. Clonality analysis detected three founder clones maintained during progression and metastasis. Tumor clones present within the PPTID metastases but not the pineal midline tumor harbored mutations in APC and TIMP2.

While the majority of H3K27M mutations are found in pediatric midline gliomas, it is increasingly recognized that this mutation is present in a wider range of lesions with a varied morphological appearance. The present case appears to be the first description of H3K27M mutation in PPTID. Somatic mutations in H3F3A, FGFR1, and NF1 have been suggested to be driver mutations in pediatric midline gliomas. Their clonality and presence in over 80% of tumor cells in our patient’s PPTID are consistent with similarly crucial roles in early tumorigenesis, with progression mediated by copy number variations and chromosomal aberrations involving known oncogenes and tumor suppressors. The roles of APC and TIMP2 mutations in progression and metastasis remain to be investigated.

Restricted access

Brian M. Shear, Lan Jin, Yawei Zhang, Wyatt B. David, Elena I. Fomchenko, E. Zeynep Erson-Omay, Anita Huttner, Robert K. Fulbright and Jennifer Moliterno

OBJECTIVE

Intracranial epidermoid tumors are slow-growing, histologically benign tumors of epithelial cellular origin that can be symptomatic because of their size and mass effect. Neurosurgical resection, while the treatment of choice, can be quite challenging due to locations where these lesions commonly occur and their association with critical neurovascular structures. As such, subtotal resection (STR) rather than gross-total resection (GTR) can often be performed, rendering residual and recurrent tumor potentially problematic. The authors present a case of a 28-year-old man who underwent STR followed by aggressive repeat resection for regrowth, and they report the results of the largest meta-analysis to date of epidermoid tumors to compare recurrence rates for STR and GTR.

METHODS

The authors conducted a systemic review of PubMed, Web of Science, and the Cochrane Collaboration following the PRISMA guidelines. They then conducted a proportional meta-analysis to compare the pooled recurrence rates between STR and GTR in the included studies. The authors developed fixed- and mixed-effect models to estimate the pooled proportions of recurrence among patients undergoing STR or GTR. They also investigated the relationship between recurrence rate and follow-up time in the previous studies using linear regression and natural cubic spline models.

RESULTS

Overall, 27 studies with 691 patients met the inclusion criteria; of these, 293 (42%) underwent STR and 398 (58%) received GTR. The average recurrence rate for all procedures was 11%. The proportional meta-analysis showed that the pooled recurrence rate after STR (21%) was 7 times greater than the rate after GTR (3%). The average recurrence rate for studies with longer follow-up durations (≥ 4.4 years) (17.4%) was significantly higher than the average recurrence rate for studies with shorter follow-up durations (< 4.4 years) (5.7%). The cutoff point of 4.4 years was selected based on the significant relationship between the recurrence rate of both STR and GTR and follow-up durations in the included studies (p = 0.008).

CONCLUSIONS

STR is associated with a significantly higher rate of epidermoid tumor recurrence compared to GTR. Attempts at GTR should be made during the initial surgery with efforts to optimize success. Surgical expertise, as well as the use of adjuncts, such as intraoperative MRI and neuromonitoring, may increase the likelihood of completing a safe GTR and decreasing the long-term risk of recurrence. The most common surgical complications were transient cranial nerve palsies, occurring equally in STR and GTR cases when reported. In all postoperative epidermoid tumor cases, but particularly following STR, close follow-up with serial MRI, even years after surgery, is recommended.

Restricted access

Mark W. Youngblood, Daniel Duran, Julio D. Montejo, Chang Li, Sacit Bulent Omay, Koray Özduman, Amar H. Sheth, Amy Y. Zhao, Evgeniya Tyrtova, Danielle F. Miyagishima, Elena I. Fomchenko, Christopher S. Hong, Victoria E. Clark, Maximilien Riche, Matthieu Peyre, Julien Boetto, Sadaf Sohrabi, Sarah Koljaka, Jacob F. Baranoski, James Knight, Hongda Zhu, M. Necmettin Pamir, Timuçin Avşar, Türker Kilic, Johannes Schramm, Marco Timmer, Roland Goldbrunner, Ye Gong, Yaşar Bayri, Nduka Amankulor, Ronald L. Hamilton, Kaya Bilguvar, Irina Tikhonova, Patrick R. Tomak, Anita Huttner, Matthias Simon, Boris Krischek, Michel Kalamarides, E. Zeynep Erson-Omay, Jennifer Moliterno and Murat Günel

OBJECTIVE

Recent large-cohort sequencing studies have investigated the genomic landscape of meningiomas, identifying somatic coding alterations in NF2, SMARCB1, SMARCE1, TRAF7, KLF4, POLR2A, BAP1, and members of the PI3K and Hedgehog signaling pathways. Initial associations between clinical features and genomic subgroups have been described, including location, grade, and histology. However, further investigation using an expanded collection of samples is needed to confirm previous findings, as well as elucidate relationships not evident in smaller discovery cohorts.

METHODS

Targeted sequencing of established meningioma driver genes was performed on a multiinstitution cohort of 3016 meningiomas for classification into mutually exclusive subgroups. Relevant clinical information was collected for all available cases and correlated with genomic subgroup. Nominal variables were analyzed using Fisher’s exact tests, while ordinal and continuous variables were assessed using Kruskal-Wallis and 1-way ANOVA tests, respectively. Machine-learning approaches were used to predict genomic subgroup based on noninvasive clinical features.

RESULTS

Genomic subgroups were strongly associated with tumor locations, including correlation of HH tumors with midline location, and non-NF2 tumors in anterior skull base regions. NF2 meningiomas were significantly enriched in male patients, while KLF4 and POLR2A mutations were associated with female sex. Among histologies, the results confirmed previously identified relationships, and observed enrichment of microcystic features among “mutation unknown” samples. Additionally, KLF4-mutant meningiomas were associated with larger peritumoral brain edema, while SMARCB1 cases exhibited elevated Ki-67 index. Machine-learning methods revealed that observable, noninvasive patient features were largely predictive of each tumor’s underlying driver mutation.

CONCLUSIONS

Using a rigorous and comprehensive approach, this study expands previously described correlations between genomic drivers and clinical features, enhancing our understanding of meningioma pathogenesis, and laying further groundwork for the use of targeted therapies. Importantly, the authors found that noninvasive patient variables exhibited a moderate predictive value of underlying genomic subgroup, which could improve with additional training data. With continued development, this framework may enable selection of appropriate precision medications without the need for invasive sampling procedures.