Genomic analysis of human brain metastases treated with stereotactic radiosurgery reveals unique signature based on treatment failure.

Stereotactic radiosurgery (SRS) has been shown to be efficacious for the treatment of limited brain metastasis (BM); however, the effects of SRS on human brain metastases have yet to be studied. We performed genomic analysis on resected brain metastases from patients whose resected lesion was previously treated with SRS. Our analyses demonstrated for the first time that patients possess a distinct genomic signature based on type of treatment failure including local failure, leptomeningeal spread, and radio-necrosis. Examination of the center and peripheral edge of the tumors treated with SRS indicated differential DNA damage distribution and an enrichment for tumor suppressor mutations and DNA damage repair pathways along the peripheral edge. Furthermore, the two clinical modalities used to deliver SRS, LINAC and GK, demonstrated differential effects on the tumor landscape even between controlled primary sites. Our study provides, in human, biological evidence of differential effects of SRS across BM's.

Genomic Analysis of Human Brain Metastases Treated with Stereotactic Radiosurgery Under the Phase-II Clinical Trial (NCT03398694) Reveals DNA Damage Repair at the Peripheral Tumor Edge.

Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.

Facial Nerve Preservation With Inferior Long-Axis Dissection of Large Vestibular Schwannomas.

OBJECTIVE: To describe a tumor resection using the inferior long-axis (ILA) technique for cisternal facial nerve dissection in large vestibular schwannomas (VS). STUDY DESIGN: Retrospective case series from 2018 to 2021. SETTING: Tertiary academic medical center. PATIENTS: Patients who underwent surgical resection with ILA facial nerve dissection of VS (>2.0 cm measured parallel to the petrous ridge) and had at least 3-month follow-up. INTERVENTIONS: Cisternal facial nerve dissection during retrosigmoid or translabyrinthine approach using standardized ILA technique developed by author R.N. MAIN OUTCOME MEASURES: Immediate postoperative and last follow-up facial nerve function with House-Brackmann scores of I to II defined as "good" facial nerve function and House-Brackmann scores III to VI defined as "poor" function. Extent of resection was also assessed. RESULTS: A total of 48 patients underwent large VS resection with ILA dissection of tumor off of the facial nerve from 2018 to 2021. Mean (standard deviation) tumor size was 3.11 (0.76) cm. Mean (standard deviation) follow-up was 9.2 (9.0) months. Gross-total resection or near-total resection were achieved in 75% (radiographic estimate) to 83% (surgeon estimate) of cases. End-of-case facial nerve stimulation at 0.05 mAmp with a response of at least 240 mV was achieved in 80.4% of patients. Good facial nerve function was observed in 72% immediately postoperatively, 70% 1-month postoperatively, and 82% of patients at last follow-up. CONCLUSIONS: The ILA technique is now the method of choice of the senior surgeon (R.N.) when performing microsurgical dissection of the cisternal facial nerve, with which he has achieved high rates of total or near-total resection with excellent facial nerve preservation.

Efficacy of pre-operative stereotactic radiosurgery followed by surgical resection and correlative radiobiological analysis for patients with 1-4 brain metastases: study protocol for a phase II trial.

BACKGROUND: Stereotactic radiosurgery (SRS) has emerged as a common adjuvant modality used with surgery for resectable brain metastases (BMs). However, the optimal sequence of the multi-modality therapy has not been established. The goal of the study is to evaluate 6-month local control utilizing pre-operative SRS followed by surgical resection for patients with 1-4 brain metastases. METHODS: This prospective, single arm, phase II trial will recruit patients with up to 4 brain metastases and at least one resectable lesion. All lesions will be treated with SRS and symptomatic lesions will be resected within 1-4 days after SRS. Patients will be monitored for 6-month local control, in-brain progression free survival, distant in-brain failure, rate of leptomeningeal spread, radiation necrosis and overall survival. Additionally, we will also perform correlative radiobiological molecular studies to assess the effect of radiation dosing on the tumor tissue and clinical outcomes. We expect that pre-operative SRS to the gross tumor prior to surgical resection will improve local control and decrease leptomeningeal failure. DISCUSSION: Our study is the second prospective trial to investigate the efficacy of pre-operative SRS in the treatment of multiple BMs. In addition, the correlative molecular studies will be the first to investigate early response of BMs at a cellular and genetic level in response to radiation doses and potentially provide molecular prognostic markers for local control and overall survival. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03398694 (registration date: January 12, 2018).

Endoscopic Endonasal Surgery for the Resection of a Cavernous Hemangioma with a Sellar Extension.

Cavernous hemangiomas with an intrasellar extension are very rare, generally benign lesions that manifest by the compression of nearby structures. The presenting symptoms usually range from visual disturbances to an endocrine imbalance. Occasional extension into the cavernous sinus has been reported, which can cause cranial nerve compression. We present the case of a 69-year-old man presenting with facial pain and decreased libido. On investigation, a lesion was identified and the parasellar region was homogeneously hyper-intense on gadolinium-enhanced magnetic resonance imaging (MRI). Endoscopic endonasal surgery remains one of the favored approaches for the resection of sellar lesions. Such pathology needs to remain on the neurosurgeon's differential diagnosis, making an intraoperative frozen section of these lesions a useful tool in the surgeon's armamentarium, to guide further surgical resection.

Neurenteric cysts of the spine.

Neurenteric cysts account for 0.7-1.3% of spinal axis tumors. These rare lesions result from the inappropriate partitioning of the embryonic notochordal plate and presumptive endoderm during the third week of human development. Heterotopic rests of epithelium reminiscent of gastrointestinal and respiratory tissue lead to eventual formation of compressive cystic lesions of the pediatric and adult spine. Histopathological analysis of neurenteric tissue reveals a highly characteristic structure of columnar or cuboidal epithelium with or without cilia and mucus globules. Patients with symptomatic neurenteric cysts typically present in the second and third decades of life with size-dependent myelopathic and/or radicular signs. Magnetic resonance imaging and computed tomography are essential diagnostic tools for the delineation of cyst form and overlying osseous architecture. A variety of approaches have been employed in the treatment of neurenteric cysts each with a goal of total surgical resection. Although long-term outcome analyses are limited, data available indicate that surgical intervention in the case of neurenteric cysts results in a high frequency of resolution of neurological deficit with minimal morbidity. However, recurrence rates as high as 37% have been reported with incomplete resection secondary to factors such as cyst adhesion to surrounding structure and unclear dissection planes. Here we present a systematic review of English language literature from January 1966 to December 2009 utilizing MEDLINE with the following search terminology: neurenteric cyst, enterogenous cyst, spinal cord tumor, spinal dysraphism, intraspinal cyst, intramedullary cyst, and intradural cyst. In addition, the references of publications returned from the MEDLINE search criteria were surveyed in order to examine other pertinent reports.

Transgenic mice expressing LHX3 transcription factor isoforms in the pituitary: effects on the gonadotrope axis and sex-specific reproductive disease.

The LHX3 transcription factor plays critical roles in pituitary and nervous system development. Mutations in the human LHX3 gene cause severe hormone deficiency diseases. The gene produces two mRNAs which can be translated to three protein isoforms. The LHX3a protein contains a central region with LIM domains and a homeodomain, and a carboxyl terminus with the major transactivation domain. LHX3b is identical to LHX3a except that it has a different amino terminus. M2-LHX3 lacks the amino terminus and LIM domains of LHX3a/b. In vitro experiments have demonstrated these three proteins have different biochemical and gene regulatory properties. Here, to investigate the effects of overexpression of LHX3 in vivo, the alpha glycoprotein subunit (alphaGSU) promoter was used to produce LHX3a, LHX3b, and M2-LHX3 in the pituitary glands of transgenic mice. Alpha GSU-beta galactosidase animals were generated as controls. Male alphaGSU-LHX3a and alphaGSU-LHX3b mice are infertile and die at a young age as a result of complications associated with obstructive uropathy including uremia. These animals have a reduced number of pituitary gonadotrope cells, low circulating gonadotropins, and possible sex hormone imbalance. Female alphaGSU-LHX3a and alphaGSU-LHX3b transgenic mice are viable but have reduced fertility. By contrast, alphaGSU-M2-LHX3 mice and control mice expressing beta galactosidase are reproductively unaffected. These overexpression studies provide insights into the properties of LHX3 during pituitary development and highlight the importance of this factor in reproductive physiology.

Cyclooxygenase-2 expression in hamster and human pancreatic neoplasia.

Cyclooxygenase-2 (COX-2) has been implicated in the development of gastrointestinal malignancies. The aim of the present study was to determine COX-2 expression/activity throughout stages of experimental and human pancreatic neoplasia. COX-2 immunohistochemistry was performed in pancreata of hamsters subjected to the carcinogen N-nitrosobis-(2-oxopropyl)amine (BOP) and in human pancreatic tumors. COX-2 activity was determined by prostaglandin E2 assay in tumor versus matched normal pancreatic tissues. The activity of the COX inhibitor sulindac was tested in the PC-1 hamster pancreatic cancer model. COX-2 expression was elevated in all pancreatic intraepithelial neoplasias (PanINs) and adenocarcinomas. In BOP-treated hamsters, there were significant progressive elevations in COX-2 expression throughout pancreatic tumorigenesis. In human samples, peak COX-2 expression occurred in PanIN2 lesions and remained moderately elevated in PanIN3 and adenocarcinoma tissues. COX-2 activity was significantly elevated in hamster and human pancreatic cancers compared to pair-matched normal pancreas. Furthermore, hamster pancreatic tumor engraftment/formation in the PC-1 hamster pancreatic cancer model was reduced 4.9-fold by oral administration of sulindac. Increased COX-2 expression is an early event in pancreatic carcinogeneses. The BOP-induced hamster carcinogenesis model is a representative model used to study the role of COX-2 in well-differentiated pancreatic tumorigenesis. COX inhibitors may have a role in preventing tumor engraftment/formation.

Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor.

FSH is a critical hormone regulator of gonadal function that is secreted from the pituitary gonadotrope cell. Human patients and animal models with mutations in the LHX3 LIM-homeodomain transcription factor gene exhibit complex endocrine diseases, including reproductive disorders with loss of FSH. We demonstrate that in both heterologous and pituitary gonadotrope cells, specific LHX3 isoforms activate the FSH beta-subunit promoter, but not the proximal LHbeta promoter. The related LHX4 mammalian transcription factor can also induce FSHbeta promoter transcription, but the homologous Drosophila protein LIM3 cannot. The actions of LHX3 are specifically blocked by a dominant negative LHX3 protein containing a Kruppel-associated box domain. Six LHX3-binding sites were characterized within the FSHbeta promoter, including three within a proximal region that also mediates gene regulation by other transcription factors and activin. Mutations of the proximal binding sites demonstrate their importance for LHX3 induction of the FSHbeta promoter and basal promoter activity in gonadotrope cells. Using quantitative methods, we show that the responses of the FSHbeta promoter to activin do not require induction of the LHX3 gene. By comparative genomics using the human FSHbeta promoter, we demonstrate structural and functional conservation of promoter induction by LHX3. We conclude that the LHX3 LIM homeodomain transcription factor is involved in activation of the FSH beta-subunit gene in the pituitary gonadotrope cell.

Transcriptional control during mammalian anterior pituitary development.

The mammalian anterior pituitary gland is a compound endocrine organ that regulates reproductive development and fitness, growth, metabolic homeostasis, the response to stress, and lactation, by actions on target organs such as the gonads, the liver, the thyroid, the adrenals, and the mammary gland. The protein and peptide hormones that control these physiological parameters are secreted by specialized pituitary cell types that derive from a common origin in the early ectoderm. Collectively, the broad physiological importance of the pituitary gland, its intriguing organogenesis, and the clinical and agricultural significance of its actions, have established pituitary development as an excellent model system for the study of the gene-regulatory cascades that guide vertebrate cell determination and differentiation. We review the transcriptional pathways that regulate the commitment of the individual pituitary cell lineages and that subsequently modulate trophic hormone gene activity in the differentiated cells of the mature gland.