Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.

Absence of neurotoxicity with perineural injection of ultrasound gels: assessment using an animal model.

BACKGROUND: Ultrasound gels may contain propylene glycol and glycerol, which are neurotoxic in high concentrations. If the needle passes through gel during regional anesthesia, gel may be injected near the nerve. It is unknown if this practice poses a risk for neurotoxicity. Using an animal model, we assessed the histological changes of perineural propylene glycol on nerves. We then assessed three commonly used sterile gels for evidence of neurotoxicity. METHODS: Micro-ultrasound guided perineural sciatic nerve injections were performed in mice. Propylene glycol (PG) 2.5%, 10%, 35%, 70% (v/v) or saline was injected. Nerves were assessed after three days for evidence of neurotoxicity. Aquasonic® 100 Ultrasound Gel, K-Y® Lubricating Jelly, and PDI® Lubricating Jelly were also studied against saline controls. RESULTS: Confluent areas of axonal degeneration and intraneural inflammation occurred in 5 of 9 specimens injected with 70% PG. At 35%, 2 of 8 specimens showed patchy changes not present at lower concentrations. No degeneration occurred with Aquasonic® 100 or PDI® Lubricating Jelly. In the K-Y® group, one gel and one saline specimen demonstrated confluent degenerative changes. CONCLUSIONS: Similar to glycerol, 70% PG may cause confluent areas of axon and myelin degeneration with associated intraneural inflammation. The concentration of PG present in ultrasound gels is unlikely to cause neurotoxicity. Aquasonic® 100 and PDI® Lubricating Jelly did not cause neurotoxicity. The results for K-Y® Lubricating Jelly are inconclusive. There is no evidence that passing the needle through the studied gels during regional anesthesia procedures is harmful.

Recurrent anaplastic transformation of a Vermian region rosette forming glioneuronal tumour - A rare entity. Case report and review of literature.

INTRODUCTION AND IMPORTANCE: Rosette forming Glioneuronal tumours (RGNT) are rare WHO grade I tumours. They have been recognised as a sole entity in the WHO classification since 2007. They are typically described as having a favourable prognosis. Since their description as a distinct entity, there have been only four reports of malignant or anaplastic transformation of RGNT. We report a case of recurrent RGNT with new anaplastic histopathological features. CASE PRESENTATION: We present the case of a 48-year-old female who presented with a vermian region RGNT. The tumour recurred six years after initial surgical resection with new anaplastic transformation. Despite further surgery, chemotherapy, and radiation, the lesion continued to recur with high grade features. CLINICAL DISCUSSION: RGNT is a rare variant of a mixed glial-neuronal tumour. It has been defined as a WHO grade I lesion with a favourable prognostic course. There is growing evidence that this neoplasm can demonstrate malignant transformation with aggressive behaviour. CONCLUSION: Recurrent RGNT is a rare entity. There is a growing bank of literature surrounding this relatively new entity to aid patients and clinicians alike in management decisions. To our knowledge, we report one of only few cases of anaplastic transformation of a RGNT. A high degree of suspicion should be maintained for patients with recurrent RGNT and in suitable cases, surgical resection with adjuvant chemo-irradiation should be pursued.

Rosette-forming glioneuronal tumour: imaging features, histopathological correlation and a comprehensive review of literature.

BACKGROUND: Rosette-forming glioneuronal tumour (RGNT) is a rare and novel brain tumour. We present a case of rosette forming glioneuronal tumour of the fourth ventricle and highlight the imaging and histological features of this tumour entity. We also performed a comprehensive review of the imaging features, treatments and outcomes of all past cases and make recommendations on diagnosis and management. METHOD: We conducted a PUBMED search using the words 'rosette forming glioneuronal tumour', and identified 48 cases of rosette forming glioneuronal tumour. We reviewed the location, imaging features of this rare tumour entity as well as the treatment and follow-up. We also present a case of a 42-year-old man with an incidental finding of a solid-cystic midline mass in the posterior fossa at the level of fourth ventricle with morphological features and immunohistochemical characteristic of a RGNT (WHO Grade I). FINDINGS: RGNT is commonly found in association with the fourth ventricle often with local extension; however, it is known to occur at sites outside of its usual location. RGNT can demonstrate solid, cystic or mixed features on MRI and frequently shows focal contrast enhancement. It is often associated with an element of hydrocephalus. Gross or subtotal tumour resection was the most common treatment of choice. Due to the intimate relationship of these tumours to key neural structures in the cerebellum, variable degrees of postoperative neurological deficits were reported in half of the patients. Among the reported cases, no evidence of recurrence following gross or subtotal resection of tumour was seen in the majority of patients. However, owing to lack of lengthy follow-up, we recommend routine imaging follow-up. CONCLUSION: Knowledge of this tumour is of importance as they are relatively slow growing and exhibit benign histological characteristics, thus depending on its location maybe amenable to gross total resection.

MGMT promoter methylation and immunoexpression in aggressive pituitary adenomas and carcinomas.

MGMT promoter hypermethylation of aggressive pituitary adenomas and pituitary carcinomas and low protein expression are implicated in improved response to treatment with temozolomide (TMZ). The aim of the present study was to investigate MGMT promoter methylation and immunoexpression in an aggressive subset of pituitary adenomas and carcinomas. Our material consisted of 12 silent subtype 3 (SS3) adenomas, 10 primary carcinomas, and 4 disseminated metastases. Two different tissue samples of 7 of the 12 SS3 adenomas and all carcinomas were analyzed for MGMT promoter methylation and immunohistochemical expression of MGMT. Immunoexpression was assessed semi-quantitatively as a percentage of immunoreactive nuclei. Overall 33% of carcinomas exhibited homogenous MGMT methylation in tumor and metastatic specimens. Low immunohistochemical MGMT expression was noted in 50% of carcinomas. Overall, 42% of the SS3 adenomas exhibited MGMT promoter methylation. MGMT immunostaining was predominantly negative (92%), with homogenous immunostaining results across different samples. Whereas all the methylated SS3 adenomas had low MGMT immunoreactivity, five unmethylated adenomas exhibited absent/low MGMT expression. There was no relationship between methylation status and MGMT immunoexpression was not apparent. MGMT methylation and low immunohistochemical expression seen in a subset of carcinomas and SS3 adenomas, suggesting that a subset of tumors may respond to treatment with TMZ. Heterogeneous MGMT methylation status in SS3 adenomas and the lack of concordance between methylation and immunohistochemical expression of MGMT suggest complex regulatory mechanisms, highlighting the need for improved methods in the research on a correlation between MGMT changes and response to TMZ.

MGMT immunoexpression in aggressive pituitary adenoma and carcinoma.

Recent case reports have documented the efficacy of temozolomide therapy in some aggressive pituitary adenomas and pituitary carcinomas resistant to multimodality therapy. Evidence suggests that low O6-methylguanine-DNA methyltransferase (MGMT) immunoexpression correlates with response to temozolomide chemotherapy. Herein, we aimed to study MGMT immunoexpression in a spectrum of pituitary tumors, indolent, aggressive and malignant. A literature review of the use of temozolomide in pituitary tumors was also performed. Immunohistochemistry for MGMT was performed on 60 pituitary tumors identified in the Mayo Clinic Tissue Registry and the consultation files of one of us (BWS). The group included 30 pituitary carcinomas (15 ACTH, 10 PRL, 1 FSH/LH, 1 TSH, 1 silent subtype 3 and 2 null cell). Tissue from recurrences was available in 17 cases. In addition, 30 functionally different pituitary adenomas were studied, including 15 invasive and 15 non-invasive adenomas. Overall, 32 cases of pituitary tumors (54%) demonstrated low MGMT immunoexpression. This included 17 of 30 (57%) carcinomas, 9 of 15 (60%) invasive adenomas, and 6 of 15 cases (40%) of non-invasive pituitary adenomas. There was no significant change in MGMT immunoexpression between primary and recurrent tumors. Prolactin-producing carcinomas had the highest proportion of tumors (80%) with low expression. A significant proportion of pituitary adenomas and carcinomas demonstrate low MGMT immunoexpression. In an effort to anticipate the likelihood of a temozolomide response, all cases of aggressive pituitary tumors should be assessed for MGMT expression.

Rare Primary Pleomorphic Adenoma in Posterior Fossa.

BACKGROUND: Pleomorphic adenoma is a benign neoplastic tumor of the salivary gland. Salivary gland tumors in the intracranial cavity are generally restricted to the pituitary gland and sellar region. To our knowledge, there has been only 1 previous case report of a primary central nervous system pleomorphic adenoma outside of the sellar region. In that case report of a posterior fossa pleomorphic adenoma, typical myxochondroid stroma was not identified on histology, and its pathogenesis was not explored. CASE DESCRIPTION: A 71-year-old woman presented with a 6-week history of occipital headache and unsteadiness. Contrast-enhanced computed tomography and magnetic resonance imaging studies revealed a solitary large posterior fossa tumor in the left cerebellopontine angle measuring 47 × 43 × 45 mm. The tumor resulted in moderate hydrocephalus and significant mass effect with compression of the pons and medulla. She underwent a stereotactic right ventriculoperitoneal shunt insertion followed by a stereotactic craniotomy and complete excision of the tumor. The operation went uneventfully, and the patient had an uncomplicated recovery. Histopathologic examination revealed a benign pleomorphic adenoma (benign salivary gland tumor) with a classic appearance comprising an admixture of ductal epithelial cells, myoepithelial elements, and nodules of myxochondroid stroma. No extracranial source has been identified despite extensive investigation and 8 years of follow-up. CONCLUSIONS: This case study illustrates a classic primary central nervous system pleomorphic adenoma in an unusual intracranial site. Its pathogenesis is postulated to involve salivary gland heterotopia.

Papillary tumour of the pineal region.

Papillary tumour of the pineal region (PTRR) is one of the new tumour entities to be included in the latest World Health Organization classification of central nervous system tumours. We report two illustrative patients, a 25-year-old female who presented following a head injury sustained from a fall due to gait disturbances, and a 42-year-old man who presented with headaches. Histology of both cases showed distinct papillary growth patterns with lining of the papillae by multi-layered cuboidal to columnar cells, prominent perivascular rosette and focal true rosette formation. Immunohistochemistry exhibited strong cytokeratin immunoreactivity in addition to CD56, focal S100, glial fibrillary acidic protein and neuron specific enolase positivity which supported a diagnosis of PTPR in both patients. Postoperatively, both patients underwent courses of adjuvant radiation therapy. One patient reported local recurrence of the tumour 23 months after surgery. While PTPR may have been misdiagnosed in the past, clear and consistent characteristics are beginning to be elucidated in the published reports and literature, which have been reviewed. As a relatively new distinct clinicopathological entity, prognostic data are limited and guidelines for treatment protocols are still being investigated in view of its propensity for local recurrence.

Treatment of pituitary neoplasms with temozolomide: a review.

Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had high-level MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression.