Synchronous identification of a dysembryoplastic neuroepithelial tumor (DNET) and an oligodendroglioma in a patient: A case report.

Synchronous gliomas of different histopathology are quite rare in non-syndromic, non-irradiated patients. Although "mixed" gliomas are not infrequent, and malignant gliomas often contain areas of disparate differentiation (e.g., glioblastoma with ependymal differentiation), it is unusual to find gliomas of different lineage presenting concurrently. We present a case of synchronous gliomas, one dysembryoplastic neuroepithelial tumor (DNET) and the other oligodendroglioma.

Treatment of brain metastases.

Brain metastases are associated with substantial morbidity and mortality. Key prognostic classification systems for brain metastases are reviewed. The role of surgery, particularly for single brain metastases, is discussed. This is followed by an overview of radiation, both whole brain and focal, in the treatment of brain metastases. Finally, we review examples of important concepts regarding the role of systemic therapy in the treatment of brain metastases.

Hypertriglyceridemia, lipemia, and elevated liver enzymes associated with prolonged propofol anesthesia for craniotomy.

: Lipemic blood was noted in the surgical field by a neurosurgeon after 12.5 hours of anesthesia consisting of infusions of propofol (total dose, 14,956 mcg) and remifentanil (total dose, 25,091 mcg). For most of that time, the rate of propofol was 120-160 mcg·kg-1·min-1 and never exceeded 160 mcg·kg-1·min-1. Lipemia was confirmed by allowing a sample of the patient's blood to settle in a syringe. The triglyceride concentration was 15.8 mmol/L. There was no metabolic acidosis or other indications of propofol infusion syndrome. Postoperatively, liver enzymes were elevated (peak aspartate aminotransferase, 420 units/L) but returned to nearly normal within 5 days. The patient recovered from surgery uneventfully. Reports of intraoperative lipemia during propofol anesthesia are very rare but raise concerns about the safety of prolonged propofol infusion.

Impact of Fractionation Regimen on Local Control Following Frameless Linear Accelerator-Based Image-Guided Stereotactic Radiosurgery and Radiotherapy for Intracranial Meningioma.

OBJECTIVE: Stereotactic radiosurgery (SRS) is an established treatment for intracranial meningioma, yet this approach is often precluded by tumor size or proximity to critical structures. Fractionated radiotherapy (RT) may be employed to address these limitations. We performed a comparison of local control (LC) outcomes between 3 stereotactic techniques. METHODS: A retrospective review was performed of 543 consecutive patients with 613 histologically-proven World Health Organization grade I or radiographically-defined benign intracranial meningioma treated with SRS (median dose: 1250 cGy) (n = 211), fractionated SRS (2500 cGy in 500 cGy fractions) (n = 170), or conventionally fractionated stereotactic radiotherapy (FSRT) (median dose: 5022 cGy in ≤200 cGy fractions) (n = 232) in the definitive (n = 475) or postoperative (n = 138) setting between January 2008 and December 2021. Postoperative treatment was delivered upfront after a subtotal resection (n = 43) or for recurrent disease (n = 95). RESULTS: Median follow-up per lesion was 8.0 years. LC for all lesions at 5/10/14 years was 97.4%/86.8%/86.8%. Base of skull location (P = 0.01), tumor volume ≥5 cc (P = 0.01), and recurrent disease (P = 0.02) were associated with inferior LC. No difference was observed in LC by fractionation regimen; LC at 5/10 years was 97.3%/85.7% for SRS, 97.5%/89.1% for fractionated SRS, and 97.5%/86.3% for FSRT. Dose escalation above 1250 cGy for SRS or above 5040 cGy for FSRT did not result in improved LC. CONCLUSIONS: Durable LC was observed at long-term follow-up of intracranial meningioma treated with stereotactic radiosurgery and RT. LC outcomes were similar across the 3 fractionation regimens, suggesting that clinicians may tailor RT recommendations based on clinical factors without concern for reduced efficacy.

Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci.

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.

Spontaneous subdural fluid collections following transection of a fatty filum terminale: case report and review of the literature.

We present the case of a 6-year-old girl who developed bilateral subdural fluid collections following transection of her fatty filum terminale. The patient presented to our emergency department 3 weeks subsequent to surgery, reporting symptoms of headache, nausea, and vomiting. The presence of bilateral subdural fluid collections was confirmed by head computerized tomography. Subdural fluid collections and hematomas have been associated with intracranial hypotension and excessive cerebrospinal fluid leakage; however, there are relatively few cases of subdural fluid collections/hematomas following spine surgery reported in the literature. To our knowledge, this is a unique description of development and resolution of subdural fluid collections following surgical transection of a fatty filum terminale.

Astrocytes promote progression of breast cancer metastases to the brain via a KISS1-mediated autophagy.

Formation of metastases, also known as cancer dissemination, is an important stage of breast cancer (BrCa) development. KISS1 expression is associated with inhibition of metastases development. Recently we have demonstrated that BrCa metastases to the brain exhibit low levels of KISS1 expression at both mRNA and protein levels. By using multicolor immunofluorescence and coculture techniques here we show that normal adult astrocytes in the brain are capable of promoting metastatic transformation of circulating breast cancer cells localized to the brain through secretion of chemokine CXCL12. The latter was found in this study to downregulate KISS1 expression at the post-transcriptional level via induction of microRNA-345 (MIR345). Furthermore, we demonstrated that ectopic expression of KISS1 downregulates ATG5 and ATG7, 2 key modulators of autophagy, and works concurrently with autophagy inhibitors, thereby implicating autophagy in the mechanism of KISS1-mediated BrCa metastatic transformation. We also found that expression of KISS1 in human breast tumor specimens inversely correlates with that of MMP9 and IL8, implicated in the mechanism of metastatic invasion, thereby supporting the role of KISS1 as a potential regulator of BrCa metastatic invasion in the brain. This conclusion is further supported by the ability of KISS1, ectopically overexpressed from an adenoviral vector in MDA-MB-231Br cells with silenced expression of the endogenous gene, to revert invasive phenotype of those cells. Taken together, our results strongly suggest that human adult astrocytes can promote brain invasion of the brain-localized circulating breast cancer cells by upregulating autophagy signaling pathways via the CXCL12-MIR345- KISS1 axis.

Acquired chiari malformation type I associated with a fatty terminal filum. Case report.

The authors report the case of a 3-year-old girl with a Chiari malformation Type I (CM-I) and concomitant fatty terminal filum. This child was examined prior to the onset of CM-I as well as after, and the authors present magnetic resonance (MR) images documenting that the malformation was acquired as the child grew in height. This case contributes to the literature describing an acquired CM-I associated with a fatty filum and is the first published account to include MR imaging obtained before and after the onset of the malformation.

Recurrent Supplementary Motor Area Syndrome Following Repeat Brain Tumor Resection Involving Supplementary Motor Cortex.

BACKGROUND: Supplementary motor area (SMA) syndrome occurs after surgery involving the SMA and is characterized by contralateral hemiparesis with or without speech impairment (dependent on involvement of the dominant SMA), which is transient and characteristically resolves over the course of weeks to months. Recurrent SMA syndrome after repeat craniotomy has not been previously described. OBJECTIVE: To describe the presentation and clinical course of patients who developed recurrent SMA syndrome after redo resection of tumors involving the SMA. METHODS: We performed a retrospective review of 15 patients who underwent repeated resection of low-grade glioma from the superior and middle frontal gyrus. Of these patients, we identified 6 cases of recurrent SMA syndrome. RESULTS: Six patients had a documented SMA syndrome occurring after initial and subsequent resection of tumor in proximity to the SMA. Intraoperative localization of eloquent motor and language cortex was achieved in each patient by using a combination of somatosensory evoked potentials and electrocortical stimulation mapping. Location of tumor and extent of resection was examined with magnetic resonance imaging. CONCLUSION: This series demonstrates that recurrent SMA syndrome occurs in patients undergoing repeat resection of tumors involving the SMA. The presence of recurrent SMA syndrome provides support for reorganization of SMA function to adjacent ipsilateral cortex after resection. Patients with recurrent neoplasms of the SMA should be counseled on the possibility of recurrent SMA syndrome.

Prevention of experimental cerebral vasospasm by intracranial delivery of a nitric oxide donor from a controlled-release polymer: toxicity and efficacy studies in rabbits and rats.

BACKGROUND AND PURPOSE: A reduction in the local availability of nitric oxide (NO) may play a role in the etiology of chronic cerebral vasospasm after subarachnoid hemorrhage (SAH). We investigated the toxicity and efficacy of a locally delivered NO donor from a controlled-release polymer in preventing experimental cerebral vasospasm in rats and rabbits, respectively. METHODS: Diethylenetriamine/NO (DETA/NO) was incorporated into controlled release ethylene-vinyl acetate (EVAc) polymers. Twenty-eight rats were used in a dose-escalation toxicity study to establish a maximally tolerated dose of DETA/NO-EVAc polymer. In the efficacy experiment, 20 rabbits were assigned to 4 experimental groups (n=5 per group): sham operation; SAH only; SAH+empty EVAc polymer; and SAH+DETA/NO-EVAc polymer. Treatment was initiated 30 minutes after blood deposition. Basilar artery lumen patency was assessed 72 hours after hemorrhage to evaluate the efficacy of DETA/NO in preventing cerebral vasospasm. RESULTS: In the toxicity study, a dose of 3.4 mg/kg was identified as the LD(20) (dose with 20% mortality during the study period) of this DETA/NO formulation. Brain histology revealed hemorrhage and ischemic changes at the implantation site associated with high concentrations of DETA/NO. In the efficacy study, treatment with DETA/NO-EVAc polymer resulted in a significant decrease in basilar artery vasospasm compared with no treatment (93.0+/-4.9% versus 71.4+/-11.9%; P=0.035) or compared with treatment with blank EVAc polymer (93.0+/-4.9% versus 73.2+/-6.4%; P=0.003). CONCLUSIONS: Local delivery of DETA/NO prevents vasospasm in the rabbit basilar artery. Local delivery of DETA/NO via polymers is a safe and effective strategy for preventing cerebral vasospasm after SAH in this model.

Toxicity of intracranial and intraperitoneal O6-benzyl guanine in combination with BCNU delivered locally in a mouse model.

PURPOSE: The DNA-repair protein, O6-alkylguanine-DNA alkyl transferase, may account for resistance of CNS tumors to DNA-alkylating drugs, such as bis-(2-chloroethyl)-1-nitrosourea (BCNU). The therapeutic effects of BCNU can be potentiated by inhibiting the repair protein with an alkylated guanine analog, O6-benzyl guanine (O6BG). To investigate potential toxicity of this inhibition, we examined the effects of O6BG in mice treated with intracranial (i.c.) BCNU given via a biodegradable polymer. METHODS: Mice were treated with escalating doses of BCNU chronically delivered i.c., and with chronically delivered O6BG. The O6BG was delivered via a 7-day intraperitoneal (i.p.) or i.c. osmotic minipump. Toxicity of the combination therapies was measured from survival data. Bone marrow response was estimated from white blood cell counts. RESULTS: Combining systemic (i.p.) O6BG with locally (i.c.) delivered BCNU resulted in a decrease in the maximum tolerated dose (MTD) of local BCNU. With local delivery of O6BG, the MTD of BCNU in combination with O6BG was increased. CONCLUSIONS: Based on the results of this study, a dose escalation study will be necessary when combining systemic O6BG with the higher doses of i.c. BCNU.

Developmental venous anomalies and sinus pericranii in the blue rubber-bleb nevus syndrome. Case report.

Blue rubber-bleb nevus syndrome (BRBNS) is a developmental disorder that originally was identified by the presence of distinctive cutaneous and gastrointestinal hemangiomas. More recently it has been recognized that the number of affected organs is larger and that BRBNS includes central nervous system vascular malformations. A 52-year-old woman in whom intracranial vascular malformations had been diagnosed earlier presented for evaluation. At birth, several blue nevi had been noted on her tongue, lips, and neck. Cerebral angiography demonstrated an extensive network of developmental venous anomalies and a left anterior sinus pericranii. The literature on BRBNS and developmental venous anomalies is reviewed.

Radiosensitization of malignant gliomas following intracranial delivery of paclitaxel biodegradable polymer microspheres.

OBJECT: The aim of this study was to demonstrate that paclitaxel could function as a radiosensitizer for malignant glioma in vitro and in vivo. METHODS: The radiosensitizing effect of paclitaxel was tested in vitro using the human U373MG and rat 9L glioma cell lines. Cell cycle arrest in response to paclitaxel exposure was quantified by flow cytometry. Cells were subsequently irradiated, and toxicity was measured using the clonogenic assay. In vivo studies were performed in Fischer 344 rats implanted with intracranial 9L gliosarcoma. Rats were treated with control polymer implants, paclitaxel controlled-release polymers, radiotherapy, or a combination of the 2 treatments. The study end point was survival. RESULTS: Flow cytometry demonstrated G2-M arrest in both U373MG and 9L cells following 6-12 hours of paclitaxel exposure. The order in which the combination treatment was administered was significant. Exposure to radiation treatment (XRT) during the 6-12 hours after paclitaxel treatment resulted in a synergistic reduction in colony formation. This effect was greater than the effect from either treatment alone and was also greater than the effect of radiation exposure followed by paclitaxel. Rats bearing 9L gliosarcoma tumors treated with paclitaxel polymer administration followed by single-fraction radiotherapy demonstrated a synergistic improvement in survival compared with any other treatment, including radiotherapy followed by paclitaxel treatment. Median survival for control animals was 13 days; for those treated with paclitaxel alone, 21 days; for those treated with XRT alone, 21 days; for those treated with XRT followed by paclitaxel, 45 days; and for those treated with paclitaxel followed by XRT, more than 150 days (p < 0.0001). CONCLUSIONS: These results indicate that paclitaxel is an effective radiosensitizer for malignant gliomas because it renders glioma cells more sensitive to ionizing radiation by causing G2-M arrest, and induces a synergistic response to chemoradiotherapy.

Advanced neuroimaging studies in a patient with brain metastases from transitional cell carcinoma of the bladder.

BACKGROUND AND PURPOSE: The differential diagnosis in single or oligo-brain lesions in metastatic cancer patients remains broad. Advanced imaging studies can be employed to help refine the differential and potentially guide treatment. METHODS: Case report of a 52-year-old male patient with known transitional cell carcinoma of the bladder presented with headaches, cognitive symptoms, and episodic presyncope. Brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and octreotide scans were performed to evaluate the underlying etiology of his symptoms. RESULTS: MRI revealed two enhancing mass lesions in left temporal and left cerebellar locations. Both lesions were octreotide avid and MRS of the temporal lesion showed a single large lipid peak at 1.3 ppm, a small NAA peak, and a markedly increased choline:creatine ratio that was relatively characteristic for metastases. Pathology from surgical resection revealed transitional cell carcinoma of the bladder. CONCLUSIONS: Resection of both lesions revealed metastatic transitional cell carcinoma. This is the first report of octreotide scan characteristics in a patient with transitional cell carcinoma with central nervous system (CNS) metastases. The octreotide avidity of these transitional cell CNS metastases suggests the presence of somatostatin receptors that may be considered as a potential therapeutic target.

Gliadel for brain metastasis.

With therapies for systemic malignancy improving, life expectancy for cancer patients is becoming increasingly dependent on control of brain metastatic disease. Despite improvements in surgical and radiotherapy modalities for control of brain metastasis, the prognosis for patients with brain metastases is poor. The development of controlled release polymers has lead to novel new therapies for malignant brain tumors consisting of direct surgical delivery of chemotherapy agents to the tumor bed and sustained chemotherapy release over a prolonged period of time. Although there is a large body of literature in support of BCNU polymer wafer for primary brain malignancy and experimental brain metastases, clinical studies evaluating the BCNU polymer wafer for brain metastatic disease are relatively sparse. In this review, we discuss the role of the BCNU polymer wafer for brain metastasis focusing specifically on rationale for use of locally delivered sustained release polymers, history of the BCNU polymer wafer, and emerging studies examining the role of the BCNU polymer wafer for metastatic brain tumors.

MicroRNAs in brain metastases: big things come in small packages.

Metastatic brain tumors provide a formidable obstacle in the survival of affected cancer patients, an obstacle that current treatment is essentially ineffective against. Our understanding of the metastatic cascade has demonstrated the role of incorrectly regulated protein expression and proved it to be a crucial component of this process. Recently, molecular studies have emphasized the role of microRNAs, small non-coding RNAs that alter protein expression, in the regulation of both normal and abnormal biological processes, including cancer and its metastasis to the brain. Furthermore, studies have demonstrated the ability to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on microRNA profiles. Interestingly, manipulation of microRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy, and individually directed therapy, using microRNA in the treatment of metastatic brain tumors may prove very useful. In this review, we focus on the multiple potential microRNA targets for the treatment of metastatic brain lesions as well as current and future directions for its use in gene therapy.

Chemokines in tumor progression and metastasis.

Chemokines play a vital role in tumor progression and metastasis. Chemokines are involved in the growth of many cancers including breast cancer, ovarian cancer, pancreatic cancer, melanoma, lung cancer, gastric cancer, acute lymphoblastic leukemia, colon cancer, non-small lung cancer, non-hodgkin's lymphoma, etc. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signaling. This review focuses on the role of chemokines in key processes that facilitate tumor progression including proliferation, senescence, angiogenesis, epithelial mesenchymal transition, immune evasion and metastasis.