Akihide Kondo

Phase IIa clinical study of [(18)F]fluciclovine: efficacy and safety of a new PET tracer for brain tumors.

Objective[18F]Fluciclovine (anti-[18F]FACBC) has demonstrated diagnostic efficacy for cancers of the brain where [18F]fludeoxyglucose has limitations. We conducted a phase IIa study of anti-[18F]FACBC to assess its accumulation pattern and safety in patients with malignant glioma.MethodsFive patients with glioma scheduled for brain tumor resection received anti-[18F]FACBC. Brain positron emission tomography (PET) was performed following intravenous administration of anti-[18F]FACBC, and subsequently, preoperative gadolinium contrast-enhanced T1-weighted (CE-T1W) magnetic resonance imaging (MRI) was performed for surgery. Specimens for histopathological evaluation were collected during surgery, and their location was precisely determined on CE-T1W MRI and anti-[18F]FACBC PET/CT images. In addition, tumor extent defined on the MRI and PET/CT images was compared. To determine time–activity curves for anti-[18F]FACBC uptake in brain tumor and normal tissues, regions of interest were set in the brain tumor, contralateral normal tissue and the cerebellum, and their standardized uptake values (SUV) were calculated. The safety of anti-[18F]FACBC was assessed based on subjective symptoms and objective findings, electrocardiograms, vital signs, laboratory results, and the incidence of adverse events.ResultsAnti-[18F]FACBC accumulated in the malignant gliomas of all patients. CE-T1W MRI detected gliomas in all patients, but anti-[18F]FACBC PET/CT generally delineated wider regions of tumor extent than CE-T1W MRI. Two of the histopathologically confirmed tumors were located in regions that were defined using anti-[18F]FACBC PET/CT, but not using CE-T1W MRI. Two patients experienced three mild adverse events: one complained of a dull headache and later a mild headache, and the other showed general malaise. These symptoms resolved spontaneously without treatment. Only the mild headache could not be ruled out from having a causal relationship with anti-[18F]FACBC. Favorable T/N ratios regarding anti-[18F]FACBC uptake between tumors and normal control tissues were demonstrated in this trial.ConclusionsIt is suggested that anti-[18F]FACBC PET/CT has the ability to delineate glioma spread that is undetectable using CE-T1W MRI. Anti-[18F]FACBC is safe in patients with malignant glioma.This study was registered in the Japan Pharmaceutical Information Center Clinical Trials Information, which is one of the World Health Organization registries (registration number: JapicCTI-111387).

Longitudinal assessment of regional directed delivery in a rodent malignant glioma model: Laboratory investigation

OBJECT Direct delivery of chemotherapeutic agents for the treatment of brain tumors is an area of focus in the development of therapeutic paradigms because this method of delivery circumvents the blood-brain barrier without causing adverse systemic side effects. Few studies have investigated longitudinal tumor response to this type of therapy. In this study, the authors examined the time course of tumor response to direct delivery of a chemotherapeutic agent in a rodent malignant glioma model. METHODS To visualize tumor response to chemotherapy, the authors used bioluminescence imaging in a rodent model. Rat 9L gliosarcoma cells expressing a luciferase gene were inoculated into adult male rat striata. Ten days following surgery the animals were randomly divided into 4 groups. Groups 1 and 2 received 20 and 40 microl carboplatin (1 mg/ml), respectively, via convection-enhanced delivery (CED); Group 3 received 60 mg/kg carboplatin intraperitoneally; and Group 4 received no treatment. Tumor growth was correlated with luminescence levels twice weekly. RESULTS Differential growth curves were observed for the 4 groups. Systemically treated rats showed decreasing photon flux emission at 15.0 + or - 4.7 days; rats treated with 20- or 40-microl CED showed decreased emissions at 4.0 + or - 2.0 and 3.2 + or - 1.3 days after treatment, respectively. Histopathologically, 6 of 12 CED-treated animals exhibited no residual tumor at the end point of the study. CONCLUSIONS Direct and systemic delivery of carboplatin was examined to determine how the method of drug delivery affects tumor growth. The present report is one of the first in vivo studies to examine the time course of tumor response to direct drug delivery. The results indicate that direct drug delivery may be a promising option for treating gliomas.

An experimental brainstem tumor model using in vivo bioluminescence imaging in rat

PurposeCurrently, there is no conclusive treatment for brainstem tumor. To facilitate the development of new treatments, it is essential to establish predictive preclinical in vivo models in which therapeutic modalities can be evaluated. Although a few rodent models have been reported, there is no novel approach that can monitor tumor response qualitatively and quantitatively.Materials and methodsBioluminescence imaging was used to characterize a rat brainstem tumor model. In this model, 9L gliosarcoma cells, transduced with an onco-retroviral vector containing the luciferase coding sequence, were inoculated into Fisher 344 rats.ResultHistopathological assessment showed successful cell implantation into the brainstem. There was a strong correlation between pathological tumor volume and luminescence strength. Longitudinal quantitative responses of the tumor after application of a therapeutic agent were also demonstrated.ConclusionThis study demonstrates a robust rodent model with the ability to monitor brainstem tumor growth and response to chemotherapeutic agents.

A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain

Malignant rhabdoid tumors (MRTs) are deadly embryonal tumors of the infancy. With poor survival and modest response to available therapies, more effective and less toxic treatments are needed. We hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors.

Microsurgical anatomy of the maxillary artery for extracranial-intracranial bypass in the pterygopalatine segment of the maxillary artery

The extracranial‐intracranial (EC‐IC) bypass using the maxillary artery (MA) has been successfully completed using a radial artery (RA) graft but the complicated anatomy and narrow exposure make it difficult. The purpose of this article is to define the microsurgical exposure of the MA through the middle fossa and describe the branches, diameter, and length of the MA available for the EC‐IC bypass in the sphenopalatine fossa and anterior part of the infratemporal fossa. 5 cadaveric specimens were dissected bilaterally (10 MA dissections) to define the microsurgical anatomy of the MA through an intracranial approach. The exposable branches of the MA at the level of the infratemporal and sphenopalatine fossae were the anterior deep temporal, posterior superior alveolar, and infraorbital arteries. The origin of each branch could be exposed. The available section of the MA for use as a donor vessel is between the origin of the anterior deep temporal artery and the infraorbital artery. The mean exposable length of the MA was 19.4 mm. The mean outer diameter of the donor MA was 3.2 mm. Tension‐free EC‐IC bypass was possible using a RA graft between the MA and the middle cerebral artery, the MA and the supraclinoid internal carotid artery (ICA), or the MA and the petrous ICA. Exposure of the MA at the infratemporal and sphenopalatine fossae is complicated but provides length and diameter suitable as a donor artery for the EC‐IC bypass. Clin. Anat. 31:724–733, 2018.

Overexpression of TEAD4 in atypical teratoid/rhabdoid tumor: New insight to the pathophysiology of an aggressive brain tumor

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant embryonal brain tumor that occurs mainly in early childhood. Although most of the tumors are characterized by inactivating mutations of the tumor suppressor gene, SMARCB1, the biological basis of its tumorigenesis and aggressiveness is still unknown.

Decreased Expression of hsa-miR-4274 in Cerebrospinal Fluid of Normal Pressure Hydrocephalus Mimics with Parkinsonian Syndromes

Background: Patients presenting with the classical idiopathic normal pressure hydrocephalus (iNPH) triad often show additional parkinsonian spectrum signs. Accurate differential diagnosis strongly influences the long-term outcome of cerebrospinal fluid (CSF) shunting. Objective: The aim of this study was to find potential CSF microRNA (miRNA) biomarkers for NPH mimics with parkinsonian syndromes that can reliably distinguish them from iNPH patients. Methods: Two cohorts of 81 patients (cohort 1, n = 55; cohort 2, n = 26) with possible iNPH who were treated in two centers between January 2011 and May 2014 were studied. In both cohorts, CSF samples were obtained from patients clinically diagnosed with iNPH (n = 21 and n = 10, respectively), possible iNPH with parkinsonian spectrum (PS) (n = 18, n = 10, respectively), possible iNPH with Alzheimer’s disease (AD) (n = 16), and non-affected elderly individuals (NC) (n = 6). A three-step qRT-PCR analysis of the CSF samples was performed to detect miRNAs that were differentially expressed in the groups. Results: The expression of hsa-miR-4274 in CSF was decreased in both cohorts of PS group patients (cohort 1: p < 0.0001, cohort 2: p < 0.0001), and was able to distinguish PS from iNPH with high accuracy (area under the curve = 0.908). The CSF concentration of hsa-miR-4274 also correlated with the specific binding ratio of ioflupane (123I) dopamine transporter scan (r = –0.494, p = 0.044). By contrast, the level of hsa-miR-4274 was significantly increased in the PS group after CSF diversion. Conclusion: Levels of CSF hsa-miR-4274 can differentiate PS from patients with iNPH, AD, and NC. This may be clinically useful for diagnostic purposes and predicting shunt treatment responses.

Microsurgical anatomy and approaches around the lateral recess with special reference to entry into the pons

OBJECTIVE The lateral recess is a unique structure communicating between the ventricle and cistern, which is exposed when treating lesions involving the fourth ventricle and the brainstem with surgical approaches such as the transcerebellomedullary fissure approach. In this study, the authors examined the microsurgical anatomy around the lateral recess, including the fiber tracts, and analyzed their findings with respect to surgical exposure of the lateral recess and entry into the lower pons. METHODS Ten cadaveric heads were examined with microsurgical techniques, and 2 heads were examined with fiber dissection to clarify the anatomy between the lateral recess and adjacent structures. The lateral and medial routes directed to the lateral recess in the transcerebellomedullary fissure approach were demonstrated. A morphometric study was conducted in the 10 cadaveric heads (20 sides). RESULTS The lateral recess was classified into medullary and cisternal segments. The medial and lateral routes in the transcerebellomedullary fissure approach provided access to approximately 140º-150º of the posteroinferior circumference of the lateral recess. The floccular peduncle ran rostral to the lateral recess, and this region was considered to be a potential safe entry zone to the lower pons. By appropriately selecting either route, medial-to-lateral or lateral-to-medial entry axis is possible, and combining both routes provided wide exposure of the lower pons around the lateral recess. CONCLUSIONS The medial and lateral routes of the transcerebellomedullary fissure approach provided wide exposure of the lateral recess, and incision around the floccular peduncle is a potential new safe entry zone to the lower pons.

Prosthetic material degeneration over time as a possible factor in delayed recurrence of hemifacial spasm after successful microvascular decompression

Background: The effectiveness of microvascular decompression in treating hemifacial spasm is widely accepted. However, some experience recurrence of hemifacial spasm after successful decompression surgery. Especially, delayed recurrence more than 5 years after surgery is rare and the cause of this phenomenon is unknown. Case Description: A female underwent microvascular decompression to treat her hemifacial spasm 6 years ago. Six years later, her hemifacial spasm recurred and she underwent a second surgery. The second surgery revealed that the sponge had become fragile, losing the ability to absorb the impact of pulsatile compression of the offending artery on the root exit zone of her facial nerve. Conclusion: We report a case in which degeneration of material, a sponge (polyurethane), used in decompression surgery caused delayed recurrence of hemifacial spasm. The selection of appropriate prosthetic materials is essential in such functional surgeries.

Communicating hydrocephalus and coexisting nonenhancing tumor: An ominous sign for patients with neurofibromatosis type 1?

A 26-year-old woman with familial neurofibromatosis type 1 sustained headache that worsened for 1 month. Neuroimaging revealed a mild ventriculomegaly and nonenhancing lesion in the pons. In spite of repeated cerebrospinal fluid examinations and magnetic resonance imaging, the etiology was not determined. The affected pons markedly enlarged in the following 2 months, with extensive leptomeningeal dissemination. Biopsy through hemilaminectomy of the T9 was diagnosed as glioblastoma multiforme. Prompt histologic examination should be performed when patients with familial neurofibromatosis type 1 manifest communicating hydrocephalus coexistent with a nonenhancing tumor.