Laser Interstitial Thermal Therapy in Glioblastoma

Laser interstitial thermal therapy is a minimally invasive ablative technique that continues to gain popularity in treatment of a variety of intracranial and spinal disorders. In the field of neuro-oncology it continues to be used for treatment of a variety of intracranial neoplasms, including glioblastoma—the most common malignant primary brain tumor. Maximizing the extent of resection in patients with glioblastoma was shown to prolong patient survival. Many patients present, however, with tumors that are nonresectable due to proximity to eloquent cortical or subcortical areas, or involvement of deep brain structures. LITT procedure, on the other hand, is minimally invasive and involves placing a laser catheter under stereotactic guidance and monitoring the size of the lesion produced as a result of laser ablation using MR thermography in real time. Therefore, a number of studies explored the potential of laser ablation to accomplish significant cytoreduction and thus potentially improve patient’s outcomes and prolong survival. The following chapter will review the principles of laser ablation and its current role in treatment of glioblastoma

Toktrapport fra det norsk/russiske økotoktet i Barentshavet og nærliggende områder

The aim of the joint Norwegian/Russian ecosystem survey in the Barents Sea and adjacent waters, August-October (BESS) is to monitor the status and changes in the Barents Sea ecosystem and provide data to support stock advice and research. The survey has since 2004 been conducted annually in the autumn, as a collaboration between the Institute of Marine Research (IMR) in Norway and the Polar branch of the VNIRO (PINRO) in Russia. The general survey plan and tasks were agreed upon at the annual IMR-PINRO Meeting in March 2022. Ship routes and other technical details are agreed on by correspondence between the survey coordinators. BESS aims at covering the entire Barents Sea. Ecosystem stations are distributed in a 35×35 nautical mile regular grid, and the ship tracks follow this design. Exceptions are the area around Svalbard (Spitsbergen), some additional bottom trawl hauls for demersal fish survey indices estimation, and additional acoustic transects for the capelin stock size estimation. Survey start for the Russian vessel was significantly delayed, resulting in REEZ being covered two-three months later than NEEZ. This resulted in reduced area coverage, decrease in the numbers of trawl hauls, and lack of standard pelagic trawl sampling. In NEEZ, RV “Kronprins Haakon” was cancelled due to difficult economic situation, making it necessary to allocate one of the two remaining vessels to the area west and north of Svalbard (Spitsbergen). This resulted in low coverage in this area, and problems with synoptic coverage in north-east of Svalbard (Spitsbergen) and thus increased uncertainty in assessment of demersal fish (e.g. Greenland halibut) and capelin. The 19-th joint Barents Sea autumn Ecosystem Survey (BESS) was carried out in two periods. The Norwegian research vessels “G.O. Sars” and “Johan Hjort” covered NEEZ in the period 16-th August to 03-th October, providing data to stock assessment, 0-group fish abundance indices, and state and changes descriptions which is comparable with earlier survey years in NEEZ. The Russian research vessel “Vilnyus” covered REEZ in the periods 20-th to 30-th September and 22-th October to 3-rd December. Survey coordinators in 2022 were Dmitry Prozorkevich (PINRO) and Geir Odd Johansen (IMR). Exchange of Russian and Norwegian experts between each country’s respective vessels did not take place in 2022. We would like to express our sincere gratitude to all the crew and scientific personnel onboard RVs “Vilnyus”, “G.O. Sars” and “Johan Hjort” for their dedicated work, as well as all the people involved in planning and reporting of BESS 2022. This report is a summary of observations and status assessment based on the survey data. Even though the survey was not well completed, the data obtained are the main source of knowledge about the ecosystem of the Barents Sea.Survey report from the joint Norwegian/Russian Ecosystem Survey in the Barents Sea and the adjacent waters August- December 2022publishedVersio

Neuregulin1-ErbB4 signaling mediates synaptic maturation and induces dendritic branching in hippocampal neurons

Central nervous system (CNS) synapse formation is a complex process that ensures precise alignment, as well as complementarity of the presynaptic and postsynaptic components. Numerous players are involved in different stages of CNS synaptogenesis, however, the list is far from complete. Neuregulin-1 (NRG1) and its receptor ErbB4 tyrosine kinase are widely expressed in the developing and adult brain. ErbB4 is specifically expressed in inhibitory GABAergic interneurons. Moreover, ErbB4 is localized to synapses and associates through it PDZ-binding motif with the postsynaptic density protein PSD-95, a major scaffolding protein involved in glutamatergic synapse stabilization and maturation. Given its location, ErbB4 is capable to take part in synapse development in GABAergic interneurons; however, little is known of its function at the synapse. In the following work, we manipulated levels of ErbB4 protein expression in primary hippocampal neuron cultures to determine the role of ErbB4 at the synapse. We found that cells overexpressing the receptor formed larger excitatory and inhibitory presynaptic terminals, while the number of synapses per unit length remained the same. This process did not depend on the kinase domain activity. Moreover, highly clustered exogenous ErbB4 recruited PSD-95 to the site of the synapse, a process dependent on the PDZ interaction, since deletion of the PDZ binding motif severely perturbed ErbB4 localization. However, ErbB4 is not a synapse inducing factor, since expression in heterologous cells failed to induce presynaptic differentiation.Medicine, Faculty ofGraduat

Laser Interstitial Thermal Therapy for Posterior Fossa Lesions: An Initial Experience

© 2018 Elsevier Inc. Background: The application of laser interstitial thermal therapy (LITT) for intracranial lesions in the posterior fossa tumors remains challenging due to the smaller size of this compartment as well as the thickness and angle of the occipital bone. In this study, we reviewed our experience with this treatment modality for posterior fossa lesions. Methods: We retrospectively reviewed our series of 8 patients with posterior fossa tumors treated with LITT from an Institutional Review Board–approved brain tumor database (2012–2017) of more than 200 cases at our institution. Results: The 8 patients underwent LITT targeting 3 metastases, 2 pilocytic astrocytomas, 2 zones of radiation necrosis after radiosurgery, and 1 glioblastoma (GBM). The mean preoperative lesion volume was 4.35 cm3. A 6 months postsurgery, the mean lesion volume had decreased from 9.64 cm3 to 5.72 cm3. Two of the tumors (the GBM and a metastatic adenocarcinoma) progressed after 8.5 and 7.5 months, respectively, with mortality after 1.1 and 1.6 years, respectively. Surgical resection was performed in a patient with metastatic adenocarcinoma tumor at 7.7 months after LITT. All other lesions remained stable or were diminished at a median follow-up of 14.8 months (range, 0.4–37.5 months). Magnetic resonance imaging (MRI) on the first postoperative day, showed an increase in mean tumor-related edema volume from 9.45 cm3 to 14.10 cm3. After a postoperative follow-up of at least 1 month, this mean decreased to 8.70 cm3. One case each of transient partial unilateral sixth cranial nerve palsy, superficial wound infection, and a late obstructive hydrocephalus were noted postoperatively. No mortality was associated with the procedure. Conclusions: LITT is a safe and feasible treatment modality even in challenging locations like the posterior fossa. However, surgical indications should be tailored for each individual patient based on the size and location of tumor

Impact of Multi-modality Monitoring Using Direct Electrical Stimulation to Determine Corticospinal Tract Shift and Integrity in Tumors using the Intraoperative MRI

Abstract Introduction  Preserving the integrity of the corticospinal tract (CST) while maximizing the extent of tumor resection is one of the key principles of brain tumor surgery to prevent new neurologic deficits. Our goal was to determine the impact of the use of perioperative diffusion tensor imaging (DTI) fiber-tracking protocols for location of the CSTs, in conjunction with intraoperative direct electrical stimulation (DES) on patient neurologic outcomes. The role of combining DES and CST shift in intraoperative magnetic resonance imaging (iMRI) to enhance extent of resection (EOR) has not been studied previously. Methods  A total of 53 patients underwent resection of tumors adjacent to the motor gyrus and the underlying CST between June 5, 2009, and April 16, 2013. All cases were performed in the iMRI (BrainSuite 1.5 T). Preoperative DTI mapping and intraoperative cortical and subcortical DES including postoperative DTI mapping were performed in all patients. There were 32 men and 21 women with 40 high-grade gliomas (76%), 4 low-grade gliomas (8%), and 9 (17%) metastases. Thirty-four patients (64%) were newly diagnosed, and 19 (36%) had a previous resection. There were 31 (59%) right-sided and 22 (42%) left-sided tumors. Eighteen patients (34%) had a re-resection after the first intraoperative scan. Most patients had motor-only mapping, and one patient had both speech and motor mapping. Relative to the resection margin, the CST after the first iMRI was designated as having an outward shift (OS), inward shift (IS), or no shift (NS). Results  A gross total resection (GTR) was achieved in 41 patients (77%), subtotal resection in 4 (7.5%), and a partial resection in 8 (15%). Eighteen patients had a re-resection, and the mean EOR increased from 84% to 95% ( p  = 0.002). Of the 18 patients, 7 had an IS, 8 an OS, and in 3 NS was noted. More patients in the OS group had a GTR compared with the IS or NS groups ( p  = 0.004). Patients were divided into four groups based on the proximity of the tumor to the CST as measured from the preoperative scan. Group 1 (32%) included patients whose tumors were 0 to 5 mm from the CST based on preoperative scans; group 2 (28%), 6 to 10 mm; group 3 (13%), 11 to 15 mm; and group 4 (26%), 16 to 20 mm, respectively. Patients in group 4 had fewer neurologic complications compared with other groups at 1 and 3 months postoperatively ( p  = 0.001 and p  = 0.007, respectively) despite achieving a similar degree of resection ( p  = 0.61). Furthermore, the current of intraoperative DES was correlated to the distance of the tumor to the CST, and the regression equation showed a close linear relationship between the two parameters. Conclusions  Combining information about intraoperative CST and DES in the iMRI can enhance resection in brain tumors (77% had a GTR). The relative relationship between the positions of the CST to the resection cavity can be a dynamic process that could further influence the surgeon's decision about the stimulation parameters and EOR. Also, the patients with an OS of the CST relative to the resection cavity had a GTR comparable with the other groups

Phase 0 and Window of Opportunity Clinical Trial Design in Neuro-Oncology: A RANO Review

Glioblastoma is a devastating disease with poor prognosis. Few effective chemotherapeutics are currently available, and much effort has been extended to identify new drugs capable of slowing tumor progression. The phase 0 trial design was developed to facilitate early identification of promising agents for cancer that should undergo accelerated approval. This design features an early in-human study that enrolls a small number of patients that receive sub-therapeutic doses of medication with the goals of describing pharmacokinetics through drug blood level measurements, and by determining intra-tumoral concentrations of the investigational compound as well as pharmacodynamics by studying the biochemical and physiological effects of drugs. In neuro-oncology, however, the presence of the blood-brain barrier and difficulty in obtaining brain tumor tissue warrant a separate set of considerations. In this manuscript, we critically reviewed the protocols used in all brain tumor related in-human phase 0 and phase 0-like ("window of opportunity") studies between 1993 and 2018, as well as ongoing clinical trials, and identified major challenges in trial design as applied to central nervous system tumors that include surgical specimen collection and storage, brain tumor drug level analysis, and confirmation of drug action. We therefore propose that phase 0 trials in neuro-oncology should include 1) only patients in whom a resection of the tumor is planned, 2) use of clinical doses of an investigational agent, 3) tissue sampling from enhancing and non-enhancing portions of the tumor, and 4) assessment of drug-specific target effects. Standardization of clinical protocols for phase 0/window of opportunity studies can help accelerate the development of effective treatments for glioblastoma

Pathologic Correlation of Cellular Imaging Using Apparent Diffusion Coefficient Quantification in Patients with Brain Metastases After Gamma Knife Radiosurgery

© 2019 Elsevier Inc. Objective: To evaluate the role of apparent diffusion coefficient (ADC) in differentiating radiation necrosis (RN) from recurrent tumor after Gamma Knife radiosurgery (GKRS) for brain metastases (BMs). Methods: Forty-one patients with BM who underwent surgical intervention after GKRS at Cleveland Clinic (2006–2017) were included in this retrospective study. The ADC values of the growing lesions and the contralateral hemisphere were calculated using picture archiving and communication system. These values were correlated to the percentage of RN identified on pathologic evaluation of the surgical specimen. Results: The median age of the patients was 59 years (range, 25–86 years), and lung cancer (63.4%) was the most common malignancy. Median initial (pre-GKRS) target volume of the lesions was 5.4 cc (range, 0.135–45.6 cc), and median GKRS dose was 18.0 Gy. Surgical resection or biopsy was performed at a median of 176 days after GKRS. Two variables were statistically significant predictors of predominate RN (75%–100%) in the surgical specimen: 1) ADC of the lesion on the preresection magnetic resonance imaging (MRI) and 2) initial pre-GKRS target volume. ADC \u3e1.5 × 10−3 mm2/s within the lesion on MRI predicted significant RN on pathologic evaluation of the lesion (P \u3c 0.05). Similarly, when the target volume before GKRS was large (\u3e10 cc), the risk of identifying significant necrosis in the pathologic specimen was elevated (P \u3c 0.05). Conclusions: Our data suggest that the combination of lesion ADC on MRI prior to surgical intervention and the initial target volume can predict RN with reasonable accuracy