Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioma

Brain Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroepithelioma

This is a device feasibility study, therefore participants will only be enrolled into the investigational arm and will receive the RNS System Implantation.

Following resection consistent with SoC, if there is evidence of residual tumor which cannot be resected due to invasion of hand-M1 but which is small enough to be covered by two four-electrode strips, these strips will be placed on the functional cortex of interest and secured to the dura. The location of the leads will be registered into the navigation software (either Medtronic Stealth or Brainlab). The dura will then be closed as watertight as possible, and the RNS System will be incorporated into the craniotomy on closure Prior to closure, four bone screws will be placed and registered to the intraoperative navigation system as internal fiducials to be retrieved for future procedures.

RNS System Implantation

Sarah Cornell

Max Krucoff, MD

This study uses a cranial implant to deliver cortical stimulation that, when paired with physiotherapy, will remap the brain so that critical brain functions can be protected during brain tumor surgery. This pilot study will provide initial evidence for the safety and feasibility of such a protocol which will lead to future pivotal trials that could radically change eloquent area brain surgery. For patients with otherwise incompletely resectable brain tumors, this could mean a longer life expectancy and a better quality of life.

Study Protocol: Participants will undergo a standard-of-care craniotomy for resection of low-grade glioma. If part of the lesion cannot be removed due to involvement of functional cortex, RNS (Responsive Neurostimulation System \[RNS; NeuroPace, Inc.\]) electrodes will be implanted over the tumor-invaded area(s) in five participants. Stimulation will then be optimized for each individual to disrupt the function of the invaded cortical node (e.g., hand motor area -\> hand dysfunction) (Aim 1). Over the next two months, outpatient physiotherapy will work to overcome the stim-induced deficits through gradual increases in stimulation amplitude as other, non-stimulated brain regions begin to assume its function (Aim 2). Once complete, participants will return to the OR for device explantation, repeated intraoperative mapping, and extended resection (if safe) (Aim 3).

Aim 1: Optimize stimulation to maximize stim-induced deficits and minimize side effects Rationale: To induce plasticity, stimulation parameters must be individually tuned to maximize effect and minimize side effects. Approach: After device implantation and prior to hospital discharge, stimulus settings (frequency, pulse-width, and amplitude) will be optimized to the relevant clinical response while minimizing adverse effects (e.g., focal tonus, myoclonus, or seizures) while still in the safe, inpatient setting. Outcomes: Primary Endpoints: 1) stim-induced focal clinical deficit as measured on the relevant clinical scale (e.g., manual motor score \[0-5\], picture naming \[x/10\]), repetition \[x/3\]); 2) stim-induced side effects (e.g., seizures).

Aim 2: Evaluate extent of remapping and safety of outpatient stimulation-physiotherapy protocol. Rationale: The ability to deliver chronic, outpatient stimulation is vital for practical clinical translation, yet neither its safety nor efficacy has been demonstrated. Approach: After Aim 1, a physiotherapist will assign a personalized, outpatient therapy regimen aimed at overcoming stim-induced deficits. Participants will have daily virtual sessions and return to clinic 2x/week for amplitude increases to re-induce deficits that therapy has overcome. This will continue until stimulation no longer can induce a deficit, suggesting successful functional remapping and enabling a return to the OR for further resection. Outcomes: Primary Endpoints: 1) absence of stim-related ER visits, readmissions, or serious adverse events (safety), 2) changes in intraop stimulation maps from surgery 1 to surgery 2 (induced remapping).

Aim 3: Evaluate ability to extend surgical resections and associated neurological outcomes. Rationale: Any change in functional boundaries will only be useful if it results in a safe, extended resection. Approach: Each surgery will proceed with standard-of-care intraoperative functional mapping techniques and decision making. Neurological examinations will be performed preoperatively, daily while inpatient, then again at 2-weeks and 3-months postoperatively. Extent of resection will be evaluated as 3D residual tumor volume on postoperative MRI. Outcomes: Primary Endpoint: 1) Change in residual tumor volume after second versus first resection, 2) new neurological deficits 3-months after second resection compared to before second resection. Secondary Endpoint: 1) New, temporary neurological deficits after the second surgery

A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas

Inducing Functional Plasticity in Glioma-Involved Functional Cortex With Deficit-Inducing Cortical Stimulation and Targeted Behavioral Therapy to Increase Extent of Resection

Calculated as: Tumor volume after second surgery - tumor volume before second surgery. Determination of volumes will be made by an attending radiologist without knowledge of clinical outcome. Manual segmentation will be performed to measure tumor volumes based on fluid-attenuated inversion recovery (FLAIR) axial slices.

Calculated as manual muscle score (MMS) before stimulation - MMS after stimulation.

MMS is a zero-to-five scale assessed as the following:

5 - normal strength 4 - give away weakness 3 - movement against gravity 2 - movement in anti-gravity position

1 - muscle twitch 0 - no movement

3a. Calculated as picture naming score (x/10) before stimulation minus after stimulation.

3b. Calculated as sentence repitition score (x/3) before stimulation minus after stimulation.

Reported as number of unintended stimulation effects, such as myoclonus, tonus, seizures, or unpleasant sensations

Reported as number of stimulation- or physiotherapy related ER visits, readmissions, or serious adverse events

This outcome will be reported as a descriptive variable, calculated as changes in the intraoperative stimulation map obtained during surgery 2 compared to surgery 1

Any new, permanent neurological deficits resulting from the second surgery

Medical College of Wisconsin

Assistant Professor of Neurological Surgery

EG will perform complementary cognitive and physical training (120 min./5/per week during study observation)

CG will be provided with normal hospital care during RT and next will conduct a normal daily activity at home.

Patients selected to EG will carry out complementary cognitive and physical training under supervision of rehabilitation staff. For neuropsychological exercises, the investigators will use the RehaCom system - high quality scientific neurocognitive disorder therapy programs and software. (Time: 30 min./5 times/week per patient during RT). In this time, EG patients will do physical training (such as cycling, running on properly calibrated equipment for the circulatory system parameter measurement (1hour/ 5 days/ week), and neuromuscular and cognitive reeducation exercises using a technically advanced tool - Neuroforma computer software - 30 min/ 5 times/ week). After the end of RT, patients in EG will do a special exercise training at home under supervision of staff from the Department of Rehabilitation, and cognitive training using special tasks (3 times an hour/per week) at home, and two times/week using RehaCom and Neuroforma (60 min/sesion) in our cancer ceter.

Exercise treatment

Katarzyna Hojan, MD, PhD

Ewa Tańska, PhD

Primary and secondary brain tumors are a constant challenge for the medicine. Tissue sensitivity to ionizing radiation differs and depends on numerous factors and the same dose of radiation may produce different effects in particular structures of the CNS. It can also affect the surrounding healthy tissues and lead to adverse effects like the cognitive or physical function impairment. One of brain structures most sensitive to ionizing radiation is the limbic system, especially the hippocampus, because it is here that the postnatal neurogenesis takes place via neural stem cells, which are a self-renewing population of precursor cells. There have been no studies that would thoroughly examine the impact of different CNS radiation therapy techniques on the cognitive function, potential neuroplasticity markers or blood-brain barrier damage in brain tumor patients with a concomitant use of neurocognitive combination therapies or physical exercise, and their impact on the CNS function.

The aim of the study is to assess the impact of selected RT techniques: IMRT, WBRT, and CyberKnife (SRS) on the processes regulating cognitive and physical function in patients with primary (Group III and IV, WHO, 2016) and metastatic CNS tumors. The secondary objective is the analysis of the effect of selected forms of neurorehabilitation on the parameters studied. The study will be a prospective clinical trial conducted in 150 patients. Patient evaluation will be carried out before RT, after RT, during a follow-up visit-3 months after RT, and finally after 6 months. The methods will be used: analysis of the blood-brain barrier permeability markers including exact connection proteins, markers confirming neuroplasticity of the brain, cerebral secretory activity, and onco- and anti-neuronal antibody activity, brain structure analysis (MRI) and volume testing of selected brain structures, and assessment of cognitive and physical function of the patients. The study will be a part of the search trend aiming to explain the mechanism of the formation of cognitive-behavioral disorders in humans based on the most fundamental principles governing information processing in CNS, and the impact of neoplasia and ionizing radiation on selected brain structures and functions. The results of the study might become a starting point for the formulation of new guidelines on the level of physical activity or cognitive exercise in patients treated with CNS radiation therapy.

Every year, thousands of patients worldwide undergo radiotherapy (RT) for primary brain tumors (BT) and brain metastases originating from extracranial tumors. Radiation injury is multifactorial and is characterized by e.g. vascular abnormalities, inflammation, gliosis, demyelination, and often at high doses, white matter necrosis. Standard treatment of BT includes high dose megavoltage radiation to the cranial vault, but 50-90% of overall survivors exhibit impaired cognition and functional dysfunction. The radiation cognitive syndrome is still poorly understood, and there is no effective prevention or long-term treatment. Therefore, the investigators will analyze specific molecular markers which may have a relationship with morfological changes in the brain, its secretive and imunological role as well as cognitive function and postulate that previously undetected and comparatively subtle early manifestations of irradiation damage to CNS may synergize over time to form macro- and microstructural abnormalities. The investigators plan to corroborate a hypothesis that impairment of cognitive and motor functions in patients undergoing RT can be limited. In study, the investigators will quantitatively and objectively evaluate the effects of exercise on brain activity during cognitive and physical training in BT patients treated with RT. Therefore, specific objectives include: 1. Analysis of the molecular mechanism in BBB disruption. 2. Multidimensional analysis of specific neuroplasticity markers, onconeural-antibodies etc. 3. Assessment of the volume of the brain structures and their morphology. 4. Analysis of the results of neurocognitive and functional tests.

Significance of the project The Response Assessment in Neuro-Oncology working group recommended that neurocognitive outcome should be considered one of the primary endpoints in BT clinical trials. Despite the importance and clear concern about radiation-induced cognitive decline, the pathophysiology driving the progression of this syndrome remains poorly understood, and there are no effective preventative measures or long-term treatments. To date, there has been no study comparing different techniques of irradiation, namely intensity-modulated photon RT (IMRT), whole brain RT (WBRT), and stereotactic radiosurgery (CyberKnife), in BT patients in the aspect of pathophysiology of BBB or immunological aspects, as well as neurogenesis, neuroplasticity. These methods will be rely on a detailed understanding of radiation dose-volume effects, which link the incidence and severity of neurocognitive and functional impairment to specific volumes and morphology of normal brain. Possible explanations for the preservation of cognition and behavior include the resiliency of the cerebellum, frontal and tempo-parietal lobes, the hippocampus-mammillary complex and other supratentorial regions. Radiation is now known to suppress the proliferation of progenitor cells and their differentiation into neurons. The relatively recent discovery of neural stem cells in discrete areas of the brain is the impetus behind the most recent potential target for radiation. Early changes below the gross anatomical level, including a decline in neurogenesis, microvascular damage, subtle loss of white matter integrity, and disturbances of neuronal morphophysiology, may interact and progressively alter neuronal stem cell niches to impede neuronal function, viability, and progenitor cell differentiation. Therefore, the investigators will thoroughly observe the mechanism of neurogenesis and the possible improvement of neuroprotection and neuroregeneration in BT patients undergoing various forms of RT. Previous research has shown that physical exercise in healthy people is associated with increased structural and functional integrity in regions that overlap with brain functions, including the frontal, motor cortex, and the cerebellum. The precise neurobiological mechanism for cognitive effects of rehabilitation remains unknown, however a vast rodent literature supports a central role of protective neurotrophins, which have been shown to facilitate production of new neurons in the hippocampus, promote synaptic plasticity in cerebral cortex, and enhance growth and protection of neurovasculature and suggests exercise may promote formation and strengthening of connections between the hippocampus and its widespread cortical connections, which improve cognitive and behaviour functioning. However, the specific brain structure and function regions activated during rehabilitation exercise in patients with BT during oncological treatment still remain largely undefined. The study results obtained in this project will provide new knowledge about metabolic and structural pathways of the CNS in the context of RT and will also provide the basis for the development of regenerative medicine in oncology.

Work plan The investigators will conduct study in the Greater Poland Cancer Centre. The participants will be enrolled in this study according study criteria from the Department of Radiotherapy after medical assessment by an oncologist (physician). Evaluation of the all subjects will be carried out: at baseline (T0), one month after RT (T1), and control (T2) - 3 months after RT and final (T3) - 6 months after RT (unless there is a deterioration of health making the assessment impossible, or death). The investigators will monitor the patients by:

A. Analysis of the patient's blood serum: 1/ markers of BBB disruption: S-100β and circulating tight junction-related proteins (occludin, claudin-5, zonula occludens-1); 2/ factors with potential effect on neuroplasticity - immune-cell production of neurotrophins e.g. brain-derived neurotrophic factor, beta-nerve growth factor, neurotrophin-3, neurotrophin-4/5; 3/ activity of carnosinase and its isoenzymes; 4/ onconeural antibodies (anti-Hu, anti-Ri, anti-Yo, anti-Ma/Ta, anti-Cv2, and anti-amphiphysin as well as anti-myelin, anti-MAG, anti-GAD) and anti-surface neuronal antigens (anti-NMDA, anti-AMPA, anti-GABA, anti-DPPX, anti-LGI1, anti-CASPR) to investigate correlations with types of BT, RT, and possible paraneoplastic syndromes or cognitive impairment.

B. Assessment of brain structures and volume testing of selected brain structures.

C. Cognitive and functional assessment using clinical tests. All participants groups treated with different RT techniques (three groups) will by randomly divided to two subgroups: exercise subgroup - EG (these are the patients who will have regular cognitive and physical training) and second subgroup (control group - CG).

Analysis of risk in planned study will be connected with failure to reach targeted number of patients (the investigators will enlarge the recruitment pool across additionally cancer hospitals) or increase dropout rate (motivational information will be provided to participants and clinicians). The Greater Poland Cancer Centre has very modern research infrastructure allowing for execution of the proposed project.

Methods of research The study protocol was accepted by the Ethics Committee of Poznan University of Medical Sciences (No. 703/18), and each recruited participant will be given a written informed consent. The investigators will enroll patients with BT using the updated 2016 edition of the World Health Organization Classification of Tumors of CNS which uses molecular parameters and the histology to define the main tumor categories for the first time. The investigators will analyze 150 patients together with three different CNS groups of tumors: from III and IV brain tumor groups, and metastatic tumors. The study will include patients with BT enrolled to RT, between 18-70 y o , in good general health conditions (according to Eastern Cooperative Oncology Group 0-2), after obtaining informed consent for participation in the study. The investigators are planning to exclude patients with numerous tumors (\> 2), with psychological or psychiatric illnesses treated pharmacologically, or with other neurological disorders (e.g. sclerosis multiplex, Parkinson's disease, meningitis, etc.), or significant clinical circulatory failure (\> III NYHA). Enrolled patients will be treated with the one of three RT techniques in the Department of Radiotherapy: 1) CyberKnife, which relies on precise 3D imaging and localization to deliver ablative doses of radiation to the tumor, and can significantly reduce exposure of healthy brain tissue (18 Gy per dose to total 66 Gy) or 2) IMRT using conventional fractionation of 1.8 Gy per day to total dose 54 Gy or 2 Gy per dose to the total dose 60 Gy) or 3) WBRT as the treatment choice for metastatic tumors - the fractionation schedule used is 30 Gy delivered in 10 fractions or 20 Gy in 5 days. Participants randomly selected to EG will perform cognitive and physical training (120 min./5 times per week during study observation) conducted by rehabilitation staff who will be employed for this project: physiotherapist and neuropsychologist. For neuropsychological rehabilitation, the investigators will use the RehaCom system - a special neurocognitive programs and software. During RT, EG will do physical training (such as cycling, running on properly calibrated equipment as well as neuromuscular reeducation exercises using advanced technical tool - Neuroforma computer software) with maximum heart rate to 70%HRmax. After RT, participants in EG will do special exercise training at home under supervision of the hospital staff. Participants from CG will be provided with normal hospital care during RT and next will conduct a normal daily activity at home. According to the study evaluation plan, all participants will be observed before and after end of RT, and during control visits (T2, T3) at cancer center. Patients' blood samples will be collected in the Laboratory Ward in the morning, before breakfast according to the study plan. The investigators will evaluate individual markers in the Department of Radiobiology in collaboration from the Department of Neurochemistry and Neuropathology at Poznan University of Medical Sciences, because the Radiobiology Laboratory is fully equipped with all specialized, high-tech instruments required for the execution of this project.. In the Department of Rehabilitation in cancer center, all study participants will be evaluated in terms of cognitive and physical functioning. Raw cognitive test scores will be compared with published normative values according to age and to education. The investigators will include in the study evaluation with the use of Mini-Mental State Examination (MMSE), Benton Visual Retention Test (BVRT), California Verbal Learning Test (CVLT), Color trials test (CTT), Wisconsin Card Sorting Test (WCST), Trail Making Test A and B (TMT A \& B), Montreal Cognitive Assessment (MoCA) 7.2 scale, and Addenbrooke's Cognitive Examination III (ACE III) test as well as the Psychology Experiment Building Language (PEBL) software for objective evaluation of selected cognitive and behavior functions. For general assessment of physical, psychological and social function the investigators will use the Functional Independence Measures (FIM) scale. This will be an unprecedented study yielding unique results on neuroscience in the process of cancer treatment with modern techniques.

The Cognitive-Behavioral Dysfunctions and the Potential of Neuroplasticity in Brain Tumors Patients During Radiotherapy

Analysis of the Cognitive-behavioral Dysfunctions Profile and the Potential of Neuroplasticity in Patients With Brain Tumors Subjected to Selected Radiotherapy Techniques and the Possibility of Their Compensation by Psycho-physical Training

The study will include neurological examination and clinimetric evaluation according the Polish Psychological Association with the use of Montreal Cognitive Assessment (MoCA) 7.2 scale as well as the Psychology Experiment Building Language (PEBL) software for objective evaluation of selected cognitive and behavior functions.

For general assessment of physical, psychological and social function the investigators will use the Functional Independence Measures (FIM; min. 0 - max.126) system. Higher scores means better outcome. It is the scoring system that may be able to objectively determine impairments in different domains.

The astrocytic protein S-100β will be estimated using enzyme-linked immunoassay (ELISA).

To estimate circulating tight junction-related proteins (OCLN, CLDN5, ZO-1) concentrations, rabbit anti - human OCLN antibodies will be used.

Onconeural antibodies will be identified with indirect immunofluorescence and confirmed with Line blott with the use of recombinants.

Anti-neural antibodies will be tested by means of indirect immunofluorescence only.

Superficial anti-neuronal antibodies will be identified in patients' serum by means of cell-based assay.

The investigators will assess volumetry and morphology of selected brain structures from MRI scans. Hippocampus, thalamus, cerebellum, brainstem, frontal and tempo-parietal lobes, and total brain volume will be determined from the T1-weighted MRI with FreeSurfer, an automated segmentation tool.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study Using Brain Stimulation and Behavioral Therapy to Increase Extent of Resection in Low-Grade Gliomas	NCT04745156	Glioma Glioma Intracra... Gliomas Benign Brain Tumor Brain Cancer Motor Cortex; L...	RNS System Impl...	18 Years - 65 Years	Medical College of Wisconsin
The Cognitive-Behavioral Dysfunctions and the Potential of Neuroplasticity in Brain Tumors Patients During Radiotherapy	NCT05192447	Brain Tumors Radiotherapy	Exercise treatm...	18 Years - 70 Years	The Greater Poland Cancer Centre

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