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| Name | Class |
|---|---|
| University of Turin, Italy | OTHER |
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Background Lower-grade-gliomas affect young patients, thus the longest progression-free-survival (PFS) with a high level quality of life is crucial. Surgery most significantly impacts on tumor natural history, postponing recurrence, improving symptoms, decreasing the need of adjuvant therapies, with extent of resection, gross-total and supra-total (GTR and STR), strongly associating with longest PFS. Achievement of GTR or STR depends on the degree of functional reorganization induced by glioma. Consequently, a successful treatment fostering neural circuit reorganization before surgery, would increase the chance of GRT/STR.
Hypothesis The plastic potential of motor system suggests that reorganization of circuits controlling hand movements could be presurgically fostered in LGG patients by enhancing plasticity with up-front motor-rehabilitation and/or by decreasing tumor infiltration with up-front chemotherapy. Advanced neuroimaging allows to infer the neuroplasticity potential. Intraoperative assessment of the motor circuits functionality will validate reliability of preoperative analyses.
Aims The project has 4 aims, investigating: A) the presurgical functional (FC) and structural (SC) connectomics of the hand-motor network to picture the spontaneous reorganization and the influence of clinical, imaging and histomolecular variables; B) the dynamic of FC and SC after tumor resection; C) changes in FC and SC maps after personalized upfront motor rehabilitation and/or chemotherapy; D) the effect of FC and SC upfront treatment on the achievement of GTR/STR preserving hand dexterity.
Experimental Design Resting-state fMRI and diffusion-MRI will provide FC and SC maps pre- and post-surgery; personalized up-front motor rehabilitation and/or chemotherapy will be administered; Intraoperative brain mapping procedures will generate data to validate the maps.
Expected Results
Impact On Cancer Results will increase the achievement of GTR/STR, preserving motor integrity, with dramatic impact on LGGs natural history.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Spontaneous motor reorganization: observation | Active Comparator | Only neurological and neuropsychological assessment as per normal clinical routine and conventional and advanced functional, resting-state MRI acquisitions |
|
| Enhanced motor reorganization: upfront Motor Rehabilitation | Experimental | Patients submitted to motor rehabilitation program aimed at learning unimanual and bimanual coordinated sequences, along with personalized exercise according to tumor location (frontal vs parietal). For 6 months each patient will perform the motor training program in outpatient training session, checked by a physiotherapist for corrected execution at home 3 times/week, and is assessed for the correct training execution and progresses in training sessions each month, by physical therapists at the Rehabilitation Unit and on a weekly schedule by on-line distant monitoring (telemedicine). |
|
| Enhanced motor reorganization: upfront Chemotherapy | Experimental | Temozolomide-based regimen of 6 months duration is applied. Treatment will be discontinued in case of toxicity (G2-G4). |
|
| Enhanced motor reorganization: upfront Chemotherapy + Motor Rehabilitation | Experimental | Temozolomide-based regimen of 6 months duration is applied. Treatment will be discontinued in case of toxicity (G2-G4). Patients will also be submitted to motor rehabilitation program aimed at learning unimanual and bimanual coordinated sequences, along with personalized exercise according to tumor location (frontal vs parietal). For 6 months each patient will perform the motor training program in outpatient training session, checked by a physiotherapist for corrected execution at home 3 times/week, and is assessed for the correct training execution and progresses in training sessions each month, by physical therapists at the Rehabilitation Unit and on a weekly schedule by on-line distant monitoring (telemedicine). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Resting State Functional Magnetic Resonance Imaging (rs-fMRI) | Diagnostic Test | rs-fMRI + neurological and neuropsychological evaluation at preoperative timepoint and 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop |
| Measure | Description | Time Frame |
|---|---|---|
| Muscle power | MRC Muscle power assessment (0-5) | ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop |
| Motor praxia | ARAT test (Grasp, Grip, Pinch, each consisting of 3 items scoring 0 [not performed, 1/2 abnormal, 3 ok]), De Renzi test (24 complex gestures with individual scoring 0-3 [0 no execution/always abnormal, 2/1 ok after 1 or 2 trials, 3 ok] each evaluating one or more among finger movements [total score 0-36], hand movements [total score 0-36], hand and finger position [total score 0-36], sequence of movements [total score 0-36], meaningful gestures [total score 0-36], meaningless gestures [total score 0-36]; tool pantomime for 10 objects individual score 0 if always incorrect, 1 if correct after command repetition, 2 correct immediately, total score range 0-20) | ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop |
| Measure | Description | Time Frame |
|---|---|---|
| Comprehensive neuropsychological assessment | Language: Naming test; Fhonemic and Semantic Fluency Verbal and Spatial Memory: 15 Rey's Words; Recall Rey figure; Visuo-spatial test: Rey's Copy; Cancellation Test Attention and Executive Functions: Attentive matrice and Trail Making test For each listed test, equivalent score, from 0 to 4, is used. Mood Disorders. HADS test (score 0-21 : 0-7= Normal; 8-21 Mood disorders |
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Inclusion Criteria (ARM 1):
Inclusion Criteria (ARM 2/3/4):
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lorenzo Bello, MD | Contact | 0039-340-217-1453 | lorenzo.bello@unimi.it |
| Name | Affiliation | Role |
|---|---|---|
| Lorenzo Bello, MD | University of Milan | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| IRCCS Ospedale Galeazzi Sant'Ambrogio | Recruiting | Milan | Lombardy | 20157 | Italy |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24500420 | Background | Bello L, Riva M, Fava E, Ferpozzi V, Castellano A, Raneri F, Pessina F, Bizzi A, Falini A, Cerri G. Tailoring neurophysiological strategies with clinical context enhances resection and safety and expands indications in gliomas involving motor pathways. Neuro Oncol. 2014 Aug;16(8):1110-28. doi: 10.1093/neuonc/not327. Epub 2014 Feb 4. | |
| 26318368 |
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Patients immediately candidate for resection will be assessed neurologically, neuropsychologically and by functional MRI. Extent of resection will be assessed on <48hrs and 2-month MRI. Neurological and neuropsychological assessment will be performed during regular follow-up. Patients not requiring an adjuvant treatment according to tumor board meeting will be submitted to functional MRI at 4-8 and 12 months from surgery. Patients not immediately eligible for resection will be submitted to biopsy for histomolecular definition. Patients not requiring radiation therapy will be submitted to neurological, neuropsychological, and functional MRI evaluation. Upon clinical context, patients will undergo motor rehabilitation and/or chemotherapy. After 3-6 months, patients will undergo functional MRI and evaluated for surgery. Neurological and neuropsychological evaluation will be performed at treatment initiation, every month during treatment, at admission for surgery and 1 month after surgery.
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|
| Up-front Motor Rehabilitation | Behavioral | personalized motor rehabilitation for 6 months + rs-fMRI + neurological and neuropsychological evaluation before starting motor rehabilitation, at 2-3 months during rehabilitation, 6-9 months during rehabilitation, before surgery (if surgery indicated by tumour board), 1 month postop, 2-3 months postop |
|
| Up-front Chemotherapy | Drug | Temozolomide at either 6 cycles consisting of 150-200 mg per square meter for 5 days during each 28-day cycle, or metronomic schedule, + rs-fMRI + neurological and neuropsychological evaluation before starting motor rehabilitation, at 2-3 months during rehabilitation, 6-9 months during rehabilitation, before surgery (if surgery indicated by tumour board), 1 month postop, 2-3 months Post |
|
| ARM 1: preop, 1-2 months postop, 3-4 months postop, 6-8 months postop, 12 months postop; ARM 2/3/4: before starting treatment, at 2-3 and 6-9 months during treatment, before surgery (if indicated), 1 month postop, 2-3 months postop |
| Castellano A, Donativi M, Ruda R, De Nunzio G, Riva M, Iadanza A, Bertero L, Rucco M, Bello L, Soffietti R, Falini A. Evaluation of low-grade glioma structural changes after chemotherapy using DTI-based histogram analysis and functional diffusion maps. Eur Radiol. 2016 May;26(5):1263-73. doi: 10.1007/s00330-015-3934-6. Epub 2015 Aug 30. |
| 27246771 | Background | Cochereau J, Deverdun J, Herbet G, Charroud C, Boyer A, Moritz-Gasser S, Le Bars E, Molino F, Bonafe A, Menjot de Champfleur N, Duffau H. Comparison between resting state fMRI networks and responsive cortical stimulations in glioma patients. Hum Brain Mapp. 2016 Nov;37(11):3721-3732. doi: 10.1002/hbm.23270. |
| 27920095 | Background | Fornia L, Ferpozzi V, Montagna M, Rossi M, Riva M, Pessina F, Martinelli Boneschi F, Borroni P, Lemon RN, Bello L, Cerri G. Functional Characterization of the Left Ventrolateral Premotor Cortex in Humans: A Direct Electrophysiological Approach. Cereb Cortex. 2018 Jan 1;28(1):167-183. doi: 10.1093/cercor/bhw365. |
| 31504261 | Background | Fornia L, Rossi M, Rabuffetti M, Leonetti A, Puglisi G, Vigano L, Simone L, Howells H, Bellacicca A, Bello L, Cerri G. Direct Electrical Stimulation of Premotor Areas: Different Effects on Hand Muscle Activity during Object Manipulation. Cereb Cortex. 2020 Jan 10;30(1):391-405. doi: 10.1093/cercor/bhz139. |
| 34963652 | Background | Fornia L, Rossi M, Rabuffetti M, Bellacicca A, Vigano L, Simone L, Howells H, Puglisi G, Leonetti A, Callipo V, Bello L, Cerri G. Motor impairment evoked by direct electrical stimulation of human parietal cortex during object manipulation. Neuroimage. 2022 Mar;248:118839. doi: 10.1016/j.neuroimage.2021.118839. Epub 2021 Dec 25. |
| 32362441 | Background | Howells H, Puglisi G, Leonetti A, Vigano L, Fornia L, Simone L, Forkel SJ, Rossi M, Riva M, Cerri G, Bello L. The role of left fronto-parietal tracts in hand selection: Evidence from neurosurgery. Cortex. 2020 Jul;128:297-311. doi: 10.1016/j.cortex.2020.03.018. Epub 2020 Apr 10. |
| 32714384 | Background | Kong NW, Gibb WR, Badhe S, Liu BP, Tate MC. Plasticity of the Primary Motor Cortex in Patients with Primary Brain Tumors. Neural Plast. 2020 Jul 3;2020:3648517. doi: 10.1155/2020/3648517. eCollection 2020. |
| 31347684 | Background | Puglisi G, Howells H, Sciortino T, Leonetti A, Rossi M, Conti Nibali M, Gabriel Gay L, Fornia L, Bellacicca A, Vigano L, Simone L, Catani M, Cerri G, Bello L. Frontal pathways in cognitive control: direct evidence from intraoperative stimulation and diffusion tractography. Brain. 2019 Aug 1;142(8):2451-2465. doi: 10.1093/brain/awz178. |
| 30364930 | Background | Raffin E, Siebner HR. Use-Dependent Plasticity in Human Primary Motor Hand Area: Synergistic Interplay Between Training and Immobilization. Cereb Cortex. 2019 Jan 1;29(1):356-371. doi: 10.1093/cercor/bhy226. |
| 29473778 | Background | Rossi M, Fornia L, Puglisi G, Leonetti A, Zuccon G, Fava E, Milani D, Casarotti A, Riva M, Pessina F, Cerri G, Bello L. Assessment of the praxis circuit in glioma surgery to reduce the incidence of postoperative and long-term apraxia: a new intraoperative test. J Neurosurg. 2019 Jan 1;130(1):17-27. doi: 10.3171/2017.7.JNS17357. Epub 2018 Feb 23. |
| 31100730 | Background | Rossi M, Ambrogi F, Gay L, Gallucci M, Conti Nibali M, Leonetti A, Puglisi G, Sciortino T, Howells H, Riva M, Pessina F, Navarria P, Franzese C, Simonelli M, Ruda R, Bello L. Is supratotal resection achievable in low-grade gliomas? Feasibility, putative factors, safety, and functional outcome. J Neurosurg. 2019 May 17;132(6):1692-1705. doi: 10.3171/2019.2.JNS183408. Print 2020 Jun 1. |
| 31398706 | Background | Rossi M, Conti Nibali M, Vigano L, Puglisi G, Howells H, Gay L, Sciortino T, Leonetti A, Riva M, Fornia L, Cerri G, Bello L. Resection of tumors within the primary motor cortex using high-frequency stimulation: oncological and functional efficiency of this versatile approach based on clinical conditions. J Neurosurg. 2019 Aug 9;133(3):642-654. doi: 10.3171/2019.5.JNS19453. Print 2020 Sep 1. |
| 33476393 | Background | Rossi M, Sciortino T, Conti Nibali M, Gay L, Vigano L, Puglisi G, Leonetti A, Howells H, Fornia L, Cerri G, Riva M, Bello L. Clinical Pearls and Methods for Intraoperative Motor Mapping. Neurosurgery. 2021 Feb 16;88(3):457-467. doi: 10.1093/neuros/nyaa359. |
| 33049063 | Background | Rossi M, Gay L, Ambrogi F, Conti Nibali M, Sciortino T, Puglisi G, Leonetti A, Mocellini C, Caroli M, Cordera S, Simonelli M, Pessina F, Navarria P, Pace A, Soffietti R, Ruda R, Riva M, Bello L. Association of supratotal resection with progression-free survival, malignant transformation, and overall survival in lower-grade gliomas. Neuro Oncol. 2021 May 5;23(5):812-826. doi: 10.1093/neuonc/noaa225. |
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| 33293629 | Background | Weller M, van den Bent M, Preusser M, Le Rhun E, Tonn JC, Minniti G, Bendszus M, Balana C, Chinot O, Dirven L, French P, Hegi ME, Jakola AS, Platten M, Roth P, Ruda R, Short S, Smits M, Taphoorn MJB, von Deimling A, Westphal M, Soffietti R, Reifenberger G, Wick W. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat Rev Clin Oncol. 2021 Mar;18(3):170-186. doi: 10.1038/s41571-020-00447-z. Epub 2020 Dec 8. |
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| ID | Term |
|---|---|
| D005910 | Glioma |
| ID | Term |
|---|---|
| D018302 | Neoplasms, Neuroepithelial |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009375 | Neoplasms, Glandular and Epithelial |
| D009380 | Neoplasms, Nerve Tissue |
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