Federico Pessina

Tailoring neurophysiological strategies with clinical context enhances resection and safety and expands indications in gliomas involving motor pathways

BACKGROUND Resection of motor pathway gliomas requires the intraoperative recognition of essential cortical-subcortical motor structures. The degree of involvement of motor structures is variable, and increases as result of treatments patients are submitted to. Intraoperative neurophysiology offers various stimulation modalities, which efficiency is based on the ability to recognize essential sites with the highest possible resolution in most clinical conditions. Two stimulation paradigms evolved for intraoperative guidance of motor tumors removal: the 60 Hz-technique [low frequency (LF)] and the pulse-technique [high frequency-(HF)], delivered by bipolar or monopolar probe respectively. Most surgical teams rely on to either of the 2 techniques. The key point is the integration of the choice of the stimulation modality with the clinical context. METHODS In 591 tumors involving the corticospinal tract, the use of HF and LF was tailored to the clinical context defined by patient clinical history and tumor features (by imaging). The effect was evaluated on the feasibility of mapping, the impact on immediate and permanent morbidity, the extent of resection, and the number of patients treated. RESULTS By integrating the choice of the probe and the stimulation protocol with patient clinical history and tumor characteristics, the best probe-frequency match was identified for the different sets of clinical conditions. This integrative approach allows increasing the extent of resection and patient functional integrity, and greatly expands the number of patients who could benefit from surgery. CONCLUSIONS The integration of stimulation modalities with clinical context enhances the extent and safety of resection and expands the population of patients who could benefit from surgical treatment.

Investigation on the role of integrated PET/MRI for target volume definition and radiotherapy planning in patients with high grade glioma

PURPOSE To evaluate the impact of fluid-attenuated-inversion-recovery MRI (FLAIR/MRI) and Carbon-11-labeled-methionine PET (11C-MET-PET) on high grade glioma (HGG) tumor volume delineation for radiotherapy planning. MATERIAL AND METHODS Sixty-nine patients with HGG were evaluated. The clinical target volumes (CTV1, generated by adding a 10mm margin to FLAIRMRI area, CTV2 by adding a 20mm margin to enhanced T1MRI) and biological target volume (BTV) were delineated on pre-operative MRI images and 11CMETPET respectively. RESULTS The overlap between CTV1 and CTV2 showed a low correlation between the two volumes with CTV1 not always fully included into the CTV2. In all cases the whole BTV was included into the CTV1, while in 35/69 patients (50%) part of BTV was outside the CTV2 despite larger margins were added. In all cases recurrences were within the CTV1 volume and in 19/38 (50%) partially outside the CTV2. In all patients relapse corresponded to the BTV area. CONCLUSIONS Our data suggest that the target volume definition using FLAIR-MRI is more adequate compared to enhanced T1MRI. 11C-METPET uptake could help identify microscopic residual areas.

Monopolar high-frequency language mapping: can it help in the surgical management of gliomas? A comparative clinical study

OBJECT Intraoperative language mapping is traditionally performed with low-frequency bipolar stimulation (LFBS). High-frequency train-of-five stimulation delivered by a monopolar probe (HFMS) is an alternative technique for motor mapping, with a lower reported seizure incidence. The application of HFMS in language mapping is still limited. Authors of this study assessed the efficacy and safety of HFMS for language mapping during awake surgery, exploring its clinical impact compared with that of LFBS. METHODS Fifty-nine patients underwent awake surgery with neuropsychological testing, and LFBS and HFMS were compared. Frequency, type, and site of evoked interference were recorded. Language was scored preoperatively and 1 week and 3 months after surgery. Extent of resection was calculated as well. RESULTS High-frequency monopolar stimulation induced a language disturbance when the repetition rate was set at 3 Hz. Interference with counting (p = 0.17) and naming (p = 0.228) did not vary between HFMS and LFBS. These results held true when preoperative tumor volume, lesion site, histology, and recurrent surgery were considered. Intraoperative responses (1603) in all patients were compared. The error rate for both modalities differed from baseline values (p < 0.001) but not with one another (p = 0.06). Low-frequency bipolar stimulation sensitivity (0.458) and precision (0.665) were slightly higher than the HFMS counterparts (0.367 and 0.582, respectively). The error rate across the 3 types of language errors (articulatory, anomia, paraphasia) did not differ between the 2 stimulation methods (p = 0.279). CONCLUSIONS With proper setting adjustments, HFMS is a safe and effective technique for language mapping.

Hypofractionated Stereotactic Radiation Therapy in Recurrent High-Grade Glioma: A New Challenge

Purpose The aim of this study was to evaluate outcomes of hypofractionated stereotactic radiation therapy (HSRT) in patients re-treated for recurrent high-grade glioma. Materials and Methods From January 2006 to September 2013, 25 patients were treated. Six patients underwent radiation therapy alone, while 19 underwent combined treatment with surgery and/or chemotherapy. Only patients with Karnofsky Performance Status (KPS) > 70 and time from previous radiotherapy greater than 6 months were re-irradiated. The mean recurrent tumor volume was 35 cm3 (range, 2.46 to 116.7 cm3), and most of the patients (84%) were treated with a total dose of 25 Gy in five fractions (range, 20 to 50 Gy in 5-10 fractions). Results The median follow-up was 18 months (range, 4 to 36 months). The progression-free survival (PFS) at 1 and 2 years was 72% and 34% and the overall survival (OS) 76% and 50%, respectively. No severe toxicity was recorded. In univariate and multivariate analysis extent of resection at diagnosis significantly influenced PFS and OS (p < 0.01). Patients with smaller recurren tumor volume treated had better local control and survival. Indeed, the 2-year PFS was 40% (≤ 50 cm3) versus 11% (p=0.1) and the 2-year OS 56% versus 33% (> 50 cm3), respectively (p=0.26). Conclusion In our experience, HSRT could be a safe and feasible therapeutic option for recurrent high grade glioma even in patients with larger tumors. We believe that a multidisciplinary evaluation is mandatory to assure the best treatment for selected patients. Local treatment should also be considered as part of an integrated approach.

Outcome Evaluation of Oligometastatic Patients Treated with Surgical Resection Followed by Hypofractionated Stereotactic Radiosurgery (HSRS) on the Tumor Bed, for Single, Large Brain Metastases

Purpose The aim of this study was to evaluate the benefit of a combined treatment, surgery followed by adjuvant hypofractionated stereotactic radiosurgery (HSRS) on the tumor bed, in oligometastatic patients with single, large brain metastasis (BM). Methods and Materials Fom January 2011 to March 2015, 69 patients underwent complete surgical resection followed by HSRS with a total dose of 30Gy in 3 daily fractions. Clinical outcome was evaluated by neurological examination and MRI 2 months after radiotherapy and then every 3 months. Local progression was defined as radiographic increase of the enhancing abnormality in the irradiated volume, and brain distant progression as the presence of new brain metastases or leptomeningeal enhancement outside the irradiated volume. Surgical morbidity and radiation-therapy toxicity, local control (LC), brain distant progression (BDP), and overall survival (OS) were evaluated. Results The median preoperative volume and maximum diameter of BM was 18.5cm3 (range 4.1–64.2cm3) and 3.6cm (range 2.1-5-4cm); the median CTV was 29.0cm3 (range 4.1–203.1cm3) and median PTV was 55.2cm3 (range 17.2–282.9cm3). The median follow-up time was 24 months (range 4–33 months). The 1-and 2-year LC in site of treatment was 100%; the median, 1-and 2-year BDP was 11.9 months, 19.6% and 33.0%; the median, 1-and 2-year OS was 24 months (range 4–33 months), 91.3% and 73.0%. No severe postoperative morbidity or radiation therapy toxicity occurred in our series. Conclusions Multimodal approach, surgery followed by HSRS, can be an effective treatment option for selected patients with single, large brain metastases from different solid tumors.

Vertebral metastases reirradiation with volumetric-modulated arc radiotherapy

PURPOSE To assess the feasibility, acute toxicity, clinical improvement, local control and survival for spinal metastatic patients re-irradiated using volumetric-modulated-arc-radiotherapy (VMAT). METHODS AND MATERIALS Between February 2009 and November 2010, 31 patients were treated. Surgery was performed in six before re-irradiation. The clinical target volume (CTV) was defined as the whole vertebrae with recurrence excluding the central section of spinal canal. Planning target volume was defined as CTV+0-5mm in the three directions. Dose was prescribed in order to have biological equivalent dose to the spinal cord from the two courses lower than 120 Gy(2) to 1 cc of the volume. Clinical improvement, toxicity and recurrence were evaluated. All patients had back pain before treatment and 15 (48%) neurological deficit. RESULTS Clinical remission of pain was obtained in 29 patients (93%). Neurological improvement was observed in 73% of patients. No acute or late toxicities were recorded. No recurrence occurred. Median survival was 10 months (range 6-24). At the last follow-up 19 patients (61%) were alive and 12 (39%) dead from systemic disease progression. The 1 and 2 year survival were 55% and 35%, respectively. CONCLUSION In patients with spinal metastases recurrence re-irradiation with VMAT is feasible and provides clinical benefit in most patients.

Brain and Music: An Intraoperative Stimulation Mapping Study of a Professional Opera Singer

BACKGROUND Music is one of the most sophisticated and fascinating functions of the brain. Yet, how music is instantiated within the brain is not fully characterized. Singing is a peculiar aspect of music, in which both musical and linguistic skills are required to provide a merged vocal output. Identifying the neural correlates of this process is relevant for both clinical and research purposes. CASE DESCRIPTION An adult white man with a presumed left temporal glioma was studied. He is a professional opera singer. A tailored music evaluation, the Montreal Battery of Evaluation of Amusia, was performed preoperatively and postoperatively, with long-term follow-up. Intraoperative stimulation mapping (ISM) with awake surgery with a specific music evaluation battery was used to identify and preserve the cortical and subcortical structures subserving music, along with standard motor-sensory and language mapping. A total resection of a grade I glioma was achieved. The Montreal Battery of Evaluation of Amusia reported an improvement in musical scores after the surgery. ISM consistently elicited several types of errors in the superior temporal gyrus and, to a lesser extent, in the inferior frontal operculum. Most errors occurred during score reading; fewer errors were elicited during the assessment of rhythm. No spontaneous errors were recorded. These areas did not overlap with eloquent sites for counting or naming. CONCLUSIONS ISM and a tailored music battery enabled better characterization of a specific network within the brain subserving score reading independently from speech with long-term clinical impact.

Are three weeks hypofractionated radiation therapy (HFRT) comparable to six weeks for newly diagnosed glioblastoma patients? Results of a phase II study

BACKGROUND The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT).. The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness. METHODS Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function. RESULTS A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome.Conclusion HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment.Background The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT). The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness. Methods Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function. Results A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome. Conclusion HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment.

Maximize surgical resection beyond contrast-enhancing boundaries in newly diagnosed glioblastoma multiforme: is it useful and safe? A single institution retrospective experience

The extent of surgical resection (EOR) has been recorded as conditioning outcome in glioblastoma multiforme (GBM) patients but no significant improvements were recorded in survival. The study aimed to evaluate the impact of EOR on survival, investigating the role of fluid-attenuated inversion recovery (FLAIR) abnormalities removal. 282 newly diagnosed GBM patients were treated with surgery followed by concurrent and adjuvant chemo-radiotherapy. The EOR was defined as: SUPr, in case of resection amounting to 100% of enhanced and FLAIR areas; gross total (GTR) in case of resection between 90 and 100% of enhanced areas with variable amount of FLAIR abnormalities; sub-total (STR), between 10 and 89%; biopsy (B) <10%. FLAIR-RTV was dichotomized in percentage values to identify the best separation threshold for progression free survival (PFS) and overall survival (OS). SUPr was obtained in 21 patients (7.4%), GTR in 60 (21.3%), STR in 143 (50.7%) and biopsy only in 58 (20.6%). The median, 1, 2-year PFS were 10.4 ± 0.4 months, 39.0 ± 3.0, and 17.0 ± 2.0%; the median, 1, 2-year OS were 14.5 ± 0.5 months, 63.3 ± 3.0, and 23.1 ± 3.1%. EOR was significantly influencing survival (p < 0.001). The median, 1, 2-year OS were 28.6 ± 5.2 months, 90.0 ± 6.0, 71.0 ± 10.0% for patients underwent SUPr vs. 16.2 ± 1.2 months, 81.0 ± 5.0, 24.0 ± 6.0% for GTR. The FLAIR removal threshold conditioning survival was 45%. Minor complications were recorded in 14 (5%) patients and major in 8 (2.8%). surgical resection beyond contrast-enhancing boundaries could represent a promising strategy to improve outcome in GBM patients. The identification of a FLAIR-RTV threshold can be useful in clinical practice and it was recorded as factor influencing survival.

Broca’s Area as a Pre-articulatory Phonetic Encoder: Gating the Motor Program

The exact nature of the role of Broca’s area in control of speech and whether it is exerted at the cognitive or at the motor level is still debated. Intraoperative evidence of a lack of motor responses to direct electrical stimulation (DES) of Broca’s area and the observation that its stimulation induces a “speech arrest” without an apparent effect on the ongoing activity of phono-articulatory muscles, raises the argument. Essentially, attribution of direct involvement of Broca’s area in motor control of speech, requires evidence of a functional connection of this area with the phono-articulatory muscles’ motoneurons. With a quantitative approach we investigated, in 20 patients undergoing surgery for brain tumors, whether DES delivered on Broca’s area affects the recruitment of the phono-articulatory muscles’ motor units. The electromyography (EMG) of the muscles active during two speech tasks (object picture naming and counting) was recorded during and in absence of DES on Broca’s area. Offline, the EMG of each muscle was analyzed in frequency (power spectrum, PS) and time domain (root mean square, RMS) and the two conditions compared. Results show that DES on Broca’s area induces an intensity-dependent “speech arrest.” The intensity of DES needed to induce “speech arrest” when applied on Broca’s area was higher when compared to the intensity effective on the neighboring pre-motor/motor cortices. Notably, PS and RMS measured on the EMG recorded during “speech arrest” were superimposable to those recorded at baseline. Partial interruptions of speech were not observed. Speech arrest was an “all-or-none” effect: muscle activation started only by removing DES, as if DES prevented speech onset. The same effect was observed when stimulating directly the subcortical fibers running below Broca’s area. Intraoperative data point to Broca’s area as a functional gate authorizing the phonetic translation to be executed by the motor areas. Given the absence of a direct effect on motor units recruitment, a direct control of Broca’s area on the phono-articulatory apparatus seems unlikely. Moreover, the strict correlation between DES-intensity and speech prevention, might attribute this effect to the inactivation of the subcortical fibers rather than to Broca’s cortical neurons.