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Alexandre Carpentier, Alexandre Blanquet, and Bernard George

Object

Radical resection of chordomas seems to improve a patient's long-term prognosis. At the suboccipital and cervical levels, the vertebral artery (VA) is often considered as a limit in surgical possibilities. The authors report on the management of the VA in a series of 36 patients with chordomas located in the cervical region.

Methods

Over an 11-year period, 36 patients with chordomas located at the suboccipital (28 patients) or cervical (eight patients) level were treated in the authors' neurosurgical department. In 30 patients, the tumors extended laterally toward the VA and required surgical control of the VA. Sixteen of these 30 patients harbored primary tumor, whereas 14 were treated for recurrent disease.

The VA was encased in the tumor in 23 patients, with stenosis in six cases. A balloon occlusion test was performed in seven patients and the VA was resected in four. Extensive resection, via a lateral approach on one (22 cases) or on both (eight cases) sides, did not cause any permanent postoperative deficits. In five patients a complementary approach was performed: posterolateral in one and transoral in four. Spinal fixation was performed via the lateral approach (eight cases) or via a complementary posterior approach (five cases). All but two patients underwent radiotherapy, including 10 who underwent proton-beam radiotherapy.

Conclusions

Chordomas extending laterally to the VA can be radically resected via a lateral approach without causing significant morbidity. A complementary approach is often necessary. The best results are achieved in patients with primary compared with recurrent tumor.

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Alexandre Carpentier, Marc Polivka, Alexandre Blanquet, Guillaume Lot, and Bernard George

Object. Chordoma is a locally invasive tumor with a high tendency for recurrence for which radical resection is generally recommended. To assess the benefits of aggressive treatment of chordomas, the authors compared results in patients treated aggressively at the first presentation of this disease with results in patients who were similarly treated, but after recurrence.

Methods. Among 36 patients with cervical chordomas who were treated at the authors' institution, 22 underwent primary aggressive treatment (Group A) and 14 were treated secondarily after tumor recurrence (Group B). Two cases were excluded from Group A because of unrelated early deaths and three from Group B because of insufficient pre- or postoperative data. Most tumors were located at the suboccipital level and only eight cases at a level below C-2. Radiotherapy and proton therapy were similarly conducted in both groups of patients.

The actuarial survival rates were 80 and 65% at 5 and 10 years, respectively, in Group A patients and 50 and 0% at 5 and 10 years, respectively, in Group B patients (p = 0.049, log-rank test). The actuarial recurrence-free rates were 70 and 35% at 5 and 10 years, respectively, in Group A and 0% at 3 years in Group B (p < 0.0001, log-rank test). The numbers of recurrences per year were 0.15 in Group A and 0.62 in Group B (p > 0.05). All other parameters that were analyzed (patient age, delay before diagnosis, clinical symptoms, chondroid type of lesion, and histological features) did not prove to influence prognosis in a statistically significant manner.

Conclusions. Aggressive therapy, combining as radical a resection as possible with radiotherapy, seems to improve the prognoses of suboccipital and cervical chordomas when applied at the patient's first presentation with the disease.

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Kévin Beccaria, Michael Canney, Guillaume Bouchoux, Stéphanie Puget, Jacques Grill, and Alexandre Carpentier

Pediatric brain tumors are the most common solid tumor and the first cause of cancer death in childhood, adolescence, and young adulthood. Current treatments are far from optimal in most of these tumors and the prognosis remains dismal for many of them. One of the main causes of the failure of current medical treatments is in part due to the existence of the blood-brain barrier (BBB), which limits drug delivery to tumors. Opening of the BBB with low-intensity pulsed ultrasound (LIPU) has emerged during the last 2 decades as a promising technique for enhancing drug delivery to the brain. In preclinical models, enhanced delivery of a wide range of therapeutic agents, from low-molecular-weight drugs, to antibodies and immune cells, has been observed as well as tumor control and increased survival. This technique has recently entered clinical trials with extracranial and intracranial devices. The safety and feasibility of this technique has furthermore been shown in patients treated monthly for recurrent glioblastoma receiving carboplatin chemotherapy. In this review, the characteristics of the BBB in the most common pediatric brain tumors are reviewed. Then, principles and mechanisms of BBB disruption with ultrasound (US) are summarized and described at the histological and biological levels. Lastly, preclinical studies that have used US-induced BBB opening in tumor models, recent clinical trials, and the potential use of this technology in pediatrics are provided.

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Aymeric Amelot, Maximilien Riche, Samuel Latreille, Vincent Degos, Alexandre Carpentier, Bertrand Mathon, and Anne-Marie Korinek

OBJECTIVE

The authors sought to evaluate the roles of perioperative antibiotic prophylaxis in noninstrumented spine surgery (NISS), both in postoperative infections and the impact on the selection of resistant bacteria. To the authors’ knowledge, only one prospective study recommending preoperative intravenous (IV) antibiotics for prophylaxis has been published previously.

METHODS

Two successive prospective IV antibiotic prophylaxis protocols were used: from 2011 to 2013 (group A: no prophylactic antibiotic) and from 2014 to 2016 (group B: prophylactic cefazolin). Patient infection rates, infection risk factors, and bacteriological status were determined.

RESULTS

In total, 2250 patients (1031 in group A and 1219 in group B) were followed for at least 1 year. The authors identified 72 surgical site infections, 51 in group A (4.9%) and 21 in group B (1.7%) (p < 0.0001). A multiple logistic regression hazard model identified male sex (HR 2.028, 95% CI 1.173–3.509; p = 0.011), cervical laminectomy (HR 2.078, 95% CI 1.147–3.762; p = 0.016), and postoperative CSF leak (HR 43.782, 95% CI 10.9–189.9; p < 0.0001) as independent predictive risk factors of infection. In addition, preoperative antibiotic prophylaxis was the only independent favorable factor (HR 0.283, 95% CI 0.164–0.488; p < 0.0001) that significantly reduced infections for NISS. Of 97 bacterial infections, cefazolin-resistant bacteria were identified in 26 (26.8%), with significantly more in group B (40%) than in group A (20.9%) (p = 0.02).

CONCLUSIONS

A single dose of preoperative cefazolin is effective and mandatory in preventing surgical site infections in NISS. Single-dose antibiotic prophylaxis has an immediate impact on cutaneous flora by increasing cefazolin-resistant bacteria.

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Alexandre C. Carpentier, R. Todd Constable, Michael J. Schlosser, Alain de Lotbinière, Joseph M. Piepmeier, Dennis D. Spencer, and Issam A. Awad

Object. Functional magnetic resonance (fMR) imaging of the motor cortex is a potentially powerful tool in the preoperative planning of surgical procedures in and around the rolandic region. Little is known about the patterns of fMR imaging activation associated with various pathological lesions in that region or their relation to motor skills before surgical intervention.

Methods. Twenty-two control volunteers and 44 patients whose pathologies included arteriovenous malformations (AVMs; 16 patients), congenital cortical abnormalities (11 patients), and tumors (17 patients) were studied using fMR imaging and a hand motor task paradigm. Activation maps were constructed for each participant, and changes in position or amplitude of the motor activation on the lesion side were compared with the activation pattern obtained in the contralateral hemisphere. A classification scheme of plasticity (Grades 1–6) based on interhemispheric pixel asymmetry and displacement of activation was used to compare maps between patients, and relative to hand motor dexterity and/or weakness.

There was 89.4% interobserver agreement on classification of patterns of fMR imaging activation. Displacement of activation by mass effect was more likely with tumors. Cortical malformations offer a much higher functional reorganization than AVMs or tumors. High-grade plasticity is recruited to compensate for severe motor impairment.

Conclusions. Pattern modification of fMR imaging activation can be systematized in a classification of motor cortex plasticity. This classification has shown good correlation among grading, brain lesions, and motor skills. This proposal of a classification scheme, in addition to facilitating data collection and processing from different institutions, is well suited for comparing risks associated with surgical intervention and patterns of functional recovery in relation to preoperative fMR imaging categorization. Such studies are underway at the authors' institution.

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Catherine Horodyckid, Michael Canney, Alexandre Vignot, Raphael Boisgard, Aurélie Drier, Gilles Huberfeld, Chantal François, Annick Prigent, Mathieu D. Santin, Clovis Adam, Jean-Claude Willer, Cyril Lafon, Jean-Yves Chapelon, and Alexandre Carpentier

OBJECTIVE

The main limitation to the efficacy of chemotherapy for brain tumors is the restricted access to the brain because of the limited permeability of the blood-brain barrier (BBB). Previous animal studies have shown that the application of pulsed ultrasound (US), in combination with the intravenous injection of microbubbles, can temporarily disrupt the BBB to deliver drugs that normally cannot reach brain tissue. Although many previous studies have been performed with external focused US transducers, the device described in the current work emits US energy using an unfocused transducer implanted in the skull thickness. This method avoids distortion of the US energy by the skull bone and allows for simple, repetitive, and broad disruption of the BBB without the need for MRI monitoring. The purpose of the present study was to determine if the BBB can be safely and repeatedly disrupted using such an implantable unfocused US device in a primate model.

METHODS

An 11.5-mm-diameter, 1-MHz, planar US device was implanted via a bur hole into the skull of 3 primates (2 Papio anubis [olive] baboons and 1 Macaca fascicularis [macaque]) for 4 months. Pulsed US sonications were applied together with the simultaneous intravenous injection of sulfur hexafluoride microbubbles (SonoVue) every 2 weeks to temporarily disrupt the BBB. In each primate, a total of 7 sonications were performed with a 23.2-msec burst length (25,000 cycles) and a 1-Hz pulse repetition frequency at acoustic pressure levels of 0.6–0.8 MPa. Potential toxicity induced by repeated BBB opening was analyzed using MRI, PET, electroencephalography (EEG), somatosensory evoked potential (SSEP) monitoring, behavioral scales, and histopathological analysis.

RESULTS

The T1-weighted contrast-enhanced MR images acquired after each sonication exhibited a zone of hypersignal underneath the transducer that persisted for more than 4 hours, indicating a broad region of BBB opening in the acoustic field of the implant. Positron emission tomography images with fluorine-18–labeled fluorodeoxyglucose (FDG) did not indicate any changes in the cerebral metabolism of glucose. Neither epileptic signs nor pathological central nerve conduction was observed on EEG and SSEP recordings, respectively. Behavior in all animals remained normal. Histological analysis showed no hemorrhagic processes, no petechia, and extravasation of only a few erythrocytes.

CONCLUSIONS

The studies performed confirm that an implantable, 1-MHz US device can be used to repeatedly open the BBB broadly in a large-animal model without inducing any acute, subacute, or chronic lesions.

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Kevin Beccaria, Michael Canney, Lauriane Goldwirt, Christine Fernandez, Julie Piquet, Marie-Cécile Perier, Cyril Lafon, Jean-Yves Chapelon, and Alexandre Carpentier

OBJECT

The blood-brain barrier (BBB) limits the intracerebral penetration of drugs and brain tumor treatment efficacy. The effect of ultrasound-induced BBB opening on the intracerebral concentration of temozolomide (TMZ) and irinotecan (CPT-11) was assessed.

METHODS

This study was performed using 34 healthy New Zealand rabbits. Half had unilateral BBB opening, and half served as controls. Sonications were performed by pulsing a 1.05-MHz planar ultrasound transducer with a duty cycle of 2.5% and an in situ acoustic pressure level of 0.6 MPa after injection of a microbubble ultrasound contrast agent. Drugs were injected either 5 minutes before (ChemoPreUS) or 15 minutes after (ChemoPostUS) the ultrasound sonication. The plasma and intracerebral concentrations of both drugs were quantified using ultra-performance liquid chromatography.

RESULTS

The mean intracerebral tissue-to-plasma drug concentration ratio in the control hemispheres was 34% for TMZ and 2% for CPT-11. After BBB opening, these values increased by up to 21% for TMZ and up to 178% for CPT-11. Intracerebral concentrations of drugs were enhanced in regions where the BBB was opened compared with the contralateral hemisphere (p < 0.01 and p < 0.0001 for CPT-11, p = 0.02 and p = 0.03 for TMZ, in ChemoPreUS and ChemoPostUS, respectively) and compared with the control group (p < 0.001 and p < 0.0001 for CPT-11, p < 0.01 and p = 0.02 for TMZ, in ChemoPreUS and ChemoPostUS, respectively). The intracerebral distribution of drugs was heterogeneous, depending on the distance from the ultrasound source.

CONCLUSIONS

Ultrasound-induced opening of the BBB significantly enhances the intracerebral concentration of both TMZ and CPT-11 in rabbits.

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Nicolas Asquier, Guillaume Bouchoux, Michael Canney, Cyril Martin, Bruno Law-Ye, Delphine Leclercq, Jean-Yves Chapelon, Cyril Lafon, Ahmed Idbaih, and Alexandre Carpentier

OBJECTIVE

One of the goals in this study was to set up a semiautomatic method to estimate blood-brain barrier disruption obtained in patients with glioblastoma by using an implantable, unfocused, ultrasound device. Another goal was to correlate the probability of significant ultrasound-induced signal enhancement (SUISE) with local acoustic pressure in the brain.

METHODS

Gd-enhanced MR images acquired before and after ultrasound treatments were analyzed prospectively. The image sets were segmented, normalized, and coregistered to evaluate contrast enhancement. The volume of SUISE was calculated with voxels labeled as gray or white matter, in a cylindrical region of interest, and with enhancement above a given threshold. To validate the method, the resulting volumes of SUISE were compared to qualitative grades previously assigned by 3 clinicians for 40 ultrasound treatments in 15 patients. A parametric study was performed to optimize the algorithm prediction of the qualitative grades. The 3D acoustic field in the brain was estimated from measurements in water combined with simulations accounting for ultrasound attenuation in brain and overlaid on each MR image to correlate local acoustic pressure with the probability of SUISE (defined as enhancement > 10%).

RESULTS

The algorithm predicted grade 2 or 3 and grade 3 openings with areas under the receiver operating characteristic curve of 0.831 and 0.995, respectively. The probability of SUISE was correlated with local acoustic pressure (R2 = 0.98) and was 3.33 times higher for gray matter than for white matter.

CONCLUSIONS

An algorithm for evaluating blood-brain barrier disruption was validated and can be used for future clinical trials to further understand and quantify this technique in humans.

Clinical trial registration no.: NCT02253212 (clinicaltrials.gov)

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Gaston Tabourel, Louis-Marie Terrier, Arnaud Dubory, Joseph Cristini, Louis-Romée Le Nail, Ann-Rose Cook, Kévin Buffenoir, Hugues Pascal-Moussellard, Alexandre Carpentier, Bertrand Mathon, and Aymeric Amelot

OBJECTIVE

Survival scoring systems for spine metastasis (SPM) were designed to help surgical practice. The authors sought to validate the prognostic accuracy of the main preoperative scoring systems for SPM.

METHODS

It was hypothesized that true patient survival in SPM was better than that predicted using prognosis scores. To investigate this hypothesis, the authors designed a French national retrospective study of a prospectively collected multicenter database involving 739 patients treated for SPM between 2014 and 2017.

RESULTS

In this series, the median survival time for all patients from an SPM diagnosis was 17.03 ± 1.5 months. Sensitivity and specificity were estimated using the area under the curve (AUC). The AUC of Tomita’s prognosis score was the lowest and poorest (0.4 ± 0.023, range 0.35–0.44), whereas the AUC of the Tokuhashi score was the highest (0.825). The Lei score presented an AUC of 0.686 ± 0.022 (range 0.64–0.7), and the Rades score showed a weaker AUC (0.583 ± 0.020, range 0.54–0.63). Differences among AUCs were all statistically significant (p < 0.001). The modified Bauer score and the Rades score had the highest rate of agreement in predicting survival, with a weighted Cohen’s kappa of 0.54 and 0.41, respectively, indicating a moderate agreement. The revised Tokuhashi and Lei scores had a fair rate of agreement (weighted Cohen’s kappa = 0.24 and 0.22, respectively). The van der Linden and Tomita scores demonstrated the worst performance, with only a “slight” rate of agreement (weighted Cohen’s kappa = 0.19 and 0.16, respectively) between what was predicted and the actual survival.

CONCLUSIONS

The use of prognostic scoring systems in the estimation of survival in patients with SPM has become obsolete and therefore underestimates survival. Surgical treatment decisions should no longer be based on survival estimations alone but must also take into account patient symptoms, spinal instability, and quality of life.

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Kevin Beccaria, Michael Canney, Lauriane Goldwirt, Christine Fernandez, Clovis Adam, Julie Piquet, Gwennhael Autret, Olivier Clément, Cyril Lafon, Jean-Yves Chapelon, and Alexandre Carpentier

Object

The blood-brain barrier (BBB) is a major impediment to the intracerebral diffusion of drugs used in the treatment of gliomas. Previous studies have demonstrated that pulsed focused ultrasound (US) in conjunction with a microbubble contrast agent can be used to open the BBB. To apply the US-induced opening of the BBB in clinical practice, the authors designed an innovative unfocused US device that can be implanted in the skull and used to transiently and repeatedly open the BBB during a standard chemotherapy protocol. The goal of this preliminary work was to study the opening of the BBB induced by the authors' small unfocused US transducer and to evaluate the effects of the sonications on brain parenchyma.

Methods

Craniectomy was performed in 16 healthy New Zealand White rabbits; epidural application of a single-element planar ultrasonic transducer operating at 1 MHz was then used with a pulse-repetition frequency of 1 Hz, pulse lengths of 10–35 msec, in situ acoustic pressure levels of 0.3–0.8 MPa, and sonication for 60–120 seconds. SonoVue was intravenously injected during the US applications, and opening of the BBB was determined by detecting extravasation of Evans blue dye (EBD) in brain tissues, quantitative measurement of EBD with UV-visible spectrophotometry, and contrast enhancement after Gd injection in 4.7-T MRI. A histological study was performed to determine adverse effects.

Results

An opening of the BBB was observed over a large extent of the US beam in the brain corresponding to in situ pressures of greater than 0.2 MPa. The BBB opening observed was highly significant for both EBD (p < 0.01) and MRI Gd enhancement (p < 0.0001). The BBB opening was associated with minor adverse effects that included perivascular red blood cell extravasations that were less than 150 μm in size and not visible on MR images. Moderate edema was visible on FLAIR sequences and limited to the extent of the sonication field.

Conclusions

The results demonstrate that the BBB can be opened in large areas of the brain in rabbits with lowpower, pulsed, and unfocused US with limited damage to healthy tissue.