Long term follow-up of patients with newly diagnosed glioblastoma treated by intraoperative photodynamic therapy: an update from the INDYGO trial (NCT03048240).

PURPOSE: Glioblastoma remains incurable despite optimal multimodal management. The interim analysis of open label, single arm INDYGO pilot trial showed actuarial 12-months progression-free survival (PFS) of 60% (median 17.1 months), actuarial 12-months overall survival (OS) of 80% (median 23.1 months). We report updated, exploratory analyses of OS, PFS, and health-related quality of life (HRQOL) for patients receiving intraoperative photodynamic therapy (PDT) with 5-aminolevulinic acid hydrochloride (5-ALA HCl). METHODS: Ten patients were included (May 2017 - April 2021) for standardized therapeutic approach including 5-ALA HCl fluorescence-guided surgery (FGS), followed by intraoperative PDT with a single 200 J/cm2 dose of light. Postoperatively, patients received adjuvant therapy (Stupp protocol) then followed every 3 months (clinical and cerebral MRI) and until disease progression and/or death. Procedure safety and toxicity occurring during the first four weeks after PDT were assessed. Data concerning relapse, HRQOL and survival were prospectively collected and analyzed. RESULTS: At the cut-off date (i.e., November 1st 2023), median follow-up was 23 months (9,7-71,4). No unacceptable or unexpected toxicities and no treatment-related deaths occurred during the study. Kaplan-Meier estimated 23.4 months median OS, actuarial 12-month PFS rate 60%, actuarial 12-month, 24-month, and 5-year OS rates 80%, 50% and 40%, respectively. Four patients were still alive (1 patient free of recurrence). CONCLUSION: At 5 years-follow-up, intraoperative PDT with surgical maximal excision as initial therapy and standard adjuvant treatment suggests an increase of time to recurrence and overall survival in a high proportion of patients. Quality of life was maintained without any severe side effects. TRIAL REGISTRATION NCT NUMBER: NCT03048240. EudraCT number: 2016-002706-39.

Hearing Outcomes from Gamma Knife Treatment for Intracanalicular Vestibular Schwannomas with Good Initial Hearing.

Background: The objective of this study was to describe the long-term hearing outcomes of gamma knife treatment for unilateral progressing vestibular schwannomas (VS) presenting with good initial hearing using audiologic data. Methods: A retrospective review was performed between 2010 and 2020 to select patients with progressing unilateral VS and good hearing (AAO-HNS class A) treated with stereotactic gamma knife surgery (GKS). Their audiograms were analyzed along with treatment metrics and patient data. Results: Hearing outcomes with a median follow-up of 5 years post-treatment showed statistically significant loss of serviceable hearing: 34.1% of patients maintained good hearing (AAO-HNS class A), and 56.1% maintained serviceable hearing (AAO-HNS class A and B). Non-hearing outcomes are favorable with excellent tumor control and low facial nerve morbidity. Conclusions: Hearing declines over time in intracanalicular VS treated with GKS, with a significant loss of serviceable hearing after 5 years. The mean cochlear dose and the presence of cochlear aperture obliteration by the tumor are the main statistically significant factors involved in the hearing outcomes.

Impact of biologically effective dose on tremor decrease after stereotactic radiosurgical thalamotomy for essential tremor: a retrospective longitudinal analysis.

Stereotactic radiosurgery (SRS) is one of the surgical alternatives for drug-resistant essential tremor (ET). Here, we aimed at evaluating whether biologically effective dose (BEDGy2.47) is relevant for tremor improvement after stereotactic radiosurgical thalamotomy in a population of patients treated with one (unplugged) isocenter and a uniform dose of 130 Gy. This is a retrospective longitudinal single center study. Seventy-eight consecutive patients were clinically analyzed. Mean age was 69.1 years (median 71, range 36-88). Mean follow-up period was 14 months (median 12, 3-36). Tremor improvement was assessed at 12 months after SRS using the ET rating assessment scale (TETRAS, continuous outcome) and binary (binary outcome). BED was defined for an alpha/beta of 2.47, based upon previous studies considering such a value for the normal brain. Mean BED was 4573.1 Gy2.47 (median 4612, 4022.1-4944.7). Mean beam-on time was 64.7 min (median 61.4; 46.8-98.5). There was a statically significant correlation between delta (follow-up minus baseline) in TETRAS (total) with BED (p = 0.04; beta coefficient - 0.029) and beam-on time (p = 0.03; beta coefficient 0.57) but also between TETRAS (ADL) with BED (p = 0.02; beta coefficient 0.038) and beam-on time (p = 0.01; beta coefficient 0.71). Fractional polynomial multivariate regression suggested that a BED > 4600 Gy2.47 and a beam-on time > 70 min did not further increase clinical efficacy (binary outcome). Adverse radiation events (ARE) were defined as larger MR signature on 1-year follow-up MRI and were present in 7 out of 78 (8.9%) cases, receiving a mean BED of 4650 Gy2.47 (median 4650, range 4466-4894). They were clinically relevant with transient hemiparesis in 5 (6.4%) patients, all with BED values higher than 4500 Gy2.47. Tremor improvement was correlated with BED Gy2.47 after SRS for drug-resistant ET. An optimal BED value for tremor improvement was 4300-4500 Gy2.47. ARE appeared for a BED of more than 4500 Gy2.47. Such finding should be validated in larger cohorts.

The Use of Image Guided Programming to Improve Deep Brain Stimulation Workflows with Directional Leads in Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a preferred treatment for parkinsonian patients with severe motor fluctuations. Proper targeting of the STN sensorimotor segment appears to be a crucial factor for success of the procedure. The recent introduction of directional leads theoretically increases stimulation specificity in this challenging area but also requires more precise stimulation parameters. OBJECTIVE: We investigated whether commercially available software for image guided programming (IGP) could maximize the benefits of DBS by informing the clinical standard care (CSC) and improving programming workflows. METHODS: We prospectively analyzed 32 consecutive parkinsonian patients implanted with bilateral directional leads in the STN. Double blind stimulation parameters determined by CSC and IGP were assessed and compared at three months post-surgery. IGP was used to adjust stimulation parameters if further clinical refinement was required. Overall clinical efficacy was evaluated one-year post-surgery. RESULTS: We observed 78% concordance between the two electrode levels selected by the blinded IGP prediction and CSC assessments. In 64% of cases requiring refinement, IGP improved clinical efficacy or reduced mild side effects, predominantly by facilitating the use of directional stimulation (93% of refinements). CONCLUSIONS: The use of image guided programming saves time and assists clinical refinement, which may be beneficial to the clinical standard care for STN-DBS and further improve the outcomes of DBS for PD patients.

Microsurgical resection of gliomas of the cingulate gyrus: a systematic review and meta-analysis.

Cingulate gyrus gliomas are rare among adult, hemispheric diffuse gliomas. Surgical reports are scarce. We performed a systematic review of the literature and meta-analysis, with the aim of focusing on the extent of resection (EOR), WHO grade, and morbidity and mortality, after microsurgical resection of gliomas of the cingulate gyrus. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we reviewed articles published between January 1996 and December 2022 and referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies of microsurgical series reporting resection of gliomas of the cingulate gyrus. Primary outcome was EOR, classified as gross total (GTR) versus subtotal (STR) resection. Five studies reporting 295 patients were included. Overall GTR was 79.4% (range 64.1-94.7; I2= 88.13; p heterogeneity and p < 0.001), while STR was done in 20.6% (range 5.3-35.9; I2= 88.13; p heterogeneity < 0.001 and p= 0.008). The most common WHO grade was II, with an overall rate of 42.7% (24-61.5; I2= 90.9; p heterogeneity, p< 0.001). Postoperative SMA syndrome was seen in 18.6% of patients (10.4-26.8; I2= 70.8; p heterogeneity= 0.008, p< 0.001), postoperative motor deficit in 11% (3.9-18; I2= 18; p heterogeneity= 0.003, p= 0.002). This review found that while a GTR was achieved in a high number of patients with a cingulate glioma, nearly half of such patients have a postoperative deficit. This finding calls for a cautious approach in recommending and doing surgery for patients with cingulate gliomas and for consideration of new surgical and management approaches.

Benefits of combined use of 68-Ga Dotatoc and 5-ALA fluorescence for recurrent atypical skull-base meningioma after previous microsurgery and Gamma Knife radiosurgery: a case report.

BACKGROUND: Studies of novel microsurgical adjuncts, such as 5-aminolevulinic acid (5-ALA) fluorescence have shown various fluorescence patterns within meningiomas, opening new avenues for complete microsurgical resection. Here, we present a recurrent, radiation-induced meningioma, previously operated on two occasions (initial gross total resection and subtotal 12 years later) and also irradiated by Gamma Knife radiosurgery (GKR, 6 years after the first surgery). We thought to assess the usefulness of 68-Ga Dotatoc in surgical target planning and of 5-ALA as an adjunct for maximal microsurgical excision. CASE REPORT: We report on a 43 years-old Caucasian male diagnosed with atypical, radiation induced WHO II meningioma, with left basal temporal bone implantation. Hodgkin lymphoma treated with cranial and mediastinal radiation during infancy marked his personal history. He underwent a first gross total microsurgical resection, followed 6 and 12 years later by Gamma Knife radiosurgery (GKR) and second subtotal microsurgical resection, respectively. Magnetic resonance imaging (MRI) displayed new recurrence 13 years after initial diagnosis. He was clinically asymptomatic but routine Magnetic resonance imaging showed constant progression. There was strong 68-Ga Dotatoc uptake. We used 5-ALA guided microsurgical resection. Intraoperative views confirmed strong fluorescence, in concordance with both preoperative Magnetic resonance imaging enhancement and 68-Ga Dotatoc. The tumor was completely removed, with meningeal and bone resection. CONCLUSION: The authors conclude that fluorescence-guided resection using 5-ALA is useful for recurrent atypical, radiation-induced meningioma even despite previous irradiation and multiple recurrences.

Resection of the contrast-enhancing tumor in diffuse gliomas bordering eloquent areas using electrophysiology and 5-ALA fluorescence: evaluation of resection rates and neurological outcome-a systematic review and meta-analysis.

Independently, both 5-aminolevulinic acid (5-ALA) and intraoperative neuromonitoring (IONM) have been shown to improve outcomes with high-grade gliomas (HGG). The interplay and overlap of both techniques are scarcely reported in the literature. We performed a systematic review and meta-analysis focusing on the concomitant use of 5-ALA and intraoperative mapping for HGG located within eloquent cortex. Using PRISMA guidelines, we reviewed articles published between May 2006 and December 2022 for patients with HGG in eloquent cortex who underwent microsurgical resection using intraoperative mapping and 5-ALA fluorescence guidance. Extent of resection was the primary outcome. The secondary outcome was new neurological deficit at day 1 after surgery and persistent at day 90 after surgery. Overall rate of complete resection of the enhancing tumor (CRET) was 73.3% (range: 61.9-84.8%, p < .001). Complete 5-ALA resection was performed in 62.4% (range: 28.1-96.7%, p < .001). Surgery was stopped due to mapping findings in 20.5% (range: 15.6-25.4%, p < .001). Neurological decline at day 1 after surgery was 29.2% (range: 9.8-48.5%, p = 0.003). Persistent neurological decline at day 90 after surgery was 4.6% (range: 0.4-8.7%, p = 0.03). Maximal safe resection guided by IONM and 5-ALA for high-grade gliomas in eloquent areas is achievable in a high percentage of cases (73.3% CRET and 62.4% complete 5-ALA resection). Persistent neurological decline at postoperative day 90 is as low as 4.6%. A balance between 5-ALA and IONM should be maintained for a better quality of life while maximizing oncological control.

Combined use of intraoperative MRI and awake tailored microsurgical resection to respect functional neural networks: preliminary experience.

INTRODUCTION: The combined use of intraoperative MRI and awake surgery is a tailored microsurgical resection to respect functional neural networks (mainly the language and motor ones). Intraoperative MRI has been classically considered to increase the extent of resection for gliomas, thereby reducing neurological deficits. Herein, we evaluated the combined technique of awake microsurgical resection and intraoperative MRI for primary brain tumours (gliomas, metastasis) and epilepsy (cortical dysplasia, non-lesional, cavernomas). PATIENTS AND METHODS: Eighteen patients were treated with the commonly used "asleep awake asleep" (AAA) approach at Lille University Hospital, France, from November 2016 until May 2020. The exact anatomical location was insular with various extensions, frontal, temporal or fronto-temporal in 8 (44.4%), parietal in 3 (16.7%), fronto-opercular in 4 (22.2%), Rolandic in two (11.1%), and the supplementary motor area (SMA) in one (5.6%). RESULTS: The patients had a mean age of 38.4 years (median 37.1, range 20.8-66.9). The mean surgical duration was 4.1 hours (median 4.2, range 2.6-6.4) with a mean duration of intraoperative MRI of 28.8 minutes (median 25, range 13-55). Overall, 61% (11/18) of patients underwent further resection, while 39% had no additional resection after intraoperative MRI. The mean preoperative and postoperative tumour volumes of the primary brain tumours were 34.7 cc (median 10.7, range 0.534-130.25) and 3.5 cc (median 0.5, range 0-17.4), respectively. Moreover, the proportion of the initially resected tumour volume at the time of intraoperative MRI (expressed as 100% from preoperative volume) and the final resected tumour volume were statistically significant (p= 0.01, Mann-Whitney test). The tumour remnants were commonly found posterior (5/9) or anterior (2/9) insular and in proximity with the motor strip (1/9) or language areas (e.g. Broca, 1/9). Further resection was not required in seven patients because there were no remnants (3/7), cortical stimulation approaching eloquent areas (3/7) and non-lesional epilepsy (1/7). The mean overall follow-up period was 15.8 months (median 12, range 3-36). CONCLUSION: The intraoperative MRI and awake microsurgical resection approach is feasible with extensive planning and multidisciplinary collaboration, as these methods are complementary and synergic rather than competitive to improve patient oncological outcomes and quality of life.

How to combine the use of intraoperative magnetic resonance imaging (MRI) and awake craniotomy for microsurgical resection of hemorrhagic cavernous malformation in eloquent area: a case report.

BACKGROUND: Cavernous malformations are clusters of abnormal and hyalinized capillaries without interfering brain tissue. Here, we present a cavernous malformation operated under awake conditions, due to location, in an eloquent area and using intraoperative magnetic resonance imaging due to patient's movement upon the awake phase. CASE PRESENTATION: We present the pre-, per-, and postoperative course of an inferior parietal cavernous malformation, located in eloquent area, in a 27-year-old right-handed Caucasian male, presenting with intralesional hemorrhage and epilepsy. Preoperative diffusion tensor imaging has shown the cavernous malformation at the interface between the arcuate fasciculus and the inferior fronto-occipital fasciculus. We describe the microsurgical approach, combining preoperative diffusion tensor imaging, neuronavigation, awake microsurgical resection, and intraoperative magnetic resonance imaging. CONCLUSION: Complete microsurgical en bloc resection has been performed and is feasible even in eloquent locations. Intraoperative magnetic resonance imaging was considered an important adjunct, particularly used in this case as the patient moved during the "awake" phase of the surgery and thus neuronavigation was not accurate anymore. Postoperative course was marked by a unique, generalized seizure without any adverse event. Immediate and 3 months postoperative magnetic resonance imaging confirmed the absence of any residue. Pre- and postoperative neuropsychological exams were unremarkable.

Unruptured cerebral arteriovenous malformation in children: Outcome in treated and untreated patients.

BACKGROUND: The management of unruptured cerebral arteriovenous malformation (URCAVM) is highly controversial; however, data regarding URCAVM in children are scarce. MATERIAL AND METHODS: We retrospectively reviewed consecutive children followed for URCAVM in our department between 2001 and 2021. RESULTS: Out of 36 patients, 12 were initially managed by observation, and 24 underwent first-line treatment: 8 by microsurgery, 10 by radiosurgery, 2 by embolization, and 4 by combined treatment. Mean follow-up of the whole group was 63months. Complete cure of the malformation was obtained in 14 patients (58%) in the treatment group: 8/8 in the microsurgery group, 5/10 in the radiosurgery group, 1/4 in the combined treatment group, and none in the embolization group. Two of the initially non-treated patients presented cerebral hemorrhage, with significant neurological consequences. In the treatment group, 5 patients presented new neurological deficits, only 1 of which, however, was functionally significant. Headache improved in 11 cases, mostly in the treatment group. Overall, 6 patients in the treatment group became asymptomatic, versus none in the observation group. CONCLUSIONS: The treatment of URCAVM is a reasonable option in many pediatric cases, considering the cumulative risk of cerebral hemorrhage during the child's lifetime, as well as the symptoms specific to URCAVM. Microsurgery, when feasible, offers the best functional results and control of the AVM; however, the risk-benefit ratio should be weighed on a case-by-case basis. More studies will be needed to inform treatment decisions in pediatric URCAVM.

Radiobiology of Radiosurgery for Neurosurgeons.

Stereotactic radiosurgery (SRS) is a precise focusing of radiation to a targeted point or larger area of tissue. With advances in technology, the radiobiological understanding of this modality has trailed behind. Although found effective in both short- and long-term follow-up, there are ongoing evolution and controversial topics such as dosing pattern, dose per fraction in hypo-fractionnated regimens, inter-fraction interval, and so on. Radiobiology of radiosurgery is not a mere extension of conventional fractionation radiotherapy, but it demands further evaluation of the dose calculation on the linear linear-quadratic model, which has also its limits, biologically effective dose, and radiosensitivity of the normal and target tissue. Further research is undergoing to understand this somewhat controversial topic of radiosurgery better.

Frameless robot-assisted stereotactic biopsies for lesions of the brainstem-a series of 103 consecutive biopsies.

PURPOSE: Targeted treatment for brainstem lesions requires above all a precise histopathological and molecular diagnosis. In the current technological era, robot-assisted stereotactic biopsies represent an accurate and safe procedure for tissue diagnosis. We present our center's experience in frameless robot-assisted biopsies for brainstem lesions. METHODS: We performed a retrospective analysis of all patients benefitting from a frameless robot-guided stereotactic biopsy at our University Hospital, from 2001 to 2017. Patients consented to the use of data and/or images. The NeuroMate® robot (Renishaw™, UK) was used. We report on lesion location, trajectory strategy, histopathological diagnosis and procedure safety. RESULTS: Our series encompasses 96 patients (103 biopsies) treated during a 17 years period. Mean age at biopsy: 34.0 years (range 1-78). Most common location: pons (62.1%). Transcerebellar approach: 61 procedures (59.2%). Most common diagnoses: diffuse glioma (67.0%), metastases (7.8%) and lymphoma (6.8%). Non conclusive diagnosis: 10 cases (9.7%). After second biopsy this decreased to 4 cases (4.1%). Overall biopsy diagnostic yield: 95.8%. Permanent disability was recorded in 3 patients (2.9%, all adults), while transient complications in 17 patients (17.7%). Four cases of intra-tumoral hematoma were recorded (one case with rapid decline and fatal issue). Adjuvant targeted treatment was performed in 72.9% of patients. Mean follow-up (in the Neurosurgery Department): 2.2 years. CONCLUSION: Frameless robot-assisted stereotactic biopsies can provide the initial platform towards a safe and accurate management for brainstem lesions, offering a high diagnostic yield with low permanent morbidity.

Interstitial Photodynamic Therapy for Glioblastomas: A Standardized Procedure for Clinical Use.

Glioblastomas (GBMs) are high-grade malignancies with a poor prognosis. The current standard of care for GBM is maximal surgical resection followed by radiotherapy and chemotherapy. Despite all these treatments, the overall survival is still limited, with a median of 15 months. For patients harboring inoperable GBM, due to the anatomical location of the tumor or poor general condition of the patient, the life expectancy is even worse. The challenge of managing GBM is therefore to improve the local control especially for non-surgical patients. Interstitial photodynamic therapy (iPDT) is a minimally invasive treatment relying on the interaction of light, a photosensitizer and oxygen. In the case of brain tumors, iPDT consists of introducing one or several optical fibers in the tumor area, without large craniotomy, to illuminate the photosensitized tumor cells. It induces necrosis and/or apoptosis of the tumor cells, and it can destruct the tumor vasculature and produces an acute inflammatory response that attracts leukocytes. Interstitial PDT has already been applied in the treatment of brain tumors with very promising results. However, no standardized procedure has emerged from previous studies. Herein, we propose a standardized and reproducible workflow for the clinical application of iPDT to GBM. This workflow, which involves intraoperative imaging, a dedicated treatment planning system (TPS) and robotic assistance for the implantation of stereotactic optical fibers, represents a key step in the deployment of iPDT for the treatment of GBM. This end-to-end procedure has been validated on a phantom in real operating room conditions. The thorough description of a fully integrated iPDT workflow is an essential step forward to a clinical trial to evaluate iPDT in the treatment of GBM.

Gamma Knife radiosurgery as salvage therapy for gangliogliomas after initial microsurgical resection.

INTRODUCTION: Gangliogliomas (GG) are considered WHO grade I rare tumors. While they commonly manifest as temporal lobe epilepsy, they can be located anywhere in the brain. Primary treatment is complete microsurgical resection. Remnant or recurrent GG can benefit from radiation therapy. Here, we present a series of GG who received Gamma Knife radiosurgery (GKR) after initial microsurgery. METHODS: Between October 2009 and February 2020, four patients benefitted from such approach. The median age at surgery was 16 years (mean 17, 11-25) and at the time of GKR was 22.5 years (mean 23, 19-28). Initial clinical symptom was epilepsy in 3 cases and incidental in one. Biopsy was firstly performed in one case. One patient had stereotactic electroencephalography. The respective anatomical locations were right parieto-occipital, sylvian, left paraventricular and left inferior parietal. RESULTS: Gamma Knife radiosurgery was performed after a median time of 3.5 years after initial gross total microsurgical resection (GTR). The median follow-up after GKR was 54 months (mean 58.5, 6-120). The median marginal dose was 18 Gy (mean 17.5, 16-18). The median target volume was 0.5 mL (mean 0.904, 0.228-2.3). The median prescription isodose volume was 0.6 mL (mean 0.9, 0.3-2.4). At last follow-up, GG majorly decreased in 3 patients, remained stable in one. CONCLUSION: Gamma Knife radiosurgery is safe and effective for remnant GG after GTR. Primary treatment remains microsurgical resection, especially in cases with symptomatic mass effect or with epilepsy. Single fraction GKR can be a valuable option for remnant or recurrent tumors after initial resection.

Is interstitial photodynamic therapy for brain tumors ready for clinical practice? A systematic review.

BACKGROUND: Interstitial photodynamic therapy (iPDT), inserting optical fibers inside brain tumors, has been proposed for more than 30 years. While a promising therapeutic option, it is still an experimental treatment, with different ways of application, depending on the team performing the technique. OBJECTIVE: In this systematic review, we reported the patient selection process, the treatment parameters, the potential adverse events and the oncological outcomes related to iPDT treatment applied to brain tumors. METHODS: We performed a search in PubMed, Embase and Medline based on the following Mesh terms: "interstitial" AND "photodynamic therapy" AND "brain tumor" OR "glioma" OR glioblastoma" from January 1990 to April 2020. We screened 350 studies. Twelve matched all selection criteria. RESULTS: 251 patients underwent iPDT. Tumors were mainly de novo or recurrent high-grade gliomas (171 (68%) of glioblastomas), located supratentorial, with a median volume of 12 cm3. Hematoporphyrin derive agent (HpD) or protoporphyrin IX (PpIX) induced by 5-aminolevulinic acid (5-ALA) was used as a photosensitizer. Up to 6 optical fibers were introduced inside the tumor, delivering 200 mW/cm at a wavelength of 630 nm. Overall mortality was 1%. Transient and persistent morbidity were both 5%. No permanent deficit occurred using 5-ALA PDT. Tumor response rate after iPDT was 92% (IQR, 67; 99). Regarding glioblastomas, progression-free-survival was respectively 14.5 months (IQR, 13.8; 15.3) for de novo lesions and 14 months (IQR, 7; 30) for recurrent lesions, while overall survival was respectively 19 months (IQR, 14; 20) and 8 months (IQR, 6.3; 8.5). In patients harboring high-grade gliomas, 33 (13%) were considered long-term survivors (> 2 years) after iPDT. CONCLUSION: Regardless of heterogeneity in its application, iPDT appears safe and efficient to treat brain tumors, especially high-grade gliomas. Stand-alone iPDT (i.e., without combined craniotomy and intracavitary PDT) using 5-ALA appears to be the best option in terms of controlling side effects: it avoids the occurrence of permanent neurological deficits while reducing the risks of hemorrhage and sepsis.

Gamma Knife surgery for recurrent or persistent Cushing disease: long-term results and evaluation of biological effective dose in a series of 26 patients.

INTRODUCTION: Here we report long-term results after stereotactic radiosurgery (SRS) with Gamma Knife (GKRS) for Cushing disease. We further evaluated the potential role of the biological effective dose (BED) in the cure of this disease. METHODS: A retrospective review of a prospectively collected database (n = 26) was undertaken at Lille University Hospital, France. The mean follow-up period was 66 months (median 80, range 19–108). The mean marginal prescribed dose was 28.5 Gy (median 27.5, range 24–35) and the mean BED was 208.5 Gy2.47 (median 228.1, range 160–248). We divided patients with endocrine remission into a high BED group (160–228 Gy2.47, n = 6) and a low BED group (228–248 Gy2.47, n = 12). RESULTS: Eighteen (69.2%) patients had endocrine remission in the absence of any pharmacological therapy after a mean of 36 months (median 24, range 6–98). The actuarial probability of endocrine remission was 59% at 3 years and 77.6% at 7 years, which remained stable up to 10 years. There was a tendency to a higher overall probability of biological remission associated with higher BED values (77% versus 66% at last follow-up), although this did not reach statistical significance. Of note, the numbers of patients reflecting this actuarial probability at 12, 24, 36, 51 and 96 months were 21, 15, 11, 7 and 3, respectively. Tumour control was achieved in all cases (mean decrease in size for patients experiencing one was 29.4%, range 0–100%). Seven patients developed new pituitary insufficiency after GKRS. CONCLUSONS: Gamma Knife radiosurgery offers high rates of tumour control and endocrine remission on a long-term basis for ACTH-secreting pituitary adenomas. In this small series, higher BED values appeared to be associated with better endocrine remission rates. Owing to the limited sample size, such results should be validated in a larger cohort.

Repeat stereotactic radiosurgery for progressive vestibular schwannomas after previous radiosurgery: a systematic review and meta-analysis.

Vestibular schwannomas (VS) are slow-growing intracranial extraaxial benign tumors, developing from the vestibular part of the eight cranial nerves. Stereotactic radiosurgery (SRS) has now a long-term scientific track record as first intention treatment for small- to medium-sized VS. Though its success rate is very high, SRS for VS might fail to control tumor growth in some cases. However, the literature on repeat SRS after previously failed SRS remains scarce and reported in a low number of series with a limited number of cases. Here, we aimed at performing a systematic review and meta-analysis of the literature on repeat SRS for VS. Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2020 and referenced in PubMed. Tumor control and cranial nerve outcomes were evaluated with separate meta-analyses. Eight studies comprising 194 patients were included. The overall rate of patients treated in repeat SRS series as per overall series with first SRS was 2.2% (range 1.2-3.2%, p < 0.001). The mean time between first and second SRS was 50.7 months (median 51, range 44-64). The median marginal dose prescribed at first SRS was 12 Gy (range 8-24) and at second SRS was 12 Gy (range 9.8-19). After repeat SRS, tumor stability was reported in 61/194 patients, i.e., a rate of 29.6% (range 20.2-39%, I2 = 49.1%, p < 0.001). Tumor decrease was reported in 83/194 patients, i.e., a rate of 54.4% (range 33.7-75.1%, I2 = 89.1%, p < 0.001). Tumor progression was reported in 50/188 patients, i.e., a rate of 16.1% (range 2.5-29.7%, I2 = 87.1%, p = 0.02), rarely managed surgically. New trigeminal numbness was reported in 27/170 patients, i.e., a rate of 9.9% (range 1.4-18.3%, p < 0.02). New facial nerve palsy of worsened of previous was reported in 8/183 patients, i.e., a rate of 4.3% (range 1.4-7.2%, p = 0.004). Hearing loss was reported in 12/22 patients, i.e., a rate of 54.3% (range 24.8-83.8%, I2 = 70.7%, p < 0.001). Repeat SRS after previously failed SRS for VS is associated with high tumor control rates. Cranial nerve outcomes remain favorable, particularly for facial nerve. The rate of hearing loss appears similar to the one related to first SRS.

Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial.

PURPOSE: Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The unfavorable prognosis despite maximal therapy relates to high propensity for recurrence. Thus, overall survival (OS) is quite limited and local failure remains the fundamental problem. Here, we present a safety and feasibility trial after treating GBM intraoperatively by photodynamic therapy (PDT) after 5-aminolevulinic acid (5-ALA) administration and maximal resection. METHODS: Ten patients with newly diagnosed GBM were enrolled and treated between May 2017 and June 2018. The standardized therapeutic approach included maximal resection (near total or gross total tumor resection (GTR)) guided by 5-ALA fluorescence-guided surgery (FGS), followed by intraoperative PDT. Postoperatively, patients underwent adjuvant therapy (Stupp protocol). Follow-up included clinical examinations and brain MR imaging was performed every 3 months until tumor progression and/or death. RESULTS: There were no unacceptable or unexpected toxicities or serious adverse effects. At the time of the interim analysis, the actuarial 12-months progression-free survival (PFS) rate was 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months). CONCLUSIONS: This trial assessed the feasibility and the safety of intraoperative 5-ALA PDT as a novel approach for treating GBM after maximal tumor resection. The current standard of care remains microsurgical resection whenever feasible, followed by adjuvant therapy (Stupp protocol). We postulate that PDT delivered immediately after resection as an add-on therapy of this primary brain cancer is safe and may help to decrease the recurrence risk by targeting residual tumor cells in the resection cavity. Trial registration NCT number: NCT03048240. EudraCT number: 2016-002706-39.