Long duration of immunotherapy before radiosurgery might improve intracranial control of melanoma brain metastases.

PURPOSE: Despite significant advances that have been made in management of metastatic melanoma with immune checkpoint therapy, optimal timing of combination immune checkpoint therapy and stereotactic radiosurgery is unknown. We have reported toxicity and efficiency outcomes of patients treated with concurrent immune checkpoint therapy and stereotactic radiosurgery. PATIENTS AND METHODS: From January 2014 to December 2016, we analyzed 62 consecutive patients presenting 296 melanoma brain metastases, treated with gamma-knife and receiving concurrent immune checkpoint therapy with anti-CTLA4 or anti-PD1 within the 12 weeks of SRS procedure. Median follow-up time was 18 months (mo) (13-22). Minimal median dose delivered was 18 gray (Gy), with a median volume per lesion of 0.219 cm3. RESULTS: The 1-year control rate per irradiated lesion was 89% (CI 95%: 80.41-98.97). Twenty-seven patients (43.5%) developed distant brain metastases after a median time of 7.6 months (CI 95% 1.8-13.3) after gamma-knife. In multivariate analysis, positive predictive factors for intracranial tumor control were: delay since the initiation of immunotherapy exceeding 2 months before gamma-knife procedure (P=0.003) and use of anti-PD1 (P=0.006). Median overall survival (OS) was 14 months (CI 95%: 11-NR). Total irradiated tumor volume<2.1 cm3 was a positive predictive factor for overall survival (P=0.003). Ten patients (16.13%) had adverse events following irradiation, with four grade≥3. Predictive factors of all grade toxicity were: female gender (P=0.001) and previous treatment with MAPK (P=0.05). CONCLUSION: A long duration of immune checkpoint therapy before stereotactic radiosurgery might improve intracranial tumor control, but this relationship and its ideal timing need to be assessed in prospective trials.

Hypofractionated postoperative stereotactic radiotherapy for large resected brain metastases.

PURPOSE: The aim of the present retrospective study was to report outcomes after hypofractionated stereotactic radiotherapy (HSRT) for resected brain metastases (BM). PATIENTS AND METHODS: We reviewed results of patients with resected BM treated with postoperative HSRT (3×7.7Gy to the prescription isodose 70%) between May 2013 and June 2020. Local control (LC), distant brain control (DBC), overall survival (OS), leptomeningeal disease relapse (LMDR), and radiation necrosis (RN) occurrence were reported. RESULTS: Twenty-two patients with 23 brain cavities were included. Karnofsky Performance status (KPS) was≥70 in 77.3%. Median preoperative diameter was 37mm [21.0-75.0] and median planning target volume (PTV) was 23 cm3 [9.9-61.6]. Median time from surgery to SRT was 69 days [7-101] and 48% of patients had a local relapse on pre-SRT imaging. Median follow-up was 17.5 months [1.6-95.9]. One and two-year LC rates were 60.9 and 52.2% respectively. One and 2-year DBC rates were 45.5 and 40.9%. Median OS was 16.5 months. Four patients (18.2%) presented LMDR during follow-up. RN occurred in 6 patients (27.2%). Three factors were associated with OS: ECOG-PS (P=0.009), KPS (P=0.04), cystic or solid nature of the metastasis before surgery (P=0.037). Several factors were related to RN occurrence: PTV diameter and volume, Normal brain V21, V21 and V24 isodoses volumes. CONCLUSION: HSRT is the most widely used scheme for larger brain cavities after surgery. The optimal dose and scheme remain to be defined as well as the optimal delay between postoperative SRT and surgery. Dose escalation may be necessary, especially in case of subtotal resection.

Radiotherapy of non-tumoral refractory neurological pathologies.

Intracranial radiotherapy has been improved, primarily because of the development of stereotactic approaches. While intracranial stereotactic body radiotherapy is mainly indicated for treatment of benign or malignant tumors, this procedure is also effective in the management of other neurological pathologies; it is delivered using GammaKnife® and linear accelerators. Thus, brain arteriovenous malformations in patients who are likely to experience permanent neurological sequelae can be managed by single session intracranial stereotactic body radiotherapy, or radiosurgery, in specific situations, with an advantageous benefit/risk ratio. Radiosurgery can be recommended for patients with disabling symptoms, which are poorly controlled by medication, such as trigeminal neuralgia, and tremors, whether they are essential or secondary to Parkinson's disease. This literature review aims at defining the place of intracranial stereotactic body radiotherapy in the management of patients suffering from non-tumoral refractory neurological pathologies. It is clear that the multidisciplinary collaboration of experienced teams from Neurosurgery, Neurology, Neuroradiology, Radiation Oncology and Medical Physics is needed for the procedures using high precision radiotherapy techniques, which deliver high doses to locations near functional brain areas.

Stereotactic radiotherapy for large solitary brain metastases.

PURPOSE: To assess effectiveness and toxicity levels of stereotactic radiation therapy without whole brain radiation therapy in patients with solitary brain metastases larger than 3cm. PATIENTS AND METHODS: Between June 2007 and March 2009, 12 patients received fractionated stereotactic radiation therapy and 24 patients underwent stereotactic radiosurgery. For the fractionated stereotactic radiation therapy group, 3×7.7Gy were delivered to the planning target volume (PTV); median volume and diameter were 29.4 cm(3) and 4.4cm, respectively. For the stereotactic radiosurgery group, 14Gy were delivered to the PTV; median volume and diameter were 15.6 cm(3) and 3.7cm, respectively. RESULTS: Median follow-up was 218 days. For the fractionated stereotactic radiation therapy group, local control rates were 100% at 360 days and 64% at 720 days; for the stereotactic radiosurgery group, rates were 58% at 360 days and 48% at 720 days (P=0.06). Median survival time was 504 days for the fractionated stereotactic radiation therapy group and 164 days for the stereotactic radiosurgery group (P=0.049). Two cases of grade 2 toxicity were observed in the fractionated stereotactic radiation therapy group, and 6 cases of grade 1-2 toxicity, in the stereotactic radiosurgery group. CONCLUSIONS: This study provides data to support that fractionated stereotactic radiation therapy without whole brain radiation therapy with a margin dose of 3 fractions of 7.7Gy for treatment of solitary large brain metastases is efficient and well-tolerated. Because of the significant improvement in overall survival, this schedule should be assessed in a randomized trial.

[Medical devices needed for stereotactic radiosurgery and intracranial stereotactic radiotherapy]. / Équipements requis pour la mise en œuvre de la radiochirurgie et de la radiothérapie en conditions stéréotaxiques intracrânienne.

Since the previous special issue of Cancer Radiothérapie dedicated to radiosurgery in 1998, many important technological and computer developments have improved external beam radiotherapy treatment device performances. Whereas the Gamma Knife(®) was the gold standard for intracranial radiosurgery, new linear accelerator developments have led to new possibilities for the clinicians. This article describes quickly the different devices available for cranial radiosurgery or fractionated stereotactic radiotherapy.

[History of radiosurgery]. / Historique de la radiochirurgie.

Within the last decades, radiosurgery, also known as stereotactic radiotherapy, has become more and more popular as a non-invasive treatment of small benign tumours, arteriovenous malformations, metastases, and also some functional neurological structures, such as the fifth cranial nerve for trigeminal neuralgesia. It allows precisely delivering very high dose in a small volume under stereotactic conditions with minimal irradiation of tissue around the area. The first equipment devoted to radiosurgery was the Leksell Gamma Knife®. It is now challenged by some linear accelerators providing radiosurgery technology, such as the CyberKnife®, the Novalis Tx® radiosurgery platform, and the True Beam® linear accelerator.

Problematic differential diagnosis between cerebellar liponeurocytoma and anaplastic oligodendroglioma.

A cerebellar tumour, first diagnosed as an anaplastic oligodendroglioma, received radiation therapy (45 Gy) following gross total resection. The second histological study revealed a liponeurocytoma, a benign tumour not requiring adjuvant therapy. This case emphasizes the importance of considering this diagnosis to prevent unnecessary irradiation of such rumours.

[Results of salvage stereotactic radiosurgery in 14 patients with grade III or IV gliomas]. / Résultats de l'irradiation en conditions stéréotaxiques de rattrapage de 14 patients atteints d'un gliome de grade III ou IV.

AIMS: To determine local control and overall survival rates of 14 patients treated for a grade III or IV glioma relapsing in a previously irradiated area and re-irradiated by stereotactic radiosurgery. PATIENTS AND METHODS: From January 1997 to October 2001, 14 patients (median age 52 Years, age range 49-58 Years, Karnofski performance score 80 to 100) received radiosurgery for a relapse of grade III (3 patients) and or grade IV (10 patients) malignant gliomas. Before relapse, all patients had undergone surgery and had been given with a classical radiation protocol. Median maximum diameter and Volume of the tumors were 38.5mm (24-86mm) and 7cm3 (2-35cm3), respectively. RESULTS: Median maximal dose at the isocenter and median minimal dose at the periphery of the lesion were 21Gy (16-38Gy) and 13Gy (9-17Gy), respectively. Mean follow-up was 8.5 Months (1-29). Median overall survival was 11.6 Months; 6-Month, 1- and 2-Year overall survival rates were 85p.100, 36p.100 and 12p.100, respectively. At univariate analysis, only histological grade was a significant prognostic factor of overall survival (p=0.03). Median disease-free survival was 8.2 Months while 6-Month and 1-Year disease-free survival rates were 69p.100 and 14p.100, respectively. According to univariate analysis, histological grade (p=0.033) and minimal dose delivered at the margin of the target Volume (p=0.02) were prognostic factors for disease-free survival. Two patients developed a symptomatic radionecrosis. CONCLUSION: Radiosurgery of relapsed primitive high-grade brain tumors is efficient and overall survival rates were encouraging.

Long-term survival after gene therapy for a recurrent glioblastoma.

A patient presenting with a recurrent glioblastoma (GBM) survived 3 years after suicide gene therapy and finally died of a disseminated breast cancer with no indication of tumor recurrence on MRI. Postmortem analysis showed no evidence of recurrence of the GBM, neither near the initial tumor localization nor in any other area of the brain. Such an evolution is unusual in the course of this disease and may suggest in this particular case a cure of the GBM.

Role of the supplementary motor area in motor deficit following medial frontal lobe surgery.

OBJECTIVE: Patients undergoing surgical resection of medial frontal lesions may present a transient postoperative deficit that remains largely unpredictable. The authors studied the role of the supplementary motor area (SMA) in the occurrence of this deficit using fMRI. METHODS: Twenty-three patients underwent a preoperative fMRI before resection of medial frontal lesions. Tasks included self-paced flexion/extension of the left and right hand, successively. Preoperative fMRI data were compared with postoperative MRI data and with neurologic outcome. RESULTS: Following surgery, 11 patients had a motor deficit from which all patients recovered within a few weeks or months. The deficit was similar across patients, consisting of a global reduction in spontaneous movements contralateral to the operated side with variable severity. SMA activation was observed in all patients. The deficit was observed when the area activated in the posterior part of the SMA (SMA proper) was resected. CONCLUSIONS: fMRI is able to identify the area at risk in the SMA proper whose resection is highly related to the occurrence of the motor deficit. The clinical characteristics of this deficit support the role of the SMA proper in the initiation and execution of the movement.

Radiosurgery for re-irradiation of brain metastasis: results in 54 patients.

PURPOSE: To evaluate in terms of probabilities of local-regional control and survival, as well as of treatment-related toxicity, results of radiosurgery for brain metastasis arising in previously irradiated territory. PATIENTS AND METHODS: Between January 1994 and March 2000, 54 consecutive patients presenting with 97 metastases relapsing after whole brain radiotherapy (WBRT) were treated with stereotactic radiotherapy. Median interval between the end of WBRT and radiosurgery was 9 months (range 2-70). Median age was 53 years (24-80), and median Karnofski performance status (KPS) 70 (60-100). Forty-seven patients had one radiosurgery, five had two and two had three. Median metastasis diameter and volume were 21 mm (6-59) and 1.2 cc (0.1-95.2), respectively. A Leksell stereotactic head frame (Leksell Model G, Elektra, Instrument, Tucker, GA) was applied under local anesthesia. Irradiation was delivered by a gantry mounted linear accelerator (linacs) (Saturne, General Electric). Median minimal dose delivered to the gross disease was 16.2 Gy (11.8-23), and median maximal dose 21.2 Gy (14- 42). RESULTS: Median follow-up was 9 months (1-57). Five metastases recurred. One- and 2-year metastasis local control rates were 91.3 and 84% and 1- and 2-year brain control rates were 65 and 57%, respectively. Six patients died of brain metastasis evolution, and three of leptomeningeal carcinomatosis. One- and 2-year overall survival rates were 31 and 28%, respectively. According to univariate analysis, KPS, RPA class, SIR score and interval between WBRT and radiosurgery were prognostic factors of overall survival and brain free-disease survival. According to multivariate analysis, RPA was an independent factor of overall survival and brain free-disease survival, and the interval between WBRT and radiosurgery longer than 14 months was associated with longer brain free-disease survival. Side effects were minimal, with only two cases of headaches and two of grade 2 alopecia. CONCLUSION: Salvage radiosurgery of metastasis recurring after whole brain irradiation is an effective and accurate treatment which could be proposed to patients with a KPS>70 and a primary tumour controlled or indolent. We recommend that a dose not exceeding 14 Gy should be delivered to an isodose representing 70% of the maximal dose since local control observed rate was similar to that previously published in literature with upper dose and side effects were minimal.

Extent of tumor-brain interface: a new tool to predict evolution of malignant gliomas.

OBJECT: Tumor size is one of the features commonly used in oncology to predict disease evolution. However, for most primary brain tumors it is not predictive of outcome. Taking advantage of a gene therapy trial in which recurrences of glioblastoma were targeted with suicide genes, the authors developed a new parameter: the extent of tumor-brain interface--also called surface of tumor volume (STV)--to better describe three-dimensional conformation and the relationship between tumors and the surrounding normal tissue. Correlations between the STV and the usual clinical parameters were analyzed. METHODS: Between 1995 and 1998, 16 patients presenting with recurrent glioblastomas were enrolled in this study. Preoperative magnetic resonance images were analyzed on a separate workstation; the interface between tumor and normal brain tissue was measured on each 3-mm-thick section to assess STV. The mean STV was 29.2 cm2, and the mean tumor volume (TV) was 23.8 cm3. The STV was significantly correlated with survival (Spearman test: r = -0.54, p = 0.03), but TV was not (Spearman test: r = -0.39, p = 0.15). A separate analysis of responding and nonresponding patients showed that, as expected, STV was negatively correlated with survival among nonresponding patients (p = 0.04), but that among responding patients there was a positive tendency between STV and survival. CONCLUSIONS: These findings indicate that STV may be a useful tool for predicting the evolution of malignant glioma. Moreover, in future gene therapy trials in which such in situ approaches are used, increasing density and improved distribution of transfer cells should be taken into consideration as an important issue for efficacy.

Correspondence between functional magnetic resonance imaging somatotopy and individual brain anatomy of the central region: comparison with intraoperative stimulation in patients with brain tumors.

OBJECT: The goal of this study was to determine the somatotopical structure-function relationships of the primary motor cortex in individual patients by using functional magnetic resonance (fMR) imaging. This was done to assess whether there is a displacement of functional areas compared with anatomical landmarks in patients harboring brain tumors close to the central region, and to validate these findings with intraoperative cortical stimulation. METHODS: One hundred twenty hemispheres in 60 patients were studied by obtaining blood oxygen level-dependent fMR images in patients while they performed movements of the foot, hand, and face on both sides. There was a good correspondence between anatomical landmarks in the deep portion of the central sulcus on axial slices and the somatotopical organization of primary motor areas. Pixels activated during hand movements were centered on a small characteristic digitation; those activated during movements in the face and foot areas were located in the lower portion of the central sulcus (lateral to the hand area) and around the termination of the central sulcus, respectively. In diseased hemispheres, signal-intensity changes were still observed in the projection of the expected anatomical area. The fMR imaging data mapped intraoperative electrical stimulation in 92% of positive sites. CONCLUSIONS: There was a high correspondence between the somatotopical anatomy and function in the central sulcus, which was similar in normal and diseased hemispheres. The fMR imaging and electrical stimulation data were highly concordant. These findings may enable the neurosurgeon to locate primary motor areas more easily during surgery.

Intracranial aneurysm on CTA: demonstration using a transparency volume-rendering technique.

We report an interesting transparency study using a volume-rendering technique applied to CT angiography in a patient with a sylvian aneurysm. On a single view, all the information required for the aneurysmal treatment could be analyzed. Comparison with maximum intensity projection and virtual endoscopy reconstructions was performed.

A phase I/II study of herpes simplex virus type 1 thymidine kinase "suicide" gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma.

Despite extensive surgery for glioblastoma, residual tumor cells always lead to relapse. Gene therapy based on retrovirus-mediated gene transfer of herpes simplex virus type 1 thymidine kinase (HSV-1 TK), which specifically sensitizes dividing cells to ganciclovir (GCV) toxicity, may help eradicate such cells. During glioblastoma surgery, HSV-1 TK retroviral vector-producing cells (M11) were injected into the surgical cavity margins after tumor debulking. After a 7-day transduction period, GCV was administered for 14 days. Safety was assessed by clinical and laboratory evaluations, and efficacy was assessed by MRI-based relapse-free survival at month 4 and by overall survival. Twelve patients with recurrent glioblastoma were treated without serious adverse events related to M11 cell administration or GCV. Quality of life was not negatively influenced by this treatment. Overall median survival was 206 days, with 25% of the patients surviving longer than 12 months. At 4 months after treatment, 4 of 12 patients had no recurrence; their median overall survival was 528 days, compared with 194 days for patients with recurrence (p=0.03 by the log rank test). One patient is still free of detectable recurrence, steroid free and independent, 2.8 years after treatment. Thus, brain injections of M11 retroviral vector-producing cells for glioblastoma HSV-1 TK gene therapy were well tolerated and associated with significant therapeutic responses. These results warrant further development of this therapeutic strategy in brain tumor, including recurrent glioblastoma.

Intracranial aneurysm: inner view and neck identification with CT angiography virtual endoscopy.

We describe a virtual endoscopy tool applied on CT angiography acquisitions to analyze the neck and inner structures of an intracranial aneurysm. This technique, applied on a basilar artery aneurysm, accurately described its morphology and helped in making a choice between surgical and endovascular treatment.

Tumorigenicity of cerebellar primitive neuro-ectodermal tumors in athymic mice correlates with poor prognosis in children.

The histogenesis of medulloblastoma, also described as a cerebellar primitive neuro-ectodermal tumor (PNET), remains controversial and unresolved. In addition, genetic markers which characterize cerebellar PNETs with poor prognosis in children have not been identified. Since xenografts can be valuable tools for better understanding the genetic events involved in cerebellar PNETs, small fragments of tumor samples from 17 children with newly diagnosed cerebellar PNETs were transplanted s.c. into female athymic Swiss mice. Eleven were non-metastatic and 6 were metastatic PNETs. Eight tumors (47%) were tumorigenic. Histological analysis showed 6 typical medulloblastomas, 1 PNET with melanin pigment and 1 PNET with a rhabdoid phenotype. Wide heterogeneity was observed in tumor growth, with a doubling time ranging from 8 to 81 days after the first passage. Tumorigenicity was correlated with the metastatic phenotype of the tumor (p < 0.001). All the patients but one with a tumorigenic tumor relapsed and died. The survival of patients with a non-tumorigenic PNET (67%) was significantly higher than that of patients with a tumorigenic PNET (13%) (p < 0.02). None of the xenografts or tumors from patients exhibited N-myc-gene alteration. Only one xenograft showed c-myc amplification, with an abnormal 15-kilobase fragment. None of the 17 tumors from patients showed amplification or c-myc-gene rearrangement. In conclusion, tumorigenicity of cerebellar PNETs strongly correlates both with the metastatic phenotype of the tumors and with the disease-free survival of the patients. In addition, genetic events other than c-myc-gene amplification might be involved in cerebellar PNETs with poor prognosis.