Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

[A Case Report of Spontaneous Cerebrospinal Fluid Otorrhea].

Spontaneous cerebrospinal fluid(CSF)otorrhea is less common than CSF leakage caused by trauma, and rarely occurs in adults. We report an adult case of CSF otorrhea. A 71-year-old woman with no traumatic or otologic history was hospitalized due to bacterial meningitis. After hospitalization, CSF leakage started suddenly from the left external ear canal. A high resolution CT scan with intrathecal administration of contrast material revealed CSF leakage in the left ear canal and multiple bone erosions in both the tegmen mastoideum and the posterior fossa aspect of the petrous bone. We performed closure and surgery via the middle fossa approach. We identified a bone defect in the tegmen mastoideum but could not detect any obvious abnormality in the dura mater. We placed both a pericranial flap and a free abdominal fat on the middle base of the skull as sealing materials. There was no recurrence of CSF otorrhea following surgery. In this surgery, the use of a multilayered closure technique is very important to avoid the recurrence of CSF leakage.

Gamma Knife surgery for patients with jugular foramen schwannomas: a multiinstitutional retrospective study in Japan.

OBJECTIVE This study aimed to explore the efficacy and safety of stereotactic radiosurgery in patients with jugular foramen schwannomas (JFSs). METHODS This study was a multiinstitutional retrospective analysis of 117 patients with JFSs who were treated with Gamma Knife surgery (GKS) at 18 medical centers of the Japan Leksell Gamma Knife Society. The median age of the patients was 53 years. Fifty-six patients underwent GKS as their initial treatment, while 61 patients had previously undergone resection. At the time of GKS, 46 patients (39%) had hoarseness, 45 (38%) had hearing disturbances, and 43 (36%) had swallowing disturbances. Eighty-five tumors (73%) were solid, and 32 (27%) had cystic components. The median tumor volume was 4.9 cm3, and the median prescription dose administered to the tumor margin was 12 Gy. Five patients were treated with fractionated GKS and maximum and marginal doses of 42 and 21 Gy, respectively, using a 3-fraction schedule. RESULTS The median follow-up period was 52 months. The last follow-up images showed partial remission in 62 patients (53%), stable tumors in 42 patients (36%), and tumor progression in 13 patients (11%). The actuarial 3- and 5-year progression-free survival (PFS) rates were 91% and 89%, respectively. The multivariate analysis showed that pre-GKS brainstem edema and dumbbell-shaped tumors significantly affected PFS. During the follow-up period, 20 patients (17%) developed some degree of symptomatic deterioration. This condition was transient in 12 (10%) of these patients and persistent in 8 patients (7%). The cause of the persistent deterioration was tumor progression in 4 patients (3%) and adverse radiation effects in 4 patients (3%), including 2 patients with hearing deterioration, 1 patient with swallowing disturbance, and 1 patient with hearing deterioration and hypoglossal nerve palsy. However, the preexisting hoarseness and swallowing disturbances improved in 66% and 63% of the patients, respectively. CONCLUSIONS GKS resulted in good tumor control in patients with either primary or residual JFSs. Although some patients experienced some degree of symptomatic deterioration after treatment, persistent adverse radiation effects were seen in only 3% of the entire series at the last follow-up. Lower cranial nerve deficits were extremely rare adverse radiation effects, and preexisting hoarseness and swallowing disturbances improved in two-thirds of patients. These results indicated that GKS was a safe and reasonable alternative to surgical resection in selected patients with JFSs.

¹H-MRS of intracranial meningiomas: what it can add to known clinical and MRI predictors of the histopathological and biological characteristics of the tumor?

OBJECTIVE: The main goal of the present study was evaluation of proton magnetic resonance spectroscopy (¹H-MRS) in diagnosis of histopathologically aggressive intracranial meningiomas. METHODS: Single-voxel ¹H-MRS of 100 intracranial meningiomas was performed before their surgical resection. Investigated metabolites included mobile lipids, lactate, alanine, N-acetylaspartate (NAA), and choline-containing compounds (Cho). According to criteria of World Health Organization (WHO) 82 meningiomas were assigned histopathological grade I, 11 grade II, and 7 grade III. The MIB-1 index varied from 0% to 27.3% (median, 1.6%). In 43 cases tight adhesion of the tumor to the pia mater or brain tissue was macroscopically identified at surgery. The consistency of 49 meningiomas was characterized as soft, 26 as hard, and 25 as mixed. RESULTS: No one metabolic parameter had statistically significant association with histopathological grade and subtype, invasive growth, and consistency of meningioma. Univariate statistical analysis revealed greater ¹H-MRS-detected Cho content (P=0.0444) and lower normalized NAA/Cho ratio (P=0.0203) in tumors with MIB-1 index 5% and more. However, both parameters lost their statistical significance during evaluation in the multivariate model along with other clinical and radiological variables. It was revealed that non-benign histopathology of meningioma (WHO grade II/III) is mainly predicted by irregular shape (P=0.0076) and large size (P=0.0316), increased proliferative activity by irregular shape (P=0.0056), and macroscopically invasive growth by prominent peritumoral edema (P=0.0021). CONCLUSION: While ¹H-MRS may be potentially used for the identification of meningiomas with high proliferative activity, it, seemingly, could not add substantial diagnostic information to other radiological predictors of malignancy in these tumors.

Gamma knife radiosurgery for benign tumors with symptoms from brainstem compression.

PURPOSE: This study evaluated the role of radiosurgery in the management of symptomatic patients with brainstem compression from benign basal tumors. METHODS AND MATERIALS: Over a 17-year, period 246 patients (202 vestibular schwannomas and 44 meningiomas) with brainstem compression from benign skull-base tumors were managed with Gamma Knife radiosurgery. Median tumor volumes were 3.9 cm(3) (range, 0.8-39.0 mL) and 6.6 mL (range, 1.6-25.1 mL) for vestibular schwannomas and meningiomas, respectively. For both tumors, a median marginal dose of 13 Gy was prescribed. Median follow-up of patients was 65 months for vestibular schwannomas and 60 months for meningiomas. Patients were categorized into four groups on the basis of the tumor-brainstem relationship on neuroimaging. RESULTS: Preservation of function was stratified according to grade of brainstem compression. We analyzed the effect of radiosurgery on symptoms of brainstem compression. The tumor control rate was 100 % for meningioma and 97% for vestibular schwannomas (although 5% required an additional procedure such as a ventriculoperitoneal shunt). In patients with vestibular schwannoma, serviceable hearing was preserved in 72.0%. Balance improved in 31.9%, remained unchanged in 56.5%, and deteriorated in 11.6% of patients who had imbalance at presentation. Balance improved significantly in patients who had less tumor compression (p = 0.0357) after radiosurgery. Symptoms improved in 43.2% of patients with meningioma. CONCLUSION: Radiosurgery is a minimally invasive option for patients with benign basal tumors that indent or distort the brainstem. A high tumor growth control rate and satisfactory rate of neurological preservation and symptom control can be obtained with radiosurgery.

Metabolic alterations in the peritumoral brain in cases of meningiomas: 1H-MRS study.

The objective of the present study was metabolic characterization of the peritumoral brain in the vicinity of meningiomas using proton magnetic resonance spectroscopy ((1)H-MRS). Data of long-echo (TR: 2000 ms, TE: 136 ms) single-voxel spectroscopic investigations were obtained during preoperative examination of 81 patients (19 men and 62 women; mean age, 56.5 years). Twenty-seven neoplasms were disclosed incidentally. Moderate-to-severe peritumoral edema was presented in 20 cases. Invasive growth of the tumor was macroscopically identified during surgery in 35 cases. Analyzed metabolites included N-acetylaspartate (NAA), choline-containing compounds (Cho), mobile lipids (Lip) and lactate (Lac). Compared to distant normal-appearing white matter (1)H-MRS of the brain in the vicinity of meningiomas disclosed statistically significant decrease of NAA content (P=0.0019). Investigated metabolic parameters depended on the presence of invasive tumor growth and prominent peritumoral edema, as well as on the size of the neoplasm, its location, and the patient's age. More severe (1)H-MRS-detected peritumoral metabolic abnormalities associated with invasive growth of meningioma might be used for its prediction. The presence of meningioma-related neurological symptoms was mainly determined by the size of the tumor, while might be also associated with lower normalized NAA/Cho ratio and more frequent presence of a Lip peak in the peritumoral brain. In conclusion, decrease of NAA content constitutes the most prominent (1)H-MRS-detected brain abnormality in the vicinity of intracranial meningiomas. Peritumoral spectroscopic alterations are determined by a variety of factors, can be predictive for invasive tumor growth and may correspond to presented neurological symptoms.

Spectroscopy-supported frame-based image-guided stereotactic biopsy of parenchymal brain lesions: comparative evaluation of diagnostic yield and diagnostic accuracy.

OBJECTIVE: Comparative evaluation of diagnostic efficacy of stereotactic brain biopsy performed with and without additional use of spectroscopic imaging ((1)H-MRS) for target selection was done. METHODS: From 2002 to 2006, 30 patients with parenchymal brain lesions underwent (1)H-MRS-supported frame-based stereotactic biopsy, whereas in 39 others MRI-guided technique was used. Comparison of diagnostic yield of the procedure in these two groups was performed. Additionally, the diagnostic accuracy was evaluated in 37 lesions, which were surgically resected within 1 month thereafter. RESULTS: Stereotactic biopsy permitted establishment of a definitive histopathological diagnosis in 57 cases and diagnosis of low-grade glioma without specific tumor typing in 8 cases. In 4 cases tissue sampling was non-diagnostic. In 5 out of 8 cases with incomplete diagnosis and in all non-diagnostic cases target selection was performed without the use of (1)H-MRS (P=0.2073). The diagnostic yields of (1)H-MRS-supported and MRI-guided procedures were 100% and 90%, respectively (P=0.1268). Comparison of the histopathological diagnoses after stereotactic biopsy and surgical resection revealed complete diagnostic agreement in 13 cases, minor disagreement in 14 cases, and major disagreement in 10 cases. Among these last 10 cases, initial undergrading of non-enhancing WHO grade III gliomas was the most common (7 cases). The diagnostic accuracy of (1)H-MRS-supported and MRI-guided procedures was 67% and 79%, respectively (P=0.4756). CONCLUSION: While in the present study the diagnostic yield of (1)H-MRS-supported frame-based stereotactic brain biopsy was 100%, its statistically significant diagnostic advantages over MRI-guided technique were not proved. Optimal selection of the spectroscopic target for tissue sampling remains unclear.

Management and prognosis of cysts developed on long-term follow-up after Gamma Knife radiosurgery for intracranial arteriovenous malformations.

BACKGROUND: Delayed cyst formation is a well-recognized complication after radiosurgery for intracranial AVM. The objective of the present study was the evaluation of the different management options for these lesions and the corresponding prognosis of patients. METHODS: Between 2000 and 2005, 12 patients with intracranial AVM initially treated by GKR were reevaluated at Tokyo Women's Medical University because of delayed cyst formation in the vicinity of the target area. There were 7 men and 5 women. The mean age of the patients was 31.8 years at the time of GKR and 41.1 years at the time of complication. The average period between treatment and diagnosis of the complication constituted 6.7 years. All AVMs had lobar location and showed complete angiographic obliteration after GKR. RESULTS: The most common neurological signs and symptoms at the time of cyst presentation were headache (10 cases) and seizures (4 cases). Two patients were asymptomatic. Three patients underwent surgery soon after the diagnosis of the cyst, whereas initial observation was done in another 9. Among the latter, 5 patients had to be treated surgically thereafter because of persistent or aggravated neurological symptoms associated with radiological cyst expansion. Four other patients, including both asymptomatic ones, are in stable condition without surgery. Follow-up after treatment of the cyst varied from 7 to 60 months (average, 34.3 months). All patients are in good condition. CONCLUSIONS: Although delayed formation of cysts after GKR for intracranial AVM should be considered as a complication of the radiosurgical treatment, it has a relatively good prognosis. Observation can be recommended as initial option for compensated and asymptomatic patients.

Outcome after pituitary radiosurgery for thalamic pain syndrome.

PURPOSE: To evaluate outcomes after pituitary radiosurgery in patients with post-stroke thalamic pain syndrome. METHODS AND MATERIALS: From 2002 to 2006, 24 patients with thalamic pain syndrome underwent pituitary radiosurgery at Tokyo Women's Medical University and were followed at least 12 months thereafter. The radiosurgical target was defined as the pituitary gland and its connection with the pituitary stalk. The maximum dose varied from 140 to 180 Gy. Mean follow-up after treatment was 35 months (range, 12-48 months). RESULTS: Initial pain reduction, usually within 48 h after radiosurgery, was marked in 17 patients (71%). However, in the majority of cases the pain recurred within 6 months after treatment, and at the time of the last follow-up examination durable pain control was marked in only 5 patients (21%). Ten patients (42%) had treatment-associated side effects. Anterior pituitary abnormalities were marked in 8 cases and required hormonal replacement therapy in 3; transient diabetes insipidus was observed in 2 cases, transient hyponatremia in 1, and clinical deterioration due to increase of the numbness severity despite significant reduction of pain was seen once. CONCLUSIONS: Pituitary radiosurgery for thalamic pain results in a high rate of initial efficacy and is accompanied by acceptable morbidity. It can be used as a primary minimally invasive management option for patients with post-stroke thalamic pain resistant to medical therapy. However, in the majority of cases pain recurrence occurs within 1 year after treatment.

Outcome after radiosurgery for brain metastases in patients with low Karnofsky performance scale (KPS) scores.

PURPOSE: The objective of this retrospective study was evaluation of the outcome after stereotactic radiosurgery (SRS) in patients with intracranial metastases and poor performance status. METHODS AND MATERIALS: Forty consecutive patients with metastatic brain tumors and Karnofsky performance scale (KPS) scores < or =50 (mean, 43 +/- 8; median, 40) treated with SRS were analyzed. Poor performance status was caused by presence of intracranial metastases in 28 cases (70%) and resulted from uncontrolled extracerebral disease in 12 (30%). RESULTS: Survival after SRS varied from 3 days to 11.5 months (mean, 3.8 +/- 2.9 months; median, 3.3 months). Survival probability constituted 0.50 +/- 0.07 at 3 months and 0.20 +/- 0.05 at 6 months posttreatment. Cause of low KPS score (p = 0.0173) and presence of distant metastases beside the brain (p = 0.0308) showed statistically significant associations with overall survival in multivariate Cox proportional hazards regression analysis. Median survival was 6.0 months if low KPS score was caused by cerebral disease and distant metastases in regions beyond the brain were absent, 3.3 months if low KPS score was caused by cerebral disease and distant metastases in regions beyond the brain were present, and 1.0 month if poor performance status resulted from extracerebral disease. CONCLUSIONS: Identification of the cause of low KPS score (cerebral vs. extracerebral) in patients with metastatic brain tumor(s) may be important for prediction of the outcome after radiosurgical treatment. If poor patient performance status without surgical indications is caused by intracranial tumor(s), SRS may be a reasonable treatment option.

Current treatment strategy for vestibular schwannoma: image-guided robotic microradiosurgery.

OBJECT: Gamma Knife surgery (GKS) is becoming a standard treatment for vestibular schwannoma (VS); it is ranked with microsurgery from the perspective of tumor control and audiofacial nerve function preservation. A new treatment technique that will improve the tumor shrinkage ratio, shorten the patient's recovery time, and even recover some cranial nerve function is described. METHODS: Along with advances in the GKS system, the authors have developed magnetic resonance imaging sequences specific to particular treatments. These newly developed sequences provide much clearer visualization of the distribution of the cranial nerves, especially in the area from the cisterns to the internal acoustic meatus. Magnetic resonance images have been fused with computed tomography scans to facilitate better delineation of the anatomical relationships. These dose-planning images allow for a higher isodose line (80%) inside the tumor. The aim is to shrink the tumor and not just to control it. To date 130 patients have been treated with GKS in conjunction with this new technique. Of the 130, 91 patients were observed for more than 12 months. The tumor shrinkage rate was 65.9% (76% for patients with > 24 months of follow up), the facial nerve preservation rate was 98.9%, the hearing preservation rate was 92.3%, and four (4%) of 91 patients recovered hearing function. Transient tumor enlargement was observed in most cases, but no severe complications were found. CONCLUSIONS: Although these results are preliminary, they would appear to represent a potential breakthrough in the treatment of VS. Longer follow-up periods and additional cases will firmly establish this method as an absolute treatment option for patients with a VS.

Image-guided microradiosurgery for skull base tumors: advantages of using gadolinium-enhanced constructive interference in steady-state imaging.

Gamma Knife surgery (GKS) is image-guided surgery for brain tumors. Precise tumor visualization is needed in dose planning to control tumor progression. The surrounding vital structures must also be clearly defined to allow the preservation of their function. A special magnetic resonance (MR) imaging sequence was chosen for use with GKS to treat skull base and suprasellar tumors. Gadolinium-enhanced 0.5-mm constructive interference in steady-state (CISS) slices were obtained in skull base and suprasellar tumors. Each structure that was adjacent to the tumor could be visualized more clearly by using this imaging technique because the tumor became transparent even though there was no change in the appearance of the surrounding structures after injection of Gd. Use of this technique in acoustic tumors allowed the seventh and eighth cranial nerves to be visualized in the cisternal and intrameatal portions; both of which were distinguishable from the tumor. Suprasellar tumor could be distinguished from the adjacent optic pathway. The use of Gd-enhanced CISS imaging allowed for optimal dose planning with very high conformity in every tumor. Achieving this high conformity allowed the preservation of adjacent structures and their functions. Establishing optimal dose planning in brain tumors is very important to overcome the problem of producing new neurological deficits in patients who may already be suffering disease-related deficits. The use of this special CISS MR imaging sequence may help accomplish this goal.

How soon will the patient with metastasis return for radiosurgery?

OBJECT: Stereotactic radiosurgery for brain metastasis has become one of the standard treatment options in recent years. Some patients must undergo repeated stereotactic radiosurgery for new lesions. The authors retrospectively reviewed their data to estimate how soon the patients undergo repeated radiosurgery for new lesions. METHODS: Between October 1999 and March 2006, 1081 patients with brain metastases underwent Gamma Knife surgery (GKS) at Tokyo Women's Medical University. One hundred and forty-nine patients in whom GKS had been performed two or more times were evaluated. There were 68 men and 81 women with a median age of 61 years (range 29-90 years). The authors analyzed data on patient age, number of treated lesions, and period between GKSs. Follow-up imaging was performed in almost all patients every 2 to 3 months after GKS. The number of lesions treated in a single session varied from one to 35. The median interval between GKSs was 26 weeks (range 3-175 weeks) for patients with breast cancer and 23 weeks (range 4-179 weeks) for patients with non-small cell lung carcinoma. CONCLUSIONS: It would appear that follow-up imaging studies should be obtained every 2 to 3 months after GKS to monitor patients for tumor recurrence.

Age-related changes in lateral ventricle morphology in craniosynostotic rabbits using magnetic resonance imaging.

BACKGROUND AND AIMS: Craniosynostosis occurs in 300-500 per 1,000,000 live births and results in secondary craniofacial, ocular, and intracranial anomalies. Neurologic problems associated with craniosynostosis include changes in intracranial morphology such as dilation of the cerebral ventricles, however, clinical studies are confounded by small sample sizes, heterogenous samples, and lack of age-matched controls. The present study was designed to assess age-related changes in the lateral ventricle volume of the brain in normal rabbits and rabbits with naturally-occurring coronal suture synostosis using serial magnetic resonance imaging. METHODS: Eighteen rabbits (6 wild-type controls, 6 with early-onset [ approximately 21 days gestation], and 6 with delayed-onset [approximately 25 days post-gestation] coronal suture synostosis) had magnetic resonance imaging (MRI) at 10, 25, and 42 days of age. RESULTS: The results demonstrate that rabbits with early-onset synostosis had significantly (p<0.001) dilated and larger lateral ventricles (by 77% at 10 days of age) than wild-type and delayed-onset synostosis rabbits, which progressively worsened by day 42. CONCLUSION: This finding suggests that uncorrected coronal suture synostosis may have early effects on lateral ventricle volume hypertrophy, possibly through obstructed cerebrospinal fluid and/or venous drainage and circulation.