A simple score to estimate the likelihood of pseudoprogression vs. recurrence following stereotactic radiosurgery for brain metastases: The Bergen Criteria.

BACKGROUND: A major challenge in the follow-up of patients treated with stereotactic radiosurgery (SRS) for brain metastases (BM) is to distinguish pseudoprogression (PP) from tumor recurrence (TR). The aim of the study was to develop a clinical risk assessment score. METHODS: Follow-up images of 87 of 97 consecutive patients treated with SRS for 348 BM were analyzed. Of these, 100 (28.7%) BM in 48 (53.9%) patients responded with either TR (n = 53, 15%) or PP (n = 47, 14%). Differences between the 2 groups were analyzed and used to develop a risk assessment score (the Bergen Criteria). RESULTS: Factors associated with a higher incidence of PP vs. TR were as follows: prior radiation with whole brain radiotherapy or SRS (P = .001), target cover ratio ≥98% (P = .048), BM volume ≤2 cm3 (P = .054), and primary lung cancer vs. other cancer types (P = .084). Based on the presence (0) or absence (1) of these 5 characteristics, the Bergen Criteria was established. A total score <2 points was associated with 100% PP, 2 points with 57% PP and 43% TR, 3 points with 57% TR and 43% PP, whereas >3 points were associated with 84% TR and 16% PP, P < .001. CONCLUSION: Based on 5 characteristics at the time of SRS the Bergen Criteria could robustly differentiate between PP vs. TR following SRS. The score is user-friendly and provides a useful tool to guide the decision making whether to retreat or observe at appropriate follow-up intervals.

Predictors of quality of life and survival following Gamma Knife surgery for lung cancer brain metastases: a prospective study.

OBJECTIVE Lung cancer (LC) patients who develop brain metastases (BMs) have a poor prognosis. Estimations of survival and risk of treatment-related deterioration in quality of life (QOL) are important when deciding on treatment. Although we know of several prognostic factors for LC patients with BMs, the role of QOL has not been established. Authors of this study set out to evaluate changes in QOL following Gamma Knife surgery (GKS) for BMs in LC patients and QOL as a prognostic factor for survival. METHODS Forty-four of 48 consecutive LC patients with BMs underwent GKS in the period from May 2010 to September 2011, and their QOL was prospectively assessed before and 1, 3, 6, 9, and 12 months after GKS by using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire. A mixed linear regression model was used to identify potential predictive factors for QOL and to assess the effect of GKS and the disease course on QOL at follow-up. RESULTS Mean QOL as measured by the brain cancer subscale (BRCS) of the FACT-BR remained stable from baseline (score 53.0) up to 12 months post-GKS (57.1; p = 0.624). The BRCS score improved for 32 patients (72.3%) with a total BM volume ≤ 5 cm3. Mean improvement in these patients was 0.45 points each month of follow-up, compared to a decline of 0.50 points each month despite GKS treatment in patients with BM volumes > 5 cm3 (p = 0.04). Asymptomatic BMs (p = 0.01), a lower recursive partitioning analysis (RPA) classification (p = 0.04), and a higher Karnofsky Performance Scale (KPS) score (p < 0.01) at baseline were predictors for a high, stable QOL after GKS. After multivariate analysis, a high KPS score (p < 0.01) remained the only positive predictor of a high, stable QOL post-GKS. Median survival post-GKS was 5.6 months (95% CI 1.0-10.3). A higher BRCS score (p = 0.01), higher KPS score (p = 0.01), female sex (p = 0.01), and the absence of liver (p = 0.02), adrenal (p = 0.02), and bone metastases (p = 0.03) predicted longer survival in unadjusted models. However, in multivariate analyses, a higher BRCS score (p < 0.01), female sex (p = 0.01), and the absence of bone metastases (p = 0.02) at GKS remained significant predictors. Finally, the BRCS score's predictive value for survival was compared with the values for the variables behind well-known prognostic indices: age, KPS score, extracranial disease status, and number and volume of BMs. Both BRCS score (p = 0.01) and BM volume (p = 0.05) remained significant predictors for survival in the final model. CONCLUSIONS Patient-reported QOL according to the BRCS is a predictor of survival in patients with BMs and may be helpful in deciding on the optimal treatment. Gamma Knife surgery is a safe and effective therapeutic modality that improves QOL for LC patients with a BM volume ≤ 5 cm3 at treatment. Careful follow-up and salvage therapy on demand seem to prevent worsening of QOL due to relapse of BMs.

Quality of life is maintained using Gamma Knife radiosurgery: a prospective study of a brain metastases patient cohort.

OBJECTIVE Gamma Knife radiosurgery (GKRS) is increasingly used in the management of brain metastases (BMs), but few studies have evaluated how GKRS impacts quality of life (QOL). The aim of this study was to monitor QOL as the primary end point following GKRS in a patient cohort with BM. METHODS The study included 97 consecutive patients with 1-6 BMs treated with GKRS between May 2010 and September 2011. QOL was assessed at baseline and at 1, 3, 6, 9, and 12 months postoperatively using the Functional Assessment of Cancer Therapy-Brain (FACT-BR) questionnaire with the brain cancer subscale (BRCS) questionnaire. Factors predicting QOL were identified by mixed linear regression analyses. Local control and toxicity were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) and the European Organisation for Research and Treatment/Radiation Therapy Oncology Group (EORTC/RTOG) criteria of late effects, respectively. RESULTS Compliance was high from baseline (97%) to 12-month follow-up (78%). Mean BRCS scores remained high during follow-up: they improved in 66% of patients and remained unchanged in 6% at 9 months. Local control (p = 0.018), improved symptoms (p = 0.005), and stable extracerebral disease (p = 0.001) correlated with high QOL-BRCS score. High baseline recursive partitioning analysis class predicted improved QOL (p = 0.031), whereas high Karnofsky Performance Scale score (p = 0.017), asymptomatic BMs (p = 0.001), and no cognitive deficits (p = 0.033) or seizures (p = 0.040) predicted high, stable QOL-BRCS during the 12-month follow-up. CONCLUSIONS QOL remained stable for up to 12 months following GKRS for the total cohort. High QOL was reported if local control occurred, cerebral symptoms improved/stabilized, or the need for steroids declined, which all reflected successful GKRS. Conversely, low QOL accompanied progression of intra- and extracerebral disease. Based on the study findings, GKRS appears to be a safe and effective treatment option for patients with BMs.

Long-term quality of life in patients with vestibular schwannoma: an international multicenter cross-sectional study comparing microsurgery, stereotactic radiosurgery, observation, and nontumor controls.

OBJECT: The optimal treatment for sporadic vestibular schwannoma (VS) is highly controversial. To date, the majority of studies comparing treatment modalities have focused on a narrow scope of technical outcomes including facial function, hearing status, and tumor control. Very few publications have investigated health-related quality of life (HRQOL) differences between individual treatment groups, and none have used a disease-specific HRQOL instrument. METHODS: All patients with sporadic small- to medium-sized VSs who underwent primary microsurgery, stereotactic radiosurgery (SRS), or observation between 1998 and 2008 were identified. Subjects were surveyed via postal questionnaire using the 36-Item Short Form Health Survey (SF-36), the 10-item Patient-Reported Outcomes Measurement Information System short form (PROMIS-10), the Glasgow Benefit Inventory (GBI), and the Penn Acoustic Neuroma Quality-of-Life (PANQOL) scale. Additionally, a pool of general population adults was surveyed, providing a nontumor control group for comparison. RESULTS: A total of 642 respondents were analyzed. The overall response rate for patients with VS was 79%, and the mean time interval between treatment and survey was 7.7 years. Using multivariate regression, there were no statistically significant differences between management groups with respect to the PROMIS-10 physical or mental health dimensions, the SF-36 Physical or Mental Component Summary scores, or the PANQOL general, anxiety, hearing, or energy subdomains. Patients who underwent SRS or observation reported a better total PANQOL score and higher PANQOL facial, balance, and pain subdomain scores than the microsurgical cohort (p < 0.02). The differences in scores between the nontumor control group and patients with VS were greater than differences observed between individual treatment groups for the majority of measures. CONCLUSIONS: The differences in HRQOL outcomes following SRS, observation, and microsurgery for VS are small. Notably, the diagnosis of VS rather than treatment strategy most significantly impacts quality of life. Understanding that a large number of VSs do not grow following discovery, and that intervention does not confer a long-term HRQOL advantage, small- and medium-sized VS should be initially observed, while intervention should be reserved for patients with unequivocal tumor growth or intractable symptoms that are amenable to treatment. Future studies assessing HRQOL in VS patients should prioritize use of validated disease-specific measures, such as the PANQOL, given the significant limitations of generic instruments in distinguishing between treatment groups and tumor versus nontumor subjects.

Increased survival using delayed gamma knife radiosurgery for recurrent high-grade glioma: a feasibility study.

OBJECTIVE: The current study retrospectively assessed delayed gamma knife radiosurgery (GKRS) in the management of high-grade glioma recurrences. METHODS: A total of 55 consecutive patients with high-grade glioma comprising 68 World Health Organization (WHO) III and WHO IV were treated with GKRS for local recurrences between 2001 and 2007. All patients had undergone microsurgery and radiochemotherapy, considered as standard therapy for high-grade glioma. Complete follow-up was available in all patients; median follow-up was 17.2 months (2.5-114.2 months). Median tumor volume was 5.2 mL, prescription dose was 20 Gy (14-22 Gy), and median max dose was 45 Gy (30-77.3 Gy). RESULTS: The patients with WHO III tumors showed a median survival of 49.6 months with and a 2-year survival of 90%. After GKRS of the recurrences, these patients showed a median survival of 24.2 months and a 2-year survival of 50%. The patients with WHO IV tumors had a median survival of 24.5 months with a 2-year survival of 51.4%. After the recurrence was treated with GKRS, the median survival was 11.3 months and a 2-year survival: 22.9% for the WHO IV patients. CONCLUSION: The current study shows a survival benefit for high-grade glioma recurrences when GKRS was administered after standard therapy. This is a relevant improvement compared with earlier studies that had had not been able to provide a beneficial effect timing radiosurgery in close vicinity to EBRT.

Gamma knife surgery as monotherapy with clinically relevant doses prolongs survival in a human GBM xenograft model.

OBJECT: Gamma knife surgery (GKS) may be used for recurring glioblastomas (GBMs). However, patients have then usually undergone multimodal treatment, which makes it difficult to specifically validate GKS independent of established treatments. Thus, we developed an experimental brain tumor model to assess the efficacy and radiotoxicity associated with GKS. METHODS: GBM xenografts were implanted intracerebrally in nude rats, and engraftment was confirmed with MRI. The rats were allocated to GKS, with margin doses of 12 Gy or 18 Gy, or to no treatment. Survival time was recorded, tumor sections were examined, and radiotoxicity was evaluated in a behavioral open field test. RESULTS: In the first series, survival from the time of implantation was 96 days in treated rats and 72 days in controls (P < 0.001). In a second experiment, survival was 72 days in the treatment group versus 54 days in controls (P < 0.006). Polynuclear macrophages and fibrosis was seen in groups subjected to GKS. Untreated rats with GBM xenografts displayed less mobility than GKS-treated animals in the open field test 4 weeks after treatment (P = 0.04). CONCLUSION: GKS administered with clinically relevant doses prolongs survival in rats harboring GBM xenografts, and the associated toxicity is mild.

Targeting glioblastoma with NK cells and mAb against NG2/CSPG4 prolongs animal survival.

Glioblastoma (GBM) is the most malignant brain tumor where patients' survival is only 14.6 months, despite multimodal therapy with debulking surgery, concurrent chemotherapy and radiotherapy. There is an urgent, unmet need for novel, effective therapeutic strategies for this devastating disease. Although several immunotherapies are under development for the treatment of GBM patients, the use of natural killer (NK) cells is still marginal despite this being a promising approach to treat cancer. In regard of our knowledge on the role of NG2/CSPG4 in promoting GBM aggressiveness we investigated the potential of an innovative immunotherapeutic strategy combining mAb9.2.27 against NG2/CSPG4 and NK cells in preclinical animal models of GBM. Multiple immune escape mechanisms maintain the tumor microenvironment in an anti-inflammatory state to promote tumor growth, however, the distinct roles of resident microglia versus recruited macrophages is not elucidated. We hypothesized that exploiting the cytokine release capabilities of activated (NK) cells to reverse the anti-inflammatory axis combined with mAb9.2.27 targeting the NG2/CSPG4 may favor tumor destruction by editing pro-GBM immune responses. Combination treatment with NK+mAb9.2.27 diminished tumor growth that was associated with reduced tumor proliferation, increased cellular apoptosis and prolonged survival compared to vehicle and monotherapy controls. The therapeutic efficacy was mediated by recruitment of CCR2low macrophages into the tumor microenvironment, increased ED1 and MHC class II expression on microglia that might render them competent for GBM antigen presentation, as well as elevated IFN-γ and TNF-α levels in the cerebrospinal fluid compared to controls. Depletion of systemic macrophages by liposome-encapsulated clodronate decreased the CCR2low macrophages recruited to the brain and abolished the beneficial outcomes. Moreover, mAb9.2.27 reversed tumor-promoting effects of patient-derived tumor-associated macrophage/microglia(TAM) ex vivo.Taken together, these findings indicate thatNK+mAb9.2.27 treatment may be an amenable therapeutic strategy to treat NG2/CSPG4 expressing GBMs. We provide a novel conceptual approach of combination immunotherapy for glioblastoma. The results traverse beyond the elucidation of NG2/CSPG4 as a therapeutic target, but demonstrate a proof of concept that this antibody may hold potential for the treatment of GBM by activation of tumor infiltrated microglia/macrophages.

Conservative management or gamma knife radiosurgery for vestibular schwannoma: tumor growth, symptoms, and quality of life.

BACKGROUND: There are few reports about the course of vestibular schwannoma (VS) patients following gamma knife radiosurgery (GKRS) compared with the course following conservative management (CM). In this study, we present prospectively collected data of 237 patients with unilateral VS extending outside the internal acoustic canal who received either GKRS (113) or CM (124). OBJECTIVE: The aim was to measure the effect of GKRS compared with the natural course on tumor growth rate and hearing loss. Secondary end points were postinclusion additional treatment, quality of life (QoL), and symptom development. METHODS: The patients underwent magnetic resonance imaging scans, clinical examination, and QoL assessment by SF-36 questionnaire. Statistics were performed by using Spearman correlation coefficient, Kaplan-Meier plot, Poisson regression model, mixed linear regression models, and mixed logistic regression models. RESULTS: Mean follow-up time was 55.0 months (26.1 standard deviation, range 10-132). Thirteen patients were lost to follow-up. Serviceable hearing was lost in 54 of 71 (76%) (CM) and 34 of 53 (64%) (GKRS) patients during the study period (not significant, log-rank test). There was a significant reduction in tumor volume over time in the GKRS group. The need for treatment following initial GKRS or CM differed at highly significant levels (log-rank test, P < .001). Symptom and QoL development did not differ significantly between the groups. CONCLUSION: In VS patients, GKRS reduces the tumor growth rate and thereby the incidence rate of new treatment about tenfold. Hearing is lost at similar rates in both groups. Symptoms and QoL seem not to be significantly affected by GKRS.

Establishment of a novel dsRed NOD/Scid mouse strain to investigate the host and tumor cell compartments.

Here we describe a NOD/Scid mouse strain expressing the dsRed transgene. The strain is maintained by inbreeding of homozygous dsRed NOD/Scid siblings, and expresses red fluorescence from various organs. The model allows engraftment of human tumor tissue, and engrafted tumors were separated into stromal and malignant cell compartments. Furthermore, we compared tumor-associated and normal fibroblast for expression of fibroblast-associated markers, and identified a marker panel that was upregulated in the tumor-associated fibroblasts. In conclusion, we propose that this model may be used in a variety of studies of tumor progression and to elucidate the role of the tumor microenvironment.

Gamma knife surgery of colorectal brain metastases: a high prescription dose of 25 Gy may improve growth control.

OBJECTIVE: There are few reports on the effect of gamma knife surgery (GKS) for brain metastases from colorectal cancer. The purpose of this study was to identify prognostic factors for local control, complications, and survival in our series of patients treated with GKS. METHODS: Eighty patients (36 males, 44 females) with 140 metastases who received GKS between 1996 and 2008 were retrospectively reviewed. The mean tumor volume was 6.13 (0.01-35.5) cm(3); the prescription dose was 21.1 (10-25.1) Gy and the maximum dose 42.7 (17.2-66.7) Gy; and the tumor cover was 95.0% (72%-100%). RESULTS: Growth control was achieved in 93 of 121 tumors (76.9%) and 42 of 68 (61.8%) patients, while treatment failure was seen in 28 of 121 tumors (23.1%). Local control was better if a high prescription dose of 25 Gy was used, 88.4% vs. 71.4% (P = 0.017), or if tumor volume was <5 cm(3) (86.4%), compared with 69.9% for 5-20 cm(3) and 51.9% for >20 cm(3) (P = 0.002). The hazard ratio for local failure with lower prescription doses was 2.8 (P = 0.026) in the unadjusted, and 8.5 (P = 0.055) in the adjusted multivariate analysis (tumor volumes >5 cm(3)). The median survival was 6 months (range 0-75) after GKS. Age <70 years (P < 0.001) and high RPA class (P = 0.032) were associated with longer survival. Fifteen patients (22.1%) had persistent edema on follow-up MRI, possibly because of radiation damage to the tumor. Radiation-induced edema was asymptomatic in 93.8%. We found neither a decrease in the incidence of new metastases nor improved survival when whole-brain radiation therapy was given prior to GKS. CONCLUSIONS: GKS provides reasonable local tumor control. Local control rate is highest if the margin dose is 25 Gy and the tumor volume <5 cm(3). Radiation edema was common but rarely symptomatic. Survival is longest for young, well-functioning patients.

Gamma knife treatment of growing vestibular schwannoma in Norway: a prospective study.

PURPOSE: Gamma Knife radiosurgery (GKRS) has been increasingly used in the treatment of vestibular schwannoma (VS). Very few studies relate tumor control and post-treatment growth rates to pretreatment growth rates. METHODS AND MATERIALS: We prospectively included 45 consecutive VS patients who were initially treated conservatively and then received GKRS between 2000 and 2007 because of demonstrated tumor growth. Pretreatment and post-treatment tumor volumes were estimated. Patients underwent audiograms, reported their symptoms, and responded to the Short Form General Health Survey (SF-36) questionnaire on each visit. RESULTS: Volume doubling times before and after treatment were 1.36 years (95% confidence intervals, 1.14-1.68) and -13.1 years (95% confidence intervals, -111.0 to -6.94), respectively. Tumor control, defined as a post-GKRS growth rate ≤ 0, was achieved in 71.1% of patients, with highest odds for tumor control among older patients and those with larger tumors. The 5-year retreatment-free survival rate was 93.9% (95% confidence intervals, 76.5-98.5). None of the clinical endpoints investigated showed statistically significant changes after GKRS, but improvement was seen in a few SF-36 parameters. CONCLUSIONS: GKRS alters the natural course of the tumor by reducing growth. Mathematic models yield poorer tumor control rates than those found by clinical assessment. Symptoms were unaffected by treatment, but quality of life was improved.

γ knife surgery versus reoperation for recurrent glioblastoma multiforme.

BACKGROUND: The optimal management of patients with recurrent glioblastoma multiforme (GBM) is a subject of controversy. These patients may be candidates for both reoperation and/or gamma knife surgery (GKS). Few studies have addressed the role of GKS for relapsing gliomas, and the results have not been compared with reoperation. To validate the efficacy and safety of GKS, we compared the survival and complication rates of GKS and reoperation for recurrent GBMs. METHODS: This study retrospectively reviewed 77 consecutive patients with histopathologically confirmed GBMs retreated for recurrent GBM between 1996 and 2007. Thirty-two patients underwent GKS, 26 reoperation and 19 both procedures. RESULTS: The median time from the second intervention to tumor progression was longer after GKS than after resection, P = 0.009. Median survival after retreatment was 12 months for the 51 patients receiving GKS compared with 6 months for reoperation only (P = 0.001, hazard ratio [HR] 2.4), and 19 months versus 16 months from the time of primary diagnosis (P = 0.021, HR 1.8). A multivariate analysis adjusted for possible confounding factors (tumor volume, recursive partitioning analysis class, neurological deficits, time to recurrence, adjuvant therapy, and tumor location) showed significantly longer survival for patients treated with GKS, both from retreatment (P = 0.013, HR 4.1) and from primary diagnosis (P = 0.002, HR 5.8). The adjusted results were still significant after separate analysis according to tumor volume <5 mL, 5 to 20 mL, and >20 mL. The complications rate was 9.8% after GKS and 25.2% after reoperation. CONCLUSIONS: GKS may be an alternative to open surgery for small GBMs at the time of recurrences, with a significantly lower complication rate and a possible survival benefit compared with reoperation.

Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients.

BACKGROUND: Radiosurgery is the main alternative to microsurgical resection for benign meningiomas. OBJECTIVE: To assess the long-term efficacy and safety of radiosurgery for meningiomas with respect to tumor growth and prevention of associated neurological deterioration. Medium- to long-term outcomes have been widely reported, but no large multicenter series with long-term follow-up have been published. METHODS: From 15 participating centers, we performed a retrospective observational analysis of 4565 consecutive patients harboring 5300 benign meningiomas. All were treated with Gamma Knife radiosurgery at least 5 years before assessment for this study. Clinical and imaging data were retrieved from each center and uniformly entered into a database by 1 author (A.S.). RESULTS: Median tumor volume was 4.8 cm³, and median dose to tumor margin was 14 Gy. All tumors with imaging follow-up < 24 months were excluded. Detailed results from 3768 meningiomas (71%) were analyzed. Median imaging follow-up was 63 months. The volume of treated tumors decreased in 2187 lesions (58%), remained unchanged in 1300 lesions (34.5%), and increased in 281 lesions (7.5%), giving a control rate of 92.5%. Only 84 (2.2%) enlarging tumors required further treatment. Five- and 10-year progression-free survival rates were 95.2% and 88.6%, respectively. Tumor control was higher for imaging defined tumors vs grade I meningiomas (P < .001), for female vs male patients (P < .001), for sporadic vs multiple meningiomas (P < .001), and for skull base vs convexity tumors (P < .001). Permanent morbidity rate was 6.6% at the last follow-up. CONCLUSION: Radiosurgery is a safe and effective method for treating benign meningiomas even in the medium to long term.

Gamma knife surgery in brain melanomas: absence of extracranial metastases and tumor volume strongest indicators of prolonged survival.

OBJECTIVE: To review a series of patients who underwent Gamma Knife surgery (GKS) to identify prognostic factors for local growth control and survival. METHODS: During the period 1996-2006, 77 patients (42 men and 35 women) with a total of 143 metastases underwent GKS. A solitary lesion was present in 40 patients (51.9%). RESULTS: Growth control was achieved in 114 of 128 (89.1%) tumors and 59 of 70 (84.3%) patients. The median survival was 7 months (range 0-73 months) after GKS and 67 months (range 4-327 months) from the time of diagnosis. Patients with absence of extracranial disease lived longer than patients with more widespread disease-median 16 months (range 3-52 months) versus 6 months (range 0-73 months; P = 0.014). A total tumor volume of less than 5 cc was associated with longer survival (P = 0.041). Survival was significantly longer in recursive partitioning analysis (RPA) class 1 (22 months) than RPA class 2 (7 months) and RPA class 3 (3 months; P = 0.008). Even in cases of treatment failure with tumor growth or appearance of new metastases, GKS slowed down the cerebral disease with no significant reduction in the duration of survival. CONCLUSIONS: GKS for melanoma brain metastasis provides a high rate of local tumor control. Survival is longest for well-functioning patients with absence of extracranial metastases or with an intracerebral total tumor volume less than 5 cc.

Vestibular schwannoma: surgery or gamma knife radiosurgery? A prospective, nonrandomized study.

OBJECTIVE: To conduct a prospective, open, nonrandomized study of treatment-associated morbidity in patients undergoing microsurgery or gamma knife radiosurgery (GKRS) for vestibular schwannomas. METHODS: Ninety-one patients with vestibular schwannomas with a maximum tumor diameter of 25 mm in the cerebellopontine angle were treated according to a prospective protocol either by GKRS (63 patients) or open microsurgery (28 patients) using the suboccipital approach. Primary end points included hearing function, according to the Gardner-Robertson scale, and facial nerve function, according to the House-Brackmann scale at 2 years. Clinical data included a balance platform test, score for tinnitus and vertigo using a visual analog scale, and working ability. Patients responded to the quality-of-life questionnaires Short-Form 36 and Glasgow Benefit Inventory. RESULTS: Three elderly GKRS patients withdrew; all remaining patients were followed for 2 years. Both primary end points were highly significant in favor of GKRS (P < 0.001). Evidence of reduced facial nerve function (House-Brackmann grade 2 or poorer) at 2 years was found in 13 of 28 open microsurgery patients and 1 of 60 GKRS patients. Thirteen of 28 patients who underwent surgery had serviceable hearing (Gardner-Robertson grade A or B) preoperatively, but none had serviceable hearing postoperatively. Twenty-five of 60 GKRS patients had serviceable hearing before treatment, and 17 (68%) of them had serviceable hearing 2 years after treatment. The tinnitus and vertigo visual analog scale score, as well as balance platform tests, did not change significantly after treatment, and working status did not differ between the groups at 2 years. Quality of life was significantly better in the GKRS group at 2 years, based on the Glasgow Benefit Inventory questionnaire. One GKRS patient required operative treatment within the 2-year study period. CONCLUSION: This is the second prospective study to demonstrate better facial nerve and hearing outcomes from GKRS than from open surgery for small- and medium-sized vestibular schwannomas.

Gamma knife stereotactic radiosurgery of Nelson syndrome.

OBJECTIVE: Gamma knife radiosurgery (GKR) can be used as primary or adjuvant therapy for the treatment of an ACTH-producing pituitary tumor after bilateral adrenalectomy, called Nelson syndrome (NS). We have examined the effect of GKR on tumor growth and ACTH-hypersecretion, and characterized the adverse events of this treatment in patients with NS. DESIGN: Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. Patients then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. SUBJECTS: Ten patients treated with GKR for NS after previous bilateral adrenalectomy. The mean follow-up was 7 years. No patient was lost to follow-up. RESULTS: Tumor growth was stopped in all patients. The ACTH levels declined in eight patients, and normalized in one patient. There was a significant drop in ACTH levels, with a half-time of 2.8 years. No patient developed visual field defects or any other cranial nerve dysfunction as a result of treatment. Four patients started hormone substitution therapy during the follow-up period. The substitution therapy of three pituitary axes present at GKR treatment could be stopped during the same period. One patient developed a glioblastoma in the left parieto-occipital region 14 years after GKR, far from the field of treatment. As the radiation level was below 1Gy to this area, it is unlikely that the GKR treatment itself induced the malignant tumor. CONCLUSION: In patients with NS, GKR is an effective adjuvant treatment, carrying relatively few adverse effects. Although the risk of developing a secondary neoplasia after GKR is present, it is probably extremely low.

Gamma knife stereotactic radiosurgery for acromegaly.

BACKGROUND: Gamma knife radiosurgery (GKR) is an adjuvant treatment for acromegaly if surgery fails to normalize GH hypersecretion. OBJECTIVE: To examine the effect of GKR on tumor growth and hypersecretion, and to characterize the adverse effect of this treatment. DESIGN: Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. PATIENTS then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. SETTING: Norwegian National Center for gamma knife treatment. PATIENTS: Sixty-one patients treated with GKR for acromegaly. Out of 55, 53 living patients underwent a detailed survey. The mean follow-up was 5.5 years. No patient was lost to follow-up. RESULTS: Tumor growth was stopped in all patients. At 3, 5, and 10 years after GKR, 45, 58, and 86% of patients had normal IGF-I levels. Consecutive hormone value analysis showed that patients receiving GH-suppressive medication had a more rapid decline in hypersecretion than those who did not receive such medication. Evaluated by survey baseline values alone, non-elevated IGF-I and GH levels below 5 mIU/l were found in 38%. GH-suppressive medication was terminated in 16 out of 40 patients following GKR. Nine out of 53 surveyed patients (17%) had normal IGF-I and GH nadir below 2.6 mIU/l at glucose tolerance tests, while not on hormone-suppressive medication. Two patients developed minor visual field defects. Eight patients started hormone substitution therapy during the follow-up period. CONCLUSION: GKR is an effective adjuvant treatment for residual acromegaly, carrying few side effects.

Human glioblastoma biopsy spheroids xenografted into the nude rat brain show growth inhibition after stereotactic radiosurgery.

BACKGROUND: The Gamma Knife is currently used to boost treatment of malignant gliomas. However, few experimental studies have focused on its radiobiological effects. In this work, the growth and invasiveness of human glioblastoma spheroids xenografted into nude rat brains were assessed after radiosurgery. Temporary in vitro as well as long-term in vivo radiation effects were studied. METHODS: Glioblastoma biopsy spheroids were irradiated with 12 or 24 Gy. Short-term in vitro spheroid viability and tumour cell migration was determined by microscopic techniques. Pre-irradiated glioblastoma spheroids were implanted into brains of immunosuppressed rats. Long-term tumour development was assessed by magnetic resonance (MR) imaging, and animal survival was recorded. An immunohistochemical analysis was performed on the sectioned rat brains. RESULTS: Both un-irradiated and irradiated spheroids remained viable during 2 months in culture, but a dose-dependent inhibition of tumour growth and migration was seen. MR imaging 4 weeks after implantation also showed a dose-dependent inhibition in tumour development. Median animal survival times were 25.5 days (control group), 43 days (12 Gy group) and 96 days (24 Gy group). The study of in vivo long-term radiation effects on the remaining viable tumour population showed no difference in Ki-67 labelling index and microvascular density before and after radiosurgery. CONCLUSIONS: A dose-dependent inhibition of tumour growth and invasion, as well as a dose-dependent increase in animal survival was observed. The model system described is well suited for assessing the radiobiological effects of Gamma Knife radiosurgery. The results indicate that radiosurgery of malignant gliomas might be effective in controlling tumour progression in selected glioblastoma patients.

Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery.

OBJECTIVE: The aim of the present study was to evaluate the overall treatment efficacy (tumor control, facial nerve function, complications) and quality of life for patients treated primarily for unilateral vestibular schwannomas of 30 mm or less, either by microsurgery or by gamma knife (GK) radiosurgery. The results for the two treatment groups are compared with each other, with main emphasis on the long-term quality of life. METHODS: This is a retrospective study of 189 consecutive patients, 86 treated by microsurgery and 103 by gamma knife. The mean observation time was 5.9 years. All patients had a magnetic resonance imaging scan and clinical evaluation performed toward the end of the study. To evaluate the quality of life, we used two standardized questionnaires, the Glasgow Benefit Inventory and Short-Form 36. The questionnaires were sent to the 168 living patients. The reply rate was 83.3%. RESULTS: A total of 79.8% of the patients in the microsurgery group and 94.8% of the GK patients had a good facial nerve function (House-Brackmann Grade 1-2). Hearing was usually lost after microsurgery, whereas the GK patients had preserved hearing, which often became reduced over the years after the treatment. The treatment efficacy, defined as no need for additional treatment, was similar for the two treatment modalities. Quality of life was reduced compared with normative data, being most reduced in the microsurgery group. Some of the quality of life questions showed an association with facial nerve function and sex. CONCLUSION: Posttreatment facial nerve function, hearing, complication rates, and quality of life were all significantly in favor of GK radiosurgery.

Cerebral atypical teratoid/rhabdoid tumor of infancy: long-term survival after multimodal treatment, also including triple intrathecal chemotherapy and gamma knife radiosurgery--case report.

Cerebral atypical teratoid/rhabdoid tumors (AT/RT) of infancy are highly malignant and have a poor prognosis. The authors report on one case with long-term survival. The patient was a 1 year-old boy presenting with a large AT/RT in the right temporal lobe. He was treated with complete surgery, followed by multiagent chemotherapy. Later he had a second resection and intrathecal chemotherapy and Gamma knife radiosurgery was added to the treatment. Except for a well-controlled temporal epilepsy, the boy is doing well after 6 years follow-up. AT/RT should be treated in a multimodal way. Intrathecal chemotherapy and Gamma knife radiosurgery of single recurrent or residual tumors might increase survival.