Growth dynamics of incidental meningiomas: A prospective long-term follow-up study.

Background: There is no consensus on the management of incidental meningiomas. The literature on long-term growth dynamics is sparse and the natural history of these tumors remains to be illuminated. Methods: We prospectively assessed long-term tumor growth dynamics and survival rates during active monitoring of 62 patients (45 female, mean age 63.9 years) harboring 68 tumors. Clinical and radiological data were obtained every 6 months for 2 years, annually until 5 years, then every second year. Results: The natural progression of incidental meningiomas during 12 years of monitoring was growth (P < .001). However, mean growth decelerated at 1.5 years and became insignificant after 8 years. Self-limiting growth patterns were seen in 43 (63.2%) tumors, non-decelerating in 20 (29.4%) and 5 (7.4%) were inconclusive due to  ≤ 2 measurements. Decelerating growth persisted once established. Within 5 years, 38 (97.4%) of 39 interventions were initiated. None developed symptoms prior to intervention. Large tumors (P < .001) involving venous sinuses (P = .039) grew most aggressively. Since inclusion 19 (30.6%) patients have died of unrelated causes and 2 (3%) from grade 2 meningiomas. Conclusion: Active monitoring seems a safe and appropriate first-line management of incidental meningiomas. Intervention was avoided in  > 40% with indolent tumors in this cohort. Treatment was not compromised by tumor growth. Clinical follow-up seems sufficient beyond 5 years if self-limiting growth is established. Steady or accelerating growth warrant monitoring until they reach a stable state or intervention is initiated.

First use of radiation for the treatment of arteriovenous malformation.

In 1921, Norwegian neurosurgeon Vilhelm Magnus (1871-1929) described the first use of radiation for the treatment of an arteriovenous malformation (AVM) in his monograph, Bidrag til hjernechirurgiens klinik og resultater. Seeing as this monograph has never been widely translated nor digitized, the authors discuss the impact of Magnus' original work and the ethics surrounding its citation. The senior author of this paper gained access to and directly translated key sections of Magnus' publication. Without Norwegian language skills, reading and understanding Magnus' text would have been impossible. Magnus described the use of radiation therapy in a single patient found to have an AVM (or "angioma"). He states that she was "well" 8 years later. No other information on that treatment is given, but for good reason Magnus has been given credit in the literature for the first use of radiation of any kind to treat a person with AVM. Most papers that have referenced Magnus' monograph cite it even though it is probable that the authors did not see it, let alone read its contents. While it is appropriate that his innovation has been properly credited, the authors discuss the limits of citing publications sight unseen.

Arterial input functions in dynamic susceptibility contrast MRI (DSC-MRI) in longitudinal evaluation of brain metastases.

BACKGROUND: Dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) could be helpful to separate true disease progression from pseudo-progression in brain metastases when assessing the need for retreatment. However, the selection of arterial input functions (AIFs) is not standardized for analysis, limiting its use for this application. PURPOSE: To compare population-based AIFs, AIFs specific to each patient, and AIFs specific to every visit in the longitudinal follow-up of brain metastases. MATERIAL AND METHODS: Longitudinal data were collected from eight patients before treatment (6 of 8 patients) and after treatment (6-17 visits). Imaging was performed using a 1.5-T MRI system. Lesions were segmented by subtracting precontrast images from postcontrast images. Cerebral blood volume (rCBV) and cerebral blood flow (rCBF) were computed, and Pearson's product moment correlation coefficients were calculated to evaluate similarity of DSC parameters dependent on various AIF choices across time. AIF shape characteristics were compared. Parameter differences between white matter (WM) and gray matter (GM) were obtained to determine which AIF choice maximizes tissue differentiation. RESULTS: Although DSC parameters follow similar patterns in time, the various AIF selections cause large parameter variations with relative standard deviations of up to ±60%. AIFs sampled in one patient across sessions more similar in shape than AIFs sampled across patients. Estimates of rCBV based on scan-specific AIFs differentiated better between perfusion in WM and GM than patient-specific or population-based AIFs (P ≤ 0.02). CONCLUSION: Results indicate that scan-specific AIFs are the best choice for DSC-MRI parameter estimations in the longitudinal follow-up of brain metastases.

Dynamic susceptibility contrast MRI may contribute in prediction of stereotactic radiosurgery outcome in brain metastases.

Background: Following stereotactic radiosurgery (SRS), predicting treatment response is not possible at an early stage using structural imaging alone. Hence, the current study aims at investigating whether dynamic susceptibility contrast (DSC)-MRI estimated prior to SRS can provide predictive biomarkers in response to SRS treatment and characterize vascular characteristics of pseudo-progression. Methods: In this retrospective study, perfusion-weighted DSC-MRI image data acquired with a temporal resolution of 1.45 seconds were collected from 41 patients suffering from brain metastases. Outcome was defined based on lesion volume changes in time (determined on structural images) or death. Motion correction and manual lesion delineation were performed prior to semi-automated, voxel-wise perfusion analysis. Statistical testing was performed using linear regression and a significance threshold at P = .05. Age, sex, primary cancers (pulmonary cancer and melanoma), lesion volume, and dichotomized survival time were added as covariates in the linear regression models (ANOVA). Results: Relative cerebral blood volume (rCBV) and relative cerebral blood flow (rCBF) were found to be significantly lower prior to SRS treatment in patients with increasing lesion volume or early death post-SRS (P ≤ .01). Conclusion: Unfavorable treatment outcome may be linked to low perfusion prior to SRS. Pseudo-progression may be preceded by a transient rCBF increase post-SRS. However, results should be verified in different or larger patient material.

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.

A prospective study of the natural history of incidental meningioma-Hold your horses!

BACKGROUND: The number of incidental meningiomas has increased because of the increased availability of neuroimaging. Lack of prospective data on the natural history makes the optimal management unclear. We conducted a 5-year prospective study of incidental meningiomas to identify risk factors for tumor growth. METHODS: Sixty-four of 70 consecutive patients with incidental meningioma were included. Clinical and radiological status was obtained at 0, 0.5, 1, 1.5, 2, 3, 4, and 5 years. GammaPlan and mixed linear regression modeling were utilized for volumetric analysis with primary endpoint tumor growth. RESULTS: None of the patients developed tumor-related symptoms during the study period, although 48 (75%) tumors increased (>15%), 13 (20.3%) remained unchanged, and 3 (4.7%) decreased (>15%) in volume. Mean time to growth was 2.2 years (range, 0.5-5.0 years).The growth pattern was quasi-exponential in 26%, linear in 17%, sigmoidal in 35%, parabolic in 17%, and continuous reduction in 5%. There was significant correlation among growth rate, larger baseline tumor volume (P < .001), and age in years (<55 y: 0.10 cm3/y, 55-75 y: 0.24 cm3/y, and >75 y: 0.85 cm3/y). CONCLUSION: The majority of meningiomas will eventually grow. However, more than 60% display a self-limiting growth pattern. Our study provides level-2 evidence that asymptomatic tumors can be safely managed utilizing serial imaging until persistent radiological and/or symptomatic growth.

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.

Drug repurposing in cancer.

Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.

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.

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.

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.

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.

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.

Gamma knife surgery of meningiomas involving the cavernous sinus: long-term follow-up of 100 patients.

OBJECTIVE: Resection of meningiomas involving the cavernous sinus often is incomplete and associated with considerable morbidity. As a result, an increasing number of patients with such tumors have been treated with gamma knife surgery (GKS). However, few studies have investigated the long-term outcome for this group of patients. METHODS: 100 patients (23 male/77 female) with meningiomas involving the cavernous sinus received GKS at the Department of Neurosurgery at Haukeland University Hospital, Bergen, Norway, between November 1988 and July 2006. They were followed for a mean of 82.0 (range, 0-243) months. Only 2 patients were lost to long-term follow-up. Sixty patients underwent craniotomy before radiosurgery, whereas radiosurgery was the primary treatment for 40 patients. RESULTS: Tumor growth control was achieved in 84.0% of patients. Twelve patients required re-treatment: craniotomy (7), radiosurgery (1), or both (4). Three out of 5 patients with repeated radiosurgery demonstrated secondary tumor growth control. Excluding atypical meningiomas, the growth control rate was 90.4%. The 1-, 5-, and 10-year actuarial tumor growth control rates are 98.9%, 94.2%, and 91.6%, respectively. Treatment failure was preceded by clinical symptoms in 14 of 15 patients. Most tumor growths appeared within 2.5 years. Only one third grew later (range, 6-20 yr). The complication rate was 6.0%: optic neuropathy (2), pituitary dysfunction (3), worsening of diplopia (1), and radiation edema (1). Mortality was 0. At last follow-up, 88.0% were able to live independent lives. CONCLUSION: GKS gives long-term growth control and has a low complication rate. Most tumor growths manifest within 3 years following treatment. However, some appear late, emphasizing the need for long-term follow-up.