Bente Sandvei Skeie

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

OBJECTIVEResection 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. METHODS100 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. RESULTSTumor 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. CONCLUSIONGKS 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.

Gamma 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.

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.

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.

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.

Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

BackgroundGlioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts.MethodsTo assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.ResultsWe found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity.ConclusionTaken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.

Treatment with the PI3K inhibitor buparlisib (NVP-BKM120) suppresses the growth of established patient-derived GBM xenografts and prolongs survival in nude rats.

Glioblastomas (GBMs) are aggressive brain tumours with a dismal prognosis, despite combined surgery, radio- and chemotherapy. Close to 90 % of all GBMs harbour a deregulated PI3K pathway, which is essential in regulating central cellular functions such as proliferation, cell growth, motility and survival. Thus, PI3K represents a potential target for molecular therapy in GBM. We investigated the anti-tumour efficacy of the PI3K inhibitor buparlisib (NVP-BKM120) in GBM cell lines in vitro and in vivo, when treatment was initiated after MRI-confirmed tumour engraftment. We found that buparlisib inhibited glioma cell proliferation in a dose dependent manner, demonstrated by MTS assay, manual cell count and BrdU incorporation. A dose dependent increase in apoptosis was observed through flow cytometric analysis. Furthermore, by immunocytochemistry and western blot, we found a dose dependent inhibition of Akt phosphorylation. Moreover, buparlisib prolonged survival of nude rats harboring human GBM xenografts in three independent studies and reduced the tumours’ volumetric increase, as determined by MRI. In addition, histological analyses of xenograft rat brains showed necrotic areas and change in tumour cell nuclei in buparlisib-treated animals. The rats receiving buparlisib maintained their weight, activity level and food- and water intake. In conclusion, buparlisib effectively inhibits glioma cell proliferation in vitro and growth of human GBM xenografts in nude rats. Moreover, the compound is well tolerated when administered at doses providing anti-tumour efficacy. Thus, buparlisib may have a future role in glioma therapy, and further studies are warranted to validate this compound for human use.

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.

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.