Clinically Driven Alpha/Beta Ratios for Melanoma Brain Metastases and Investigation of Biologically Effective Dose as a Predictor for Local Control After Radiosurgery: A Proof of Concept in a Retrospective Longitudinal Series of 274 Consecutive Lesions.

BACKGROUND AND OBJECTIVES: Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios. METHODS: Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy 3 ), 5 (Gy 10 ), 10 (Gy 10 ), and 15 (Gy 15 ). RESULTS: Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy 15 , P = .006), while for LC and physical dose was 79% ( P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant ( P = .02 and .03). Fractional polynomial regression revealed BED (Gy 10 and Gy 15 ) as statistically significant ( P = .05) with BED of more than 63 Gy 10 or 49 Gy 15 as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC ( P = .001), particularly less than 40 minutes (LC below 90%, P = .05). CONCLUSION: BED Gy 10 and particularly Gy 15 were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts.

Early imaging radioresponsiveness of melanoma brain metastases as a predictor of patient prognosis.

OBJECTIVE The aim of this study was to analyze the early radiological response of melanoma brain metastases to single high-dose irradiation and to reveal possible correlations between tumor radioresponsiveness and patient clinical outcomes. METHODS The authors performed a retrospective analysis of the medical data for all patients with melanoma brain metastases who had undergone Gamma Knife radiosurgery (GKRS) and follow-up MRI examinations with standard protocols at regular 2- to 3-month intervals. Volumetric measurements of the metastases on pretreatment and initial posttreatment images were performed to assess the rate of early radiological response. Patients were divided into 2 groups according to the rate of response, and overall survival, local control, and the appearance of new metastases in the brain were compared in these groups using the long-rank test. Univariate and multivariate analyses were performed to identify predictors of clinical outcomes. RESULTS After retrospective analysis of 298 melanoma brain metastases in 78 patients, the authors determined that early radiological responses of these metastases to GKRS differ considerably and can be divided into 2 distinct groups. One group of tumors underwent rapid shrinkage after radiosurgery, whereas the other showed minor fluctuations in size (rapid- and slow-response groups, respectively). Median survival for patients with a slow response was 15.2 months compared with 6.3 months for those with a rapid response (p < 0.0001). In the multivariate analysis, improved overall survival was associated with a slow response to radiosurgery (p < 0.0001), stable systemic disease (p = 0.001), and a higher Karnofsky Performance Scale score (p = 0.001). Stratification by Recursive Partitioning Analysis, score index for radiosurgery, and diagnosis-specific Graded Prognostic Assessment classes further confirmed the difference in overall survival for patients with a slow versus rapid radiation response. Local recurrence was observed in 11% of patients with a rapid response and in 6% of patients with a slow response, at a median of more than 8 months after radiosurgery. New brain metastases were diagnosed in 67% of patients with a slow response at a median of 8.6 months after radiosurgery and in 82% of patients with a rapid response at a considerably earlier median time of 2.7 months. In the multivariate analysis, a longer time to the development of new brain metastases was associated with a slow response (p = 0.012), stable systemic disease (p = 0.034), and a single brain metastasis (p = 0.030). CONCLUSIONS Melanoma brain metastases show different early radioresponsiveness to radiosurgery. Rapid shrinkage of brain metastases is associated with poor patient prognosis, which may indicate more aggressive biological behavior of this tumor phenotype.

Microinvasive tumor endoresection in combination with ocular stereotactic radiosurgery.

OBJECTIVE The use of Gamma Knife radiosurgery (GKRS) as monotherapy in the treatment of uveal melanoma (UM) allows clinicians to achieve high local tumor control with low recurrence but does not prevent secondary enucleation due to glaucoma in cases of large tumors. The authors analyzed indications for tumor endoresection (ER), the time interval between irradiation and surgery, and the features and results of performing ER for UM after GKRS. METHODS Thirty-seven patients between 28 and 78 years of age (16 male and 11 female patients) with UM underwent GKRS with a dose of 70 to 80 Gy that was applied to the center of the tumor with complete immobilization of the eye during the procedure. Tumor resection with histological investigation was performed in 24 eyes (transscleral resection was performed in 3 eyes, and ER was performed in 21 eyes) at 3 to 97 days after GKRS, mainly during the first 2 or 3 weeks. As a rule, ER (21 eyes) was performed to treat large, centrally localized, or equatorial UMs with exudative macula-on retinal detachment that reduced vision. The average tumor height was 8.9 mm, and the average width was 13.7 mm at the base. ER for UM included phacoemulsification, microinvasive vitrectomy with transretinal tumor resection, laser photocoagulation, and application of a temporary silicone oil tamponade. Seven patients received intraocular injections of inhibitors of angiogenesis for the prevention and treatment of radiation neuroretinopathy. The follow-up period ranged from 8 to 41 months. RESULTS Preservation of the eyes without tumor recurrence was achieved in all 37 patients after GKRS (monotherapy and combined therapy). One patient died of liver metastases at 21 months after GKRS. In the ER group (21 eyes), drug-resistant glaucoma with low visual acuity appeared in 4 eyes (19%) with long-existing total exudative retinal detachment and delayed operations. Severe radiation neuroretinopathy with macular edema occurred in 4 of 21 cases (19%). Intraocular injections of inhibitors of angiogenesis significantly decreased retinal edema. Residual rhegmatogenous retinal detachment was revealed in 1 eye (4.8%). The conservation of the patient's primary vision or its improvement were observed in 11 eyes (52.4%). Useful vision more than 0.1 was achieved in 12 cases (57%), and more than 0.3 was achieved in 8 cases (38%). CONCLUSIONS As a result of this research, ER for UM after GKRS proved to be an effective method of combined eye-conserving treatment for large centrally localized or equatorial tumors at high risk of the emergence and development of toxic tumor syndrome. Perfect eye immobilization, timely ER, and multiple intraocular injections of inhibitors of angiogenesis saved not only the eye in all cases, but also useful vision in many cases. Close cooperation among radiosurgeons, ophthalmologists, and vitreoretinal surgeons is the key to effective treatment.

Reversible metabolic depression in lamprey hepatocytes during prespawning migration: dynamics of mitochondrial membrane potential.

The lamprey (Lampetra fluviatilis L.) is an extant representative of the ancient vertebrate group of Agnathans. During the prespawning migration (the river period of life from autumn until spring) lamprey hepatocytes exhibit widely different energy states: a high-energy state in autumn and spring, corresponding to a normal physiological standard, and a low-energy state in winter, which is provoked by prolonged starvation and profound metabolic arrest. In spring the restoration of energy status (return to an active state) is associated with hormonally induced lipolysis of the lipid droplets stored in the cells. Lamprey hepatocytes demonstrate an aerobic metabolism based on oxidation of free fatty acids. The dynamics of mitochondrial membrane potential (MMP) were measured throughout the prespawning migration. Pharmacological inhibition of the electron transport chain decreased the MMP and caused extensive depletion of cellular ATP without loss of cell viability. The potential molecular mechanisms responsible for winter metabolic depression in lamprey hepatocytes are discussed.