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Purpose Recent prospective data have shown that patients with solitary or oligometastatic disease to the brain may be treated with upfront stereotactic radiosurgery (SRS) with deferral of whole-brain radiation therapy (WBRT). This has been extrapolated to the treatment of patients with resected lesions. The aim of this study was to assess the risk of leptomeningeal disease (LMD) in patients treated with SRS to the postsurgical resection cavity for brain metastases compared with patients treated with SRS to intact metastases. Methods and Materials Four hundred sixty-five patients treated with SRS without upfront WBRT at a single institution were identified; 330 of these with at least 3 months' follow-up were included in this analysis. One hundred twelve patients had undergone surgical resection of at least 1 lesion before SRS compared with 218 treated for intact metastases. Time to LMD and overall survival (OS) time were estimated from date of radiosurgery, and LMD was analyzed by the use of cumulative incidence method with death as a competing risk. Univariate and multivariate analyses were performed with competing risk regression to determine whether various clinical factors predicted for LMD. Results With a median follow-up time of 9.0 months, 39 patients (12%) experienced LMD at a median of 6.0 months after SRS. At 1 year, the cumulative incidence of LMD, with death as a competing risk, was 5.2% for the patients without surgical resection versus 16.9% for those treated with surgery (Gray test, P P P =.03) were significant predictors of LMD development. The median OS times for patients undergoing surgery compared with SRS alone were 12.9 and 10.6 months, respectively (log-rank P =.06). Conclusions In patients undergoing SRS with deferral of upfront WBRT for intracranial metastatic disease, prior surgical resection and breast cancer primary are associated with an increased risk for the development of LMD.

To report outcomes of patients with medical and/or surgical refractory trigeminal neuralgia (TN) treated with gamma knife stereotactic radiosurgery (GK SRS).One hundred and forty-nine patients with 152 cases of TN treated with GK SRS were analyzed. All patients, except one, received a dose of 40Gy to the 50% isodose volume. The Barrow Neurological Institute (BNI) pain intensity score was used to grade pain. Actuarial rates of pain relief were calculated. Multiple factors were analyzed for association with pain relief.The median follow up was 27 months (4-71 months). Overall 92% of cases achieved a BNI score I-III after GK SRS. Of those who had pain relief after GK SRS, 32% developed pain recurrence defined as a BNI score of IV or V. The actuarial rate of freedom from pain recurrence (BNI scores I-III) of all treated cases at 1, 2 and 3-years was 76%, 69% and 60%, respectively. On univariate analysis age ≥70 was predictive of better pain relief (p=0.046). Type of pain, prior surgery, multiple sclerosis, number of isocenters, treated nerve length, volume and thickness and distance from the root entry zone to the isocenter were not significant for maintaining a BNI score of I-III. Those who achieved a BNI score of I or II were more likely to maintain pain relief compared to those who only achieved a BNI score of III (93% vs 38% at three years, p0.01). The rate of pain relief of twenty-seven patients who underwent repeat GK SRS was 70% and 62% at 1 and 2 years, respectively. Toxicity after first GK SRS was minimal with 25% of cases experiencing only new or worsening post-treatment numbness.GK SRS provides acceptable pain relief with limited morbidity in patients with medical and/or surgical refractory TN.

Object The aim of this study was to examine tumor volume as a prognostic factor for patients with brain metastases treated with Gamma Knife surgery (GKS). Methods Two hundred fifty patients with 1–14 brain metastases who had initially undergone GKS alone at a single institution were retrospectively reviewed. Patients who received upfront whole brain radiation therapy were excluded. Survival times were estimated using the Kaplan-Meier method. Univariate and multivariate analyses using Cox proportional hazard regression models were used to determine if various prognostic factors could predict overall survival, distant brain failure, and local control. Results Median overall survival was 7.1 months and the 1-year local control rate was 91.5%. Median time to distant brain failure was 8.0 months. On univariate analysis an increasing total tumor volume was significantly associated with worse survival (p = 0.031) whereas the number of brain metastases, analyzed as a continuous variable, was not (p = 0.082). After adjusting for age, Karnofsky Performance Scale score, and extracranial disease on multivariate analysis, total tumor volume was found to be a better predictor of overall survival (p = 0.046) than number of brain metastases analyzed as a continuous variable (p = 0.098). A total tumor volume cutoff value of ≥ 2 cm3 (p = 0.008) was a stronger predictor of overall survival than the number of brain metastases (p = 0.098). Larger tumor volume and extracranial disease, but not the number of brain metastases, were predictive of distant brain failure on multivariate analysis. Local tumor control at 1 year was 97% for lesions < 2 cm3 compared with 75% for lesions ≥ 2 cm3 (p < 0.001). Conclusions After adjusting for other factors, a total brain metastasis volume was a strong and independent predictor for overall survival, distant brain failure, and local control, even when considering the number of metastases.

Objectives Prospective data regarding the safety and efficacy of stereotactic radiosurgery (SRS) for patients with metastatic disease involving the brainstem are lacking. The aim of this study was to assess the efficacy and toxicity of SRS for patients with brainstem metastases treated at our institution. Patients and methods From September 2007 to October 2015, patients treated with SRS for brain metastases were prospectively entered into an institutional database. Forty eight patients with 51 lesions involving the brainstem with clinical follow-up were identified. Local control (LC), elsewhere brain failure (EBF) and overall survival (OS) were assessed from the date of radiosurgery using the Kaplan-Meier method. Univariate and multivariate analyses of factors related to OS were performed using a Cox proportional hazards model. Results Median clinical follow-up was 4.8 months. Median patient age was 62 (range: 28–87); non-small cell lung and breast cancer were the most common primaries at 54% and 21% respectively. Median brainstem lesion volume was 0.12 cm3 (range: 0.01–3.67 cm3). Whole brain radiotherapy was previously utilized in 19 patients (40%). The median OS was 7.6 months and the 12 month LC rate was 89%. Only 2 patients (4%) experienced grade 3 motor toxicity secondary to SRS. 11 of the 16 patients (69%) initially presenting with symptoms related to brainstem metastases had symptom improvement or resolution following SRS. On multivariate analysis, graded prognostic assessment (GPA) score > 2 was predictive of improved survival (p Conclusions SRS is associated with high LC rates and low toxicity for brainstem metastases. Improved OS was seen for patients with GPA score > 2. GPA appears to be a useful tool for assessing prognosis in patients with brainstem metastases. Small volume lesions were safely treated with or without prior whole brain radiotherapy.

STUDY DESIGN Case report. OBJECTIVE To report a rare case of alkaptonuria presenting as a T1-hyperintense disc herniation. SUMMARY OF BACKGROUND DATA A 46-year-old man without previous diagnosis of alkaptonuria underwent evaluation for progressive back pain revealing a T1-hyperintense disc herniation at the L3-L4 level. Discectomy recovered a blackened disc that was pathologically confirmed to be nucleus pulposus with alkaptonuric involvement. The differential diagnosis of a T1-hyperintense, T2-hypointense disc on magnetic resonance imaging is discussed, with emphasis on the pathophysiology of alkaptonuria. METHODS A single patient is reported. RESULTS Pathologically proven patient presentation with radiological and pathological images. CONCLUSION We report a rare case of alkaptonuria presenting as a T1-hyperintense disc herniation.

The aim of this study was to examine tumor volume as a prognostic factor for patients with brain metastases treated with Gamma Knife surgery (GKS).Two hundred fifty patients with 1-14 brain metastases who had initially undergone GKS alone at a single institution were retrospectively reviewed. Patients who received upfront whole brain radiation therapy were excluded. Survival times were estimated using the Kaplan-Meier method. Univariate and multivariate analyses using Cox proportional hazard regression models were used to determine if various prognostic factors could predict overall survival, distant brain failure, and local control.Median overall survival was 7.1 months and the 1-year local control rate was 91.5%. Median time to distant brain failure was 8.0 months. On univariate analysis an increasing total tumor volume was significantly associated with worse survival (p = 0.031) whereas the number of brain metastases, analyzed as a continuous variable, was not (p = 0.082). After adjusting for age, Karnofsky Performance Scale score, and extracranial disease on multivariate analysis, total tumor volume was found to be a better predictor of overall survival (p = 0.046) than number of brain metastases analyzed as a continuous variable (p = 0.098). A total tumor volume cutoff value of ≥ 2 cm(3) (p = 0.008) was a stronger predictor of overall survival than the number of brain metastases (p = 0.098). Larger tumor volume and extracranial disease, but not the number of brain metastases, were predictive of distant brain failure on multivariate analysis. Local tumor control at 1 year was 97% for lesions2 cm(3) compared with 75% for lesions ≥ 2 cm(3) (p0.001).After adjusting for other factors, a total brain metastasis volume was a strong and independent predictor for overall survival, distant brain failure, and local control, even when considering the number of metastases.

OBJECTIVE To define the antiplatelet efficacy and specificity of the glycoprotein IIb/IIIa complex (GPIIb/IIIa) antagonist prodrug DMP754 and its free acid form, XV459. METHODS AND MATERIALS DMP754 has an IC50 > 1 mumol/l, and, upon its conversion with esterases to its free acid form, demonstrated high potency (IC50 20-45 nmol/l) in inhibiting human platelet aggregation induced by 10 mumol/l adenosine diphosphate, 20 micrograms/ml collagen, 1 mmol/l epinephrine, 10 mumol/l platelet activating factor or 0.5 IU/ml thrombin. The in-vitro rate of hydrolysis of DMP754 or XV459 is much faster with human or canine liver esterases (t 1/2 = 2.4-23 min) than with plasma esterases (t 1/2 = 5.5-7.6 h). Platelet GpIIb/IIIa integrin binding affinity and specificity for XV459 were determined using cell binding/adhesion assays. RESULTS The range of IC50 values of XV459 in inhibiting platelet aggregation in platelet-rich plasma obtained from 12 subjects was 0.035-0.069 mumol/l with a mean IC50 of 0.050 +/- 0.003 mumol/l. Additionally, XV459 inhibited platelets obtained from mongrel dogs, baboons, sheep, guinea pigs, and mice with IC50 in the range 0.024-0.06 mumol/l, and IC50 in the range 0.16-5.8 mumol/l in pigs, rabbits, and rats. XV459 inhibited [125I]-fibrinogen binding to activated human platelets with an IC50 of 0.011 +/- 0.003 mumol/l. XV459 demonstrated a high degree of selectivity in specifically inhibiting fibrinogen binding to the platelet integrin, GPIIb/IIIa (IC50 = 0.00025 +/- 0.00005 mumol/l) compared with inhibiting other integrins (alpha v beta 3, IC50 > 10 mumol/l; or alpha v beta 5, alpha 5 beta 1, or alpha 4 beta 1, for which the IC50 exceeded 100 mumol/l). CONCLUSION DMP754 is a potent antiplatelet agent in inhibiting platelet aggregation, and has a high specificity and affinity for human platelet GPIIb/IIIa receptors.

XV454 demonstrated high potency (IC50 = 14-25 nM) in inhibiting human platelet aggregation induced by adenosine diphosphate (ADP, 10 microM), thrombin receptor agonist peptide (TRAP) (10 microM), or collagen (20 microg/ml). XV454 exhibited a high degree of selectivity for platelet alpha(IIb)beta3 in comparison with c7E3, which is a nonspecific antagonist for both alpha(IIb)beta3 and alpha(v)beta3. Both XV454 and c7E3 bind with high affinity to either activated (A) or unactivated (U) human, baboon, or canine platelets. XV454 binds with a relatively higher affinity [Kd = 0.5 nM (A), 0.6 nM (U)] as compared with c7E3 [Kd = 9.1 nM (A), 9.2 (U) nM]. XV454 demonstrated a tight association with human, baboon, and, to a lesser extent, with canine platelets (t(1/2) of dissociation = 110 +/- 6, 80 +/- 10, and 23 +/- 2 min, respectively). Both c7E3 and XV454 associate tightly with a slower dissociation rate with unactivated human platelets: t(1/2) of 42 and 116 min, respectively. In non-human primates, oral (0.1 mg/kg, p.o.) and intravenous (0.05 mg/kg, i.v. bolus administration of XV454 methyl ester pro-drug resulted a long-lasting maximal antiplatelet efficacy for < or = 72 h with significant but reversible prolongation of bleeding time and without effects on platelet count, clinical chemistry, or hemodynamic profile. In conclusion, XV454 represents a potent antiplatelet agent in inhibiting platelet aggregation along with a high affinity and relatively slow dissociation rate from human platelet GPIIb/IIIa receptors that allow a long-lasting antiplatelet efficacy after single i.v. or oral administration.

Materials/Methods: Ninety-five patients underwent GK for TGN between 12/2006-6/2009 at William Beaumont Hospital. Eighty had follow-up $6 weeks and were the subject of this report. Median patient age was 68y (30-92); 58 female, 22 male. 74% of patients had typical trigeminal pain, 11% atypical features and 11% multiple sclerosis. Thirty patients (38%) had undergone prior surgical procedures and 37 (46%) had preexisting sensory complaints. The median dose delivered was 40 Gy (range: 35-45 Gy) to the 50% isodose line (80 Gy max) using either a single (85%) or two (6%) isocenters with a 4 mm collimator, or two isocenters with a 4 and 8 mm collimator (9%). Patients were seen #2 weeks post-GK, then every 3-6 months in addition to periodic mail surveys and telephone interviews. Pain was evaluated using the Barrow Neurological Institute Pain Intensity Scale. Multiple patient and GK factors were analyzed for association with pain relief. Mean follow-up duration was 15.6 months.