PTCH1 mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Laser ablation after stereotactic radiosurgery: a multicenter prospective study in patients with metastatic brain tumors and radiation necrosis.

OBJECTIVE: Laser Ablation After Stereotactic Radiosurgery (LAASR) is a multicenter prospective study of laser interstitial thermal (LITT) ablation in patients with radiographic progression after stereotactic radiosurgery for brain metastases. METHODS: Patients with a Karnofsky Performance Scale (KPS) score ≥ 60, an age > 18 years, and surgical eligibility were included in this study. The primary outcome was local progression-free survival (PFS) assessed using the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Secondary outcomes were overall survival (OS), procedure safety, neurocognitive function, and quality of life. RESULTS: Forty-two patients­19 with biopsy-proven radiation necrosis, 20 with recurrent tumor, and 3 with no diagnosis­were enrolled. The median age was 60 years, 64% of the subjects were female, and the median baseline KPS score was 85. Mean lesion volume was 6.4 cm3 (range 0.4­38.6 cm3). There was no significant difference in length of stay between the recurrent tumor and radiation necrosis patients (median 2.3 vs 1.7 days, respectively). Progression-free survival and OS rates were 74% (20/27) and 72%, respectively, at 26 weeks. Thirty percent of subjects were able to stop or reduce steroid usage by 12 weeks after surgery. Median KPS score, quality of life, and neurocognitive results did not change significantly for either group over the duration of survival. Adverse events were also similar for the two groups, with no significant difference in the overall event rate. There was a 12-week PFS and OS advantage for the radiation necrosis patients compared with the recurrent tumor or tumor progression patients. CONCLUSIONS: In this study, in which enrolled patients had few alternative options for salvage treatment, LITT ablation stabilized the KPS score, preserved quality of life and cognition, had a steroid-sparing effect, and was performed safely in the majority of cases.

Short pauses in thalamic deep brain stimulation promote tremor and neuronal bursting.

OBJECTIVE: We conducted intraoperative measurements of tremor during DBS containing short pauses (⩽50 ms) to determine if there is a minimum pause duration that preserves tremor suppression. METHODS: Nine subjects with ET and thalamic DBS participated during IPG replacement surgery. Patterns of DBS included regular 130 Hz stimulation interrupted by 0, 15, 25 or 50 ms pauses. The same patterns were applied to a model of the thalamic network to quantify effects of pauses on activity of model neurons. RESULTS: All patterns of DBS decreased tremor relative to 'off'. Patterns with pauses generated less tremor reduction than regular high frequency DBS. The model revealed that rhythmic burst-driver inputs to thalamus were masked during DBS, but pauses in stimulation allowed propagation of bursting activity. The mean firing rate of bursting-type model neurons as well as the firing pattern entropy of model neurons were both strongly correlated with tremor power across stimulation conditions. CONCLUSIONS: The temporal pattern of stimulation influences the efficacy of thalamic DBS. Pauses in stimulation resulted in decreased tremor suppression indicating that masking of pathological bursting is a mechanism of thalamic DBS for tremor. SIGNIFICANCE: Pauses in stimulation decreased the efficacy of open-loop DBS for suppression of tremor.

Neurosurgical Techniques for Disruption of the Blood-Brain Barrier for Glioblastoma Treatment.

The blood-brain barrier remains a main hurdle to drug delivery to the brain. The prognosis of glioblastoma remains grim despite current multimodal medical management. We review neurosurgical technologies that disrupt the blood-brain barrier (BBB). We will review superselective intra-arterial mannitol infusion, focused ultrasound, laser interstitial thermotherapy, and non-thermal irreversible electroporation (NTIRE). These technologies can lead to transient BBB and blood-brain tumor barrier disruption and allow for the potential of more effective local drug delivery. Animal studies and preliminary clinical trials show promise for achieving this goal.

Neuronal oscillations in Parkinson's disease.

Parkinson's Disease (PD), characterized by tremor, rigidity, and bradykinesia, is one of the most prevalent neurodegenerative disorders in the world. The pathological hallmark of PD is the loss of dopaminergic cells in the substantia nigra and other brain regions. The pathophysiological mechanisms by which dopaminergic cell loss leads to the motor manifestations of PD are yet to be fully elucidated. A growing body of evidence has revealed abnormal neuronal oscillations within and between multiple brain regions in PD. Unique oscillatory patterns are associated with specific motor abnormalities in PD. Therapies, such as dopaminergic medication and deep brain stimulation that disrupt these abnormal neuronal oscillatory patterns produce symptomatic improvement in PD patients. These findings emphasize the importance of abnormal neuronal oscillations in the pathophysiology of PD, making the disruption of these oscillatory patterns a promising target in the development of effective PD treatments.

The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study.

Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011-December 2012) using the NeuroBlate(®) System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43 °C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow-up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 ± 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria-(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line-had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery.

The role of hypothalamic input on corticotroph maturation in fetal sheep.

Corticotropin-releasing hormone receptor type 1 (CRH-R1) expression and vasopressin type 1b (V1b) receptor protein decrease in late-gestation fetal sheep. Because hypothalamo-pituitary disconnection (HPD) has been demonstrated to prevent the morphological maturation of corticotrophs, we hypothesized that hypothalamic input is necessary for the maturational changes in CRH-R1 and V1b receptor levels. We measured CRH-R1 and V1b receptor expression in the anterior pituitaries of fetuses at 140 days gestational age (dGA) that underwent HPD or sham surgery at 120 dGA. CRH-R1 mRNA decreased similarly in HPD and sham-operated fetuses compared with 120 dGA naive fetuses. However, CRH-R1 protein levels were elevated in HPD fetuses compared with sham and were not different from 120 dGA values. V1b protein levels decreased similarly in HPD and sham-operated fetuses compared with 120 dGA naive fetuses. We conclude that hypothalamic input to the pituitary is necessary for the decrease in CRH-R1 receptor protein levels in late-gestation fetal sheep. However, hypothalamic input is not necessary for the decrease in V1b receptor expression seen in late gestation.