Correlation between initial tumor enlargement and magnetic resonance imaging characteristics following linear accelerator-based stereotactic radiosurgery for acoustic neuromas.

BACKGROUND: Initial tumor enlargement (or pseudoprogression) instead of true tumor progression is a common phenomenon in patients with acoustic neuromas who are treated with stereotactic radiosurgery (SRS). This phenomenon can affect clinical decision-making and patient management. This study assessed the correlation between initial tumor enlargement and magnetic resonance imaging characteristics in patients with acoustic neuromas who were treated with linear accelerator (LINAC)-based SRS. The long-term tumor control outcomes were also analyzed. MATERIALS AND METHODS: In total, 330 patients with sporadic acoustic neuromas who were treated with LINAC SRS between March 2006 and March 2020 were retrospectively evaluated to assess their initial tumor enlargement. The tumors were divided into homogeneously enhanced, heterogeneously enhanced, and cystic types based on the morphological characteristics noted on magnetic resonance images. Tumor control was assessed in 275 patients with a follow-up duration of more than 2 years. RESULTS: Initial enlargement was observed in 137 of 330 (41.5%) tumors as early as 3 months after LINAC SRS. Data analysis revealed that postoperative tumors with a residual volume lower than 2.5 cm3 had a lower incidence of initial enlargement (p = 0.039). No correlation was noted between the initial enlargement and morphological characteristics of tumors. In patients with a mean follow-up duration of 82.8 ± 37.2 months, heterogeneously enhanced tumors exhibited a lower control rate than homogeneously enhanced and cystic tumors (p = 0.045). No correlation was noted between initial enlargement and tumor control. CONCLUSION: Initial enlargement can occur as early as 3 months after SRS. Postoperative residual tumors with a volume lower than 2.5 cm3 exhibit a lower incidence of initial enlargement. Heterogeneously enhanced tumors have a lower local control rate.

Focused ultrasound combined with radiotherapy for malignant brain tumor: a preclinical and clinical study.

INTRODUCTION: Blood-brain barrier (BBB) remains to be the major obstacle to conquer in treating patients with malignant brain tumors. Radiation therapy (RT), despite being the mainstay adjuvant modality regardless of BBB, the effect of radiation induced cell death is hindered by the hypoxic microenvironment. Focused ultrasound (FUS) combined with systemic microbubbles has been shown not only to open BBB but also potentially increased regional perfusion. However, no clinical study has investigated the combination of RT with FUS-BBB opening (RT-FUS). METHODS: We aimed to provide preclinical evidence of RT-FUS combination in GBM animal model, and to report an interim analysis of an ongoing single arm, prospective, pilot study (NCT01628406) of combining RT-FUS for recurrent malignant high grade glioma patients, of whom re-RT was considered for disease control. In both preclinical and clinical studies, FUS-BBB opening was conducted within 2 h before RT. Treatment responses were evaluated by objective response rate (ORR) using magnetic resonance imaging, progression free survival, and overall survival, and adverse events (AE) in clinical study. Survival analysis was performed in preclinical study and descriptive analysis was performed in clinical study. RESULTS: In mouse GBM model, the survival analysis showed RT-FUS (2 Gy) group was significantly longer than RT (2 Gy) group and control, but not RT (5 Gy) group. In the pilot clinical trial, an interim analysis of six recurrent malignant high grade glioma patients underwent a total of 24 RT-FUS treatments was presented. Three patients had rapid disease progression at a mean of 33 days after RT-FUS, while another three patients had at least stable disease (mean 323 days) after RT-FUS with or without salvage chemotherapy or target therapy. One patient had partial response after RT-FUS, making the ORR of 16.7%. There was no FUS-related AEs, but one (16.7%) re-RT-related grade three radiation necrosis. CONCLUSION: Reirradiation is becoming an option after disease recurrence for both primary and secondary malignant brain tumors since systemic therapy significantly prolongs survival in cancer patients. The mechanism behind the synergistic effect of RT-FUS in preclinical model needs further study. The clinical evidence from the interim analysis of an ongoing clinical trial (NCT01628406) showed a combination of RT-FUS was safe (no FUS-related adverse effect). A comprehensive analysis of radiation dosimetry and FUS energy distribution is expected after completing the final recruitment.

Long-term follow-up and comparison of programmable and non-programmable ventricular cerebrospinal fluid shunts among adult patients with different hydrocephalus etiologies: a retrospective cohort study.

BACKGROUND: Programmable valve (PV) has been shown as a solution to the high revision rate in pediatric hydrocephalus patients, but it remains controversial among adults. This study is to compare the overall revision rate, revision cause, and revision-free survival between PV and non-programmable valve (NPV) in adult patients with different hydrocephalus etiologies. METHOD: We reviewed the chart of all patients with hydrocephalus receiving index ventricular cerebrospinal fluid (CSF) shunt operations conducted at a single institution from January 2017 to December 2017. Patients included in the study were followed up for at least 5 years. Statistical tests including independent t-test, chi-square test, and Fisher's exact test were used for comparative analysis, and Kaplan-Meier curve using log-rank test was performed to compare the revision-free survival between the PV and NPV groups. RESULTS: A total of 325 patients were included in the study, of which 181 patients were receiving PVs and 144 patients receiving NPV. There were 23 patients (12.8%) with PV and 22 patients (15.3%) with NPV receiving initial revision. No significant statistical difference in the initial revision rate was observed between the two groups (p = 0.52). No survival difference was found between the PV and NPV groups. However, better revision-free survival was noted in the PV group among idiopathic normal pressure hydrocephalus (iNPH) (p = 0.0274) and post-traumatic hydrocephalus (p = 0.017). CONCLUSIONS: The combination of the different etiologies of hydrocephalus and the features of PV and NPV results in different outcomes-revision rate and revision-free survival. PV use might be superior to NPV in iNPH and post-traumatic hydrocephalus patients. Further studies are needed to clarify the indications of PV use in adult hydrocephalus patients.

Risk factors for peritumoral edema after radiosurgery for intracranial benign meningiomas: a long-term follow-up in a single institution.

OBJECTIVE: Peritumoral edema (PTE) is recognized as a complication following stereotactic radiosurgery (SRS). The aim of this paper was to evaluate the risk of post-SRS PTE for intracranial benign meningiomas and determine the predictive factors. METHODS: Between 2006 and 2021, 227 patients with 237 WHO grade I meningiomas were treated with Novalis linear accelerator SRS. All patients were treated with a single-fraction dose of 11-20 Gy (median 14 Gy). The median tumor volume was 3.32 cm3 (range 0.24-51.7 cm3). RESULTS: The median follow-up was 52 months (range 12-178 months). The actuarial local tumor control rates at 2, 5, and 10 years after SRS were 99.0%, 96.7%, and 86.3%, respectively. Twenty-seven (11.9%) patients developed new or worsened post-SRS PTE, with a median onset time of 5.2 months (range 1.2-50 months). Only 2 patients developed post-SRS PTE after 24 months. The authors evaluated factors related to new-onset or worsened PTE after SRS. In univariate analysis, initial tumor volume > 10 cm3 (p = 0.03), total marginal dose > 14 Gy (p < 0.001), preexisting edema (p < 0.0001), tumor location (p < 0.001), parasagittal location (p < 0.0001), superior sagittal sinus (SSS) involvement (p < 0.0001), and SSS invasion (p < 0.015) were found to be significant risk factors. In multivariate analysis, total marginal dose > 14 Gy (HR 3.38, 95% CI 1.37-8.33, p = 0.008), preexisting SRS edema (HR 12.86, 95% CI 1.09-4.15, p < 0.0001), tumor location (HR 2.13, 95% CI 1.04-3.72, p = 0.027), parasagittal location (HR 8.84, 95% CI 1.48-52.76, p = 0.017), and SSS invasion (HR 0.34, 95% CI 0.13-0.89, p = 0.027) were significant risk factors. Twelve (5.3%) patients were symptomatic. Ten of 27 patients had complete resolution of neurological symptoms and edema improvement with steroid treatment. Steroid treatment failed in 2 patients, who subsequently required resection for PTE. CONCLUSIONS: Radiosurgery is a safe and effective method of treating benign intracranial meningiomas according to long-term follow-up. We also identified total marginal dose > 14 Gy, preexisting PTE, parasagittal location, and SSS invasion as predictors of post-SRS PTE. Risk factors for post-SRS PTE should be considered in meningioma treatment.

Injectable Thermo-Sensitive Chitosan Hydrogel Containing CPT-11-Loaded EGFR-Targeted Graphene Oxide and SLP2 shRNA for Localized Drug/Gene Delivery in Glioblastoma Therapy.

In this study, we aimed to develop a multifunctional drug/gene delivery system for the treatment of glioblastoma multiforme by combining the ligand-mediated active targeting and the pH-triggered drug release features of graphene oxide (GO). Toward this end, we load irinotecan (CPT-11) to cetuximab (CET)-conjugated GO (GO-CET/CPT11) for pH-responsive drug release after endocytosis by epidermal growth factor receptor (EGFR) over-expressed U87 human glioblastoma cells. The ultimate injectable drug/gene delivery system was designed by co-entrapping stomatin-like protein 2 (SLP2) short hairpin RNA (shRNA) and GO-CET/CPT11 in thermosensitive chitosan-g-poly(N-isopropylacrylamide) (CPN) polymer solution, which offers a hydrogel depot for localized, sustained delivery of the therapeutics after the in situ formation of CPN@GO-CET/CPT11@shRNA hydrogel. An optimal drug formulation was achieved by considering both the loading efficiency and loading content of CPT-11 on GO-CET. A sustained and controlled release behavior was found for CPT-11 and shRNA from CPN hydrogel. Confocal microscopy analysis confirmed the intracellular trafficking for the targeted delivery of CPT-11 through interactions of CET with EGFR on the U87 cell surface. The efficient transfection of U87 using SLP2 shRNA was achieved using CPN as a delivery milieu, possibly by the formation of shRNA/CPN polyplex after hydrogel degradation. In vitro cell culture experiments confirmed cell apoptosis induced by CPT-11 released from acid organelles in the cytoplasm by flow cytometry, as well as reduced SLP2 protein expression and inhibited cell migration due to gene silencing. Finally, in vivo therapeutic efficacy was demonstrated using the xenograft of U87 tumor-bearing nude mice through non-invasive intratumoral delivery of CPN@GO-CET/CPT11@shRNA by injection. Overall, we have demonstrated the novelty of this thermosensitive hydrogel to be an excellent depot for the co-delivery of anticancer drugs and siRNA. The in situ forming hydrogel will not only provide extended drug release but also combine the advantages offered by the chitosan-based copolymer structure for siRNA delivery to broaden treatment modalities in cancer therapy.

Brain computerized tomography reading in suspected acute ischemic stroke patients: what are essentials for medical students?

BACKGROUND: Few systematic methods prioritize the image education in medical students (MS). We hope to develop a checklist of brain computerized tomography (CT) reading in patients with suspected acute ischemic stroke (AIS) for MS and primary care (PC) physicians. METHODS: Our pilot group generated the items indicating specific structures or signs for the checklist of brain CT reading in suspected AIS patients for MS and PC physicians. These items were used in a modified web-based Delphi process using the online software "SurveyMonkey". In total 15 panelists including neurologists, neurosurgeons, neuroradiologists, and emergency department physicians participated in the modified Delphi process. Each panelist was encouraged to express feedback, agreement or disagreement on the inclusion of each item using a 9-point Likert scale. Items with median scores of 7-9 were included in our final checklist. RESULTS: Fifty-two items were initially provided for the first round of the Delphi process. Of these, 35 achieved general agreement of being an essential item for the MS and PC physicians. The other 17 of the 52 items in this round and another two added items suggested by the panelists were further rated in the next round. Finally, 38 items were included in the essential checklist items of brain CT reading in suspected AIS patients for MS and PC physicians. CONCLUSIONS: We established a reference regarding the essential items of brain CT reading in suspected AIS patients. We hope this helps to minimize malpractice and a delayed diagnosis, and to improve competency-based medical education for MS and PC physicians.

Correlations between clinical hormone change and pathological features of pituicytoma.

PURPOSE: Pituicytoma is a rare low-grade glioma arising from the pituicytes of the posterior pituitary. To date, the clinical and pathological correlates of pituicytoma have not been investigated. This study was thus designed to examine the correlation between pituicytoma and the normal pituitary gland. METHODS: The records of patients who underwent pituitary surgery at Chang Gung Memorial Hospital in Linkou, Taiwan between 2000 and 2016 were reviewed. Patients who received a pathological diagnosis of pituicytoma were included; however, those with inadequate specimens for pathological study were excluded. Clinical information, including patients' presenting symptoms, serum hormone levels, neuroimages, and specimens, were collected. Hematoxylin and eosin stains and immunohistochemical (IHC) stains were performed for differential diagnosis. RESULTS: Among the 1532 patients who underwent pituitary surgery, nine (0.59%) received a pathological diagnosis of pituicytoma. Two patients were excluded due to inadequate specimens. Among the seven remaining patients, six presented with hormone changes. The IHC stains revealed that pituicytoma has no secretory function; however, the resected pituitary glands showed positive results for hormone change. Coexisting pituicytoma and adrenocorticotropic hormone adenoma were identified in one patient with a diagnosis of Cushing disease. CONCLUSIONS: Pituicytoma revealed a negative endocrine secretory function through IHC staining. Additionally, pituicytoma is associated with hypersecretion of the pituitary gland both clinically and pathologically. Diagnosing pituicytoma before pathological confirmation is difficult because the tumour may present with hormone dysfunction. Therefore, IHC staining of specimens is useful to exclude the possibility of coexisting pituicytoma and pituitary adenoma.

Corpus callosum involvement and postoperative outcomes of patients with gliomas.

Corpus callosum involvement is associated with poorer survival in high grade glioma (HGG), but the prognostic value in low grade glioma (LGG) is unclear. To determine the prognostic impact of corpus callosum involvement on progression free survival (PFS) and overall survival (OS) in HGG and LGG, the records of 233 glioma patients treated from 2008 to 2011 were retrospectively reviewed. Preoperative magnetic resonance (MR) images were used to identify corpus callosum involvement. Age, sex, preoperative Karnofsky performance scale, postoperative Eastern Cooperative Oncology Group (ECOG) score and extent of resection (EOR) were evaluated with respect to PFS and OS. The incidence of corpus callosum involvement was similar among HGG (14 %) and LGG (14.5 %). Univariate analysis revealed that PFS and OS were significantly shorter in both WHO grade II and grade IV glioma with corpus callosum involvement (both, p < 0.05). Multivariate analysis showed that grade II glioma with corpus callosum involvement have shorter PFS (p = 0.03), while EOR, instead of corpus callosum involvement (p = 0.16), was an independent factor associated with PFS in grade IV glioma (p < 0.05). Corpus callosum involvement was no longer significantly associated with OS after adjusting age, gender, EOR, preoperative and postoperative performance status (p = 0.16, 0.17 and 0.56 in grade II, III and IV gliomas, respectively). Corpus callosum involvement happened in both LGG and HGG, and is associated with lower EOR and higher postoperative ECOG score both in LGG and HGG. Corpus callosum involvement tends to be an independent prognostic factor for PFS in LGG, but not for OS in LGG or in HGG.

Linear accelerator stereotactic radiosurgery in the management of intracranial arteriovenous malformations: long-term outcome.

BACKGROUND: Arteriovenous malformation (AVM) is one of the cerebrovascular diseases that bear a high risk of hemorrhage. The treatment modalities include microsurgical resection, endovascular embolization, stereotactic radiosurgery, or combinations that vary widely. Several large series have been reported, while data from Asian populations were few. The aim of this study was to examine the efficacy of linear accelerator stereotactic radiosurgery (LINAC SRS) for the treatment of intracranial AVMs, to evaluate the hemorrhage rate and to analyze associated factors. METHODS: One hundred and sixteen patients with AVM were treated with LINAC SRS in a single institute between September 1994 and May 2005 and were retrospectively evaluated. The demographics of patients, clinical characteristics of AVM, the treatment modalities, and the parameters of the LINAC SRS were analyzed. Delayed toxicity and hemorrhage rate after treatment were also evaluated. The AVM obliteration and bleed rates were calculated using the Kaplan-Meier method and Cox regression analyses. RESULTS: The efficacy rate with total obliteration after treatment was 81.9% (95 of 116 patients). The median interval to achieve total obliteration was 49 months. Microsurgical resection combined with SRS for residual AVMs achieved better obliteration rates compared to SRS alone (statistically significant, p = 0.001), while no significant difference was found between the embolization group and the group with no prior treatment (p = 0.895). The Spetzler-Martin grade of AVM is a relative factor of obliteration, higher grades resulting in a worse outcome (p = 0.009). Obliteration was significantly influenced by AVM volume in univariate analysis (p = 0.034), and volume <5 cm(3) contributed to improved obliteration (p = 0.01). There was no statistically significant difference in the hemorrhagic rate and the complication rate between ruptured and unruptured AVMs, while the unruptured group had a higher obliteration rate (p = 0.024). The annual hemorrhage rate after LINAC SRS treatment was 1.9%. The bleeding rate was 3.3% in the first year after radiosurgery, 2.1% in the second year, 1.9% between the second and fifth year, and 1.5% between the fifth and tenth year. Patients with hemorrhagic events before radiosurgery appeared to have a higher rebleeding risk during the latency period. Twenty-three patients (19.8%) had late adverse effects with regard to posttreatment radiological follow-up, but only 1 (0.8%) had newly developed neurological deficits. CONCLUSION: LINAC SRS achieved a high obliteration rate and reduced the risk of hemorrhage effectively in ruptured and unruptured intracranial AVMs. Prior microsurgical resection provided better outcome, while embolization showed no benefit. Adverse effects after treatment are acceptable and require long-term follow-up.

Minimally invasive endoscopic evacuation with the novel, portable Axonpen neuroendoscopic system for spontaneous intracerebral hemorrhage.

Minimally invasive surgeries have shown potential to improve mortality and clinical outcomes of spontaneous intracerebral hemorrhage (ICH). The present study assessed the first-in-human outcomes of a novel, portable neuroendoscopic system for ICH evacuation at our single center. This neuroendoscopic system integrates real-time visualization into a handpiece which has controllable suction, irrigation, and coagulation to allow a neurosurgeon to conduct minimally invasive ICH evacuation independently with bimanual dexterity. Pre- and postoperative data of ten patients who had spontaneous basal ganglia hemorrhage (mean: 46.5 ± 12.2 mL) and underwent evacuation with the specified neuroendoscopic system were collected prospectively. The mean time to receive surgery was 12.1 ± 7.6 h. Mean operative time was 3.4 ± 0.9 h. The mean hematoma volume decreased to 6.0 ± 3.9 mL at postoperative 6 h, resulting in a mean volume reduction of 86.0 ± 11.2% (P = 0.005). The median length of intensive care unit stay was 3 days (IQR, 3-4 days). At discharge, the median Glasgow Coma Scale (GCS) score significantly improved to 11.5 (IQR, 11-15; P = 0.016), and the median modified Rankin Scale (mRS) score was 4 (IQR, 4-5). Six patients (60%) showed a favorable mRS score of ≤ 3 on their last return visit. Neither death nor rebleeding occurred during the follow-up periods. Integrated design of the innovative device is valuable to optimize minimally invasive endoscopic ICH evacuation procedure. Further studies are needed to clarify long-term benefits from such type of the innovative device to early intervention of ICH.

Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation, and neuroprotection.

BACKGROUND: Spinal cord injuries (SCIs) are serious and debilitating health problems that lead to severe and permanent neurological deficits resulting from the primary mechanical impact followed by secondary tissue injury. During the acute stage after an SCI, the expression of autophagy and inflammatory responses contribute to the development of secondary injury. In the present study, we examined the multifaceted effects of rapamycin on outcomes of rats after an SCI. MATERIALS AND METHODS: We used 72 female Sprague-Dawley rats for this study. In the SCI group, we performed a laminectomy at T10, followed by impact-contusion of the spinal cord. In the control group, we performed only a laminectomy without contusion. We evaluated the effects of rapamycin using the Basso, Beattie, and Bresnahan scale for functional outcomes, Western blot analyses for analyzing LC3-II, tumor necrosis factor expression, and p70S6K phosphorylation, and an immunostaining technique for localization and enumeration of microglial and neuronal cells. RESULTS: Basso, Beattie, and Bresnahan scores after injury significantly improved in the rapamycin-treated group compared with the vehicle group (on Day 28 after the SCI; P < .05). The Western blot analysis demonstrated that rapamycin enhanced LC3-II expression and decreased p70S6K phosphorylation compared with the vehicle (P < .01), which implies promotion of autophagy through mammalian target of rapamycin inhibition. Furthermore, rapamycin treatment significantly attenuated tumor necrosis factor production and microglial expression (P < .05). Immunohistochemistry of NeuN (antibodies specific to neurons) showed remarkable neuronal cell preservation in the rapamycin-treated group compared with the vehicle-treated group (P < .05), which suggests a neuroprotective effect of rapamycin. CONCLUSIONS: Rapamycin is a novel neuroprotectant with multifaceted effects on the rat spinal cord after injury. Use of such a clinically established drug could facilitate early clinical trials in selected cases of human SCIs.

Long-term follow-up of patients with surgical intractable acromegaly after linear accelerator radiosurgery.

BACKGROUND/PURPOSE: Radiotherapy is a crucial treatment for acromegalic patients with growth hormone (GH)-secreting pituitary tumors. However, its effect takes time. We retrospectively reviewed the long-term outcome of linear accelerator stereotactic radiosurgery (LINAC SRS) for patients with acromegaly from the perspective of biochemical remission and associated factors. METHODS: Twenty-two patients presenting with residual or recurrent (GH)-secreting functional pituitary tumor between 1994 and 2004 who received LINAC SRS were enrolled and followed up for at least 3 years. Residual or recurrent tumor was defined as persistent elevated GH or insulin-like growth factor-1 (IGF-1) level and image-confirmed tumor after previous surgical treatment. Biochemical remission was defined as fasting GH less than 2.5 ng/mL with normal sex-and-age adjusted IGF-1. RESULTS: The mean follow-up period was 94.7 months (range 36-161 months). Overall mean biochemical remission time was 53 months (median 30 months). Biochemical control was achieved in 15 patients (68.2%) over the follow up period. One patient experienced recurrence after SRS and underwent another operation. Initial GH at diagnosis and pre-SRS GH correlated with biochemical control (p = 0.005 and p < 0.0001, respectively). Further evaluation demonstrated that biochemical control stabilized after 7.5 years. Overall post-SRS hormone deficit persisted in five patients (22.7%). CONCLUSION: In comparison to other radiosurgery modalities, LINAC radiosurgery also provides a satisfactory outcome. SRS has maximum effect over the first 2 years and stabilizes after 7.5 years. Moreover, SRS elicits long-term biochemical effects and requires longer follow-up for better biochemical remission.

Rathke's cleft cyst classification and outcomes after endoscopic endonasal approach.

BACKGROUND: Rathke's cleft cyst is rare, with variable characteristics and no unified categorization system. This study aimed to evaluate long-term outcomes, based on different categorizations, of symptomatic Rathke's cleft cysts treated with endoscopic endonasal approach. METHODS: This retrospective study of 38 patients with symptomatic Rathke's cleft cyst treated with endoscopic endonasal approach from 2006/06-2021/08 recorded pre- and post-operative clinical presentation, endocrine and visual tests, radiological findings, and resection status. Rathke's cleft cysts were categorized by both cyst consistency and radiological features and clinical characteristics were analyzed. RESULTS: The most common pre-operative symptoms were visual field deficit (65.8%) and hypopituitarism (39.5 %). Visual field deficit improved in 84% of affected patients, and hyperprolactinemia improved in 80% of affected patients. Pre-operative hypothyroidism and hypogonadism were associated with radiological type 3 cysts, while headache was more common in type B and C. Type 3 cysts were also associated post-operative hypogonadism and hypothyroidism. Permanent Diabetes insipidus was found in 3 patients (7.9%). Cyst height was a significant factor related to pre-operative visual field deficit and post-operative Diabetes insipidus. Residual cysts were found in 11 cases (30.6%) and 9 patients experienced regrowth/recurrence. Residual cysts were a significant factor in regrowth/recurrence. Recurrence rate and post-operative complications were not correlated with different subtypes. CONCLUSIONS: Endoscopic endonasal approach for removal of Rathke's cleft cyst is a safe and effective intervention. It leads to significant improvement in visual field deficit and recovery of hyperprolactinemia. Although the incidence of post-operative Diabetes insipidus is high, it is usually temporary. Although different categorizations are not correlated to recurrence rate, they could help predict the status of hormone deficit.

Prognostic Factors Analysis for Intracranial Cavernous Malformations Treated with Linear Accelerator Stereotactic Radiosurgery.

Stereotactic radiosurgery (SRS) is generally considered a substitute for cranial cavernous malformations (CCMs). However, prognostic factors for post-radiosurgery CCM rebleeding and adverse radiation effects have not been well evaluated, and the effect of timing and optimal treatment remains controversial. Therefore, this study evaluated prognostic factors for post-radiosurgical rebleeding and focal edematous changes in 30 patients who developed symptomatic intracranial hemorrhage due to solitary non-brainstem CCM and received linear accelerator (LINAC) SRS in a single medical center from October 2002 to June 2018. An overall post-radiosurgical annual hemorrhage rate with 4.5% was determined in this study. In addition, a higher marginal dose of >1600 centigray and earlier LINAC SRS intervention were correlated with a significantly lower post-radiosurgical annual hemorrhage rate. A lesion size larger than 3 cm3 and a coexisting developmental venous anomaly were significant risk factors for post-radiosurgical focal brain edema but mostly resulted in no symptoms and were temporary. This study demonstrated the efficacy of LINAC SRS in preventing CCM rebleeding and suggests that earlier radiosurgery treatment with a higher dose for non-brainstem symptomatic CCMs be considered.

Surgical Outcome and Evaluation of Strategies in the Management of Growth Hormone-Secreting Pituitary Adenomas After Initial Transsphenoidal Pituitary Adenectomy Failure.

Acromegaly is a systemic disease that requires multidisciplinary treatment to achieve the best clinical outcome. This study aimed to evaluate the outcomes of the endoscopic transsphenoidal approach (TSA) as the primary treatment for somatotroph adenomas and further investigate patients who had suboptimal surgical results. This retrospective study included 83 patients with somatotroph adenomas treated by TSA at our institution from 1999 to 2010. Biochemical remission was defined as hGH <1 and <2.5 ng/ml. Factors associated with failure of TSA and strategy of secondary treatments for refractory and recurrent disease were analyzed. The mean age of patients was 41.1 ± 11.3 years, and the mean follow-up time was 54.2 ± 44.3 months. Approximately 44.5% of patients had residual tumors after TSA. Larger tumor size, higher GH level before the operation, and the existence of residual tumors were associated with TSA failure. Forty-one patients had an inadequate response to TSA or a recurrent lesion, and of these patients, 37 had residual tumor after TSA. Octreotide results in good outcomes in the treatment of DGSA patients, and SRS/EXRT generates good results in treating patients who receive second treatments when remission cannot be reached 6 months after TSA operation.

A manzamine-derived compound as a potential therapeutic agent for glioma by inducing apoptosis and cell cycle arrest.

Glioma is a severe disease with a poor prognosis despite aggressive surgical resection and traditional chemotherapies. Therefore, new anti-neoplastic drugs are urgently needed. Bioactive compounds from natural products are potential sources of antiproliferative molecules, among which manzamine compounds extracted from the Formosan marine sponge Haliclona sp. have shown considerable promise as anticancer drugs. In the present study, the anti-neoplastic effect and mechanism of the manzamine derivative 1-(9'-propyl-3'-carbazole)-1, 2, 3, 4-tetrahydro-ß-carboline (PCTC) were investigated using in vitro cell lines and an in vivo subcutaneous animal model. Both cytotoxic and anti-proliferative effects were shown in human and murine glioma cell lines (A172, U87MG, and GL261), together with enhanced expressions of apoptotic enzymes and intracellular reactive oxygen species, and blockage of the G1/S phase of the cell cycle. In addition, combined treatment of GL261 cells with PCTC and temozolomide had a synergic antiproliferative effect. Significant safety, efficacy, and survival benefits were also demonstrated with PCTC treatment in the murine subcutaneous GL261 model. In conclusion, PCTC could effectively promote cell death through apoptosis and cell cycle arrest in glioma cell lines, and provide survival benefits in the animal model. Therefore, PCTC may be a clinically beneficial therapy for glioblastoma.

Robot-Assisted Radiofrequency Ablation Combined with Thermodynamic Simulation for Epilepsy Reoperations.

Repeat craniotomies to treat recurrent seizures may be difficult, and minimally invasive radiofrequency ablation is an alternative therapy. On the basis of this procedure, we aimed to develop a more reliable methodology which is helpful for institutions where real-time image monitoring or electrophysiologic guidance during ablation are not available. We used simulation combined with a robot-assisted radiofrequency ablation (S-RARFA) protocol to plan and execute brain epileptic tissue lesioning. Trajectories of electrodes were planned on the robot system, and time-dependent thermodynamics was simulated with radiofrequency parameters. Thermal gradient and margin were displayed on a computer to calculate ablation volume with a mathematic equation. Actual volume was measured on images after the ablation. This small series included one pediatric and two adult patients. The remnant hippocampus, corpus callosum, and irritative zone around arteriovenous malformation nidus were all treated with S-RARFA. The mean error percentage of the volume ablated between preoperative simulation and postoperative measurement was 2.4 ± 0.7%. No complications or newly developed neurologic deficits presented postoperatively, and the patients had little postoperative pain and short hospital stays. In this pilot study, we preliminarily verified the feasibility and safety of this novel protocol. As an alternative to traditional surgeries or real-time monitoring, S-RARFA served as successful seizure reoperation with high accuracy, minimal collateral damage, and good seizure control.

Application of neuroendoscopy in the treatment of obstructive hydrocephalus secondary to hypertensive intraventricular hemorrhage.

OBJECTIVE: Neuroendoscopy has become an integral part of neurosurgery, in particular in the ventricular system. Obstructive hydrocephalus secondary to intraventricular hemorrhage (IVH) is a good indication for neuroendoscopic surgery. We evaluated its efficacy and limitations in these patients. MATERIALS AND METHODS: During a 5-year period, 13 patients with obstructive hydrocephalus secondary to hypertensive IVH were studied. Patients with IVH with no evidence of obstructive hydrocephalus or with a large parenchymal hematoma or IVH of vascular origin were excluded. Rigid endoscope was used to evacuate hematoma in lateral ventricles and third ventricle in all patients. Glasgow Coma Scale (GCS), Graeb score and ventriculo-cranial ratio were evaluated before and after endoscopic intervention and Glasgow Outcome Scale (GOS) was appraised at 1 month and 12 months, postoperatively. RESULTS: Of the 13 patients, eight (61.5%) patients had thalamus hemorrhage. A successful endoscopic removal of intraventricular hematoma was achieved in all patients. Complications observed included, fornix contusion (1) and meningitis (1) and there was no procedure-related mortality. The mean Graeb score reduced from 8.69 ± 1.89 to 6.00 ± 2.68 (P=0.001) and ventriculo-cranial ratio decreased from 0.41 ±0.05 to 0.39 ± 0.05 (P=0.085) following the procedure. The mean GOS scores at 1 month and 12 months both were 2.7, but a bipolar distribution was observed at 12 months. The Graeb score changed significantly with positive correlation to GCS score change (=0.565 and P<0.05). CONCLUSIONS: Endoscopic management of severe IVH with obstructive hydrocephalus allows effective reduction of the amount of ventricular blood and improves level of consciousness. Future refinement in instrumentation and discreet case selection may make this method more applicable and effective.

Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study.

Asunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.