The Role of Tumor-Associated Hypothalamic Involvement in Surgical Treatment and Long-Term Outcome in Adult Patients with Craniopharyngioma.

INTRODUCTION: Hypothalamic invasion in pediatric patients with craniopharyngioma negatively influences clinical outcomes. It has been shown that radiologic classification of hypothalamic invasion can effectively predict surgical strategies to minimize postoperative comorbidities in pediatric patients. However, no comparative analysis has been performed in adult patients with craniopharyngioma. This study implements the previously established radiologic classification to characterize postoperative morbidity, surgical outcome, and distress in adult patients with craniopharyngioma. METHODS: Electronic medical records of 22 adult patients with craniopharyngioma were used to analyze patient demographics, surgical data, endocrinologic and ophthalmologic status, and histopathology in a retrospective single-center study. Questionnaires regarding postoperative distress (National Comprehensive Cancer Network Distress Thermometer and Problem List), comorbidities (Charlson Comorbidity Index), employment status, and need for supportive care were distributed. Magnetic resonance imaging scans were categorized according to Puget et al. RESULTS: Patients with hypothalamic involvement show significantly higher rates of postoperative diabetes insipidus and higher scores on the National Comprehensive Cancer Network Distress Thermometer. This significant difference was lost when considering postoperative Puget grades. Puget grades 1 and 2 were found to be associated with the use of a subfrontal surgical approach (hazard ratio, 4.080; confidence interval, 1.153-14.431; P = 0.029). CONCLUSIONS: Our results point toward a possible predictive role of preoperative hypothalamic invasion for postoperative diabetes insipidus as well as higher perceived levels of distress after surgery, which may be established in larger patient cohorts. Furthermore, a subfrontal surgical approach seems to be predicted by tumors with hypothalamic invasion. In this case, preoperative magnetic resonance imaging grading may help guide the planning of an optimal surgical strategy for adults with craniopharyngioma to reduce postoperative morbidity.

System-based approaches as prognostic tools for glioblastoma.

BACKGROUND: The evasion of apoptosis is a hallmark of cancer. Understanding this process holistically and overcoming apoptosis resistance is a goal of many research teams in order to develop better treatment options for cancer patients. Efforts are also ongoing to personalize the treatment of patients. Strategies to confirm the therapeutic efficacy of current treatments or indeed to identify potential novel additional options would be extremely beneficial to both clinicians and patients. In the past few years, system medicine approaches have been developed that model the biochemical pathways of apoptosis. These systems tools incorporate and analyse the complex biological networks involved. For their successful integration into clinical practice, it is mandatory to integrate systems approaches with routine clinical and histopathological practice to deliver personalized care for patients. RESULTS: We review here the development of system medicine approaches that model apoptosis for the treatment of cancer with a specific emphasis on the aggressive brain cancer, glioblastoma. CONCLUSIONS: We discuss the current understanding in the field and present new approaches that highlight the potential of system medicine approaches to influence how glioblastoma is diagnosed and treated in the future.

Significant Impact of Implantable Functional Electrical Stimulation on Gait Parameters: A Kinetic Analysis in Foot Drop Patients.

OBJECTIVE: Neurogenic drop foot is a common result of acquired damage of the central nervous system and can cause severe restriction of mobility. ActiGait, an implantable functional electrical stimulation device, restores ankle dorsiflexion by active peroneal nerve stimulation. The aim of our study was to evaluate its effect on foot contact pattern during normal walk. METHODS: Eight patients with drop foot who used ActiGait in everyday life performed a 20-meter comfortable walk test. Gait parameters were evaluated with an insole system (Medilogic). Percentage of biped stance in a double-step, effective foot length, width of gait, and overall plantar load were measured in comparison with and without activated drop foot stimulation. RESULTS: Effective foot length increased in all patients on average from 46.0% to 60.2% (P = 0.038). However, percentage of biped stance in a double-step showed no significant difference (31.2% vs. 27.8% on average, P = 0.063), nor did width of gait (2.6% vs. 2.4% on average, P = 0.73) and overall plantar load (3.51 N/cm2 vs. 3.39 N/cm2, P = 0.25). CONCLUSION: The ActiGait implantable drop foot stimulator significantly improves effective foot length during normal walk of patients with neurogenic drop foot. Further investigation is needed to confirm whether ActiGait has no effect on the other parameters or whether it facilitates permanent gait adaptations that persist without the activated device.

Biopsies of pediatric brainstem lesions display low morbidity but strong impact on further treatment decisions.

OBJECTIVE: The course of malignant brain stem gliomas in childhood is rarely positive. Because of limited therapeutic options and potentially hazardous biopsies oncologist often relay on MRI diagnoses only for further therapy decisions. In this study we show that brain stem biopsies display a low morbidity rate and neuropathological assessment has a considerable impact on further treatment decision. METHODS: Within 18-months five children with brainstem symptoms and the radiological diagnosis of a malignant brainstem glioma, were identified. From this time point it was possible to analyze all samples with the 450K methylome analysis. Other neuropathological techniques included classical histology with immunohistochemistry. Surgery was performed as biopsy, either microsurgical, frame-guided (Leksell), robot-assisted (ROSA) or navigated (BrainLab, two children). RESULTS: Mean age of the children was 7.5years (range: newborn to 12years). There was no biopsy-related morbidity or mortality. The mean number of taken samples was 12 (range: 1-25). Histologic diagnosis could be established in all children, however, 450K methylome diagnosis was positive in only two out of five patients. CONCLUSION: Despite the technically difficult biopsies, all specimens were sufficient for immunohistochemical diagnosis, however, 450K methylome analysis could only be better established where multiple small samples were taken, instead of few larger ones. Based on the preoperative radiological diagnosis suggesting malignant brainstem glioma, all children would have been treated with combined radiation and temozolomid chemotherapy. Nevertheless, due to the availability of histology and molecular diagnostics, individualized therapy could be performed, preventing in two out of five children from unnecessary radiation and chemotherapy.

General Anesthesia Versus Local Anesthesia in Stereotactic Biopsies of Brain Lesions: A Prospective Randomized Study.

BACKGROUND: Stereotactic biopsy of brain lesions with unknown entities is a common neurosurgical procedure to obtain tumor tissue. Pathologists can then provide an exact diagnosis on which further therapy, such as resection, radiotherapy, or chemotherapy, can be based. These procedures can be performed under local or general anesthesia. In this prospective study, we aim to show whether stress levels are higher for patients who undergo stereotactic biopsy under local or general anesthesia. METHODS: Between January 2013 and December 2014, we screened 157 patients. Of these, 43 were included and evaluated in this study. Twenty-one patients gave their written consent and were randomized for either local or general anesthesia. A Post Traumatic Stress Score (PTSS) questionnaire was filled out by the patients preoperatively and postoperatively. Also, patients who did not agree to randomization had an opportunity to fill out the PTSS questionnaire. Twenty-two patients agreed only to fill out the stress-level questionnaire but refused randomization. These patients were evaluated as a subgroup. Scores achieved in the PTSS were compared by using the Fisher exact test. RESULTS: Among the randomized patients, 9 underwent the procedure under local anesthesia and 12 under general anesthesia. Median PTSS was 24 preoperatively in the patients who received local anesthesia versus 20 among the patients with general anesthesia (P = 0.37; Fisher exact test). Postoperatively, PTSS was 29.5 in median for patients with local anesthesia versus 23 for patients with general anesthesia (P = 0.30; Fisher exact test). Postoperatively, the PTSS showed a median increase of 5.5 points in the LA and 3 points in the GA group (P = 0.87; Fisher exact test). P values of 0.05 and lower were considered statistically significant. CONCLUSIONS: The willingness of patients to undergo randomization in this setting was low (13.3%). Within this highly selective group of patients, there was no significant difference for stress levels in patients who underwent stereotactic biopsy under local anesthesia versus general anesthesia. However, median values indicate a trend for higher stress-level values for patients undergoing local anesthesia.

Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients.

BACKGROUND: The oral bioavailability of curcuminoids is low, but can be enhanced by incorporation into micelles. The major curcuminoid curcumin has antitumor effects on glioblastoma cells in vitro and in vivo. We therefore aimed to determine intratumoral concentrations and the clinical tolerance of highly bioavailable micellar curcuminoids in glioblastoma patients. METHODS: Thirteen glioblastoma patients ingested 70 mg micellar curcuminoids [57.4 mg curcumin, 11.2 mg demethoxycurcumin (DMC), and 1.4 mg bis-demethoxycurcumin (BDMC)] three times per day for 4 days (total amount of 689 mg curcumin, 134 mg DMC, and 17 mg BDMC) prior to planned resection of their respective brain tumors. Tumor and blood samples were taken during the surgery and analyzed for total curcuminoid concentrations. (31)P magnetic resonance spectroscopic imaging was performed before and after curcuminoid consumption. RESULTS: Ten patients completed the study. The mean intratumoral concentration of curcumin was 56 pg/mg of tissue (range 9-151), and the mean serum concentration was 253 ng/ml (range 129-364). Inorganic phosphate was significantly increased within the tumor (P = 0.034). The mean ratio of phosphocreatine to inorganic phosphate decreased, and the mean intratumoral pH increased (P = 0.08) after curcuminoid intervention. CONCLUSION: Oral treatment with micellar curcuminoids led to quantifiable concentrations of total curcuminoids in glioblastomas and may alter intratumoral energy metabolism.

Stereotactic biopsy of brainstem lesions: 21 years experiences of a single center.

Stereotactic biopsies are procedures performed to obtain tumor tissue for diagnostic examinations. Cerebral lesions of unknown entities can safely be accessed and tissue can be examined, resulting in correct diagnosis and according treatment. Stereotactic procedures of lesions in highly eloquent regions such as the brainstem have been performed for more than two decades in our department. In this retrospective study we focus on results, approaches, modalities of anesthesia, and complications. We performed a retrospective analysis of our prospective database, including 26 patients who underwent stereotactic biopsy of the brainstem between April 1994 and June 2015. All of the patients underwent preoperative MRI. Riechert-Mundinger-frame was used before 2000, thereafter the Leksell stereotactic frame was used. After 2000 entry and target points were calculated by using BrainLab stereotactic system. We evaluated histopathological results as well as further treatment; additionally we compared complications of local versus general anesthesia and complications of a frontal versus a trans-cerebellar approach. Median age of all patients was 33 years, and median number of tissue samples taken was 12. In all patients a final histopathological diagnosis could be established. 5 patients underwent the procedure under local anesthesia, 21 patients in general anesthesia. In 19 patients a frontal approach was performed, while in 7 patients a trans-cerebellar approach was used. Complications occurred in five patients. Thereby no significant difference was found with regard to approach (frontal versus trans-cerebellar) or anesthesia (local versus general). Stereotactic biopsies even of lesions in the brainstem are a save way to obtain tumor tissue for final diagnosis, resulting in adequate treatment. Approach can be trans-cerebellar or frontal and procedure can be performed either under local or general anesthesia without significant differences concerning complication rate.

Efficacy and safety of local versus general anesthesia in stereotactic biopsies: a matched-pairs cohort study.

BACKGROUND: Frame-based stereotactic biopsies remain the gold standard for the diagnosis of intracerebral lesions. A major advantage is the ability to perform these procedures under local anesthesia (LA). However, there is no consensus on whether or when to use LA or general anesthesia (GA). It has been postulated that the use of LA may reduce the risk of complications. This study aims to objectify the efficacy and safety of stereotactic biopsies under LA versus GA by analyzing a prospective registry for stereotactic biopsies. METHODS: A prospective registry for stereotactic procedures was analyzed for the activities performed between May 2009 and August 2011. Inclusion criteria were patients undergoing a stereotactic biopsy. Patients with functional stereotactic procedures, cyst or abscess evacuation, and children were excluded. Of the remaining 274 patients, 204 could be randomly matched considering sex, age, American Society of Anesthesiologists (ASA) classification, and type of hospitalization. The primary endpoint was the diagnostic yield. Secondary endpoints were safety and procedural time intervals. RESULTS: Ninety-six percent of diagnosis was achieved in the LA group and 94% within the GA group. There was no significant difference in the overall complication rate. However, the rate of pulmonary complications was higher in the GA group (P=0.059). The rate of bleeding was significantly higher in the LA group (P=0.003) intraoperatively. However, no significant difference was found clinically or on routine postoperative computed tomography scan reports. There was a significant reduction in the time spent in the operating room within the LA group (P<0.001). CONCLUSIONS: The type of anesthesia may not interfere with the diagnostic yield in stereotactic biopsies. Patients operated under LA are less likely to suffer pulmonary complications. Furthermore, LA could spare hospital resources in this setting.

Dietary curcumin attenuates glioma growth in a syngeneic mouse model by inhibition of the JAK1,2/STAT3 signaling pathway.

PURPOSE: Glioblastomas are the most common and most deadly primary brain tumors. Here, we evaluated the chemotherapeutic effect of the natural polyphenol curcumin on glioma cells in vitro and in vivo using an immunocompetent orthotopic mouse model. EXPERIMENTAL DESIGN: Curcumin's effects on proliferation, cell cycle, migration, invasion, JAK/STAT3 signaling, STAT3 target gene expression, and STAT3C rescue experiments were determined in murine glioma cell lines in vitro. Therapeutic effects of curcumin in vivo were evaluated in tumor-bearing mice fed a Western-type diet fortified with curcumin (0.05%, w/w) and in control animals. Tumor growth patterns and survival were evaluated by immunohistochemistry, morphometric analyses, and Kaplan-Meier plots. RESULTS: In vitro, curcumin inhibited JAK1,2/STAT3 tyrosine-phosphorylation in a dose-dependent fashion in murine glioma cell lines. Real-time RT-PCR revealed that curcumin downregulated transcription of the STAT3 target genes c-Myc, MMP-9, Snail, and Twist, and of the proliferation marker Ki67. Curcumin dose-dependently suppressed cell proliferation by inducing a G2/M phase arrest. In wound healing and Matrigel invasion assays, curcumin treatment resulted in a dose-dependent attenuation of the glioma cells' migratory and invasive behavior, which could be rescued by constitutively active STAT3C. In vivo, curcumin intake reduced the growth and midline crossing of intracranially implanted tumors and proliferation of tumor cells ensuing in significant long-term survival compared with control diet. CONCLUSION: This preclinical study shows that curcumin is capable of suppressing malignant glioma growth in vitro and in vivo. Our data suggest that the pharmacologically safe agent curcumin holds promise for clinical application in glioma therapy.

Cerebrovascular characterization of clazosentan, the first nonpeptide endothelin receptor antagonist shown to be clinically effective for the treatment of cerebral vasospasm. Part II: effect on endothelin(B) receptor-mediated relaxation.

OBJECT: The disturbed balance between nitric oxide and endothelin (ET)-1 in the cerebrovasculature seems to play a major role in the development of cerebral vasospasm after subarachnoid hemorrhage. Endothelin-1 represents the contractile part in this balance. In addition to the prevailing ET(A) receptor-dependent contractile effect, ET-1 also has ET(B) receptor-mediated vasodilatory attributes. The aim of the present study was to define the actual selectivity of clazosentan, the first putative highly ET(A) receptor-selective antagonist clinically proven to be effective in the treatment of vasospasm in the cerebrovasculature. METHODS: Rat basilar artery ring segments with endothelial function were used for the measurement of isometric force. Concentration effect curves were constructed by cumulative application of sarafotoxin S6c, ET-1, or big ET-1 in the presence or absence of clazosentan (10(-9) to 10(-6) M) after a precontraction was induced by prostaglandin F2alpha. The inhibition by clazosentan was estimated by the value of the affinity constant (pA2). The relaxation induced by sarafotoxin S6c, ET-1, and big ET-1 was inhibited in a competitive manner by clazosentan, yielding pA2 values of 7.1, 6.7, and 6.5, respectively. The selectivity to the ET(A) receptor in the cerebrovascular system was approximately two logarithmic units. CONCLUSIONS: The present investigation shows a competitive inhibition of ET(B) receptor-mediated relaxation in cerebral vessels by clazosentan in therapeutically relevant concentrations. Thus, additional clinical trials should be undertaken to evaluate clazosentan concentrations in cerebrospinal fluid. Furthermore, the present data may be taken to describe the pharmacological properties for an ET receptor antagonist specifically tailored for the treatment of pathological conditions of impaired cerebral blood flow.