Sebastian Senger

Darbepoetin-α promotes neovascularization and cell proliferation in established colorectal liver metastases.

BACKGROUND The erythropoietin-analogue darbepoetin-α (DPO) improves liver function and regeneration after hepatectomy (Phx), however, also enhances Phx-induced tumor cell engraftment and neovascularization. Because it is unknown whether DPO also enhances the growth of established tumors, we herein studied the effect of DPO on established colorectal liver metastases after Phx. METHODS CT26.WT cells were implanted into the liver of BALB/c mice. Five days after tumor establishment, animals underwent 50% Phx and received 10 μg/kgBW DPO or saline. Non-Phx animals with DPO or saline-treatment served as controls. Seven days after Phx tumors were analyzed regarding blood vessel formation, leukocyte adhesion, cell proliferation, apoptotic cell death, and growth using intravital fluorescence microscopy, histology, and immunohistochemistry. RESULTS The growth of established colorectal liver metastases was slightly stimulated after DPO-treatment in hepatectomized and non-hepatectomized animals. However, tumor vessel formation and tumor cell proliferation were significantly enhanced after DPO-treatment in hepatectomized and non-hepatectomized mice compared with controls. Apoptotic cell death and leukocyte-endothelial cell interaction were significantly reduced after DPO-treatment. CONCLUSION Our study indicates that DPO-treatment promotes neovascularization and cell proliferation in established colorectal liver metastases of hepatectomized and non-hepatectomized mice. DPO-application in patients with colorectal liver metastases might promote tumor progression and should therefore be avoided.

The use of intraoperative computed tomography navigation in pituitary surgery promises a better intraoperative orientation in special cases.

Objective: The safety of endoscopic skull base surgery can be enhanced by accurate navigation in preoperative computed tomography (CT) and magnetic resonance imaging (MRI). Here, we report our initial experience of real-time intraoperative CT-guided navigation surgery for pituitary tumors in childhood. Materials and Methods: We report the case of a 15-year-old girl with a huge growth hormone-secreting pituitary adenoma with supra- and perisellar extension. Furthermore, the skull base was infiltrated. In this case, we performed an endonasal transsphenoidal approach for debulking the adenoma and for chiasma decompression. We used an MRI neuronavigation (Medtronic Stealth Air System) which was registered via intraoperative CT scan (Siemens CT Somatom). Preexisting MRI studies (navigation protocol) were fused with the intraoperative CT scans to enable three-dimensional navigation based on MR and CT imaging data. Intraoperatively, we did a further CT scan for resection control. Results: The intraoperative accuracy of the neuronavigation was excellent. There was an adjustment of <1 mm. The navigation was very helpful for orientation on the destroyed skull base in the sphenoid sinus. After opening the sellar region and tumor debulking, we did a CT scan for resection control because the extent of resection was not credible evaluable in this huge infiltrating adenoma. Thereby, we were able to demonstrate a sufficient decompression of the chiasma and complete resection of the medial part of the adenoma in the intraoperative CT images. Conclusions: The use of intraoperative CT/MRI-guided neuronavigation for transsphenoidal surgery is a time-effective, safe, and technically beneficial technique for special cases.

Preoperative navigated transcranial magnetic stimulation in patients with motor eloquent lesions with emphasis on metastasis

Navigated transcranial magnetic stimulation (nTMS) is a frequently used, non‐invasive method to map the motor cortex. It is of great value in the preoperative workup of patients that suffer from motor eloquent brain lesions. Here, we present a single‐center experience using preoperative nTMS in cortical motor eloquent lesions with emphasis on metastasis. All patients that underwent preoperative nTMS between June 2013 and January 2016 were evaluated. A total of 61 patients underwent nTMS before undergoing surgery for a motor eloquent brain lesion. Patients suffered from cerebral metastasis (23), glioblastoma (16), high grade glioma WHO III (4), low grade glioma WHO II (4), lymphoma (2), meningioma (8), cavernous hemangioma (3), or arteriovenous malformation (1). Thirty patients (49.2%) presented with a preoperative motor deficit. One week after surgery, paresis had resolved or improved in 56.7% of the patients. Out of the patients with postoperative paresis, 89.5% experienced an improvement of motor status at follow‐up. All metastatic lesions were completely resected compared to 78.9% of non‐metastatic lesions (P = 0.02). Only 4.3% of patients with a metastatic lesion, but 26.3% of patients with a non‐metastatic lesion experienced deterioration of motor function after surgery (P = 0.04). Preoperative nTMS is suitable for mapping of a variety of motor eloquent brain lesions resulting in favorable neurological outcome. Particularly in metastatic motor eloquent lesion, motor function appears to be preserved after surgery. Clin. Anat. 29:925–931, 2016.

Superficial Temporal Artery to Middle Cerebral Artery Bypass via a Minimized Approach: Operative Nuances and Problem-Solving Aspects

BACKGROUND The minimized approach for superficial temporal to middle cerebral artery (STA-MCA) bypass surgery is frequently associated with unfamiliar situations and technical problems. OBJECTIVE Description of operative nuances and evaluation of problem-solving aspects to facilitate potential limitations related with a limited exposure approach. METHODS In patients who underwent STA-MCA bypass surgery between February 2012 and August 2014, a preoperative high-resolution computed tomography-angiography 3-dimensional dataset was obtained to select the optimal vessels for anastomosis. Intraoperative exposure was assessed under standard neuronavigation. Anastomoses were performed with specific instruments developed by the authors. Intraoperative video documentation and follow-up records were analyzed retrospectively. RESULTS Seventeen STA-MCA minimally invasive bypass procedures were performed on 12 patients. In all cases, the procedure could be performed through planned craniotomy (mean diameter 2.5 cm). All cases of the procedures dealt with the limitation of surgical field during bypass surgery. The described applications facilitated microsurgical handling in the environment of a limited exposure in all procedures. Follow-up showed all bypasses remained open. CONCLUSIONS The surgical applications, operative techniques, problem-solving aspects, and development of new instruments are described. Potentially, these suggestions may enhance the surgical confidence and convenience to perform STA-MCA bypass surgery with a minimized approach.

Darbepoetin-α Accelerates Neovascularization and Engraftment of Extrahepatic Colorectal Metastases

Purpose: Erythropoietin and its analogue darbepoetin (DPO)-α have been shown to improve liver function and regeneration after partial hepatectomy (Phx). However, previous experimental studies have also shown that DPO significantly enhances Phx-induced engraftment of colorectal liver metastases by increasing neovascularization and tumor cell proliferation. Therefore, the present study analyzed whether DPO affects engraftment and neovascularization of extrahepatic colorectal metastases after major hepatectomy. Methods: Green fluorescent protein-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Animals received a single dose of DPO (10 µg/kg body weight) at the day of tumor cell implantation (day 0). Phosphate-buffered saline-treated animals served as controls. To study whether the effect of DPO is influenced by Phx, additional animals with and without DPO treatment underwent 70% Phx at day 0. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. Results: In nonhepatectomized animals, DPO significantly accelerated tumor cell engraftment and slightly enhanced tumor neovascularization. Tumor cell migration and host tissue infiltration were not affected by DPO. In hepatectomized animals, DPO slightly enhanced tumor growth and significantly accelerated tumor neovascularization, but did not affect tumor cell migration and infiltration. Conclusion: The present study indicates that DPO accelerates extrahepatic engraftment of colorectal cancer cells, most probably by stimulating the process of neovascularization.

Preoperative navigated transcranial magnetic stimulation and tractography in transparietal approach to the trigone of the lateral ventricle

OBJECTIVE Eloquent neural structures including white matter tracts surround the trigone of the lateral ventricle. Surgical resection of trigonal tumors via the transparietal approach may cause neurological deterioration depending on the trajectory. METHODS The authors retrospectively reviewed patients with trigonal tumors that underwent combined preoperative navigated transcranial magnetic stimulation (nTMS) and optic radiation tractography to guide a transparietal approach towards the trigone. RESULTS Five patients underwent preoperative nTMS motor mapping, rTMS language mapping, nTMS-derived corticospinal tract tractography, and optic radiation tractography. The information was used to select the optimal trajectory for a transparietal approach and for intraoperative neuronavigation. Four patients underwent surgical resection. None of them experienced a new permanent deficit. CONCLUSION Combination of preoperative nTMS and optic radiation tractography facilitates the identification of the optimal parietal trajectory towards the trigone. It allows for sparing of visual and motor pathways as well as cortical language areas.

Preoperative Navigated Transcranial Magnetic Stimulation and Tractography to Guide Endoscopic Cystoventriculostomy: A Technical Note and Case Report

OBJECTIVE To report a technique for endoscopic cystoventriculostomy guided by preoperative navigated transcranial magnetic stimulation (nTMS) and tractography in a patient with a large speech eloquent arachnoid cyst. METHODS A 74-year old woman presented with a seizure and subsequent persistent anomic aphasia from a progressive left-sided parietal arachnoid cyst. An endoscopic cystoventriculostomy and endoscope-assisted ventricle catheter placement were performed. Surgery was guided by preoperative nTMS and tractography to avoid eloquent language, motor, and visual pathways. RESULTS Preoperative nTMS motor and language mapping were used to guide tractography of motor and language white matter tracts. The ideal locations of entry point and cystoventriculostomy as well as trajectory for stent-placement were determined preoperatively with a pseudo-3-dimensional model visualizing eloquent language, motor, and visual cortical and subcortical information. The early postoperative course was uneventful. At her 3-month follow-up visit, her language impairments had completely recovered. Additionally, magnetic resonance imaging demonstrated complete collapse of the arachnoid cyst. CONCLUSION The combination of nTMS and tractography supports the identification of a safe trajectory for cystoventriculostomy in eloquent arachnoid cysts.

The view through the ventricle catheter – The new ShuntScope for the therapy of pediatric hydrocephalus

PURPOSE Correct placement of the ventricle catheter directly influences the function of cerebral shunt systems. The incidence of proximal catheter misplacement reaches up to 45%. To avoid misplacements and revisions a new intra-catheter endoscope for precise ventricle catheter placement in children was evaluated. METHODS The semi-rigid ShuntScope (Karl Storz GmbH & Co.KG, Tuttlingen, Germany) with an outer diameter of 1.0 mm and an image resolution of 10,000 pixels was used in a series of 27 children and adolescents (18 males, 9 females, age range 2 months-18 years). Indications included catheter placement in aqueductal stenting (n = 4), first time shunt placement (n = 5), burr hole reservoir insertion (n = 4), catheter placement after endoscopic procedures (n = 7) and revision surgery of the ventricle catheter (n = 7). RESULTS ShuntScope guided precise catheter placement was achieved in 26 of 27 patients. In one case of aqueductal stenting, the procedure had to be abandoned. One single wound healing problem was noted as a complications. Intraventricular image quality was always sufficient to recognize the anatomical structures. In case of catheter removal, it was helpful to identify adherent vessels or membranes. Penetration of small adhesions or thin membranes was feasible. Postoperative imaging studies demonstrated catheter tip placements analogous to the intraoperative findings. CONCLUSIONS Misplacements of shunt catheters are completely avoidable with the presented intra-catheter technique including slit ventricles or even aqueductal stenting. Potential complications can be avoided during revision surgery. The implementation of the ShuntScope is recommended in pediatric neurosurgery.

Promoter methylation of RB1, P15, P16, and MGMT and their impact on the clinical course of pilocytic astrocytomas

Promoter methylation of P15, P16, RB transcriptional corepressor 1 (RB1) and O-6-methylguanine-DNA methyltransferase (MGMT) impacts the prognosis of numerous glioma subtypes. However, whether promoter methylation of these genes also has an impact on the clinical course of pilocytic astrocytoma remains unclear. Using methylation-specific polymerase chain reaction, the methylation status of the tumor suppressor genes P15, P16, RB1, and MGMT in pilocytic astrocytomas (n=18) was analyzed. Immunohistochemical staining for the R132H mutation of the isocitrate dehydrogenase (NADP(+)) 1, cytosolic (IDH1) gene was performed. Clinical data including age, gender, localization of tumor, extent of resection, treatment modality, progression-free survival and overall survival were collected. The methylation index for P15, P16, RB1 and MGMT was 0.0, 0.0, 5.6% (1/18) and 44.5% (8/18), respectively. If the MGMT promoter was methylated, the probability of relapse and second subsequent therapy was significantly increased (P=0.019). The one patient with methylation of P15 demonstrated a poor clinical course. The pilocytic astrocytomas of all 18 patients revealed wild-type IDH1. Clinically, there was a significant correlation of subtotal resection with the occurrence of relapse (P=0.005) and of the localization of the tumor with the extent of resection (P=0.031). Gross total resection was achieved significantly more often in pediatric patients than in adult patients (P=0.003). Adult patients demonstrated more relapses following the first tumor resection (P=0.001). The present study indicates that methylation of MGMT is associated with a poor clinical course and represents an age-independent risk factor for an unfavorable outcome. Other influential factors of outcome were the age of the patient and extent of resection.

Darbepoetin-α Promotes Cell Proliferation in Established Extrahepatic Colorectal Tumors after Major Hepatectomy

Background: The glycoprotein hormone erythropoietin and its analogue darbepoetin-α (DPO) have been shown to reduce the risk of acute liver failure after major hepatectomy. However, previous experimental studies have also shown that DPO significantly enhances neovascularization and tumor cell proliferation in established colorectal liver metastasis in hepatectomized and nonhepatectomized mice. The present study now analyzes whether DPO influences cell proliferation and migration as well as vascularization and growth of established colorectal metastasis at extrahepatic sites after major hepatectomy. Methods: GFP-transfected CT26.WT colorectal cancer cells were implanted into dorsal skinfold chambers of syngeneic BALB/c mice. Five days after tumor cell implantation, the animals received a single dose of DPO (10 µg/kg body weight) or phosphate-buffered saline solution (PBS) intravenously. Additional animals received a 70% hepatectomy and DPO or PBS treatment. Tumor vascularization and growth as well as tumor cell migration, proliferation and apoptosis were studied repetitively over 14 days using intravital fluorescence microscopy, histology and immunohistochemistry. Results: DPO did not influence tumor cell migration and apoptosis. In addition, DPO did not stimulate tumor cell infiltration or vascularization; however, significantly increased tumor cell proliferation was detected in hepatectomized animals. Conclusion: DPO increases cell proliferation in established extrahepatic colorectal metastases after major hepatectomy. Thus, DPO may not be recommended to stimulate regeneration of the remnant liver after major hepatectomy for colorectal liver metastasis.