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Background Lateral lumbar interbody fusion (LLIF), first described in the literature in 2006 by Ozgur et al., involves direct access to the lateral disc space via a retroperitoneal trans-psoas tubular approach. Neuromonitoring is vital during this approach since the surgical corridor traverses the psoas muscle where the lumbar plexus lies, risking injury to the lumbosacral plexus that could result in sensory or motor deficits. The risk of neurologic injury is especially higher at L4-5 due to the anatomy of the plexus at this level. Here we report our single-center clinical experience with L4-5 LLIF. Methods A retrospective chart review of all patients who underwent an L4-5 LLIF between May 2016 and March 2019 was performed. Baseline demographics and clinical characteristics, such as body mass index (BMI), medical comorbidities, surgical history, tobacco status, operative time and blood loss, length of stay (LOS), and post-op complications were recorded. Results A total of 220 (58% female and 42% male) cases were reviewed. The most common presenting pathology was spondylolisthesis. The average age, BMI, operative time, blood loss, and LOS were 64.6 years, 29 kg/m2, 214 min, 75 cc, and 2.5 days respectively. A review of post-operative neurologic deficits revealed 31.4% transient hip flexor weakness and 4.5% quadricep weakness on the approach side. At 3-week follow-up, 9.1% of patients experienced mild hip flexor weakness (4 or 4+/5), 0.9% reported mild quadricep weakness, and 9.5% reported anterior thigh dysesthesias; 93.2% of patients were discharged home and 2.3% were readmitted within the first 30 days post discharge. Female sex, higher BMI and longer operative time were associated with hip flexor weakness. Conclusions LLIF at L4-5 is a safe, feasible, and versatile approach to the lumbar spine with an acceptable approach-related sensory and motor neurologic complication rates.

Background: Overdrainage after cerebrospinal fluid diversion remains a significant morbidity. The hydrostatic, gravitational force in the upright position can aggravate this. Siphon control (SC) mechanisms, as well as programmable and flow regulating devices, were developed to counteract this. However, limited studies have evaluated their safety and efficacy. In this study, direct comparisons of the complication rates between siphon control (SC) and non-SC (NSC), fixed versus programmable, and flow- versus pressure regulating valves are undertaken. Methods: A retrospective chart review was performed over all shunt implantations from January 2011 to December 2016 within the Houston Methodist Hospital system. Complication rates within 6 months of the operative date, including infection, subdural hematoma, malfunction, and any other shunt-related complication, were analyzed via Fisher’s exact test, with P < 0.05 regarded as significant. Subgroup analyses based on diagnoses – normal pressure hydrocephalus (HCP), pseudotumor cerebri, or other HCP – were also performed. Results: The overall shunt-related complication rate in this study was 19%. Overall rates of infection, shunt failure, and readmission within 180 days were 3%, 11%, and 34%, respectively. No difference was seen between SC and NSC groups in any complication rate overall or on subgroup analyses. When comparing fixed versus programmable and flow- versus pressure-regulating valves, the latter in each analysis had significantly lower malfunction and total complication rates. Conclusions: Programmable and pressure regulating devices may lead to lower shunt malfunction and total complication rates. Proper patient selection should guide valve choice. Future prospective studies may further elucidate the difference in complication rates between these various shunt designs.

Objective To investigate potential effect of sacrifice of the superior petrosal vein (SPV) on postoperative complications after microvascular decompression (MVD). Methods Retrospective review of 98 consecutive patients undergoing MVD of cranial nerve V was performed. Frequency of division of the SPV during surgery was recorded, and postoperative complications and imaging were recorded and analyzed. In patients with complications, the specific anatomic variation of the superior petrosal venous complex was noted. Results Of 98 patients undergoing MVD, 83 (84.7%) had sacrifice of the SPV at the time of surgery, 12 (12.2%) had the SPV preserved, and 3 (3.1%) were revision operations. Four patients (4.8%) had complications deemed to be attributable to venous insufficiency or congestion. These included sigmoid sinus thrombosis with coincident cerebellar hemorrhage, midbrain and pontine infarction, hemiparesis with midbrain and pontine edema, and facial paresis with ischemia in the middle cerebellar peduncle. None of the patients with preserved SPV were symptomatic or had imaging changes consistent with venous congestion. Conclusions Sacrifice of the SPV is often performed during MVD. This is associated with a complication rate that is significant in frequency and severity compared with preserving the vein. SPV sacrifice should be limited to cases where it is deemed absolutely necessary for successful cranial nerve decompression.

Background: A minimally invasive approach to the L2-S1 disc spaces through a single, left-sided, retroperitoneal oblique corridor has been previously described. However, the size of this corridor varies, limiting access to the disc space in certain patients. Here, the authors retrospectively reviewed lumbar spine magnetic resonance imaging (MRI) in 300 patients to better define the size and variability of the retroperitoneal oblique corridor. Methods: Lumbar spine MRI from 300 patients was reviewed. The size of the retroperitoneal oblique corridor from L2-S1 was measured. It was defined as the (1) distance between the medial aspect of the aorta and the lateral aspect of the psoas muscle from L2-L5 and (2) the distance between the midpoint of the L5-S1 disc and the medial aspect of the nearest major vessel on the left at L5-S1. In addition, the rostral-caudal location of the iliac bifurcation was measured. Results: The size of the retroperitoneal oblique corridor at L2/3, L3/4, L4/5, and L5/S1 was, respectively, 17.3 ± 6.4 mm, 16.2 ± 6.3 mm, 14.8 ± 7.8 cm, and 13.0 ± 8.3 mm. The incidence of corridor size n = 158, 52.67%) followed by the L4/5 disc space (n = 74, 24.67%). Conclusion: The size of the retroperitoneal oblique corridor diminishes in a rostral-caudal direction, often limiting access to the L4/5 and L5/S1 disc spaces.

BACKGROUND: Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response through local delivery of aglatimagene besadenovec (AdV-tk) which synergizes with standard of care (SOC). METHODS: A Phase II trial was designed to evaluate overall survival (OS) after GMCI + SOC compared to a concurrent matched control group meeting protocol criteria and SOC at an institution not active in the treatment trial. Primary efficacy analysis was planned on the null hypothesis of no improvement in the 2-yr survival over the SOC group with planned subset analysis of significant disease prognostic factors. RESULTS: From 2006 to 2010, 48 patients completed SOC + GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Fever, fatigue and headache were the most common GMCI-related symptoms. Median OS was 17.1 and 13.5 months for GMCI + SOC and SOC, respectively (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.52-0.99, p = 0.0417). Median PFS was 8.1 and 6.5 months for GMCI + SOC and SOC, respectively (HR 0.66, 95% CI 0.48-0.91, p = 0.0100). OS at 1- 2- and 3-years increased from 57%, 22% and 8% to 67%, 35% and 19%, respectively. The improvement was mostly in patients that underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. CONCLUSIONS: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The 2-yr survival rate met the planned statistical threshold for significance. This is the first study to demonstrate a correlation between maximum debulking and a survival advantage using immunotherapy. These data strongly support further evaluation of GMCI for malignant gliomas.

Image-guided approaches to spinal instrumentation and interbody fusion have been widely popularized in the last decade [1-5]. Navigated pedicle screws are significantly less likely to breach [2, 3, 5, 6]. Navigation otherwise remains a point reference tool because the projection is off-axis to the surgeon's inline loupe or microscope view. The Synaptive robotic brightmatter drive videoexoscope monitor system represents a new paradigm for off-axis high-definition (HD) surgical visualization. It has many advantages over the traditional microscope and loupes, which have already been demonstrated in a cadaveric study [7]. An auxiliary, but powerful capability of this system is projection of a second, modifiable image in a split-screen configuration. We hypothesized that integration of both Medtronic and Synaptive platforms could permit the visualization of reconstructed navigation and surgical field images simultaneously. By utilizing navigated instruments, this configuration has the ability to support live image-guided surgery or real-time navigation (RTN). Medtronic O-arm/Stealth S7 navigation, MetRx, NavLock, and SureTrak spinal systems were implemented on a prone cadaveric specimen with a stream output to the Synaptive Display. Surgical visualization was provided using a Storz Image S1 platform and camera mounted to the Synaptive robotic brightmatter drive. We were able to successfully technically co-adapt both platforms. A minimally invasive transforaminal lumbar interbody fusion (MIS TLIF) and an open pedicle subtraction osteotomy (PSO) were performed using a navigated high-speed drill under RTN. Disc Shaver and Trials under RTN were implemented on the MIS TLIF. The synergy of Synaptive HD videoexoscope robotic drive and Medtronic Stealth platforms allow for live image-guided surgery or real-time navigation (RTN). Off-axis projection also allows upright neutral cervical spine operative ergonomics for the surgeons and improved surgical team visualization and education compared to traditional means. This technique has the potential to augment existing minimally invasive and open approaches, but will require long-term outcome measurements for efficacy.

Vascularized composite allotransplantation is an emerging field, but the complications of lifelong immunosuppression limit indications. Vascularized composite allotransplantation in solid organ recipients represents a unique opportunity because immunosuppression has already been accepted. This report of a simultaneous scalp, skull, kidney, and pancreas transplant represents both the first skull-scalp transplant and combination of a vascularized composite allotransplantation with double organ transplantation.A previous recipient of a kidney-pancreas transplant presented with osteoradionecrosis of the calvaria and a large area of unstable scalp following successful, curative treatment of a scalp tumor. His kidney and pancreas functions were also critically poor. A multidisciplinary, multi-institutional plan was developed to perform a simultaneous scalp, skull, and repeated kidney and pancreas transplantation, all from a single donor.Eighteen months after the patient was listed with the United Network for Organ Sharing, a donor was identified and the multiorgan vascularized composite allotransplantation was performed. Twenty physicians and 15 hours were required to perform donor and recipient procedures. The patient recovered well and was discharged on postoperative day 15. He has had one episode of scalp rejection confirmed by biopsy and treated successfully. His creatinine value is currently 0.8 mg/dl, from 5.0 mg/dl, and his blood glucose levels are normal without supplemental insulin. Aesthetic outcome is very satisfactory. The patient is now 1 year post-transplantation and doing well.Vascularized composite allotransplantation in solid organ recipients is an expansion of current indications to already immunosuppressed patients. Rejection of the vascularized composite allotransplant without solid organ rejection can occur and is treatable. Methodical planning, an interdisciplinary approach, and careful management of all organs are critical to success.Therapeutic, V.

Object Spinal extradural (epidural) arteriovenous fistulas (AVFs) are uncommon vascular lesions of the spine with arteriovenous shunting located primarily in the epidural venous plexus. Understanding the complex anatomical variations of these uncommon lesions is important for management. The authors describe the different types of spinal extradural AVFs and their endovascular management using Onyx. Methods Eight spinal extradural AVFs in 7 patients were studied using MR imaging, spinal angiography, and dynamic CT (DynaCT) between 2005 and 2009. Special consideration was given to the anatomy, pattern of venous drainage, and mass effect upon the nerve roots, spinal cord, and vertebrae. Results The neuroaxial location of the 8 spinal extradural AVFs was lumbosacral in 1 patient, lumbar in 4 patients, thoracic in 2 patients, and cervical in 1 patient. Spinal extradural AVFs were divided into 3 types. In Type A spinal extradural AVFs, arteriovenous shunting occurs in the epidural space and these types have an intradural draining vein causing venous hypertension and spinal cord edema with associated myelopathy or cauda equina syndrome. Type B1 malformations are confined to the epidural space with no intradural draining vein, causing compression of the spinal cord and/or nerve roots with myelopathy and/or radiculopathy. Type B2 malformations are also confined to the epidural space with no intradural draining vein and no mass effect, and are asymptomatic. There were 4 Type A spinal extradural AVFs, 3 Type B1s, and 1 Type B2. Onyx was used in all cases for embolization. Follow-up at 6–24 months showed that 4 patients experienced excellent recovery. Three patients with Type A spinal extradural AVFs attained good motor recovery but experienced persistent bladder and/or bowel problems. Conclusions The current description of the different types of spinal extradural AVFs can help in understanding their pathophysiology and guide management. DynaCT was found to be useful in understanding the complex anatomy of these lesions. Endovascular treatment with Onyx is a good alternative for spinal extradural AVF management.

Purpose Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O6-methylguanine–DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect. Patients and Methods Patients with newly diagnosed malignant glioma received AdV-tk at 3 × 1010, 1 × 1011, or 3 × 1011 vector particles (vp) via tumor bed injection at time of surgery followed by 14 days of valacyclovir. Radiation was initiated within 9 days after AdV-tk injection to overlap with AdV-tk activity. Temozolomide was administered after completing valacyclovir treatment. Results Accrual began December 2005 and was completed in 13 months. Thirteen patients were enrolled and 12 completed therapy, three at dose levels 1 and 2 and six at dose level 3. There were no dose-limiting or significant added toxicities. One patient withdrew before completing prodrug because of an unrelated surgical complication. Survival at 2 years was 33% and at 3 years was 25%. Patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain (FACT-Br) was stable or improved after treatment. A significant CD3+ T-cell infiltrate was found in four of four tumors analyzed after treatment. Three patients with MGMT unmethylated glioblastoma multiforme survived 6.5, 8.7, and 46.4 months. Conclusion AdV-tk plus valacyclovir can be safely delivered with surgery and accelerated radiation in newly diagnosed malignant gliomas. Temozolomide did not prevent immune responses. Although not powered for efficacy, the survival and MGMT independence trends are encouraging. A phase II trial is ongoing.

Introduction Simultaneous EEG recordings during MRI have been used as a research tool to define the epileptogenic zone. Most of the data available has relied on MRI blood oxygenation level dependent signal (BOLD) changes during interictal spikes. The literature is limited regarding BOLD changes during ictal activity. We analyzed the BOLD activation maps during a focal onset electrographic seizure in a patient with medically refractory epilepsy. In addition, limited data is available regarding evolution of changes in functional connectivity maps compared to the resting state. Methods A patient with known medically refractory focal epilepsy underwent a resting fMRI-EEG study. Our protocol includes two twenty-minute resting state scanning sessions (3 T, Philips Ingenia) with simultaneous electroencephalography recorded with a Brain Vision fMRI EEG compatible system. Post-acquisition processing was performed to eliminate MRI artifact and EEG data was reviewed. A focal seizure was identified on EEG lasting approximately 6 min. The EEG was reviewed by 2 independent epileptologists who were in agreement regarding onset and duration of seizure. Twenty-four second blocks of rfMRI data were processed using AFNI (Analysis of Functional NeuroImages) program that corresponded to the identified seizure that was recorded with simultaneous EEG recordings. Sequential 12 s delays from onset were used to evaluate seizure propagation. Utilizing general linear model (GLM) fMRI Blood-Oxygen-Level Dependent (BOLD) activation maps were created. The differences in BOLD activation maps were compared to period of baseline fMRI recording when no EEG ictal or interictal changes were identified. Results Prior presurgical workup with video EEG monitoring in our patient demonstrated seizure onset in the left frontal region. High resolution 3T MRI was normal. rfMRI BOLD activation maps revealed focal changes in the left precentral gyrus. Seizure propagation was analyzed and images reviewed. Conclusion fMRI is widely available for evaluation of patients with epilepsy and is more readily available than other technologies such as MEG. As demonstrated by our patient, simultaneous EEG and fMRI recordings may be helpful in patients in defining the epileptogenic zone and planning for implantation and respective surgery.

Stereotactic radiosurgery (SRS) is one of the least invasive treatments for trigeminal neuralgia (TN). To date, most reports have been about Cobalt-based treatments ( i.e., Gamma Knife) with limited data on image-guided stereotactic linear accelerator treatments. We describe our initial experience of using BrainLAB Novalis stereotactic system for the radiosurgical treatment of TN. A total of 20 patients were treated between July 2004 and February 2007. Each SRS procedure was performed using the BrainLAB Novalis System. Thin cuts MRI images of 1.5 mm thickness were acquired and fused with the simulation CT of each patient. Majority of the patients received a maximum dose of 90 Gy. The median brainstem dose to 1.0 cc and 0.1 cc was 2.3 Gy and 13.5 Gy, respectively. In addition, specially acquired three-dimensional fast imaging sequence employing steady-state acquisition (FIESTA) MRI was utilized to improve target delineation of the trigeminal proximal nerve root entry zone. Barrow Neurological Index (BNI) pain scale for TN was used for assessing treatment outcome. At a median follow-up time of 14.2 months, 19 patients (95%) reported at least some improvement in pain. Eight (40%) patients were completely pain-free and stopped all medications (BNI Grade I) while another 2 (10%) patients also stopped medications but reported occasional pain (BNI Grade II). Another 2 (10%) patients reported no pain and 7 (35%) patients only occasional pain while continuing medications, BNI Grade IIIA and IIIB, respectively. Median time to pain control was 8.5 days (range: 1–70 days). No patient reported severe pain, worsening pain or any pain not controlled on their previously taken medication. Intermittent or persistent facial numbness following treatments occurred in 35% of patients. No other complications were reported. Stereotactic radiosurgery using the BrainLAB Novalis system is a safe and effective treatment for TN. This information is important as more centers are obtaining image-guided stereotactic-based linear accelerators capable of performing radiosurgery.

Purpose A pilot study was designed to evaluate the safety and efficacy of a novel regimen of hypofractionated intensity-modulated radiotherapy (RT) in the adjuvant treatment of primary glioblastoma multiforme (GBM). The rationale of the study was to combine the potential radiobiologic advantage of hypofractionation to GBM with a highly conformal radiotherapeutic technique. The study was designed to measure the acute and chronic morbidity of patients treated with this regimen, response of GBM to the treatment, overall survival, and time to disease progression after therapy completion. Methods and materials Twenty eligible patients were accrued between February 1999 and May 2000 for the study. All patients had Karnofsky performance scores of ≥70. All patients were treated with intensity-modulated RT using the NOMOS Peacock system. A dose of 50 Gy was delivered in 5-Gy daily fractions within 2 weeks to enhancing primary disease, residual tumor, or surgical cavity. Simultaneously, 30 Gy was prescribed in 3-Gy daily fractions to surrounding edema. The time to progression was measured with serial neurologic examinations and MRI or CT scans after RT completion. Acute and late toxicity was graded using Radiation Therapy Oncology Group neurotoxicity scores. Results Of the 20 patients, 18 were evaluated for outcome. The median time to disease progression was 6 months after RT completion. The median overall survival was 7 months after treatment completion. All recurrences were within 2 cm of the operative bed. Neurotoxicity during therapy was minimal, with all patients experiencing Grade 0 or 1 toxicity. Late toxicity included 10 patients with Grade 0, 2 patients with Grade 2, and 3 patients with Grade 4 toxicity, manifesting as brain necrosis requiring surgical reexcision. The survival of the 3 patients with brain necrosis was 23, 20, and 9 months. Mortality in all cases was the result of tumor recurrence, with no mortality resulting from brain necrosis. Conclusion This regimen of hypofractionated intensity-modulated RT did not improve the time to disease progression or overall survival compared with historical experience using conventional fractionation. However, the treatment duration was reduced from 6 weeks to 2 weeks, which may be of palliative benefit in certain subsets of patients. This treatment regimen demonstrated a greater incidence of brain necrosis requiring surgical intervention; however, the 3 patients experiencing this toxicity had longer survival times. Future investigation may be useful to determine which fraction size may be optimal for GBM when highly conformal RT is used in the adjuvant setting.

Traumatic brain injury (TBI) is a major cause of disability and death in most Western nations and consumes an estimated $100 billion annually in the United States alone. In the last 2 decades, the management of TBI has evolved dramatically, as a result of a more thorough understanding of the physiologic events leading to secondary neuronal injury as well as advances in the care of critically ill patients. However, it is likely that many patients with TBI are not treated according to current treatment principles. This article presents an overview of the current management of patients with TBI.

Purpose: To assess the safety and efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of intracranial meningioma. Methods and Materials: Forty patients with intracranial meningioma (excluding optic nerve sheath meningiomas) were treated using IMRT with the NOMOS Peacock system between 1994 and 1999. Twenty-five patients received IMRT after surgery either as adjuvant therapy for incomplete resection or for recurrence, and 15 patients received definitive IMRT after presumptive diagnosis based on imaging. Thirty-two patients had skull base lesions, and 8 had nonskull base lesions. The prescribed dose ranged from 40 to 56 Gy (median 50.4 Gy) at 1.71 to 2 Gy per fraction, and the volume of the primary target ranged from 1.55 to 324.57 cc (median 20.22 cc). The mean dose to the target ranged from 44 to 60 Gy (median 53 Gy). Follow-up ranged from 6 to 71 months (median 30 months). Acute and chronic toxicity were assessed using Radiation Therapy Oncology Group (RTOG) morbidity criteria and tumor response was assessed by patient report, examination, and imaging. Overall survival, progression-free survival, and local control were calculated using the Kaplan-Meier method. Results: Cumulative 5-year local control, progression-free survival, and overall survival were 93%, 88%, and 89%, respectively. Two patients progressed after IMRT, one locally and one distantly. Each was treated with IMRT after multiple recurrences of benign meningioma over many years. Both were found to have malignant meningioma at the time of relapse after IMRT, and it is likely their tumors had already undergone malignant change by the time IMRT was given. Defined normal structures generally received a significantly lower dose than the target. The most common acute central nervous system (CNS) toxicity was mild headache, usually relieved with steroids. One patient experienced RTOG Grade 3 acute CNS toxicity, and 2 experienced Grade 3 or higher late CNS toxicity, with one possible treatment-related death. No toxicity was observed with mean doses to the optic nerve/chiasm up to 47 Gy and maximum doses up to 55 Gy. Conclusion: IMRT is a promising new technology that is safe and efficacious in the primary and adjuvant treatment of intracranial meningiomas. A history of local aggression may indicate malignant degeneration and predict a poorer outcome. Toxicity data are encouraging, but the potential for serious side effects exists, as demonstrated by one possible treatment-related death. Larger cohort and longer follow-up are needed to better define efficacy and late toxicity of IMRT.

Between December 1996 and September 1998, 13 patients with advanced recurrent malignant brain tumors (9 with glioblastoma multiforme, 1 with gliosarcoma, and 3 with anaplastic astrocytoma) were treated with a single intratumoral injection of 2 x 10(9), 2 x 10(10), 2 x 10(11), or 2 x 10(12) vector particles (VP) of a replication-defective adenoviral vector bearing the herpes simplex virus thymidine kinase gene driven by the Rous sarcoma virus promoter (Adv.RSVtk), followed by ganciclovir (GCV) treatment. The VP to infectious unit ratio was 20:1. Our primary objective was to determine the safety of this treatment. Injection of Adv.RSVtk in doses==2 x 10(11) VP, followed by GCV, was safely tolerated. Patients treated with the highest dose, 2 x 10(12) VP, exhibited central nervous system toxicity with confusion, hyponatremia, and seizures. One patient is living and stable 29.2 months after treatment. Two patients survived25 months before succumbing to tumor progression. Ten patients died within 10 months of treatment, 9 from tumor progression and 1 with sepsis and endocarditis. Neuropathologic examination of postmortem tissue demonstrated cavitation at the injection site, intratumoral foci of coagulative necrosis, and variable infiltration of the residual tumor with macrophages and lymphocytes.

OBJECTIVE AND IMPORTANCE: An unusual foreign body traversing the spinal canal at the foramen magnum level is described. Interesting radiological findings and a review of nonmissile penetrating injuries are presented. This case demonstrates the importance of a thorough physical examination and the use of neurodiagnostic imaging in an inebriated, uncooperative patient with neurological dysfunction. CLINICAL PRESENTATION: The patient presented with quadriparesis confounded by cocaine intoxication. A physical examination revealed only a small punctate lesion in the posterior occipital region. INTERVENTION: After detection of the foreign body, the patient underwent immediate surgical exploration and removal of the object. The dura was repaired primarily, and the patient was maintained on intravenous antibiotics for 7 days. CONCLUSION: With physical therapy, the patient was walking with assistance at 2 weeks postsurgery. Upper extremity strength, especially intrinsic hand movement, was most severely affected. At 10 months' follow-up, the patient's only deficits were mild intrinsic hand weakness and incoordination with fine finger movements. Immediate surgical exploration is indicated for patients with retained fragments and progressive neurological dysfunction.

Gene Mediated Cytotoxic Immunotherapy (GMCI) generates a polyvalent anti-tumor immune response via local delivery of aglatimagene besadenovec (AdV-tk) plus prodrug. The resulting cytotoxic nucleotide analog is toxic to cells as it halts DNA replication and repair. Tumor cell death releases tumor associated antigens, which are taken up by antigen presenting cells. There is a simultaneous stimulation of pro-inflammatory cytokines by thymidine kinase. The treatment mounts an immune response that is ongoing for many months to years. Extensive preclinical studies were performed, followed by a Phase II multicenter trial assess safety and overall survival (OS) after GMCI+SOC compared to a concurrent matched control group meeting protocol criteria and undergoing SOC. Ten 100 microliter injections of AdV-tk were made into the tumor resection bed followed by oral valacyclovir for 14 days. Results: Preclinical studies have documented that response to treatment is dependent on upregulation of antigen presenting cells and an immuno-modulating effect from interleukins, including IL-2 and IL-12. The response is greatly enhanced by the synergistic effect of radiation therapy initiated on day 3 after injection of therapy. CD4 helper cells did not appear to play an important role. Survival was greatly enhanced in those in whom an immune response can be documented either radiographically or histologically. 48 patients completed SOC+GMCI and 134 SOC in the matched cohort. There were no dose-limiting toxicities. Median OS increased by 3.6 months, from 13.5 for SOC to 17.1 months for GMCI+SOC (p = 0.0417). Survival at 1- 2- and 3-years increased from 57%, 22%, and 8% to 67%, 35%, and 19%, respectively. Improvement was mostly in patients who underwent gross total resection: median OS increased from 16.9 to 25 months (p = 0.0492); 1- 2- and 3-year survival rates from 64%, 28% and 6% to 90%, 53% and 32%. A number of patients had marked pseudoprogression, well beyond the RANO or iRANO criteria. The most robust response was in a nine year survivor who demonstrated a doubling of apparent enhancing tumor at three months after treatment. Enhancing tumor slowly resolved over a five year period, with complete resolution only seen in an MRI scan made nine years later. Many other patients had similar responses, with effects of treatment ongoing for many years, and an initial response falsely suggesting treatment failure. Conclusions: GMCI can be safely combined with SOC in newly diagnosed malignant gliomas. Survival rates compared favorably to historical reports and a matched control group. Survival outcomes were significantly improved in patients with minimal residual disease after total resection. The most robust responders had dramatic worsening of contrast enhancing lesions at three and six months after intervention, well beyond standard criteria utilized to distinguish between true disease and pseudoprogression. The results document efficacy of treatment, and illustrate the need for new tools for evaluation of pseudoprogression in CNS immunotherapy trials. Characteristics and factors predicting a robust response to treatment will be discussed, as well as important clinical findings in the responder population. Citation Format: David S. Baskin, Laura K. Aguilar, Lee A. Wheeler, Andrea G. Manzanera, Susan D. Bell, Robert Cavaliere, John M. McGregor, Simon S. Lo, John C. Grecula, Herbert B. Newton, Behnam Badie, Bin S. Teh, Edward Brian Butler, Todd W. Trask, Jana Portnow, Pamela Z. New, Estuardo Aguilar-Cordova, E. Antonio Chiocca. Phase II multicenter study of gene-mediated cytotoxic immunotherapy as an adjuvant to surgical resection for newly diagnosed malignant glioma: lessons learned from pseudo-progression and a nine-year survivor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT110.

The efficacy of adenovirus (ADV)-mediated gene therapy to treat brain tumors was tested in a syngeneic glioma model. Tumor cells were transduced in situ with a replication-defective ADV carrying the herpes simplex virus thymidine kinase (HSV-tk) gene controlled by the Rous sarcoma virus promoter. Expression of the HSV-tk gene enables the transduced cell to convert the drug ganciclovir to a form that is cytotoxic to dividing cells. Tumors were generated in Fischer 344 rats by stereotaxic implantation of 9L gliosarcoma cells into the caudate nucleus. Eight days later, the tumors were injected either with the ADV carrying the HSV-tk (ADV-tk) gene or a control ADV vector containing the β-galactosidase (ADV-βgal) gene and the rats were treated with either ganciclovir or saline. Tumor size was measured 20 days after implantation of 9L cells or at death. Rats treated with ADV-βgal and ganciclovir or with ADV-tk and saline had large tumors. No tumors were detected in animals treated with ADV-tk and with ganciclovir at doses ≥80mg/kg. An infiltrate of macrophages and lymphocytes at the injection site in animals treated with ADV-tk and ganciclovir indicated an active local immune reaction. In survival studies, all animals treated with ADV-tk and ganciclovir have remained alive longer than 80 and up to 120 days after tumor induction whereas all untreated animals died by 22 days. These results demonstrate that ADV-mediated transfer of HSV-tk to glioma cells in vivo confers sensitivity to ganciclovir, and represents a potential method of treatment of brain tumors. © 1994 Wiley-Liss, Inc.

Primary intracranial squamous cell carcinomas (SCCs) are rare and mostly associated with an intracranial epidermoid or dermoid cyst. Sarcomatoid carcinoma is a rare biphasic tumor composed of both carcinomatous and sarcomatous components and has not previously been reported as a primary intracranial tumor. Here, we present a case of a 60-year-old man with a primary intracranial sarcomatoid carcinoma, arising from the remnants of the previously resected epidermoid cyst in the cerebellopontine angle. The resected material had portions of an epidermoid cyst lined by normal and dysplastic squamous epithelia and invasive keratinizing SCC. This area was in continuity with areas of highly pleomorphic, anaplastic sarcomatoid cells. Brisk mitotic activity and extensive areas of necrosis were found. On immunohistochemical staining, the cells of the conventional SCC were positive for cytokeratin 5/6, pancytokeratin, epithelial membrane antigen, p63, and p53. The sarcomatoid cells were diffusely and strongly positive for vimentin, p53, smooth muscle actin, and, focally, muscle-specific actin. Occasional sarcomatoid cells coexpressed cytokeratin 5/6, pancytokeratin, p63, and S100 protein. The patient subsequently developed leptomeningeal spread and died 4 months after the second surgery. This rare entity expands the morphologic spectrum encountered in primary intracranial carcinoma.

The synthesis of 2,4-dichloro-5-(1-o-carboranylmethyl)-6-methylpyrimidine is described. Synthetically, this novel o-carboranyl pyrimidine is approached from ethyl 2-acetyl-4-pentynoate through alkylation of ethyl acetoacetate with propargyl bromide and subsequent condensation with thiourea to yield 6-methyl-5-(2-propynyl)-2-thio-4(1H,3H)-pyrimidinone. Hydrolysis of the 2-thione and chlorination with POCl 3 gives 2,4-dichloro-6-methyl-5-(2-propynyl)pyrimidine. Gentle refluxing of this product with B 10 H 14 /CH 3 CN in toluene yields the target, 2,4-dichloro-5-(1-o-carboranylmethyl)-6-methylpyrimidine, a potential synthon for a variety of 2,4-substituted 5-(1-o-carboranylmethyl)-6-methylpyrimidines and/or the corresponding nido-undecaborates

2010 Background: New therapies are desperately needed for malignant gliomas since aggressive standard of care (SOC) treatment with surgery, radiation, and temozolomide leads to median survival of l...

A patient sustained a cervical spine gunshot wound resulting in immediate quadriplegia and obstruction of both vertebral arteries. After an 8-hour delay, basilar artery thrombosis occurred and resulted in locked-in syndrome. Bilateral occlusion of the vertebral arteries after penetrating cervical trauma has not been reported previously. The incidence and treatment of traumatic basilar thrombosis and locked-in syndrome is reviewed. Rapid diagnosis of ascending thrombosis and prompt treatment with hyperdynamics and anticoagulation may improve outcome.

Transduction of experimental gliomas with the herpes simplex virus thymidine kinase gene (HSV-tk) using a replication-defective adenoviral vector (ADV/RSV-tk) confers sensitivity to ganciclovir (GCV) leading to tumor destruction and prolonged host survival in rodents. To determine treatment tolerance prior to clinical trials, we conducted toxicity studies in 6 adult baboons (Papio sp.). The animals received intracerebral injections of either a high dose of ADV/RSV-tk [1.5 x 10(9) plaque-forming units (pfu)] with or without GCV, or a low dose of ADV/RSV-tk (7.5 x 10(7) pfu) with GCV. The low dose corresponded to the anticipated therapeutic dose; the high dose was expected to be toxic. Magnetic resonance imaging (MRI) of the brain was obtained before treatment and at 3 and 6 weeks after treatment. Animals receiving the high-dose vector and GCV either died or became moribund and required euthanasia during the first 8 days of treatment. Necropsies revealed cavities of coagulative necrosis at the injection sites. Animals receiving only the high-dose vector were clinically normal; however, lesions were detected with MRI at the injection sites corresponding to cystic cavities at necropsy. Animals receiving the low-dose vector and GCV were clinically normal, exhibited small MRI abnormalities, and, although no gross lesions were present at necropsy, microscopic foci of necrosis were present. The vector sequence was detected by polymerase chain reaction (PCR) at the injection sites and in non-adjacent central nervous system tissue in all animals. Recombinant DNA sequence was detected outside of the nervous system in some animals, and persisted up to 6 weeks. The viral vector injections stimulated the production of neutralizing antibodies in the animals. No shedding of the vector was found in urine, feces, or serum 7 days after intracerebral injection. This study suggests that further investigations including clinical toxicity trials of this form of brain tumor therapy are warranted.