Remodeling of Metastatic Vasculature Reduces Lung Colonization and Sensitizes Overt Metastases to Immunotherapy.

Due to limited current therapies, metastases are the primary cause of mortality in cancer patients. Here, we employ a fusion compound of the cytokine LIGHT and a vascular targeting peptide (LIGHT-VTP) that homes to angiogenic blood vessels in primary tumors. We show in primary mouse lung cancer that normalization of tumor vasculature by LIGHT-VTP prevents cancer cell intravasation. Further, LIGHT-VTP efficiently targets pathological blood vessels in the pre-metastatic niche, reducing vascular hyper-permeability and extracellular matrix (ECM) deposition, thus blocking metastatic lung colonization. Moreover, we demonstrate that mouse and human metastatic melanoma deposits are targetable by VTP. In overt melanoma metastases, LIGHT-VTP normalizes intra-metastatic blood vessels and increases GrzB+ effector T cells. Successful treatment induces high endothelial venules (HEVs) and lymphocyte clusters, which sensitize refractory lung metastases to anti-PD-1 checkpoint inhibitors. These findings demonstrate an important application for LIGHT-VTP therapy in preventing metastatic development as well as exerting anti-tumor effects in established metastases.

Classification of foot drop gait characteristic due to lumbar radiculopathy using machine learning algorithms.

BACKGROUND: Recently, the study of walking gait has received significant attention due to the importance of identifying disorders relating to gait patterns. Characterisation and classification of different common gait disorders such as foot drop in an effective and accurate manner can lead to improved diagnosis, prognosis assessment, and treatment. However, currently visual inspection is the main clinical method to evaluate gait disorders, which is reliant on the subjectivity of the observer, leading to inaccuracies. RESEARCH QUESTION: This study examines if it is feasible to use commercial off-the-shelf Inertial measurement unit sensors and supervised learning methods to distinguish foot drop gait disorder from the normal walking gait pattern. METHOD: The gait data collected from 56 adults diagnosed with foot drop due to L5 lumbar radiculopathy (with MRI verified compressive pathology), and 30 adults with normal gait during multiple walking trials on a flat surface. Machine learning algorithms were applied to the inertial sensor data to investigate the feasibility of classifying foot drop disorder. RESULTS: The best three performing results were 88.45%, 86.87% and 86.08% accuracy derived from the Random Forest, SVM, and Naive Bayes classifiers respectively. After applying the wrapper feature selection technique, the top performance was from the Random Forest classifier with an overall accuracy of 93.18%. SIGNIFICANCE: It is demonstrated that the combination of inertial sensors and machine learning algorithms, provides a promising and feasible solution to differentiating L5 radiculopathy related foot drop from normal walking gait patterns. The implication of this finding is to provide an objective method to help clinical decision making.

Validation of foot pitch angle estimation using inertial measurement unit against marker-based optical 3D motion capture system.

Gait analysis is relevant to a broad range of clinical applications in areas of orthopedics, neurosurgery, rehabilitation and the sports medicine. There are various methods available for capturing and analyzing the gait cycle. Most of gait analysis methods are computationally expensive and difficult to implement outside the laboratory environment. Inertial measurement units, IMUs are considered a promising alternative for the future of gait analysis. This study reports the results of a systematic validation procedure to validate the foot pitch angle measurement captured by an IMU against Vicon Optical Motion Capture System, considered the standard method of gait analysis. It represents the first phase of a research project which aims to objectively evaluate the ankle function and gait patterns of patients with dorsiflexion weakness (commonly called a "drop foot") due to a L5 lumbar radiculopathy pre- and post-lumbar decompression surgery. The foot pitch angle of 381 gait cycles from 19 subjects walking trails on a flat surface have been recorded throughout the course of this study. Comparison of results indicates a mean correlation of 99.542% with a standard deviation of 0.834%. The maximum root mean square error of the foot pitch angle measured by the IMU compared with the Vicon Optical Motion Capture System was 3.738° and the maximum error in the same walking trail between two measurements was 9.927°. These results indicate the level of correlation between the two systems.

The application of inertial measurements unit for the clinical evaluation and assessment of gait events.

Foot drop is one of the common gait abnormalities which are difficult to detect, diagnose and evaluate. While various gait monitoring systems are available, many are computationally expensive and difficult to implement outside laboratory environments. This study introduces an in-house designed system based on inertial measurement units to capture the gait symptoms, specifically in the case of foot drop symptoms. The system specification and communication results, as well as filtering methods are discussed. Also, the pitch angle of thigh, shank and foot from a subject with no reported foot problem have been compared (gathered from identical equipment under similar conditions) to the same angle from a foot drop subject.

Autogenous skull flaps stored frozen for more than 6 months: do they remain viable?

Autogenous cranioplasties with cryopreserved skull flaps are associated with disproportionately high infection and bone resorption rates. Bone flap non-viability may be a contributing factor. Viable osteoblasts have been cultured recently from cryopreserved long bones. Cryopreserved skull bone may also remain viable based on histological observations. However, cell culture studies have not been performed on skull bone to assess viability. Bone explant cell cultures were performed on 27 skull flaps stored at -30 °C for more than 6 months. Biopsies were taken from the flaps, washed in phosphate buffer saline and cultured in Dulbecco's Modified Eagle's medium at 37 °C in 5% carbon dioxide for 3 weeks. Fresh skull bone samples served as controls. While control samples showed growth of osteoblasts, no osteoblasts were cultured from the study specimens at 3 weeks. In conclusion, skull flaps cryopreserved at -30 °C for more than 6 months are non-viable. Further research characterizing impact of different storage conditions on skull flap viability is warranted.

Bone flap storage following craniectomy: a survey of practices in major Australian neurosurgical centres.

INTRODUCTION: The resurgence of decompressive craniectomy surgeries for management of intracranial hypertension has led to a parallel increase in cranioplasty procedures for subsequent reconstruction of the resultant extensive skull defects. Most commonly, cranioplasties are performed using the patients' own cryopreserved skull flaps. Currently, there are no standardized guidelines for freeze-storage of bone flaps either nationally or internationally. In this initial study, the authors surveyed major neurosurgical centres throughout Australia to document current clinical practices. METHODOLOGY: Twenty-five neurosurgical centres affiliated with major public, teaching hospitals in all Australian states were included in the current survey study. A standardized survey guide incorporating standardized questions was used for data collection either by phone interviews and/or electronic (email) communication. Details regarding bone flap preparation following craniectomy, temperature and duration of freeze-storage, infection control/micro-contamination detection protocols, pre-implantation procedures were specifically recorded. RESULTS: Cranioplasty using cyropreserved autogenous bone flaps remains the most common (96%) mode of skull defect reconstruction in major neurosurgical centres throughout Australia. Following the initial craniotomy, the harvested skull flaps were most frequently (88%) double- or triple-bagged under dry, sterile conditions. In 16% of hospitals, skull flaps were irrigated either with antibiotic mixed-saline or Betadine prior to cryopreservation. Skull biopsies or swabs were obtained from the skull flaps for micro-contamination studies in accordance with departmental protocol in 68% of hospitals surveyed. Subsequently, the bone flaps were cryopreserved at wide ranging temperatures between -18°C to -83°C, for variable time intervals (6 months to 'until patient deceased'). Twelve neurosurgical centres (48%) elected for bone flap storage to be undertaken at the local bone bank. In the remainder (52%) of the hospitals, bone flaps were cryopreserved in locally maintained freezers. Prior to re-implantation of the skull flaps at subsequent cranioplasty surgeries, six (24%) of the neurosurgical centres had specific thawing procedures involving immersion of the frozen bone flaps in Ringer's solution and/or Betadine. Further pre-implantation bacteriological cultures from bone biopsies or swabs were obtained only in three (12%) hospitals. CONCLUSIONS: This study has documented highly varied skull flap cryopreservation and storage practices in neurosurgical centres throughout Australia. These differences may contribute to relatively high complication rates of infection and bone resorption reported in the literature. The results of the current study argue for the further need of high quality clinical and basic science research, which aims to characterize the effect of current skull flap management practices and freeze-storage conditions on the biological and biomechanical properties of skull bone.

A rare anatomical variation of the C7 pedicle and intraspinal course of the C7 nerve root.

We report a 58 year old man who presented with severe C7 radiculopathy which failed to respond to conservative measures. Subsequent CT and MR imaging of his cervical spine demonstrated C6/7 foraminal stenosis as well as unusual low take-off of the C7 nerve root in relation to a congenital low-set C7 pedicle, findings which were subsequently confirmed intra-operatively. The relevance of the bony and neural anatomy is described and its implications for surgical management are discussed. To our knowledge, this anatomical anomaly has not been previously highlighted in the published English literature.

Leptomeningeal carcinomatosis: an unusual cause of sudden onset bilateral sensorineural hearing loss.

We report a 66-year-old woman who developed sudden-onset bilateral sensorineural deafness due to leptomeningeal carcinomatosis involving the vestibulocochlear nerves. The clinical and diagnostic features of leptomeningeal carcinomatosis are discussed.

Spinal cord ganglioglioma presenting as acute paraparesis.

A 17-year-old male presented with acute onset paraparesis in the lower limbs. Urinary retention was present and the patient required catheterisation. Clinical examination confirmed severe bilateral lower limb weakness and a sensory level at T8. Magnetic resonance imaging (MRI) revealed a haemorrhagic intramedullary tumour extending from T8 to the conus. Microsurgical excision of the tumour was performed and the patient made a good functional recovery. The histology of the tumour demonstrated a ganglioglioma of the spinal cord. Acute paraparesis has not previously been reported with a spinal cord ganglioglioma. We discuss the clinical, diagnostic and pathological features of spinal cord gangliogliomas.

Origin of macrophages in a kaolin-induced model of rat syringomyelia: a study using radiation bone marrow chimeras.

STUDY DESIGN: Animal experimental study. OBJECTIVE: To study the origin of macrophages in a rat model of syringomyelia. SUMMARY OF BACKGROUND DATA: Syringomyelia is a clinically important condition in which a cystic cavity forms within the spinal cord. This leads to significant delayed neurologic deterioration, which may be manifested as weakness, numbness, or pain. The pathophysiology and mechanism of syrinx formation remain unclear. Human autopsy findings have demonstrated a prominent accumulation of macrophages in relation to the syrinx. Similar observations have also been made in a previously established rat model of syringomyelia. Little is known about the origin and precise functions of these cells. METHODS: Syrinx formation was induced by intraparenchymal injections of kaolin within the cervical spinal cords of 30 DA rat (RT7.1) radiation bone marrow chimeras reconstituted with bone marrow from RT7.2 congeneic donors. The distribution of macrophages was evaluated at survival times of 3 days, 1 week, and 4 weeks. Immunostaining of fresh-frozen spinal cord tissue was performed using specific antibodies against rat macrophage ED1 antigen and RT7.2 allele of CD45. This allowed donor-derived hematogenous (ED1+, RT7.2+) macrophages to be distinguished from native cells (ED1+, RT7.2-). RESULTS: Central canal dilatation was seen from 1 week. This was associated with extensive accumulation of ED1+ macrophages within the spinal cord parenchyma. A large influx of bone marrow-derived (ED1+, RT7.2+) macrophages was observed. However, a considerable proportion of resident microglia (RT7.2-) also upregulated ED1. These activated microglia demonstrated distinct morphologic features. CONCLUSIONS: Large numbers of macrophages were recruited from the bone marrow in kaolin-induced rat syringomyelia. However, a significant number of resident microglia upregulated their ED1 activity and appear to provide a substantial source of macrophages.

Suprapineal recess: an alternate site for third ventriculostomy? Case report.

This 30-year-old woman presented with clinical symptoms and signs of intracranial hypertension and Parinaud syndrome secondary to ventriculoperitoneal shunt dysfunction. Magnetic resonance (MR) imaging revealed gross triventricular hydrocephalus with a large suprapineal recess due to aqueductal stenosis. Using an endoscopic approach, a ventriculostomy was performed within the floor of the dilated suprapineal recess. Following this procedure the patient experienced alleviation of all her neurological symptoms and signs. Postoperative MR imaging and cerebrospinal fluid flow studies demonstrated a functioning ventriculostomy. The anatomy of the suprapineal recess and its suitability for endoscopic ventriculostomy are discussed.

Prolonged and severe dysphagia following anterior cervical surgery.

While mild swallowing difficulties are commonly reported transiently following anterior cervical surgery, marked dysphagia is unusual. The authors report a patient who experienced severe and prolonged dysphagia following elective cervical corpectomies with iliac grafting and anterior plate fusion for multilevel cervical canal stenosis. The literature is reviewed and discussed.

'Ecstasy'-induced subarachnoid haemorrhage: an under-reported neurological complication?

In the face of escalating recreational use of 'Ecstasy' (3,4-methylenedioxymethamphetamine, MDMA), physicians need to be aware of its possible adverse effects. We report two young patients who suffered subarachnoid haemorrhage following ingestion of 'Ecstasy' tablets. Angiographic studies demonstrated features consistent with vasculitis in both cases. Recognition of this association is important and highlights the significance of eliciting a careful drug history, particularly in cases of 'angiogram negative' subarachnoid haemorrhage.

Functioning paraganglioma of the thoracic spine: case report.

OBJECTIVE AND IMPORTANCE: Paragangliomas of the thoracic spine are rare. Previously described cases involved nonfunctioning tumors. This report documents the diagnosis and surgical treatment for a patient who presented with a functioning thoracic paraganglioma. CLINICAL PRESENTATION: A 53-year-old woman presented with a 10-month history of headaches, facial flushing, and palpitations associated with hypertension. Urinary catecholamine levels were markedly elevated. Magnetic resonance imaging and m-[(123)I]iodobenzylguanidine scans demonstrated an extradural tumor located within the T12 vertebra, with a significant paraspinal component. The neurological examination revealed mild hypesthesia in the right T12 dermatome. INTERVENTION: The patient underwent resection of the tumor after alpha-adrenergic receptor blockade. Grossly complete excision was achieved without neurological complications. Postoperatively, the patient was normotensive and exhibited catecholamine levels within the normal range. CONCLUSION: Functioning paragangliomas of the thoracic spine are rare lesions that are difficult to treat. Successful treatment requires careful surgical planning and expert pharmacological manipulation.

Ventriculoperitoneal shunt failure as a secondary complication of ovarian hyperstimulation syndrome. Case report.

The authors report on a patient who presented with shunt failure due to ovarian hyperstimulation syndrome (OHSS) following in vitro fertilization treatment. Shunt dysfunction was attributed to intraabdominal hypertension as a consequence of ascites. At surgery, the shunt was found to be patent. The peritoneal catheter was externalized and subsequently revised to become a ventriculoatrial shunt system. This led to clinical improvement in the patient and restoration of ventricular size. Such a shunt complication has not previously been reported. Neurosurgeons should be alerted to this possibility in view of the increasing use of assisted conception in many developed countries.