Bortezomib Is Effective in the Treatment of T Lymphoblastic Leukaemia by Inducing DNA Damage, WEE1 Downregulation, and Mitotic Catastrophe.

T lymphoblastic leukemia (T-ALL) is an aggressive haematolymphoid malignancy comprising 15% of acute lymphoblastic leukemia (ALL). Although its prognosis has improved with intensive chemotherapy, the relapse/refractory disease still carries a dismal prognosis. Thus, there is an urgent need to develop novel therapy for T-ALL. Bortezomib, a 26S proteasome inhibitor, is licensed to treat plasma cell myeloma and mantle cell lymphoma. Due to its favorable side effect profile, it is a novel agent of research interest in the treatment of ALL. Despite an increasing number of clinical trials of bortezomib in T-ALL, its detailed mechanistic study in terms of DNA damage, cell cycle, and mitotic catastrophe remains elusive. Moreover, WEE1, a protein kinase overexpressed in ALL and involved in cell-cycle regulation, has been known to be a novel therapeutic target in many cancers. But the role of bortezomib in modulating WEE1 expression in ALL still remains elusive. In this study, we demonstrate the therapeutic efficacy of bortezomib on T-ALL primary samples and cell lines. Our findings reveal that bortezomib treatment induces DNA damage and downregulates WEE1, leading to G2-M cell-cycle progression with damaged DNA. This abnormal mitotic entry induced by bortezomib leads to mitotic catastrophe in T-ALL. In conclusion, our findings dissect the mechanism of action of bortezomib and provide further insights into the use of bortezomib to treat T-ALL. Our findings suggest the possibility of novel combination therapy using proteasome inhibitors together with DNA-damaging agents in the future, which may fill the research gaps and unmet clinical needs in treating ALL.

Diagnostic radiation-induced regression of a metastatic primary intracranial germinoma: a case report.

Pineal region germinomas are sensitive to radiotherapy. Standard neurosurgical management involves obtaining a tissue biopsy and to relieve the often accompanying obstructive hydrocephalus. We present a patient with a suspected hyper-radiosensitive metastatic primary intracranial germinoma where computed tomography scanning resulted in tumor regression before radiotherapy could be administered.

"When the Benign Bleed" Vestibular Schwannomas with Clinically Significant Intratumoral Hemorrhage: A Case Series and Review of the Literature.

Vestibular schwannomas (VSs) are slow-growing benign neoplasms commonly located at the cerebellopontine angle. Although clinically significant hemorrhagic VSs are rarely encountered with only 75 patients previously reported, they could be life threatening. We discuss the presentation and outcomes of three patients with hemorrhagic VS as well as review the literature for this phenomenon. Consecutive adult patients with a histologically proven diagnosis of VS over a 9-year period were retrospectively reviewed. Fifty adult patients were identified with three (6%) having clinically significant intratumoral hemorrhage. This was defined as patients having acute to subacute symptoms with frank radiological evidence of hemorrhage. The mean age of diagnosis was 62 ± 9 years and the male-to female ratio was 2:1. The mean duration of symptoms, namely headache, vertigo, and sensorineural hearing impairment, was 26 ± 4 days with one patient presenting with acute coma. Retrosigmoid craniotomy for tumor resection was performed for all patients. Histopathological examination revealed extensive areas of microhemorrhage with considerable macrophage infiltration. All three patients were discharged with no additional neurological deficit and good functional performance. Clinically significant hemorrhagic VSs are rare, and patients may present with acute to subacute (i.e., within a month) symptoms of hearing loss headache, facial, or trigeminal nerve palsy. Macrophage infiltration is frequently encountered in tumor specimens and reflects the pivotal role of chronic inflammation in their pathophysiology. Surgical resection can lead to good outcomes with timely intervention.

Randomized, placebo-controlled, double-blind, pilot trial to investigate safety and efficacy of Cerebrolysin in patients with aneurysmal subarachnoid hemorrhage.

ASBTRACT: BACKGROUND: There are limited neuroprotective treatment options for patients with aneurysmal subarachnoid hemorrhage (SAH). Cerebrolysin, a brain-specific proposed pleiotropic neuroprotective agent, has been suggested to improve global functional outcomes in ischemic stroke. We investigated the efficacy, safety and feasibility of administering Cerebrolysin for SAH patients. METHODS: This was a prospective, randomized, double-blind, placebo-controlled, single-center, parallel-group pilot study. Fifty patients received either daily Cerebrolysin (30 ml/day) or a placebo (saline) for 14 days (25 patients per study group). The primary endpoint was a favorable Extended Glasgow Outcome Scale (GOSE) of 5 to 8 (moderate disability to good recovery) at six-months. Secondary endpoints included the modified Ranking Scale (mRS), the Montreal Cognitive Assessment (MOCA) score, occurrence of adverse effects and the occurrence of delayed cerebral ischemia (DCI). RESULTS: No severe adverse effects or mortality attributable to Cerebrolysin were observed. No significant difference was detected in the proportion of patients with favorable six-month GOSE in either study group (odds ratio (OR): 1.49; 95% confidence interval (CI): 0.43-5.17). Secondary functional outcome measures for favorable six-month recovery i.e. a mRS of 0 to 3 (OR: 3.45; 95% CI 0.79-15.01) were comparable for both groups. Similarly, there was no difference in MOCA neurocognitive performance (p-value: 0.75) and in the incidence of DCI (OR: 0.85 95% CI: 0.28-2.59). CONCLUSIONS: Use of Cerebrolysin in addition to standard-of-care management of aneurysmal SAH is safe, well tolerated and feasible. However, the neutral results of this trial suggest that it does not improve the six-month global functional performance of patients. CLINICAL TRIAL REGISTRATION: Name of Registry: ClinicalTrials.gov Trial Registration Number: NCT01787123 . Date of Registration: 8th February 2013.

Incidence, Presentation, and Risk Factors for Sodium Valproate-Associated Hyperammonemia in Neurosurgical Patients: A Prospective, Observational Study.

OBJECTIVE: Sodium valproate (VPA) is a commonly prescribed antiepileptic drug (AED) in daily neurosurgical practice. However, the incidence of VPA-associated hyperammonemia (VAH) and its life-threatening consequence, VPA-induced hyperammonemic encephalopathy (VHE), in neurosurgical patients is unknown. We determined the incidence, clinical presentation, and risk factors for VAH. METHODS: This prospective cohort study was performed on adult neurosurgical patients prescribed VPA for at least a week over a 22-month period. Blood tests for ammonia, VPA, and liver function were performed at the time of recruitment. The primary end point was VAH. Secondary end points were VHE and liver dysfunction. RESULTS: In total, 252 patients were recruited. The commonest disease etiology was brain tumors (27%, 69), followed by aneurysmal subarachnoid hemorrhage (SAH; 26%, 65). VPA was prescribed for primary seizure prophylaxis in 110 patients (44%). The mean daily dose was 1148 mg for a mean duration of 48 months. The mean serum VPA level was 417 µmol/L. In total, 92 patients (37%) were prescribed an additional AED, the most common being phenytoin (65%, 60/92). The mean serum ammonia level was 47 µmol/L. In total, 28% (71/252) of patients had VAH and only 0.7% had VHE. Independent factors were aneurysmal SAH (adjusted odds ratio [aOR] 2.1; 95% confidence interval [CI] 1.1-4.2), concomitant phenytoin (aOR 1.9; 95% CI 1.0-3.5), and phenobarbital (aOR 4.6; 95% CI 1.1-20.0). No associations with VPA dose, duration, serum levels, and liver function were observed. CONCLUSIONS: Although VAH is common among neurosurgical patients, VHE is rare. Patients with aneurysmal SAH or on concomitant enzyme-inducing AEDs are at risk. Clinicians should be vigilant for VHE symptoms in these patients.

Novel Wavelength-Specific Blue Light-Emitting Headlamp for 5-Aminolevulinic Acid Fluorescence-Guided Resection of Glioblastoma.

OBJECTIVE: Extent of resection of glioblastoma is an important predictor for overall survival, and 5-aminolevulinic acid fluorescence-guided surgery can improve outcomes. However, the technique requires the installation of a blue light module on operative microscopes and may be cost prohibitive. A novel and economical blue light-emitting headlamp was designed, and its clinical utility was explored. METHODS: A remote-controlled dual light emitting diode headlamp system was constructed with 1 diode emitting white light and the other blue. Spectrographic analysis of the blue light emitted from a commercial operative microscope and the headlamp was performed. A comparative evaluation of the 2 illumination systems was conducted for 3 patients who underwent craniotomy for glioblastoma resection. Histologic examination of the fluorescing tissue detected by the headlamp was performed, and the extent of resection was assessed by postoperative day 1 magnetic resonance imaging. RESULTS: Spectrography of blue light emitted from the headlamp system was wavelength specific with a single emission peak at 416 nm and a linewidth of 35 nm. In contrast, blue light from the microscope (peak: 426 nm) had a wider linewidth of 54 nm and was not wavelength specific with additional infrared radiation detected. Gross or near-total resection of contrast-enhancing glioblastoma was performed for all 3 patients. Intraoperatively, comparable tumor fluorescence was observed under microscope and headlamp blue light illumination. Histologic examination of tissue fluorescing under headlamp blue light confirmed the presence of glioblastoma. CONCLUSIONS: This novel proof-of-concept blue light-emitting headlamp device may offer an opportunity for institutions with limited resources to implement 5-aminolevulinic acid fluorescence-guided glioblastoma resections.

The "Negative" Impact of a Subgaleal Drain: Post-cranioplasty Negative Pressure Subgaleal Drain-induced Ascending Transtentorial Herniation.

One commonly practiced procedural step to reduce the risk of postoperative hematoma accumulation when performing cranioplasties is to place a closed negative-pressure subgaleal drain. We present a patient with sinking skin flap syndrome that underwent such a procedure and subsequently experienced immediate postoperative ascending transtentorial herniation and intracranial hemorrhage remote from the surgical site. On determining that the subgaleal drain was the responsible cause, it was immediate removed, and the patient had neurological recovery. Fewer than 30 cases of life-threatening subgaleal drain-related complications have been documented, and this is the first reported case of ascending herniation occurring after cranioplasty. This report illustrates the potential risks of subgaleal drainage, the importance of early recognition of this rare phenomenon and that intervention can be potentially life-saving.

A rare cause of sciatica discovered during digital rectal examination: case report of an intrapelvic sciatic notch schwannoma.

Intrapelvic sciatic nerve schwannomas are rare causes for non-discogenic sciatica. We describe a 44-year-old female who had a palpable mass on digital rectal examination that exhibited a positive Tinel's sign. The schwannoma was excised by a posterior transgluteal approach. Patients with negative spinal imaging should undergo pelvic scanning to rule out these tumors.

Curriculum design and attrition among undergraduate nursing students: A systematic review.

Attrition rates among nursing students are a global issue, and a possible factor in current nursing shortages. Numerous studies have been conducted to determine why students drop out of nursing programmes. The limitations of previous studies have included overly small sample sizes, being largely descriptive, and not focusing on attrition as an outcome. The aim of this study is to review the issue of attrition among undergraduate nursing students in relation to curriculum design. Five electronic databases, namely CINAHL, Medline, Cochrane Library, British Nursing Index, and PsycINFO, were adopted. Using the Population-Intervention-Comparison-Outcome model, search terms were identified, such as 'student nurse', 'undergraduate programme', 'curriculum design', and 'attrition'. Mixed Method Appraisal Tools were used to evaluate the methodological quality of the identified research papers. A total of 16 publications were reviewed and four themes were identified: pre-enrolment criteria for recruiting nursing students; curriculum content; clinical placement-related policies; and student support services. Institutional-level risk factors that could be reduced were identified, including academic failure, poor clinical performance, stress, and unrealistic expectations of nursing. This review gives insights into how a curriculum for undergraduate nursing programmes can be designed that will engage students and increase the nursing workforce.

A Giant Tumefactive Perivascular Space: A Rare Cause of Obstructive Hydrocephalus and Monoparesis.

Cerebral perivascular spaces (PVSs), otherwise known as Virchow-Robin spaces, are interstitial fluid-filled channels, <2 mm in diameter that form around arterial perforators as they course from the cortex into the brain parenchyma. In contrast, a giant tumefactive PVS is a rare entity comprising of clusters of such channels larger than 15mm resembling a neoplastic process as the name suggests. We report a 55-year-old male who presented with unsteady gait, cognitive decline, and left lower limb weakness for 6 months. Magnetic resonance imaging revealed a noncontrast enhancing multicystic intraaxial lesion of the right mesencephalon-diencephalon junction extending into the anterior third ventricle causing obstructive hydrocephalus. A ventriculoperitoneal shunt was inserted with a complete reversal of his neurological symptoms. Such PVSs can easily be misidentified for a cystic tumor, and their unique radiological features are discussed to prevent unnecessary surgery. We also demonstrate that when they cause hydrocephalus and midbrain compression symptoms cerebrospinal fluid shunting alone can result in excellent outcomes.

Pediatric Auditory Brainstem Implantation: Impact on Audiological Rehabilitation and Tonal Language Development.

OBJECTIVE: This is a retrospective review of the impact of an Auditory Brainstem Implant (ABI) on the audiological rehabilitation and tonal language development of pediatric patients with prelingual profound deafness in Hong Kong. RESULTS: From January 2009 to February 2015, 11 pediatric patients with profound prelingual deafness received an ABI in Hong Kong (age range 1.67-3.75 years). Etiologies included Cochlear Nerve Deficiency in 7, Severe Cochlear Malformations in 2, and Retrocochlear Deafness in 2. All of them were rehabilitated in Cantonese, a dialect of Chinese. Standard pediatric cochlear implant outcome measurements were used in this study that comprised of the 7-Sound Detection, Syllable Identification, Vowel Identification, Consonant Identification, Tone Imitation, Tone Production and Speech Perception Category. Audiological rehabilitation and speech development outcomes were reviewed. Age-matched outcomes of pediatric cochlear implant users were used for comparisons. CONCLUSION: Encouraging results of speech development were found, especially with continued use of the ABI. There was considerable variation in outcomes. Children with coexisting developmental and nonauditory cognitive disabilities did not perform as well. Auditory brainstem implantation is a safe and beneficial treatment for profound prelingual deafness in Cantonese-speaking pediatric patients.

Intraventricular urokinase to treat a blocked ventriculoperitoneal shunt in a glioblastoma patient with leptomeningeal spread.

Leptomeningeal spread and hydrocephalus are increasingly recognized as late disease complications of glioblastoma with almost a quarter of patients requiring early cerebrospinal fluid shunting. The neurosurgeon is challenged with maintaining shunt patency when tumor disease progression is rapid and adjuvant oncologic therapy has yet to be initiated. We describe our experience in treating a young female with diffuse glioblastoma leptomeningeal spread and communicating hydrocephalus who had several episodes of shunt obstruction due to intraluminal tumor cell-fibrin deposits. Regular intraventricular instillations of urokinase fibrinolytic therapy not only re-established shunt patency but also contributed to the resolution of her hydrocephalus.

Pendular Seesaw Nystagmus in a Patient With a Giant Pituitary Macroadenoma: Pathophysiology and the Role of the Accessory Optic System.

Seesaw nystagmus is characterized by cyclic eye movements with a conjugate torsional component and a dissociated vertical component. In the first half of the cycle, one eye elevates and intorts, whereas the other eye depresses and extorts. The pattern is reversed in the remaining half of the cycle. We describe a patient with a giant pituitary adenoma who developed pendular seesaw nystagmus. Disturbance in the visuovestibular system is postulated to contribute to this form of seesaw nystagmus. Lesions compressing the optic chiasm and the accessory optic system could interrupt the transmission of retinal error signals to the inferior olivary nucleus and the interstitial nucleus of Cajal, thus interfering with the adaptive mechanism of the vestibulo-ocular reflex and leading to pendular seesaw nystagmus.

Computed tomography interobserver agreement in the assessment of aneurysmal subarachnoid hemorrhage and predictors for clinical outcome.

BACKGROUND: The severity of aneurysmal subarachnoid hemorrhage (SAH) is often assessed by the clinical state of the patient on presentation, but radiological evaluation of the extent of hemorrhage has rarely been examined in the literature. Several CT scan based grading systems exist yet only a few studies have investigated interobserver agreement. We evaluated five radiological grading systems and assessed their clinical value for early prognostication. METHODOLOGY: This was a retrospective study of patients diagnosed with aneurysmal SAH with a CT scan performed within 72 hours of symptom onset. Four independent observers, blinded to patient outcome, evaluated each scan using the five grading systems. A separate assessor determined 6 month outcome from clinical records. The primary outcome was interobserver agreement for each grading system using the Fleiss κ statistic. The secondary endpoint was the 6 month modified Rankin Scale score, with poor outcome defined as a score of 4-6. RESULTS: 165 patients with a mean age of 59 years were assessed. Interobserver agreement for the Fisher, modified Fisher, Claassen, Barrow Neurological Institute, and Hijdra grading systems were as follows: k=0.53 (moderate), k=0.42 (moderate), k=0.38 (mild), k=0.20 (poor), and k=0.66 (good), respectively. The only independent clinical risk factor for poor outcome was a World Federation of Neurological Surgeons (WFNS) grade of 4 or 5 (adjusted OR 6.55; p<0.05). After adjusting for confounders, Fisher grade 4 (adjusted OR 17.84), modified Fisher grade 4 (adjusted OR 5.65), and Hijdra grade 3 (adjusted OR 3.34) were associated with poor outcome. Receiver operator characteristic analysis revealed that the Hijdra grading system (area under the curve=0.76) was more predictive of outcome compared with the Fisher and modified Fisher systems. A Hijdra cut-off score of 22 was associated with poor outcome (adjusted OR 5.92). CONCLUSIONS: The Hijdra grading system had the best interobserver agreement and was a better independent early predictor for 6 month clinical outcome than the other systems. A Hijdra score ≥22 was associated with poor outcome.

Moving the goalposts: A comparison of different definitions for primary external ventricular drain infection and its risk factors: A multi-center study of 2575 patients.

External ventricular drainage is the most common procedure performed in daily neurosurgical practice. One devastating complication is ventriculostomy-associated infection, but the establishment of evidence-based management guidelines has been hindered by the lack of an universal definition. There is also limited data with regard to the utility of comorbidity health indices and surgery-related factors in predicting infection. This study aims to compare the incidence of infection according to five commonly used definitions and to identify risk factors for this complication. 2575 patients from seven neurosurgical centers in Hong Kong underwent primary external ventricular drainage. The frequency of infection according to Gozal was 2.2% (n=57), 4.7% (Chi), 0.6% (Lozier), 0.8% (Lyke) and 2.8% (Scheithauer). The commonest pathogen was coagulase negative staphylococcus (39%) and 49% of all microbial isolates were multiple-drug resistant. The mean Charlson comorbidity index was 0.5±1.1. Using Gozal's definition as the primary endpoint, the index was not predictive of infection and no surgical risk factors were identified. The only significant risk factor was the performance of two or more additional neurosurgical procedures within 30days of catheterization (OR: 2.1, 95% CI 1.1-4.5). The rate of infection is relatively low, but considerable disparity exists depending on the definition used. Our data implies that patient factors, in particular the Charlson comorbidity index, and variations in surgical practice are less influential than the strict observance of infection control measures. The high incidence of antibiotic-resistant bacteria is concerning and the routine of exchange of catheters within 30days should be discouraged.

Single burr hole rigid endoscopic third ventriculostomy and endoscopic tumor biopsy: what is the safe displacement range for the foramen of Monro?

OBJECTIVE: To investigate the safe displacement range of the foramen of Monro (FM) during single burr hole rigid endoscopic third ventriculostomy (ETV) and endoscopic tumor biopsy (ETB). METHODS: Eleven patients who received ETV/ETB for third ventricular and pineal region tumor were reviewed. The burr-hole location, the size, and the virtual displacement of FM were measured using neuronavigation software. RESULTS: Hydrocephalus was resolved, and no subsequent cerebrospinal fluid (CSF) shunting was required in all cases. Histological diagnosis was established in 11 patients. Ten cases received instrumental cognitive and memory assessment postoperatively. The results were within the normal range for eight cases. The mean burr-hole location was 1.7 cm anterior to coronal suture and 3 cm from the midline. The mean diameters of FM measured on the axial, coronal, sagittal, and views were 5.7, 7.8, and 5.6 mm, respectively. The mean virtual displacements of the FM were 1.9±2.0 mm (range=0-4.8) for ETV and 2.4±2.1 mm (range=0-5.5) for ETB. The maximum displacements were 4.8 mm anteriorly for ETV and 5.5 mm posteriorly for ETB. CONCLUSION: Single burr hole rigid ETV/ETB is likely to be safe within maximum FM displacements of 4.8 mm anterior for ETV and 5.5 mm posterior for ETB. Preoperative trajectory planning using neuronavigation software is recommended.

The comparative impact of video consultation on emergency neurosurgical referrals.

OBJECTIVE: Neurosurgical resources are concentrated in tertiary referral centers, whereas emergencies identified from district general hospitals are traditionally referred by telephone consultation (TC). Recent advances in communication technology offer the alternative options of teleradiology (TR) and video consultation (VC). This study aimed to determine the differences among these three consultation methods on the basis of their process-of-care indicators, clinical outcomes, and cost-effectiveness. METHODS: Patients with emergency neurosurgical conditions (head injury, stroke, and miscellaneous) from a district general hospital were randomized to three different modes of consultation: TC, TR, or VC. Process-of-care indicators (postresuscitation Glasgow Coma Scale score, consultation time required, diagnostic accuracy, and transfer decision and safety), 6-month clinical outcome, and cost-effectiveness of the three consultation modes were correlated. RESULTS: In a 3-year period, 710 patients were recruited and randomized to the three consultation modes (n = 235, 239, and 236, respectively). Demographic and clinical data were comparable. TR and VC showed a definite advantage in diagnostic accuracy over TC (89.1 and 87.7% versus 63.8%; P < 0.001). However, duration of the corresponding consultation process was longer for TR and VC than TC (1.01 and 1.3 h versus 0.70 h). A high failure rate (30%) was noted in VC. Thirty-three percent of patients were transferred to the neurosurgical center after consultation. The difference in consultation modes did not have an impact on transfer rate and safety. There was a trend toward more favorable outcome (61%; P = 0.12) and a reduced mortality (25%; P = 0.025) in TR compared with TC (54 and 34%, respectively) and VC (54 and 33%, respectively). The mean cost per patient in the VC group was slightly higher than the other two groups (TC versus TR versus VC = 14,000 US dollars versus 14,400 US dollars versus 16,300 US dollars, respectively), but the differences were not statistically significant. CONCLUSION: Emergency neurosurgical consultation assisted by TR and VC achieved a higher diagnostic accuracy in comparison with conventional TC. Although VC did not show an advantage over TR in process-of-care indicators, clinical outcome, and cost, it has been proven to be a safe mode of consultation in emergency neurosurgery.