Nanocell-mediated delivery of miR-34a counteracts temozolomide resistance in glioblastoma.

BACKGROUND: Glioblastoma is the most common primary brain tumor and remains uniformly fatal, highlighting the dire need for developing effective therapeutics. Significant intra- and inter-tumor heterogeneity and inadequate delivery of therapeutics across blood-brain barrier continue to be significant impediments towards developing therapies which can significantly enhance survival. We hypothesize that microRNAs have the potential to serve as effective therapeutics for glioblastoma as they modulate the activity of multiple signaling pathways, and hence can counteract heterogeneity if successfully delivered. METHODS: Using a computational approach, we identified microRNA-34a as a microRNA that maximally reduces the activation status of the three core signaling networks (the receptor tyrosine kinase, p53 and Rb networks) that have been found to be deregulated in most glioblastoma tumors. Glioblastoma cultures were transfected with microRNA-34a or control microRNA to assess biological function and therapeutic potential in vitro. Nanocells were derived from genetically modified bacteria and loaded with microRNA-34a for intravenous administration to orthotopic patient-derived glioblastoma xenografts in mice. RESULTS: Overexpression of microRNA-34a strongly reduced the activation status of the three core signaling networks. microRNA-34a transfection also inhibited the survival of multiple established glioblastoma cell lines, as well as primary patient-derived xenograft cultures representing the proneural, mesenchymal and classical subtypes. Transfection of microRNA-34a enhanced temozolomide (TMZ) response in in vitro cultures of glioblastoma cells with primary TMZ sensitivity, primary TMZ resistance and acquired TMZ resistance. Mechanistically, microRNA-34a downregulated multiple therapeutic resistance genes which are associated with worse survival in glioblastoma patients and are enriched in specific tumor spatial compartments. Importantly, intravenous administration of nanocells carrying miR-34a and targeted to epidermal growth factor receptor (EGFR) strongly enhanced TMZ sensitivity in an orthotopic patient-derived xenograft mouse model of glioblastoma. CONCLUSIONS: Targeted bacterially-derived nanocells are an effective vehicle for the delivery of microRNA-34a to glioblastoma tumors. microRNA-34a inhibits survival and strongly sensitizes a wide range of glioblastoma cell cultures to TMZ, suggesting that combination therapy of TMZ with microRNA-34a loaded nanocells may serve as a novel therapeutic approach for the treatment of glioblastoma tumors.

Paediatric traumatic brain injury: Presentation, prognostic indicators and Outcome analysis from a tertiary care center in a developing country.

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in children worldwide. This study was conducted to report the presentation, management, outcomes and prognostic indicators in a large series of patients from a tertiary care centre in a developing country. It is a review of prospectively collected data of paediatric patients with TBI admitted at our centre between July 2010 and December 2013. A total of 291 patients with a mean age of 7.2±5.0 years were dichotomised into survivors and non-survivors, and variables were compared between the two groups. The mean post-resuscitation Glasgow coma scale (GCS) score was 11.6±3.9, mean Marshall Score was 2.26±0.95 and the mean revised trauma score at presentation was 10.58±1.7. Younger age, lower GCS score after resuscitation, lower revised trauma score, absent cisterns on imaging, associated subarachnoid haemorrhage (SAH) and intraventricular haemorrhage (IVH) and a lower Marshall score were associated with higher mortality.

Conservative management of significant supratentorial epidural hematomas in pediatric patients.

BACKGROUND: Radiologically significant epidural hematomas are generally treated with craniotomy and evacuation. However, pediatric patients with such hematomas may have normal neurological examinations. We aim to report the presenting features, management, and outcomes of pediatric patients who underwent conservative management of such hematomas at our center and also show that serial neurological examinations are a safe and effective way of managing these patients. METHODS: A retrospective review of pediatric patients with extradural hematoma (EDH) thickness of at least 1 cm and who were conservatively managed was performed. All patients were followed up in neurosurgery outpatient clinics after discharge at 1-month, 3-month, 6-month, and 1-year intervals. Detailed neurological examination was performed at each visit, and a standardized questionnaire was also used to document the parent's subjective opinion of the patient's quality of life. RESULTS: A total of 17 patients satisfied the study criteria and were included. Conservative management was successful in 15 patients, while a craniotomy with evacuation of hematoma had to be performed in two patients. All patients had a GOS score of 5 on 1-year follow-up, had normal schooling, and reported complete satisfaction with the management protocol. CONCLUSION: Conservative treatment is an optimal treatment option, and patients can be followed safely using a protocol of serial neurological examinations. A center must have resources to perform a craniotomy with evacuation of EDH in case of neurological worsening and be able to provide trained staff to carry out serial neurological examinations before treating these patients conservatively.

Continuous Intrathecal Medication Delivery With the IRRA flow Catheter: Pearls and Early Experience.

BACKGROUND AND OBJECTIVES: Intrathecal (IT) medications are routinely introduced through catheterization of the intraventricular space or subarachnoid space. There has been sporadic use of IT medications delivered directly to the ventricle either by intermittent injection through an external ventricular drain (EVD) or by an Ommaya reservoir with a ventricular catheter. IT medication delivery through EVD has many drawbacks, including the necessary opening of a sterile system, delivery of medication in a bolus form, and requirements to clamp the EVD after medication delivery. Despite these setbacks, IT medications delivered through EVD have been used across a wide range of applications, including antibiotic delivery treatment of vasospasm with nicardipine and delivery of tissue plasminogen activator. METHODS: We used a newly developed active fluid exchange device to treat various severe conditions involved in the cerebral ventricles. Here, we present our treatment protocols and advice on the techniques related to successful active fluid exchange therapy. RESULTS: Seventy patients have been treated with our system with various conditions, including subarachnoid hemorrhage, intraventricular hemorrhage, ventriculitis, and cerebral abscess. Total complication rate was 14% with only 1 catheter occlusion and low rates of hemorrhage, infection, and spinal fluid leak. CONCLUSION: Current continuous IT medication dosages and protocols are based on reports and consensus statements evaluating intermittent instillation of medication boluses. The pharmacokinetics of continuous dosing and the therapeutic and safety profiles of the medications need to be studied in a prospective manner to evaluate the true optimal dosing standards. Furthermore, the ability to deliver continuous, sterile medications directly through an IT route will open new avenues of pharmacotherapy that were previously closed. This report serves as a basic guide for the safe and effective use of the IRRA flow active fluid exchange catheter to deliver IT medications.

Outpatient Deep Brain Stimulation Surgery Is a Safe Alternative to Inpatient Admission.

BACKGROUND: Deep brain stimulation (DBS) is usually performed as an inpatient procedure. The COVID-19 pandemic effected a practice change at our institution with outpatient DBS performed because of limited inpatient and surgical resources. Although this alleviated use of hospital resources, the comparative safety of outpatient DBS surgery is unclear. OBJECTIVE: To compare the safety and incidence of early postoperative complications in patients undergoing DBS procedures in the outpatient vs inpatient setting. METHODS: We retrospectively reviewed all outpatient and inpatient DBS procedures performed by a single surgeon between January 2018 and November 2022. The main outcome measures used for comparison between the 2 groups were total complications, length of stay, rate of postoperative infection, postoperative hemorrhage rate, 30-day emergency department (ED) visits and readmissions, and IV antihypertensive requirement. RESULTS: A total of 44 outpatient DBS surgeries were compared with 70 inpatient DBS surgeries. The outpatient DBS cohort had a shorter mean postoperative stay (4.19 vs 39.59 hours, P = .0015), lower total complication rate (2.3% vs 12.8%, P = .1457), and lower wound infection rate (0% vs 2.9%, P = .52) compared with the inpatient cohort, but the difference in complications was not statistically significant. In the 30-day follow-up period, ED visits were similar between the cohorts (6.8% vs 7.1%, P = .735), but no outpatient DBS patient required readmission, whereas all inpatient DBS patients visiting the ED were readmitted ( P = .155). CONCLUSION: Our study demonstrates that DBS can be safely performed on an outpatient basis with same-day hospital discharge and close continuous monitoring.

An Early Presentation Of Supraglottic Laryngeal Paraganglioma: Case Report And Review Of Literature.

A thirty-year-old male presented with progressive hoarseness and dysphagia for solids. Fibre optic laryngoscopy showed a right supraglottic mass. Subsequent CT imaging showed the location and extent of the mass. Biopsy revealed a Paraganglioma with cytokeratin negative and chromogranin positive cells. The mass was subsequently removed without complications. Follow up also showed no complications. Hoarseness and dysphagia resolved following tumour excision.

Primary Hydatid Disease Of Chest Wall.

Hydatid disease-a parasitic medical condition caused by echinococcus, is one of the oldest diseases known to mankind. Primary hydatid disease of the chest wall is very rare and only nine cases have been reported so far in the literature. This study presents a case of primary hydatid chest wall in a patient with right infraclavicular swelling that increased in size suddenly. A 35 year-old lady presented to the Surgical Unit of Khyber Teaching Hospital with a two and a half year history of right infraclavicular chest wall lump which increased in size abruptly Upon investigation the Computed tomographic (CT) scan of the chest showed a complex multiseptated hypodense lesion in the right pectoralis muscle with no involvement of underlying clavicle or rib. She was booked for exploration under general anaesthesia electively. The lump revealed multiple daughter cysts with the characteristics of germinal layers and ecto cysts of hydatid cysts. The patient had a stable recovery in the postoperative period and was sent home on medical treatment. On follow up she was fine; the wound had healed and there was no swelling in the surgical site. Primary hydatid disease of the chest wall is a very rare disease, so this case is a piece of good evidence to consider hydatid cyst in the differential diagnosis of any cystic mass in any part of the body, especially in endemic areas. Radical peri-cystectomy followed by chemotherapy with albendazole is all that is needed for the treatment.

Dermatological disorders related to cultural practices in black Africans of Sierra Leone.

OBJECTIVE: To describe various skin manifestations directly or indirectly related to the prevalent cultural practices in the local community of black Africans of Sierra Leone. STUDY DESIGN: An observational study. PLACE AND DURATION OF THE STUDY: Eastern province (Kenema) of Sierra Leone from November 2004 to October 2005. PATIENTS AND METHODS: Local black patients of all age groups presenting in Dermatology Outpatient Department of Pak Field Hospital (established as a part of UN peacekeeping mission in Sierra Leone) were included. After clinical history and physical examination, lesions were photographed. Laboratory investigations were carried out when indicated. Skin diseases were broadly classified into two major categories i.e. related to cultural practices and not related to cultural practices. Non-black settlers in the area and UN troops were excluded. Data was recorded and analyzed by Microsoft Excel. RESULTS: A total of 3011 patients belonging to different local tribes having a variety of skin disorders were seen during the study period. Patients ranged from 1 month to 73 years of age with almost equal gender ratio. Vast majority were from very low socioeconomic group. Skin manifestations related to cultural practices were seen in more than 20% patients and most prevalent were alopecia and hypertrophic scars followed by pomade acne, pseudofolliculitis and contact dermatitis. CONCLUSION: Prevalent cultural practices in black Africans do play a role in causation of various skin disorders. For a dermatologist, it becomes imperative to be cognizant of the signs and symptoms associated with these practices for proper diagnosis and appropriate treatment.

Endoscopic third ventriculostomy for obstructive hydrocephalus: Outcome analysis of 120 consecutively treated patients from a developing country.

OBJECTIVES: Endoscopic third ventriculostomy (ETV) for the treatment of obstructive hydrocephalus is a relatively new concept amongst neurosurgeons of the developing world. Therefore, this study was conducted to report our experience, patient selection, success rates and complications of ETV and compare our results with the literature from the developed countries. METHODS: We performed ETV on 120 patients at our centre and prospectively collected their clinical data on pre designed questionnaires. Success was defined as clinical improvement on 3rd month post operative clinic visit. The data was analyzed using SPSS version 20. RESULTS: There were 79 male and 41 female patients. The mean age was 36.1 ± 14.3 years. Overall, ETV was successful in 107 (89.2%) of patients. 4 patients had intra operative bleeding, 4 patients developed CSF leaks while 1 patient had a transient gaze palsy. There was no mortality. CONCLUSION: ETV is a very effective treatment modality for treating obstructive hydrocephalus in well selected patients and can be successfully practiced by neurosurgeons in the developing countries.

Estimating national road crash fatalities using aggregate data.

Injuries and fatalities from road traffic crashes have emerged a major public health challenge in Pakistan. Reliable estimates of road crash fatalities (RCF) of a country, is a vital element needed for identification and control of key risk factors, road-safety improvement efforts and prioritizing national health. Reliability of current annual RCF estimates for Pakistan becomes highly questionable due to serious underreporting. This study aimed to predict annual RCF for Pakistan using data from World Health Organization and International Road Federation sources. An ordinary least square (OLS) regression model that relates fatality rate with different explanatory variables was developed. RCF were predicted for Pakistan for year 2012 and 2013, and results were compared with national police reported estimates. Study results indicated that there is serious underreporting of RCF in Pakistan and immediate measures are needed to improve the existing road crash recording and reporting system at the national and subnational levels.

Prevalence of Post-Traumatic Stress Disorder Due to Community Violence Among University Students in the World's Most Dangerous Megacity: A Cross-Sectional Study From Pakistan.

Community violence among the youth can lead to a number of adverse psychiatric outcomes including post-traumatic stress disorder (PTSD). However, little research has been conducted in non-Western countries to assess this problem. This study aims to fill the void by assessing the lifetime exposure to traumatic events and burden of probable PTSD among university students in Karachi, Pakistan. A cross-sectional study was conducted at four private institutions in Karachi. Self-administered questionnaires were filled out by 320 students. Lifetime exposure and symptoms of PTSD were assessed using modified Composite International Diagnostic Interview (CIDI) and Post-Traumatic Stress Disorder Checklist-Civilian Version (PCL-C) questionnaires, respectively. A PCL-C score of 44 or above was used as cutoff for probable PTSD. Pearson chi-square test was used to assess the association between PTSD and different variables at a level of significance of 5%. Ninety-three percent of the respondents reported having lifetime exposure to at least one traumatic event with sudden unexpected death of a loved one (n = 187) and assaultive violence (n = 169) being the commonest reported traumatic events. Positive association for PTSD was seen with enduring physical attacks and motor vehicle accidents. Over a quarter of the students screened positive for probable PTSD, among them almost one third were male and 17% were female. Our results indicate a high exposure to violent events and elevated rates of lifetime PTSD among urban youth. Reduction in violence and better access to mental health facilities is warranted to decrease the health burden of PTSD in Pakistan.

Multiple cerebral hydatid cysts in 8-year-old boy: A case report and literature review of a rare presentation.

BACKGROUND: Multiple cerebral hydatid cysts are very rare with only a few reports in the literature detailing diagnostic workup, medical management, surgical techniques, possible complications, and outcomes. CASE DESCRIPTION: We present the case of an 8-year-old boy who presented with progressively worsening headaches, vomiting, and intermittent fever since 20 days. Diagnostic workup was performed, and magnetic resonance imaging revealed multiple intracranial cysts predominantly in the right frontal region with significant mass effect. A total of 19 intracranial cysts were removed surgically, and the child recovered uneventfully. CONCLUSIONS: Neurosurgeons should keep hydatidosis in the list of differentials when evaluating patients with cystic diseases of the brain. Although the removal of such cysts is challenging, outcomes are excellent when cysts are evacuated without rupture and patients show complete resolution of symptoms.

Enduring improvement in Oswestry Disability Index outcomes following lumbar microscopic interlaminar decompression: An appraisal of prospectively collected patient outcomes.

OBJECTIVES: Our present study aims to assess the short and long-term postoperative outcome of microscopic interlaminar decompression from a neurosurgical center in a developing country and also aims to further determine any predictors of functional outcome. MATERIALS AND METHODS: All patients with moderate to severe symptomatic stenosis undergoing elective posterior lumbar spinal decompression were prospectively enrolled in a database. Preoperative, 2 weeks and 2 years postoperative Oswestry Disability Index (ODI) scores were determined for all patients. These scores were retrospectively compared using repeated measures analysis of variance. Further, linear regression modelling was applied to determine the effect of preoperative ODI, body mass index, age, prior physiotherapy, duration of symptoms, and single or multiple level decompression on the change in ODI at 2 weeks and 2 years follow-up respectively. RESULTS: A total of 60 consecutive patients (40 males, 20 females) were included for statistical analysis. The percentage of patients with a minimum clinically important difference (MCID), using an ODI threshold value of 10, was 86.7% (n = 52) at the 2 weeks postoperative follow-up. At the 2 years follow-up assessment, 3.3% (n = 2) patients who had earlier not achieved MCID did so, 78.3% (n = 47) of patients were found to have a change in ODI score of <10 or no change, while 18.3% (n = 11) reported a deterioration in their ODI scores. The preoperative ODI score was an independent predictor of change in ODI score at 2 weeks and 2 years respectively (P < 0.0005). The duration of symptoms prior to surgery was found to predict the change in ODI at 2 years follow-up (P = 0.04). CONCLUSION: The evidence regarding the long-term and short-term efficacy of microscopic interlaminar decompression in symptomatic lumbar stenosis is overwhelming. Preoperative ODI scores and duration of symptoms prior to surgery can predict postoperative outcomes.

Dhaga Technique for Tissue Plane Preservation after Decompressive Craniectomy: Comparison of New Technique with Institutional Standard.

BACKGROUND: During cranioplasty after decompressive craniectomy, the temporalis muscle is firmly attached to the dural patch and intermixed with fibrotic tissue leading to considerable difficulty in dissecting the plane between the dura, galea and the temporalis muscle. This leads to increased surgical time, intraoperative blood loss, risk of complications and also affects rehabilitation. We have developed the "dhaga technique," which aids in preserving the plane between the muscle and dura in order to improve outcomes. Here we describe our technique and also compare the "dhaga technique" with the generally accepted standard procedure. METHODS: A retrospective review was carried out of all patients undergoing cranioplasty following decompressive craniectomy either through the "dhaga technique" or the institutional standard (control group). Both techniques were compared using intra operative blood loss, duration of surgery and any complications as study variables. RESULTS: There were 133 patients were included in the study. The control group included 68 patients who underwent the procedure according to institutional standard, and 65 patients were included in the "dhaga technique group." Both groups were well matched for baseline characteristics. Patients in the "dhaga technique" group had statistically significant lower operating time (P value = 0.037) and intra operative blood loss (P value = 0.025). However, there was no significant difference in complications. CONCLUSION: The utilization of "dhaga technique" can potentially improve outcomes and reduce costs by decreasing operative time and blood loss. Moreover, the temporalis muscle preservation in the "dhaga technique" may also enhance aesthetic outcomes and chewing, which were not assessed in this study. There were no differences in complication between the two techniques.

Is surgical spinal decompression for supratentorial GBM symptomatic drop down metastasis warranted? A case report and review of literature.

BACKGROUND: Symptomatic spinal metastasis from an intracranial primary glioblastoma multiforme (GBM) is very rare. Our literature search identified a total of 42 such patients of which 11 were treated with surgical decompression for spinal metastasis with only one such report from the pediatric age group. Previous studies have reported variable outcomes after surgical management. CASE DESCRIPTION: We report the case of a 16-year-old boy who underwent surgical spinal decompression for spinal metastasis after intracranial GBM. The patient regained motor and autonomic function following surgery and reported improvement in pain. We also present findings from a literature review using the PubMed database from 1985 to June 2013 on this subject and compare radiation therapy with surgical decompression as palliative modalities in such patients. CONCLUSION: There are no evidence-based guidelines available on the subject and no treatment regimen has yet demonstrated survival benefit in these patients. Surgical decompression may be a better option for patients with focal resectable lesions and who are medically stable to tolerate the procedure.

Thoracic and lumbar spinal surgery under local anesthesia for patients with multiple comorbidities: A consecutive case series.

BACKGROUND: Although some patients with symptomatic spinal disease may benefit greatly from surgery, their multiple attendant comorbidities may make general anesthesia risky or contraindicated. However, there is scarce literature describing the efficacy and safety of local anesthesia to perform these operations. Here we report seven patients who successfully underwent spinal surgery utilizing local anesthesia to limit the risks and complications of general anesthesia. METHODS: Seven patients for whom general anesthesia was contraindicated were prospectively followed for a minimum of 3 months following spinal surgery performed under local anesthesia. Pain and functional improvement were assessed utilizing the Visual Analog Scores (VAS) and Oswestry Disability Index (ODI) scores. RESULTS: Five patients had interlaminar decompressions for stenosis alone, while two patients had laminectomies for debulking of tumors. The mean duration of surgery was 79.8 ± 16.6 min, the mean estimated blood loss was 157.1 ± 53.4 ml, the mean dose of local anesthetic was 1.9 ± 0.7 mg/kg, and the mean length of hospital stay after surgery was 3.2 ± 1.2 days. There were no intraoperative complications. The surgery resulted in improved VAS and ODI scores consistent with significant improvement in pain (P = 0.017) and functionality (P = 0.011). CONCLUSIONS: Performing spinal surgery under local anesthesia is a safe and effective alternative when patient's major comorbidities preclude a general anesthetic. For all the seven patients studied, spinal surgery, performed under a local anesthetic, resulted in a statistically significant reduction in pain and improvement in function.

Civilian craniocerebral gunshot injuries in a developing country: presentation, injury characteristics, prognostic indicators, and complications.

BACKGROUND: Civilian craniocerebral gunshot injuries (CGIs) are rare but increasing in incidence in the developing world and there is scare literature on presentation, injury characteristics, prognostic indicators, and complications of brain trauma due to projectiles. METHODS: A retrospective review of 51 civilian patients with CGI who presented to the Aga Khan University Hospital between 1998 and 2011 was carried out. Presentation, injury characteristics, and complications were analyzed with emphasis on outcomes and prognostic indicators. RESULTS: There were 43 male and 8 female patients with an average age of 28.92 (±12.33) years. Twenty-three patients had a Glasgow Coma Scale (GCS) score of 13-15, 6 patients had a GCS score of 9-12, and 22 patients had a GCS score of 3-8 on admission. The overall mortality rate was 22% (n = 11). The most common postoperative neurologic deficits were motor deficits (19 patients) followed by aphasias (11 patients). On univariate analysis, admission GCS score and bi- or multilobar injuries were found to be highly predictive of neurologic outcome. There was no difference in outcomes between penetrating and perforating injuries. We also failed to find a statistically significant correlation between ventricular injury and outcomes in our patients. CONCLUSION: Admission GCS and number of lobes involved are highly prognostic of outcome. Patients with a GCS score ≥9 and unilobar injury on computed tomographic scans may benefit the most from surgical management.

Surgical management of traumatic extra dural hematoma in children: Experiences and analysis from 24 consecutively treated patients in a developing country.

BACKGROUND: Children with epidural hematoma (EDH) present differently than adults. The outcome of treatment is also different. We aim to report our experiences with EDH in pediatric age group in terms of mode of injury, presenting features, management, and outcomes. We also aim to identify different prognostic indicators in pediatric patients with EDH. METHODS: We prospectively collected data from 24 consecutively surgically treated pediatric patients. The data collected included presenting features, radiological imaging, details of management, and outcomes. Descriptive analysis was performed and different variables were tested for any statistical significance with Glasgow Outcome Score (GOS). RESULTS: There were 19 male and 5 female patients. The mean Glasgow Coma Scale (GCS) score at presentation was 9.3 ± 4.4. Falls were the most common cause of EDH. Outcome assessment was done at 3 month follow up. A total of 15 patients had a GOS score of 5, 4 patients had a GOS score of 4, 2 patients had a GOS score of 3, while 3 patients had a GOS score of 1. On univariate analysis, admitting GCS score, patient's age, the time from injury to admission and injury to surgery, anisocoric pupils at presentation and effacement of basal cisterns were significantly associated with the outcome of GOS score. CONCLUSION: Falls are the most common mode of injury leading to EDH in children. Lower GCS at presentation, younger age at trauma, increased time since trauma to surgery and admission, anisocoria and effacement of basal cisterns are statistically significant variables in surgically treated pediatric patients of EDH that confer a poorer prognosis. A timely surgical intervention can result in excellent outcomes.

Melanotic neuroectodermal tumour of infancy: a rare brain tumour of childhood.

Melanotic neuroectodermal tumour of infancy is a rare, mostly benign but locally aggressive tumour of neural crest cell origin occurring in infants. The most commonly affected anatomic site is the maxilla. Such tumours of the brain and skull are very rare. We present the case of an 8 months old baby girl whose presenting complaint was a swelling in the scalp for 6 months. She was otherwise asymptomatic. CT imaging confirmed the presence of an osteolytic tumour in the anterior parasagittal skull with dural involvement. The tumour was surgically excised enbloc. The patient has been well at 2 years follow-up without any evidence of recurrence.