Treatment approach and survival from glioblastoma: results from a population-based retrospective cohort study from Western Norway

Objectives To evaluate treatment and survival from glioblastoma in a real-world setting. Design and settings A population-based retrospective cohort study from Western Norway. Participants 363 patients aged 18 years or older diagnosed with glioblastoma between 1 January 2007 and 31 December 2014. Primary and secondary outcome measures Overall survival and survival rates determined by Kaplan-Meier method, groups compared by log-rank test. Associations between clinical characteristics and treatment approach assessed by logistic regression. Associations between treatment approach and outcome analysed by Cox regression. Results Median overall survival was 10.2 months (95% CI 9.1 to 11.3). Resection was performed in 221 patients (60.9%), and was inversely associated with age over 70 years, higher comorbidity burden, deep-seated tumour localisation and multifocality. Median survival was 13.7 months (95% CI 12.1 to 15.4) in patients undergoing tumour resection, 8.3 months (95% CI 6.6 to 9.9) in patients undergoing biopsy and 4.5 months (95% CI 4.0 to 5.1) in patients where no surgical intervention was performed. Chemoradiotherapy according to the Stupp protocol was given to 157 patients (43%). Age over 70 years, higher comorbidity burden and cognitive impairment were associated with less intensive chemoradiotherapy. Median survival was 16.3 months (95% CI 14.1 to 18.5), 7.9 months (95% CI 6.7 to 9.0) and 2.0 months (95% CI 0.9 to 3.2) in patients treated according to the Stupp protocol, with less intensive chemoradiotherapy and with best supportive care, respectively. Surgical resection (HR 0.61 (95% CI 0.47 to 0.79)) and chemoradiotherapy according to the Stupp protocol (HR 0.09 (95% CI 0.06 to 0.15)) were strongly associated with favourable overall survival, when adjusted for clinical variables. Conclusions In a real-world setting, less than half of the patients received full-course chemoradiotherapy, with a median survival comparable to results from clinical trials. Survival was considerably worse in patients receiving less intensive treatment. Our results point out a substantial risk of undertreating glioblastoma, especially in elderly patients.publishedVersio

Impact of extent of resection on outcome from glioblastoma using the RANO resect group classification system: a retrospective, population-based cohort study

Background Extent of resection (EOR) is associated with survival in glioblastoma. A standardized classification for EOR was lacking until a system was recently proposed by the response assessment in neuro-oncology (RANO) resect group. We aimed to assess EOR in an unselected glioblastoma cohort and use this classification system to evaluate the impact on survival in a real-world setting. Methods We retrospectively identified all patients with histologically confirmed glioblastoma in Western Norway between 1.1.2007 and 31.12.2014. Volumetric analyses were performed using a semi-automated method. EOR was categorized according to the recent classification system. Kaplan–Meier method and Cox proportional hazard ratios were applied for survival analyses. Results Among 235 included patients, biopsy (EOR class 4) was performed in 50 patients (21.3%), submaximal contrast enhancement (CE) resection (EOR class 3) in 66 patients (28.1%), and maximal CE resection (EOR class 2) in 119 patients (50.6%). Median survival was 6.2 months, 9.2 months, and 14.9 months, respectively. Within EOR class 2, 80 patients underwent complete CE resection (EOR class 2A) and had a median survival of 20.0 months, while 39 patients had a near-total CE resection, with ≤1 cm3 CE residual volume (EOR class 2B), and a median survival of 11.1 months, P < 0.001. The 2-year survival rate in EOR class 2A was 40.0%, compared to 7.7% in EOR class 2B. Conclusions RANO resect group classification for the extent of resection reflected outcome from glioblastoma in a real-world setting. There was significantly superior survival after complete CE resection compared to near-total resection.publishedVersio

Butterfly glioblastoma: Clinical characteristics, treatment strategies and outcomes in a population-based cohort

Background Butterfly glioblastoma is a rare subgroup of glioblastoma with a bihemispheric tumor crossing the corpus callosum, and is associated with a dismal prognosis. Prognostic factors are previously sparsely described and optimal treatment remains uncertain. We aimed to analyze clinical characteristics, treatment strategies, and outcomes from butterfly glioblastoma in a real-world setting. Methods This retrospective population-based cohort study included patients diagnosed with butterfly glioblastoma in Western Norway between 01/01/2007 and 31/12/2014. We enrolled patients with histologically confirmed glioblastoma and patients with a diagnosis based on a typical MRI pattern. Clinical data were extracted from electronic medical records. Molecular and MRI volumetric analyses were retrospectively performed. Survival analyses were performed using the Kaplan–Meier method and Cox proportional hazards regression models. Results Among 381 patients diagnosed with glioblastoma, 33 patients (8.7%) met the butterfly glioblastoma criteria. Median overall survival was 5.5 months (95% CI 3.1–7.9) and 3-year survival was 9.1%. Hypofractionated radiation therapy with or without temozolomide was the most frequently used treatment strategy, given to 16 of the 27 (59.3%) patients receiving radiation therapy. Best supportive care was associated with poorer survival compared with multimodal treatment [adjusted hazard ratio 5.11 (95% CI 1.09–23.89)]. Conclusion Outcome from butterfly glioblastoma was dismal, with a median overall survival of less than 6 months. However, long-term survival was comparable to that observed in non-butterfly glioblastoma, and multimodal treatment was associated with longer survival. This suggests that patients with butterfly glioblastoma may benefit from a more aggressive treatment approach despite the overall poor prognosis.publishedVersio

Prevalence of neural tube defects among pregnant women in Addis Ababa: a community-based study using prenatal ultrasound examination

Purpose The primary aim of this study was to estimate the prevalence of NTDs at ultrasound examination in communities of Addis Ababa and secondarily to provide a description of the dysmorphology of the NTD cases. Methods We enrolled 958 pregnant women from 20 randomly selected health centers in Addis Ababa during the period from October 1, 2018, to April 30, 2019. Of these 958 women, 891 had an ultrasound examination after enrollment, with a special focus on NTDs. We estimated the prevalence of NTDs and compared it with previously reported hospital-based birth prevalence estimates from Addis Ababa. Results Among 891 women, 13 had twin pregnancies. We identified 15 NTD cases among 904 fetuses, corresponding to an ultrasound-based prevalence of 166 per 10,000 (95% CI: 100–274). There were no NTD cases among the 26 twins. Eleven had spina bifida (122 per 10,000, 95% CI: 67–219). Among the 11 fetuses with spina bifida, three had a cervical and one had a thoracolumbar defect while the anatomical site for 7 was not registered. Seven of the 11 spina bifida defects had skin covering, while two of the cervical lesions were uncovered. Conclusion We report a high prevalence of NTDs among pregnancies in communities of Addis Ababa based on screening by ultrasound. The prevalence was higher than in previous hospital-based studies in Addis, and the prevalence of spina bifida was particularly high.publishedVersio

EGFR Gene Overexpression Retained in an Invasive Xenograft Model by Solid Orthotopic Transplantation of Human Glioblastoma Multiforme Into Nude Mice

Orthotopic xenograft animal model from human glioblastoma multiforme (GBM) cell lines often do not recapitulate an extremely important aspect of invasive growth and epidermal growth factor receptor (EGFR) gene overexpression of human GBM. We developed an orthotopic xenograft model by solid transplantation of human GBM into the brain of nude mouse. The orthotopic xenografts sharing the same histopathological features with their original human GBMs were highly invasive and retained the overexpression of EGFR gene. The murine orthotopic GBM models constitute a valuable in vivo system for preclinical studies to test novel therapies for human GBM

Surgical treatment outcome of children with neural-tube defect: A prospective cohort study in a high volume center in Addis Ababa, Ethiopia

Introduction Prevalence of neural tube defects (NTD) is high thus many children are born with a neural tube defect in Addis Ababa, and surgical closure is a commonly performed procedure at the pediatric neurosurgical specialty center. Research question The primary aim is to study the outcomes in children undergoing surgical closure of NTDs and to identify risk factors for readmission, complications and mortality. Material and methods Single-center prospective study of all surgically treated NTDs from April 2019 to May 2020. Results A total of 228 children, mean age 11 days (median 4) underwent surgery during the study period. There were no in-hospital deaths. Perioperatively 11 (4.8%) children developed wound complications, none of them needed surgery and there was no perioperative mortality. The one-year follow-up rate was 62.7% (143/228) and neurological status remained stable since discharge in all. The readmission and reoperation rates were 38 % and 8 % and risk factors for readmission were hydrocephalus (80%) and open defects (88%). Hydrocephalus (P = 0.05) and younger age (P = 0.02) were identified as risk factors for mortality. The wound-related complication rate was 55% at and was associated with large defects (P = 0.04) and delayed closure due to late hospital presentation (P = 0.01). Discussion and conclusion The study reveals good perioperative surgical outcome and further need for systematic improvement in treatment and follow-up of NTD patients especially with hydrocephalus. We identified risk factors for wound-related complications, readmission and mortality.publishedVersio

Comparison of disintegrant-addition methods on the compounding of orodispersible tablets

Orodispersible tablets disintegrate rapidly (within 3 minutes) in the oral cavity and release the medicament before swallowing. The mode of disintegrant addition might affect the properties of orodispersible tablets. The objective of this study was to formulate and evaluate orodispersible tablets by studying different modes of disintegration addition with varying concentrations of disintegrants. The wet granulation method was used to produce the orodispersible tablets. Two methods of disintegration addition were compared (i.e., intragranular, extragranular). Three disintegrants (i.e., cornstarch, sodium starch glycolate, crospovidone) were used at three levels (5%, 10%, and 15%) in the study. The formulations were tested for the powder flowability (angle of repose) and characterized physically (hardness, weight, thickness, friability, disintegration time). The mangosteen pericarp extract was used as a model active pharmaceutical ingredient to be incorporated into the optimum formulation. It was observed that the extragranular method produced granules with better flowability compared to that of the intragranular method. Crospovidone was found as the most efficient disintegrant among the three. The optimum formulation selected was one with the highest concentration of crospovidone (15%), which showed the fastest disintegration time. The mode of disintegrant addition into the orodispersible tablets formulation was found to show a marked difference in the disintegration, as well as other physical characteristics of the orodispersible tablets where the extragranular mode of addition showed better property, which caused the orodispersible tablets to disintegrate the fastest

Osteopontin regulates human glioma cell invasiveness and tumor growth in mice

Human malignant glioma cells are characterized by local invasion. In the present study, we investigated the role of osteopontin (OPN) in the invasiveness of human glioma cells isolated from grade IV tumors. We found that the expression levels of OPN in these cell lines paralleled matrix metalloproteinase-2 (MMP-2) expression and cell invasiveness potential. When U87MG glioma cells (with a high-OPN expression level) were stably transformed with specific small hairpin RNA to knock down OPN expression, MMP-2 secretion, cell invasiveness, and tumor growth in implanted brains were dramatically reduced. Conversely, forced expression of OPN in GBM-SKH glioma cells (which expressed OPN at a low level) increased MMP-2 secretion, enhanced cell invasiveness, and increased tumor growth in a rodent xenograft model. Expression of OPN was associated with increased expression of vimentin and decreased expression of glial fibrillary acidic protein. Treatment of glioma cells with 5-aza-2′-deoxycytidine (5-aza-dC) suppressed OPN expression in a concentration-dependent manner. Suppression of OPN expression by 5-aza-dC was associated with reductions in MMP-2 secretion, vimentin expression, cell invasion, intravasation, and tumor growth. These data suggest that OPN may play important roles in regulating cell invasion in glioma cells and that 5-aza-dC may serve as a therapeutic agent for human gliomas

Targeting the NG2/CSPG4 Proteoglycan Retards Tumour Growth and Angiogenesis in Preclinical Models of GBM and Melanoma

Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy

A reproducible brain tumour model established from human glioblastoma biopsies

<p>Abstract</p> <p>Background</p> <p>Establishing clinically relevant animal models of glioblastoma multiforme (GBM) remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates.</p> <p>Methods</p> <p>In this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features.</p> <p>Results</p> <p>The tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages <it>in vivo</it>, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 <it>in vivo </it>passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms.</p> <p>Conclusions</p> <p><it>In vivo </it>passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to <it>in vitro </it>propagated cell lines for dissecting mechanisms of brain tumour progression.</p