| This thesis is composed of two major sections.The first section is a molecular experimental study exploring functional interactions between Cluster of Differentiation 147(CD 147)and hypoxia inducible factors 1 and 2 alpha(HIF-1/2α),Vascular endothelial growth factor(VEGF),and vascular endothelial growth factor receptor(VEGFR)in glioblastoma cells.The second section is a clinical study exploring the interdependence of surgical management of pineal region tumors and associated hydrocephalus.4.1 ABSTRACT 1Background:CD 147,also known as EMMPRIN,basigin,and HAb18G,is a single-chain type Ⅰtransmembrane protein.This protein is overexpressed in aggressive human cancers of CNS,head and neck,breasts,lungs,gastrointestinal,genitourinary,skin,hematological,and musculoskeletal.CD147 is integral to the diverse but complimentary hallmarks of cancers as it plays a pivotal role in cancerous proliferative signaling,growth propagation,cellular survival,replicative immortality,angiogenesis,metabolic reprogramming,immune evasion,and invasion and metastasis.Glioblastoma is the most common and most aggressive primary malignant tumor of the central nervous system,with also the worst prognosis.Despite advances in the current clinical and molecular research,surgical techniques and medical and radiological therapeutic approaches,outcomes in glioblastoma have continued to remain poor with median survival of less than two years regardless of treatment approaches.Some of the major molecules and pathways involved in malignant and adaptive behaviors of glioblastoma include P53,HIF-1α,HIF-2α,VEGF,VEGFR,Cyclophilin A(CyPA),matrix metalloproteinases(MMPs),Glucose transporters(GLUTs),monocarboxylate transporters(MCTs),integrins,PI3K/Akt/mTOR,and ERK1/2.Moreover,treatment sing anti-VEGF(Bevacizumab)in glioblastoma have shown brief improvement in progression free survival but with no change in overall survival.In other words,targeting VEGF to starve and kill glioblastoma cells only gives a pseudo therapeutic effect that does not translate into prolongation of survival in glioblastoma patients.Study Objective:Even though numerous clinical and experimental studies and.trials have shown essential and exploitable regulatory function of CD147 in malignant behaviors of most aggressive human cancers,there are very few literatures that report on the role of CD 147 in primary brain malignancy.The objective of this study therefore was to determine and explore the molecular expression and function of CD 147 in relation to that of HIF-1α,HIF-2α,VEGF,and VEGFR in human glioblastoma.Methodology:We conducted an in vitro experimental study using glioblastoma cell lines A172,Ln229,and U251.We also performed extraction and culturing of patient-derived primary glioblastoma cell.The cell lines were transfected with small interfering ribonucleic acid(siRNA)targeting CD 147 or HIF2α.We then purified the RNA and performed reverse transcription and real time quantitative polymerase chain reaction(RT-qPCR)to analyze the effect on the expression of CD 147,HIF-1α,HIF2α,VEGF,and VEGFR.Results:Messenger RNA analysis of A172,U251,and Ln229 glioblastoma cells showed that the glioblastoma cells express an equivocally significant and functional amount of CD 147,which interacts and affects the expression of HIF-1α,HIF-2α,VEGF,and VEGFR.Inhibition of CD 147 mRNA expression significantly depressed the expression of HIF-2α(p=0.0088,0.0003,<0.0001)while promoted that of HIF-1α(p=0.0033),VEGF(p=0.0320,0.0103),and VEGFR(p=0.0102,0.0066)mRNAs.Also,inhibition of HIF-2α mRNA expression also consequently inhibits that of VEGFR(p=0.0037)while significantly promoting the expression of CD 147,HIF-1α,and VEGF mRNAs.Conclusion:CD147 has a sensitive and exploitable interaction with HIF-1α,HIF-2α,VEGF,and VEGFR in glioblastoma cells.CD147,HIF-1α,HIF-2α,VEGF,and VEGFR form a web of proangiogenic molecules that should be well defined to establish the hotspot molecules to target in antiangiogenic targeted therapies to improve efficacy and survival in glioblastoma patients.4.2 Abstract 2Background and Study Objective: Pineal lesions are among the deep-seated lesions of the brain that continue to pose a serious challenge in neurosurgical care.This is due to their histological heterogeneity,complex anatomical location,age of presentation,and presentation with obstructive hydrocephalus.Presence of hydrocephalus creates a paradox of management whereby tumor resection approaches,timing,and outcomes are interdependent with treatment approaches for hydrocephalus and their outcomes.The main objective of this study was to assess the mode of interdependence and determine the more effective interventional approaches in surgical removal of pineal tumors and intervention of the associated obstructive hydrocephalus.Methodology: The study was a two-centers retrospective cohort study involving 154 patients diagnosed and treated for pineal region tumor between January 2015 and January 2021.The minimum follows up period was one year.The primary outcomes we considered included resolution of hydrocephalus and complete tumor resection as per symptoms,signs,and radiological results.Secondary outcomes were absence of procedural related complications,hydrocephalus recurrences and additional neuro-invasive procedures.Results;About seventy percent(111)patients with pineal tumors had obstructive hydrocephalus which accounted significantly for the presenting clinical symptoms(76.9 %,p=0.0001).102 patients were intervened for hydrocephalus with about half(54)also undergoing tumor resection meanwhile the other half received chemotherapy and or radiotherapy as definitive treatments for pineal tumor.Hydrocephalus intervention was performed as primary intervention by external ventricular drainage(15),endoscopic third ventriculostomy(32),ventriculoperitoneal shunt(34),and direct tumor resection(21).Tumor resection as secondary intervention was performed in 33 patients.Within a period of one year,14% of patients treated for hydrocephalus had persistent or recurrent hydrocephalus which largely occurred in patients who also had tumor removal(p=0.0001).There was a significant difference among hydrocephalus interventions approaches in terms of mean surgical interventions under general anesthesia(p=0.006),and hydrocephalus-related invasive procedures such as subdural lumber puncture and drainage(p=0.016).Among the 154 patients with pineal tumors,122(79.2%)required intervention whereby 60 patients(49.2%)underwent tumor resection with or without adjuvant chemoradiotherapy while 62 received definitive chemotherapy and or radiotherapy.Interestingly,extent of tumor resection was negatively affected by the time interval between hydrocephalus intervention and tumor resection(p=0.009).Dimensional analysis of a case with a two-week interval between hydrocephalus intervention and tumor resection showed a more than 89% negative change in tumor exposure and depth,factors that determine the safety and effectiveness of tumor resection.Conclusion: Ventriculoperitoneal shunting,endoscopic third ventriculostomy,and direct tumor resection remain the mainstay intervention options for pineal tumor-associated hydrocephalus.Although direct tumor removal has dual therapeutic potential by resolving hydrocephalus and tumor removal,the procedure itself increases the risk of hydrocephalus persistence or recurrence thus calling for pre-emptive effective plan for hydrocephalus intervention.Also,properly timed interval of hydrocephalus intervention to tumor resection could facilitate extent and safety of tumor resection. |
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