Sumedh S. Shah

Exploiting ROS and metabolic differences to kill cisplatin resistant lung cancer

Cisplatin resistance remains a major problem in the treatment of lung cancer. We have discovered that cisplatin resistant (CR) lung cancer cells, regardless of the signaling pathway status, share the common parameter which is an increase in reactive oxygen species (ROS) and undergo metabolic reprogramming. CR cells were no longer addicted to the glycolytic pathway, but rather relied on oxidative metabolism. They took up twice as much glutamine and were highly sensitive to glutamine deprivation. Glutamine is hydrolyzed to glutamate for glutathione synthesis, an essential factor to abrogate high ROS via xCT antiporter. Thus, blocking glutamate flux using riluzole (an amyotropic lateral sclerosis approved drug) can selectively kill CR cells in vitro and in vivo. However, we discovered here that glutathione suppression is not the primary pathway in eradicating the CR cells. Riluzole can lead to further decrease in NAD+ (nicotinamide adenine dinucleotide) and lactate dehydrogenase-A (LDHA) expressions which in turn further heightened oxidative stress in CR cells. LDHA knocked-down cells became hypersensitive to riluzole treatments and possessed increased levels of ROS. Addition of NAD+ re-stabilized LDHA and reversed riluzole induced cell death. Thus far, no drugs are available which could overcome cisplatin resistance or kill cisplatin resistant cells. CR cells possess high levels of ROS and undergo metabolic reprogramming. These metabolic adaptations can be exploited and targeted by riluzole. Riluzole may serve as a dual-targeting agent by suppression LDHA and blocking xCT antiporter. Repurposing of riluzole should be considered for future treatment of cisplatin resistant lung cancer patients.

Investigating the therapeutic role and molecular biology of curcumin as a treatment for glioblastoma

Objectives: Despite the aggressive standard of care for patients with glioblastoma multiforme, survival rates typically do not exceed 2 years. Therefore, current research is focusing on discovering new therapeutics or rediscovering older medications that may increase the overall survival of patients with glioblastoma. Curcumin, a component of the Indian natural spice, turmeric, also known for its antioxidant and anti-inflammatory properties, has been found to be an effective inhibitor of proliferation and inducer of apoptosis in many cancers. The goal of this study was to investigate the expanded utility of curcumin as an antiglioma agent. Methods: Using the PubMed MeSH database, we conducted a systematic review of the literature to include pertinent studies on the growth inhibitory effects of curcumin on glioblastoma cell lines based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: A total of 19 in vitro and five in vivo studies were analyzed. All of the studies indicated that curcumin decreased glioblastoma cell viability through various pathways (i.e. decrease in prosurvival proteins such as nuclear factor κB, activator protein 1, and phosphoinositide 3 kinase, and upregulation of apoptotic pathways like p21, p53, and executor caspase 3). Curcumin treatment also increased animal survival compared with control groups. Conclusions: Curcumin inhibits proliferation and induces apoptosis in certain subpopulations of glioblastoma tumors, and its ability to target multiple signaling pathways involved in cell death makes it an attractive therapeutic agent. As such, it should be considered as a potent anticancer treatment. Further experiments are warranted to elucidate the use of a bioavailable form of curcumin in clinical trials.

Microsurgical versus endovascular interventions for blood-blister aneurysms of the internal carotid artery: systematic review of literature and meta-analysis on safety and efficacy

OBJECTIVE Blood-blister aneurysms (BBAs) of the internal carotid artery (ICA) have a poor natural history associated with high morbidity and mortality. Currently, both surgical and endovascular techniques are employed to treat BBAs; thus, the authors sought to perform a meta-analysis to compare the efficacy and safety of these approaches. METHODS A literature search of PubMed, MEDLINE, and Google Scholar online databases was performed to include pertinent English-language studies from 2005 to 2015 that discussed the efficacy and safety of either surgical or endovascular therapies to treat BBAs. RESULTS Thirty-six papers describing 256 patients with BBAs treated endovascularly (122 procedures) or surgically (139 procedures) were examined for data related to therapeutic efficacy and safety. Pooled analysis of 9 papers demonstrated immediate and late (mean 20.9 months) aneurysm occlusion rates of 88.9% (95% CI 77.6%-94.8%) and 88.4% (95% CI 76.7%-94.6%), respectively, in surgically treated patients. Pooled analysis of 12 papers revealed immediate and late aneurysm obliteration rates of 63.9% (95% CI 52.3%-74.1%) and 75.9% (95% CI 65.9%-83.7%), respectively, in endovascularly treated aneurysms. Procedure-related complications and overall poor neurological outcomes were slightly greater in the surgically treated cases than in the endovascularly treated cases (27.8% [95% CI 19.6%-37.8%] vs 26.2% [95% CI 18.4%-35.8%]), indicating that endovascular therapy may provide better outcomes. CONCLUSIONS Blood-blister aneurysms are rare, challenging lesions with a poor prognosis. Although surgical management potentially offers superior aneurysm obliteration rates immediately after treatment and at the long-term follow-up, endovascular therapy may have a better safety profile and provide better functional outcomes than surgery. A registry of patients treated for BBAs may be warranted to better document the natural course of the disease as well as treatment outcomes.

BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma

BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-α1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin-proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-α1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients.

Transradial access: lessons learned from cardiology

Innovations in interventional cardiology historically predate those in neuro-intervention. As such, studying trends in interventional cardiology can be useful in exploring avenues to optimise neuro-interventional techniques. One such cardiology innovation has been the steady conversion of arterial puncture sites from transfemoral access (TFA) to transradial access (TRA), a paradigm shift supported by safety benefits for patients. While neuro-intervention has unique anatomical challenges, the access itself is identical. As such, examining the extensive cardiology literature on the radial approach has the potential to offer valuable lessons for the neuro-interventionalist audience who may be unfamiliar with this body of work. Therefore, we present here a report, particularly for neuro-interventionalists, regarding the best practices for TRA by reviewing the relevant cardiology literature. We focused our review on the data most relevant to our audience, namely that surrounding the access itself. By reviewing the cardiology literature on metrics such as safety profiles, cost and patient satisfaction differences between TFA and TRA, as well as examining the technical nuances of the procedure and post-procedural care, we hope to give physicians treating complex cerebrovascular disease a broader data-driven understanding of TRA.

Transradial cerebral angiography: techniques and outcomes

Background Despite several retrospective studies analyzing the safety and efficacy of transradial access (TRA) versus transfemoral access (TFA) for cerebral angiography, this transition for neurointerventional procedures has been gradual. Nonetheless, based on our positive initial institutional experience with TRA for mechanical thrombectomy in acute ischemic stroke patients, we have started transitioning more of our cerebral angiography cases to TRA. Here we present our single institution experience. Methods We performed a retrospective review of patients receiving TRA cerebral angiography at our institution between January 2016 and February 2017. We present our experience transitioning from TFA to TRA, including our criteria for patient selection, technical nuances, patient experience, complications, and operator learning curve. Results We included 148 angiograms performed in 141 people by one of four operators. No major complications were observed, and the technical success of the procedures was consistent with those of TFA. Marked improvement in operator efficiency was achieved in a short number of cases during this transition when looking at operator proficiency as a function of angiograms performed and days of exposure to TRA (4.3 vs 3.6 min/vessel, P<0.05). Conclusions Safety and efficiency can be preserved while transitioning to TRA. While further investigation is necessary to support transition to TRA, these findings should call for a re-evaluation of the role of TRA in catheter cerebral angiography.

Current applications and future perspectives of robotics in cerebrovascular and endovascular neurosurgery

Advances in robotic medicine have been adopted by various surgical subspecialties as the benefits of this technology become more readily apparent: precision in narrow operative windows, tremor controlled movements, and modestly improved outcomes, among others. Vascular neurosurgery, in particular, remains open to newer and more cutting edge treatment options for complex pathologies, and robotics may be on the horizon for such advances. We seek to provide a broad overview of these innovations in vascular neurosurgery for both practitioners well acquainted with robotics and those seeking to become more familiar. Technologies under development for cerebrovascular and endovascular neurosurgery include robot assisted angiography, guided operative microscopes, coil insertion systems, and endoscopic clipping devices. Additionally, robotic systems in the fields of interventional cardiology and radiology have potential applications to endovascular neurosurgery but require proper modifications to navigate complex intracerebral vasculature. Robotic technology is not without drawbacks, as broad implementation may lead to increased cost, training time, and potential delays in emergency situations. Further cultivation of current multidisciplinary technologies and investment into newer systems is necessary before robotics can make a sizable impact in clinical practice.

Off-label use of the Angioseal vascular closure device for femoral arteriotomy: retrospective analysis of safety and efficacy

Background Angioseal, an arteriotomy closure device (ACD), functions as a collagen plug that physically closes arteriotomy sites and can simultaneously induce platelet activation and aggregation. When used ‘on-label’, the safety and efficacy profile of Angioseal is superior compared with those of other ACDs. However, Angioseal is sometimes deployed in less than ideal situations. Therefore, we sought to assess the safety and efficacy of ‘off-label’ Angioseal use in patients undergoing femoral arteriotomies. Methods We performed a retrospective review of all femoral arterial angiograms executed at our institution between 2008 and 2014. Patients whose femoral punctures did not fit the criteria for on-label Angioseal use were included, and were dichotomized based on vascular closure (off-label Angioseal vs manual compression). Results Of the 521 patients (1023 angiograms) reviewed, 303 (58.2%) patients had off-label Angioseal groin punctures. Mean patient age was 46.2±14.0 years, and 113 were men. 234 patients (77%) had off-label Angioseal deployment while 69 (22%) individuals received manual pressure, serving as controls. Demographic and procedural variables were nearly identical between the two groups but the Angioseal group comprised mostly patients that underwent neurointerventional procedures and thus received intraprocedural heparinization (41%) more often than the manual compression group (19%). The overall rate of major complications associated with off-label Angioseal deployment was low (<0.85%), and clinical complications were not independently associated with Angioseal use (OR 0.76 (95% CI 0.06 to 8.86); p=0.69). Conclusions Off-label use of Angioseal was found to be safe and was not associated with an increased complication rate in our cohort.

Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives

Abstract Resistance mechanisms employed by high-grade gliomas allow them to successfully evade current standard treatment of chemotherapy and radiation treatment. Withaferin A (WA), utilized in Ayurvedic medicine for centuries, is attracting attention for its antitumor capabilities. Here we review pertinent literature on WA as a high-grade glioma treatment, and discuss the cancerous mechanisms it affects. WA is relatively nontoxic and has shown potential in crossing the blood–brain barrier. WA prevents p53 alterations and inactivates overexpressed MDM2 through ARF and ROS production. Furthermore, WA upregulates Bax, inducing mitochondrial death cascades, inhibits mutated Akt, mTOR, and NF-κB pathways, and inhibits angiogenesis in tumors. Therapy with WA for high-grade gliomas is supported through the literature. Further investigation is warranted and encouraged to fully unearth its abilities against malignant gliomas.

Spontaneous healing of a shredded esophagus after ACDF without direct repair

Esophageal perforation is a catastrophic complication of anterior cervical discectomy and fusion (ACDF). While direct surgical repair has been reported as optimal for restoration of upper gut function, we present the case of a 58-year-old woman who achieved complete resolution when treated only with debridement and drainage. We find that a supportive approach, surgical management without direct repair, may play a vital role in select patient populations in order to avoid potentially long-term consequences or radical treatments, like esophageal diversion. Decisions regarding direct repair versus debridement and inspection only should be made on a case-by-case basis through a multidisciplinary approach.