Lysine catabolism reprograms tumour immunity through histone crotonylation.

Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.

Amplifying the Noise: Oncometabolites Mask an Epigenetic Signal of DNA Damage.

A recent study (Sulkowski et al., 2020) reveals that oncometabolites, which are produced by metabolic gene mutations in many cancers, sensitize cells to PARP inhibition by antagonizing histone demethylation and obscuring epigenetic marks that are necessary for efficient DNA repair.

Genetic and epigenetic instability as an underlying driver of progression and aggressive behavior in IDH-mutant astrocytoma.

In recent years, the classification of adult-type diffuse gliomas has undergone a revolution, wherein specific molecular features now represent defining diagnostic criteria of IDH-wild-type glioblastomas, IDH-mutant astrocytomas, and IDH-mutant 1p/19q-codeleted oligodendrogliomas. With the introduction of the 2021 WHO CNS classification, additional molecular alterations are now integrated into the grading of these tumors, given equal weight to traditional histologic features. However, there remains a great deal of heterogeneity in patient outcome even within these established tumor subclassifications that is unexplained by currently codified molecular alterations, particularly in the IDH-mutant astrocytoma category. There is also significant intercellular genetic and epigenetic heterogeneity and plasticity with resulting phenotypic heterogeneity, making these tumors remarkably adaptable and robust, and presenting a significant barrier to the design of effective therapeutics. Herein, we review the mechanisms and consequences of genetic and epigenetic instability, including chromosomal instability (CIN), microsatellite instability (MSI)/mismatch repair (MMR) deficits, and epigenetic instability, in the underlying biology, tumorigenesis, and progression of IDH-mutant astrocytomas. We also discuss the contribution of recent high-resolution transcriptomics studies toward defining tumor heterogeneity with single-cell resolution. While intratumoral heterogeneity is a well-known feature of diffuse gliomas, the contribution of these various processes has only recently been considered as a potential driver of tumor aggressiveness. CIN has an independent, adverse effect on patient survival, similar to the effect of histologic grade and homozygous CDKN2A deletion, while MMR mutation is only associated with poor overall survival in univariate analysis but is highly correlated with higher histologic/molecular grade and other aggressive features. These forms of genomic instability, which may significantly affect the natural progression of these tumors, response to therapy, and ultimately clinical outcome for patients, are potentially measurable features which could aid in diagnosis, grading, prognosis, and development of personalized therapeutics.

DNA damage in IDH-mutant gliomas: mechanisms and clinical implications.

PURPOSE: Since the discovery of IDH mutations in glioma over a decade ago, significant progress has been made in determining how these mutations affect epigenetic, transcriptomic, and metabolic programs in brain tumor cells. In this article, we summarize current understanding of how IDH mutations influence DNA damage in glioma and discuss clinical implications of these findings. METHODS: We performed a thorough review of peer-reviewed publications and provide an overview of key mechanisms by which IDH mutations impact response to DNA damage in gliomas, with an emphasis on clinical implications. RESULTS: The effects of mutant IDH on DNA damage largely fall into four overarching categories: Gene Expression, Sensitivity to Alkylating Agents, Homologous Recombination, and Oxidative Stress. From a mechanistic standpoint, we discuss how mutant IDH and the oncometabolite (R)-2HG affect each of these categories of DNA damage. We also contextualize these mechanisms with respect to ongoing clinical trials. Studies are underway that incorporate current standard-of-care therapies, including radiation and alkylating agents, in addition to novel therapeutic agents that exert genotoxic stress specifically in IDH-mutant gliomas. Lastly, we discuss key unanswered questions and emerging data in this field that have important implications for our understanding of glioma biology and for the development of new brain tumor therapies. CONCLUSION: Mounting preclinical and clinical data suggest that IDH mutations alter DNA damage sensing and repair pathways through distinct mechanisms. Future studies are needed to deepen our understanding of these processes and provide additional mechanistic insights that can be leveraged for therapeutic benefit.

Bevacizumab vs laser interstitial thermal therapy in cerebral radiation necrosis from brain metastases: a systematic review and meta-analysis.

PURPOSE: Radiation necrosis (RN) represents a serious post-radiotherapy complication in patients with brain metastases. Bevacizumab and laser interstitial thermal therapy (LITT) are viable treatment options, but direct comparative data is scarce. We reviewed the literature to compare the two treatment strategies. METHODS: PubMed, EMBASE, Scopus, and Cochrane databases were searched. All studies of patients with RN from brain metastases treated with bevacizumab or LITT were included. Treatment outcomes were analyzed using indirect meta-analysis with random-effect modeling. RESULTS: Among the 18 studies included, 143 patients received bevacizumab and 148 underwent LITT. Both strategies were equally effective in providing post-treatment symptomatic improvement (P = 0.187, I2 = 54.8%), weaning off steroids (P = 0.614, I2 = 25.5%), and local lesion control (P = 0.5, I2 = 0%). Mean number of lesions per patient was not statistically significant among groups (P = 0.624). Similarly, mean T1-contrast-enhancing pre-treatment volumes were not statistically different (P = 0.582). Patterns of radiological responses differed at 6-month follow-ups, with rates of partial regression significantly higher in the bevacizumab group (P = 0.001, I2 = 88.9%), and stable disease significantly higher in the LITT group (P = 0.002, I2 = 81.9%). Survival rates were superior in the LITT cohort, and statistical significance was reached at 18 months (P = 0.038, I2 = 73.7%). Low rates of adverse events were reported in both groups (14.7% for bevacizumab and 12.2% for LITT). CONCLUSION: Bevacizumab and LITT can be safe and effective treatments for RN from brain metastases. Clinical and radiological outcomes are mostly comparable, but LITT may relate with superior survival benefits in select patients. Further studies are required to identify the best patient candidates for each treatment group.

Tractography and the connectome in neurosurgical treatment of gliomas: the premise, the progress, and the potential.

The ability of diffusion tensor MRI to detect the preferential diffusion of water in cerebral white matter tracts enables neurosurgeons to noninvasively visualize the relationship of lesions to functional neural pathways. Although viewed as a research tool in its infancy, diffusion tractography has evolved into a neurosurgical tool with applications in glioma surgery that are enhanced by evolutions in crossing fiber visualization, edema correction, and automated tract identification. In this paper the current literature supporting the use of tractography in brain tumor surgery is summarized, highlighting important clinical studies on the application of diffusion tensor imaging (DTI) for preoperative planning of glioma resection, and risk assessment to analyze postoperative outcomes. The key methods of tractography in current practice and crucial white matter fiber bundles are summarized. After a review of the physical basis of DTI and post-DTI tractography, the authors discuss the methodologies with which to adapt DT image processing for surgical planning, as well as the potential of connectomic imaging to facilitate a network approach to oncofunctional optimization in glioma surgery.

Negative prognostic impact of epidermal growth factor receptor copy number gain in young adults with isocitrate dehydrogenase wild-type glioblastoma.

PURPOSE: Young adults with isocitrate-dehydrogenase wild-type (IDH-WT) glioblastoma (GBM) represent a rare, understudied population compared to pediatric high-grade glioma, IDH-mutant GBM, or IDH-WT GBM in older patients. We aimed to explore the prognostic impact of epidermal growth factor receptor copy number gain (EGFR CN gain), one of the most common genetic alterations in IDH-WT glioma, in young adults with IDH-WT GBM. METHODS: We performed a retrospective cohort study of patients 18-45 years old with newly diagnosed, IDH-WT GBM whose tumors underwent next-generation sequencing at our institution between 2014 and 2018. The impact of EGFR CN gain on time to tumor progression (TTP) and overall survival (OS) was assessed. A validation cohort of patients 18-45 years old with IDH-WT GBM was analyzed from The Cancer Genome Atlas (TCGA). RESULTS: Ten of 28 patients (36%) from our institution had EGFR CN gain, which was associated with shorter TTP (median 6.5 vs. 11.9 months; p = 0.06) and OS (median 16.3 vs. 23.5 months; p = 0.047). The negative prognostic impact of EGFR CN gain on OS persisted in a multivariate model (HR 6.40, 95% CI 1.3-31.0, p = 0.02). In the TCGA cohort (N = 43), EGFR CN gain was associated with shorter TTP and worse OS, although these did not reach statistical significance (TTP, median 11.5 vs. 14.4 months, p = 0.18; OS, median 23.6 vs. 27.8 months; p = 0.18). CONCLUSIONS: EGFR CN gain may be associated with inferior outcomes in young adults with newly diagnosed, IDH-WT GBM, suggesting a potential role for targeting EGFR in this population.

Outcomes and Prognostic Factors in Pediatric Oligodendroglioma: A Population-Based Study.

BACKGROUND/AIMS: Pediatric oligodendroglioma (pODG) is a rare primary brain tumor that remains poorly understood. Demographics, outcomes, and prognostic factors were analyzed in 346 pODG cases from the Surveillance, Epidemiology, and End Results database. METHODS: Gender, race, age, tumor location, tumor size, tumor grade, extent of resection, and use of radiotherapy were evaluated with respect to overall survival (OS) by univariate and multivariate analysis. These factors were assessed in the pediatric cohort and 5,753 adult oligodendroglioma cases for comparison. RESULTS: The mean OS in pODG was 199.6 months. Five- and 10-year survival rates were 85 and 81%. pODG arose less frequently in the frontal lobe than adult tumors (53 vs. 22%) but was more common in the temporal lobe (32 vs. 18%) and extracortical regions (19 vs. 5%, p < 0.0001). pODG presented with smaller size (55 vs. 24%, p < 0.0001) and lower grade (72 vs. 54%, p < 0.0001) than adult tumors. Tumor location, size, grade, use of radiotherapy, and extent of resection were significant prognostic factors. Size and grade were much stronger prognostic factors in children than adults. While children with oligodendroglioma survive much longer than adults on the whole, there was no difference in outcome between children with high-grade tumors and adults with high-grade tumors. CONCLUSION: pODG differs significantly from adult oligodendroglioma along a number of demographic and tumor factors at a population level, and key prognostic factors influence survival differently in pODG than in adult disease.

Concussion and football: a review and editorial.

The issue of concussion in football is of substantial interest to players, coaches, fans, and physicians. In this article, we review specific cultural hindrances to diagnosis and treatment of concussion in football. We review current trends in management and identify areas for improvement. We also discuss the obligations that physicians, particularly neurosurgeons and neurologists, have toward brain-injured football players and the larger societal role they may play in helping to minimize football-associated brain injury.

Adverse Events With the Use of rhBMP-2 in Thoracolumbar and Lumbar Spine Fusions: A 9-Year Institutional Analysis.

STUDY DESIGN: Retrospective chart review. OBJECTIVE: To describe the adverse outcomes associated with the use of rhBMP-2 in thoracolumbar and lumbar fusions. SUMMARY OF BACKGROUND DATA: rhBMP-2 has been increasingly used in spinal fusions over the past decade. Early studies reported that the use of rhBMP-2 is associated with decreased operative time, blood loss, and pain scores, as well as improved fusion rates. Recent investigations have shown rhBMP-2 to be associated with various complications occurring at incidences ranging from 0% to 100%. METHODS: Using the institutional electronic medical records, we retrospectively reviewed all patients between January 2002 and September 2010 that underwent thoracolumbar and lumbar spine fusion with BMP. Patient demographics, operative, and outcome/complication information was collected. RESULTS: A total of 547 patient charts were reviewed with a mean follow-up time of 17 months. Mean age was 58 years. Forty-one percent of patients had undergone previous spine surgery. Thirty-nine percent of patients had a PLIF/TLIF, 29% underwent a PLF, and 20% an ALIF. No relevant differences in the patient characteristics and complications were identified between the various surgical approaches. For all approaches, having undergone a previous spine surgery was associated with increased incidence of radiculitis, reoperation, and pseudoarthrosis (P=0.005, 0.0008, 0.05, respectively) as compared with those without previous spine surgery. Being a current smoker at the time of operation was associated with increased rate of radiculitis (P=0.03) as compared with nonsmokers. CONCLUSIONS: The use of rhBMP-2, in this study, had an incidence of radiculitis, pseudoarthrosis, and reoperation that was similar to the rates in historical controls without rhBMP-2. Complications do not differ by surgical approach, but are more likely in current smokers and those undergoing revision surgery. A prospective study is warranted to further delineate the adverse event profile of rhBMP-2 and the variables that are likely to affect it (ie, type of surgery, carrier, and dose).

Quality of life outcomes following surgery for patients with coexistent cervical stenosis and multiple sclerosis.

PURPOSE: To investigate the quality of life outcomes following surgical treatment of patients with coexisting multiple sclerosis (MS) and cervical stenosis with associated myelopathy (CS). METHODS: A retrospective review of the medical records and of prospectively acquired quality of life (QOL) data was performed for all patients with symptoms of myelopathy and coexisting diagnoses of MS and CS that underwent cervical decompression surgery between 2008 and 2011. The study population was matched (1:4) to a control cohort of patients that did not have MS but presented with similar myelopathic symptoms due to cervical stenosis, were of the same age and gender, and underwent the same cervical decompression procedure within the same year. RESULTS: Sixty-five patients were reviewed, including 13 in the MS group and 52 in the control group that were followed for an average of 22 and 18 months, respectively. Whereas patients in the MS cohort remained at a Quality-Adjusted Life-Year (QALY) gain of 0.51 both pre- and post-operatively (p = 0.96), patients in the matched control cohort improved from a preoperative QALY of 0.50 to a postoperative QALY of 0.64 (p < 0.0001). The latter represents an improvement that exceeds the minimum clinically important difference. Overall, 70% of patients in the control group experienced an improvement in QALY, compared to only 54% in the MS group (p = 0.4). CONCLUSION: Patients in the control cohort had clinically and statistically significant improvements in QALY outcomes. Those in the MS cohort averaged no change in QALY. However, only a minority of MS/CS patients had worsening QALY following surgery, and as such surgery may still be considered for these patients. It is imperative that there are preoperative discussions with the MS/CS patient regarding the likelihood that surgery will only provide limited, if any, improvements in QOL.

Variations in cost calculations in spine surgery cost-effectiveness research.

OBJECT: Cost-effectiveness research in spine surgery has been a prominent focus over the last decade. However, there has yet to be a standardized method developed for calculation of costs in such studies. This lack of a standardized costing methodology may lead to conflicting conclusions on the cost-effectiveness of an intervention for a specific diagnosis. The primary objective of this study was to systematically review all cost-effectiveness studies published on spine surgery and compare and contrast various costing methodologies used. METHODS: The authors performed a systematic review of the cost-effectiveness literature related to spine surgery. All cost-effectiveness analyses pertaining to spine surgery were identified using the cost-effectiveness analysis registry database of the Tufts Medical Center Institute for Clinical Research and Health Policy, and the MEDLINE database. Each article was reviewed to determine the study subject, methodology, and results. Data were collected from each study, including costs, interventions, cost calculation method, perspective of cost calculation, and definitions of direct and indirect costs if available. RESULTS: Thirty-seven cost-effectiveness studies on spine surgery were included in the present study. Twenty-seven (73%) of the studies involved the lumbar spine and the remaining 10 (27%) involved the cervical spine. Of the 37 studies, 13 (35%) used Medicare reimbursements, 12 (32%) used a case-costing database, 3 (8%) used cost-to-charge ratios (CCRs), 2 (5%) used a combination of Medicare reimbursements and CCRs, 3 (8%) used the United Kingdom National Health Service reimbursement system, 2 (5%) used a Dutch reimbursement system, 1 (3%) used the United Kingdom Department of Health data, and 1 (3%) used the Tricare Military Reimbursement system. Nineteen (51%) studies completed their cost analysis from the societal perspective, 11 (30%) from the hospital perspective, and 7 (19%) from the payer perspective. Of those studies with a societal perspective, 14 (38%) reported actual indirect costs. CONCLUSIONS: Changes in cost have a direct impact on the value equation for concluding whether an intervention is cost-effective. It is essential to develop a standardized, accurate means of calculating costs. Comparability and transparency are essential, such that studies can be compared properly and policy makers can be appropriately informed when making decisions for our health care system based on the results of these studies.

Classifying Glioma via Liquid Biopsy: Progress toward an Unmet Clinical Need.

The diagnosis and classification of glioma by liquid biopsy represent a critical unmet need in neuro-oncology. A recent study demonstrates targeted next-generation sequencing of cell-free DNA from cerebrospinal fluid as an evolving option for liquid biopsy in patients with glioma. See related article by Iser et al., p. 2974.

Matched three-dimensional organoids and two-dimensional cell lines of melanoma brain metastases mirror response to targeted molecular therapy.

Purpose: Despite significant advances in the treatment paradigm for patients with metastatic melanoma, melanoma brain metastasis (MBM) continues to represent a significant treatment challenge. The study of MBM is limited, in part, by shortcomings in existing preclinical models. Surgically eXplanted Organoids (SXOs) are ex vivo, three-dimensional cultures prepared from primary tissue samples with minimal processing that recapitulate genotypic and phenotypic features of parent tumors and are grown without artificial extracellular scaffolding. We aimed to develop the first matched patient-derived SXO and cell line models of MBM to investigate responses to targeted therapy. Methods: MBM SXOs were created by a novel protocol incorporating techniques for establishing glioma and cutaneous melanoma organoids. A BRAFV600K-mutant and BRAF-wildtype MBM sample were collected directly from the operating room for downstream experiments. Organoids were cultured in an optimized culture medium without an artificial extracellular scaffold. Concurrently, matched patient-derived cell lines were created. Drug screens were conducted to assess treatment response in SXOs and cell lines. Results: Organoid growth was observed within 3-4 weeks, and MBM SXOs retained histological features of the parent tissue, including pleomorphic epithelioid cells with abundant cytoplasm, large nuclei, focal melanin accumulation, and strong SOX10 positivity. After sufficient growth, organoids could be manually parcellated to increase the number of replicates. Matched SXOs and cell lines demonstrated sensitivity to BRAF and MEK inhibitors. Conclusion: Here, we describe the creation of a scaffold-free organoid model of MBM. Further study using SXOs may improve the translational relevance of preclinical studies and enable the study of the metastatic melanoma tumor microenvironment.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Bevacizumab for radiation necrosis following treatment of high grade glioma: a systematic review of the literature.

This review identifies the current literature on the use of bevacizumab for cerebral radiation necrosis in patients with high-grade gliomas, summarizes the clinical course and complications following bevacizumab, and discusses the relative costs and benefits of this therapeutic option. A Medline search was conducted of all clinical studies before September 2012 investigating outcomes following use of bevacizumab therapy for radiation necrosis in patients with high-grade gliomas. Clinical and radiographic outcomes are reviewed. Seven studies reported a total of 30 patients with high-grade gliomas treated with bevacizumab for radiation necrosis. All patients demonstrated decreased radiographic volume of edema on T1 and T2 MRI sequences. Clinical outcomes were reported for 23 patients: 16 (70 %) had improvement in neurologic signs or symptoms, 5 (22 %) had mixed results, and 2 (9 %) remained neurologically unchanged. Complications were documented in 5 of 7 studies (18 of 29 patients, 62 %) and included deep vein thrombosis, pulmonary embolism, visual field worsening, worsening hemiplegia, pneumonia, seizure, and fatigue. Only one study evaluated quality of life measures and none evaluated cost or cost effectiveness. Data regarding the use of bevacizumab to treat radiation necrosis in patients with high-grade gliomas is limited and primarily class III evidence. While bevacizumab improves neurological symptoms and reduces radiographic volume of necrosis-associated cerebral edema, it comes at the expense of a high rate of potentially serious complications. Definitive evidence for the utility, cost-effectiveness, and overall efficacy of this management strategy is currently lacking and additional investigation is warranted.

Vascular injuries during anterior exposure of the thoracolumbar spine.

BACKGROUND: The aim of this study was to evaluate the vascular injuries, repairs, and complications encountered during anterior thoracolumbar spine exposures. METHODS: The medical records of patients undergoing anterior spine exposures from January 2004 to June 2010 were retrospectively analyzed. RESULTS: A total of 269 anterior exposures were performed in 260 patients. The average patient age was 50.1 years, and the average body mass index was 29.0. Female patients represented 146 (54.3%) cases. Previous spinal surgery was noted in 145 (53.9%) cases, and 19 (7.1%) had previous anterior exposure. The median estimated blood loss (EBL) was 300 mL, and there were no postoperative mortalities. A vascular injury occurred in 37 cases (13.8%), with redo anterior exposure (n = 19, 52% vs. 11%; P < 0.001), previous spinal surgery (n = 145, 19% vs. 7%; P = 0.01), and diagnosis of a tumor (n = 14, 36% vs. 12.5%; P = 0.03) being associated with increased vascular injury. A vascular injury resulted in greater EBL (median: 800 mL vs. 300 mL; P < 0.001) and longer hospitalization (median: 7 days vs. 5 days; P = 0.04). Most frequently injured was the left common iliac vein (in 21 of the 37 [52.5%] injured cases). A vascular surgeon performed the exposure in 159 (59.1%) cases. There was a decrease in EBL (250 mL vs. 500 mL; P < 0.001), total incision time (290 minutes vs. 404 minutes; P = 0.002), and length of stay (5 days vs. 6.5 days; P < 0.001) as compared with the operations where the vascular surgeon was not involved in the exposure. These cases also had an increased incidence of any vascular injury (28 vs. 9; P = 0.04). There were no differences between groups regarding vascular injury type, repair type, or the incidence of deep venous thrombosis. CONCLUSION: Collaboration between spine and vascular teams may result in decreased blood loss and consequently improved morbidity and length of hospital stay.

Use of diffusion tensor imaging in glioma resection.

Diffusion tensor imaging (DTI) is increasingly used in the resection of both high- and low-grade gliomas. Whereas conventional MRI techniques provide only anatomical information, DTI offers data on CNS connectivity by enabling visualization of important white matter tracts in the brain. Importantly, DTI allows neurosurgeons to better guide their surgical approach and resection. Here, the authors review basic scientific principles of DTI, include a primer on the technology and image acquisition, and outline the modality's evolution as a frequently used tool for glioma resection. Current literature supporting its use is summarized, highlighting important clinical studies on the application of DTI in preoperative planning for glioma resection, preoperative diagnosis, and postoperative outcomes. The authors conclude with a review of future directions for this technology.

Lateral extracavitary, costotransversectomy, and transthoracic thoracotomy approaches to the thoracic spine: review of techniques and complications.

STUDY DESIGN: Systematic review. OBJECTIVE: The authors review complications, as reported in the literature, associated with ventral and posterolateral approaches to the thoracic spine. SUMMARY OF BACKGROUND: The lateral extracavitary, costotransversectomy, and transthoracic thoracotomy techniques allow surgeons to access the ventral thoracic spine for a wide range of spinal disorders including tumor, degeneration, trauma, and infection. Although the transthoracic thoracotomy has been used traditionally to reach the ventral thoracic spine when access to the vertebral body is required, modifications to the various dorsal approaches have enabled surgeons to achieve goals of decompression, reconstruction, and stabilization through a single approach. METHODS: A systematic Medline search from 1991 to 2011 was performed to identify series reporting clinical data related to these surgical approaches. The morbidity associated with each approach is reviewed and strategies for complications avoidance are discussed. RESULTS: Four thousand six hundred seventy-seven articles that assessed outcomes of the approaches to the thoracic spine were identified; of these 31 studies that consisted of 774 patients were selected for inclusion. A mean complication rate of 39%, 17%, and 15% for thoracotomy, lateral extracavitary, and costotransversectomy, respectively, was determined. The thoracotomy approach had the highest reoperation (3.5%) and mortality rates (1.5%). The specific complications and neurological outcomes were categorized. CONCLUSIONS: Outcomes of the surgical approaches to the thoracic spine have been reported with great detail in the literature. There are limited studies comparing the respective advantages and disadvantages and the differences in technique and outcome between these approaches. The present review suggests that in contrast to the historical experience of the laminectomy for thoracic spine disorders, these alternative approaches are safe and rarely associated with neurological deterioration. The differences between these approaches are based on their complication profiles. A thorough understanding of the regional anatomy will help avoid approach-related complications.

Emerging roles of nucleotide metabolism in cancer.

Nucleotides are substrates for multiple anabolic pathways, most notably DNA and RNA synthesis. Since nucleotide synthesis inhibitors began to be used for cancer therapy in the 1950s, our understanding of how nucleotides function in tumor cells has evolved, prompting a resurgence of interest in targeting nucleotide metabolism for cancer therapy. In this review, we discuss recent advances that challenge the idea that nucleotides are mere building blocks for the genome and transcriptome and highlight ways that these metabolites support oncogenic signaling, stress resistance, and energy homeostasis in tumor cells. These findings point to a rich network of processes sustained by aberrant nucleotide metabolism in cancer and reveal new therapeutic opportunities.