Can we Predict Drug Excretion into Saliva? A Systematic Review and Analysis of Physicochemical Properties.

BACKGROUND AND OBJECTIVES: Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. METHODS: Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. RESULTS: Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = - 0.76, p = 0.01) and polar surface area (R = - 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = - 0.65, p = 0.04) and hydrogen bond donor count (R = - 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. CONCLUSIONS: Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach to improve patient outcomes.

New Oxazolidinones for Tuberculosis: Are Novel Treatments on the Horizon?

Multidrug-resistant tuberculosis (MDR-TB) is a global health concern. Standard treatment involves the use of linezolid, a repurposed oxazolidinone. It is associated with severe adverse effects, including myelosuppression and mitochondrial toxicity. As such, it is imperative to identify novel alternatives that are better tolerated but equally or more effective. Therefore, this review aims to identify and explore the novel alternative oxazolidinones to potentially replace linezolid in the management of TB. The keywords tuberculosis and oxazolidinones were searched in PubMed to identify eligible compounds. The individual drug compounds were then searched with the term tuberculosis to identify the relevant in vitro, in vivo and clinical studies. The search identified sutezolid, tedizolid, delpazolid, eperezolid, radezolid, contezolid, posizolid and TBI-223, in addition to linezolid. An additional search resulted in 32 preclinical and 21 clinical studies. All novel oxazolidinones except posizolid and eperezolid resulted in positive preclinical outcomes. Sutezolid and delpazolid completed early phase 2 clinical studies with better safety and equal or superior efficacy. Linezolid is expected to continue as the mainstay therapy, with renewed interest in drug monitoring. Sutezolid, tedizolid, delpazolid and TBI-223 displayed promising preliminary results. Further clinical studies would be required to assess the safety profiles and optimize the dosing regimens.

Reducing hand radiation during renal access for percutaneous nephrolithotomy: a comparison of radiation reduction techniques.

Percutaneous nephrolithotomy confers the highest radiation to the urologist's hands compared to other urologic procedures. This study compares radiation exposure to the surgeon's hand and patient's body when utilizing three different techniques for needle insertion during renal access. Simulated percutaneous renal access was performed using a cadaveric patient and separate cadaveric forearm representing the surgeon's hand. Three different needle-holding techniques were compared: conventional glove (control), a radiation-attenuating glove, and a novel needle holder. Five 300-s fluoroscopy trials were performed per treatment arm. The primary outcome was radiation dose (mSv) to the surgeon's hand. The secondary outcome was radiation dose to the patient. One-way ANOVA and Tukey's B post-hoc tests were performed with p < 0.05 considered significant. Compared to the control (3.92 mSv), both the radiation-attenuating glove (2.48 mSv) and the needle holder (1.37 mSv) reduced hand radiation exposure (p < 0.001). The needle holder reduced hand radiation compared to the radiation-attenuating glove (p < 0.001). The radiation-attenuating glove resulted in greater radiation produced by the C-arm compared to the needle holder (83.49 vs 69.22 mGy; p = 0.019). Patient radiation exposure was significantly higher with the radiation-attenuating glove compared to the needle holder (8.43 vs 7.03 mSv; p = 0.027). Though radiation-attenuating gloves decreased hand radiation dose by 37%, this came at the price of a 3% increase in patient exposure. In contrast, the needle holder reduced exposure to both the surgeon's hand by 65% and the patient by 14%. Thus, a well-designed low-density needle holder could optimize radiation safety for both surgeon and patient.

Not All Flat-Panel C-Arms Are Created Equal: A Comparison of Three Major Manufacturers.

Introduction: Flat-panel detector C-arms (FCs) are reported to reduce radiation exposure and improve image quality compared with conventional image intensifier C-arms (CCs). The purpose of this study was to compare radiation exposure and image quality between three commonly used FCs. Materials and Methods: A cadaver model was placed in the prone position to simulate percutaneous nephrolithotomy. We compared the following three FCs: OEC Elite CFD from GE HealthCare, Zenition 70 from Philips, and Ziehm Vision RFD from Ziehm Imaging. To measure the radiation dose, optically stimulated luminescence dosimeters (OSLDs) were utilized during five 300-second trials, conducted under three settings: automatic exposure control (AEC), AEC with low dose (LD), and LD with the lowest pulse rate (LDLP). Ten blinded urologists evaluated the image quality. Data were statistically analyzed using the analysis of variance (ANOVA) and Tukey's B post hoc tests. Results: In the AEC setting, the Philips C-arm demonstrated lower ventral OSLD exposure (42,446 mrad) compared with both the GE (51,076 mrad) and Ziehm (83,178 mrad; p < 0.001) C-arms. Similarly, in the LD setting, the Philips C-arm resulted in less ventral OSLD exposure (25,926 mrad) than both the Ziehm (30,956 mrad) and GE (38,209 mrad; p < 0.001) C-arms. Meanwhile, in the LDLP setting, the Ziehm C-arm showed less ventral OSLD exposure (4019 mrad) than both the GE (7418 mrad) and Philips (8229 mrad; p < 0.001) C-arms. All three manufacturers received adequate image quality ratings at the AEC and LD settings. However, at LDLP, the Ziehm C-arm received inadequate ratings in 8% of images, whereas both the GE and Philips C-arms received 100% adequate ratings (p = 0.016). Conclusions: Radiation produced by flat-panel C-arms varies dramatically, with the highest exposure (Ziehm) being almost double the lowest (Philips) in AEC. Improved picture quality at the lowest settings may come at the cost of increased radiation dose. Surgeons should carefully select the machine and settings to minimize radiation exposure while still preserving the image quality.

Time Efficiency and Performance of Single-Use vs Reusable Cystoscopes: A Randomized Benchtop and Simulated Clinical Assessment.

Introduction: A flexible cystoscope is an indispensable tool for urologists, facilitating a variety of procedures in both the operating room and at bedside. Single-use cystoscopes offer benefits including accessibility and decreased burden for reprocessing. The aims of this study were to compare time efficiency and performance of single-use and reusable cystoscopes. Methods: Ten new Ambu® aScope™ 4 Cysto single-use and two Olympus CYF-5 reusable cystoscopes were compared in simulated bedside cystoscopy and benchtop testing. Ten urologists performed simulated cystoscopy using both cystoscopes in a randomized order. Times for supply-gathering, setup, cystoscopy, cleanup, and cumulative time were recorded, followed by a Likert feedback survey. For benchtop assessment, physical, optical, and functional specifications were assessed and compared between cystoscopes. Results: The single-use cystoscope demonstrated shorter supply-gathering, setup, cleanup, and cumulative times (824 vs 1231 seconds; p < 0.05) but a comparable cystoscopy time to the reusable cystoscope (202 vs 212 seconds; p = 0.32). The single-use cystoscope had a higher image resolution, but a narrower field of view. Upward deflection was greater for the single-use cystoscope (214.50° vs 199.45°; p < 0.01) but required greater force (2.5 × ). The working channel diameter and irrigation rate were greater in the reusable cystoscope. While the single-use cystoscope lacked tumor enhancing optical features, it had higher Likert scale scores for Time Efficiency and Overall Satisfaction. Conclusion: The single-use cystoscope demonstrates comparable benchtop performance and superior time efficiency compared to reusable cystoscopes. However, the reusable cystoscope has superior optical versatility and flow rate. Knowledge of these differences allows for optimal cystoscope selection based on procedure indication.

Does renal failure worsen radiation cystitis following radical prostatectomy?

OBJECTIVE: To investigate the impact of renal function on the risk, severity, and management of radiation cystitis in patients who underwent postoperative radiation therapy for prostate cancer. METHODS: Retrospective data was assessed from patients treated with adjuvant/salvage radiation therapy at a single academic institution between 2006 and 2020. The incidence, severity, and management of radiation cystitis were compared between three groups: CKD 0-2, CKD 3-4, and CKD 5. Associations of clinicopathologic factors with radiation cystitis were assessed in univariate and multivariate Cox regression models. RESULTS: A total of 110 patients who underwent radiation therapy following robot-assisted laparoscopic radical prostatectomy were included. The incidence of radiation cystitis following postoperative radiation therapy was 17% with a median presentation time of 34 months (interquartile range 16-65 months). The incidence of radiation cystitis was 100% in CKD 5 patients compared to 15% in CKD 0-2 and 17% in CKD 3-4 patients (p < 0.001). CKD 5 patients required more treatments, emergency department visits, and longer hospitalization times than CKD 0-4 patients (all p < 0.001). Multivariate analyses identified CKD 5 as the only significant factor associated with radiation cystitis (HR = 10.39, p = 0.026). CONCLUSION: End-stage renal failure is associated with the risk and severity of radiation cystitis in patients receiving postoperative radiation therapy. Knowledge of the potential morbidity of this complication in this population could guide physicians and patients as they evaluate risks and benefits prior to selecting adjuvant or salvage radiation therapy.

Is there a need to optimise pyrazinamide doses in patients with tuberculosis? A systematic review.

Pyrazinamide (PZA) is a first-line antituberculosis drug with potent sterilising activity. Variability in drug exposure may translate into suboptimal treatment responses. This systematic review, conducted according to PRISMA guidelines, aimed to evaluate the concentration-effect relationship. In vitro/in vivo studies had to contain information on the infection model, PZA dose and concentration, and microbiological outcome. Human studies had to present information on PZA dose, measures of drug exposure and maximum concentration, and microbiological response parameter or overall treatment outcome. A total of 34 studies were assessed, including in vitro (n = 2), in vivo (n = 3) and clinical studies (n = 29). Intracellular and extracellular models demonstrated a direct correlation between PZA dose of 15-50 mg/kg/day and reduction in bacterial count between 0.50-27.7 log10 CFU/mL. Consistent with this, higher PZA doses (>150 mg/kg) were associated with a greater reduction in bacterial burden in BALB/c mice models. Human pharmacokinetic studies displayed a linear positive correlation between PZA dose (i.e. 21.4-35.7 mg/kg/day) and drug exposure (AUC range 220.6-514.5 mg·h/L). Additionally, human studies confirmed a dose-effect relationship, with an increased 2-month sputum culture conversion rate at AUC/MIC targets of 8.4-11.3 with higher exposure/susceptibility ratios leading to greater efficacy. A 5-fold variability in AUC was observed at PZA dose of 25 mg/kg. A direct concentration-effect relationship and increased treatment efficacy with higher PZA exposure to susceptibility ratios was observed. Taking into account variability in drug exposure and treatment response, further studies on dose optimisation are justified.

Cancer stem cell assay-guided chemotherapy improves survival of patients with recurrent glioblastoma in a randomized trial.

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world.

Lipschitz continuity under toric equivalence for asynchronous Boolean networks.

Mathematical models rooted in network representations are becoming increasingly more common for capturing a broad range of phenomena. Boolean networks (BNs) represent a mathematical abstraction suited for establishing general theory applicable to such systems. A key thread in BN research is developing theory that connects the structure of the network and the local rules to phase space properties or so-called structure-to-function theory. While most theory for BNs has been developed for the synchronous case, the focus of this work is on asynchronously updated BNs (ABNs) which are natural to consider from the point of view of applications to real systems where perfect synchrony is uncommon. A central question in this regard is sensitivity of dynamics of ABNs with respect to perturbations to the asynchronous update scheme. Macauley & Mortveit [Nonlinearity 22, 421-436 (2009)] showed that the periodic orbits are structurally invariant under toric equivalence of the update sequences. In this paper and under the same equivalence of the update scheme, the authors (i) extend that result to the entire phase space, (ii) establish a Lipschitz continuity result for sequences of maximal transient paths, and (iii) establish that within a toric equivalence class the maximal transient length may at most take on two distinct values. In addition, the proofs offer insight into the general asynchronous phase space of Boolean networks.

RNA Secondary Structures with Given Motif Specification: Combinatorics and Algorithms.

The study of native motifs of RNA secondary structures helps us better understand the formation and eventually the functions of these molecules. Commonly known structural motifs include helices, hairpin loops, bulges, interior loops, exterior loops and multiloops. However, enumerative results and generating algorithms taking into account the joint distribution of these motifs are sparse. In this paper, we present progress on deriving such distributions employing a tree-bijection of RNA secondary structures obtained by Schmitt and Waterman and a novel rake decomposition of plane trees. The key feature of the latter is that the derived components encode motifs of the RNA secondary structures without pseudoknots associated with the plane trees very well. As an application, we present an algorithm (RakeSamp) generating uniformly random secondary structures without pseudoknots that satisfy fine motif specifications on the length and degree of various types of loops as well as helices.

Does the Novel Thulium Fiber Laser Have a Higher Risk of Urothelial Thermal Injury than the Conventional Holmium Laser in an In Vitro Study?

Introduction and Objective: The novel thulium fiber laser (TFL) has been shown to break stones more rapidly than the holmium:YAG laser (HL). However, some evidence suggests that the TFL generates more heat. The purpose of this study is to compare ureteral temperatures generated by these lasers during ureteroscopic laser lithotripsy in a benchtop model. Methods: A 1-cm BegoStone was manually impacted in the proximal ureter of a three-dimensional printed kidney-ureter model and submerged in 35.5°C saline. Lithotripsy was performed using a 7.6F flexible ureteroscope and a 200 µm laser fiber without a ureteral access sheath. The Dornier 30 W HL, Olympus 100 W HL, and Olympus 60 W TFL were compared. A needle thermocouple to measure temperature was inserted 2 mm from the laser tip. Irrigation was maintained at 35 cc/minute at room temperature using the Thermedx FluidSmart System. Intraluminal temperature was continuously recorded for 60 seconds of laser activation. Five trials were performed for each of four different power settings: 3.6, 10, 20, and 30 W. Analysis of variance and Mann-Whitney U tests were performed with p < 0.05 considered significant. Results: Intraureteral fluid temperature increased as laser power settings increased for all lasers (p < 0.05). The TFL generated higher average ureteral fluid temperatures than the Dornier and Empower HL at all power settings tested (p < 0.001). The maximum temperature for the TFL was higher than the Dornier and Empower HL at all power settings tested (p < 0.001), except at 20 W with the Empower HL. At 30 W, the TFL exceeded 43°C, the threshold for tissue damage. Conclusions: The TFL generated more heat at all settings tested. Supraphysiologic ureteral temperatures may be generated with extended use at high energy settings and low irrigation rates. Understanding the heat generation properties of both lasers could help improve the safety of ureteroscopic laser lithotripsy.

Intravascular Lymphoma with Progressive CNS Hemorrhage and Multiple Dissections.

INTRODUCTION: Intravascular lymphoma (IVL) is an uncommon and often fatal disease characterized by intraluminal proliferation of lymphomatous cells within blood vessels. Because of a heterogeneous clinical presentation and lack of sensitive diagnostic protocols, diagnosis of IVL is most often made at autopsy. However, with early diagnosis and appropriate chemotherapy, the prognosis is greatly improved and complete remission is possible. In order to broaden the possible presentations of IVL, we present a patient with an atypical manifestation of biopsy-proven intravascular large B-cell lymphoma who suffered dissections of both intracranial and extracranial arteries in addition to progressive intracranial hemorrhages. Case Report. A 47-year-old woman presented with unilateral paresthesias. She developed progressive multifocal infarcts and hemorrhage with dissections of both intracranial and extracranial arteries, resulting in coma. Brain biopsy revealed IVL. She received aggressive chemotherapy and remains in complete remission with good neurologic recovery. CONCLUSION: IVL is known to exert its pathology on small arteries and capillaries, but is not known to cause dissections of large vessels. The diagnosis should be considered in cases with unexplained arterial dissections and progressive strokes. Early diagnosis with appropriate laboratory screening and tissue confirmation by biopsy can lead to greatly improved outcomes.

Glioma Subclassifications and Their Clinical Significance.

The impact of targeted therapies in glioma has been modest. All the therapies that have demonstrated a significant survival benefit for gliomas in Phase III trials, including radiation, chemotherapy (temozolomide and PCV [procarbazine, lomustine, vincristine]), and tumor-treating fields, are based on nonspecific targeting of proliferating cells. Recent advances in the molecular understanding of gliomas suggest some potential reasons for the failure of more targeted therapies in gliomas. Specifically, the histologic-based glioma classification is composed of multiple different molecular subtypes with distinct biology, natural history, and prognosis. As a result of these insights, the diagnosis and classification of gliomas have recently been updated by the World Health Organization. However, these changes and other novel observations regarding glioma biomarkers and subtypes highlight several clinical challenges. First, the field is faced with the difficulty of reinterpreting the results of prior studies and retrospective data using the new classifications to clarify prognostic assessments and treatment recommendations for patients. Second, the new classifications and insights require rethinking the design and stratification of future clinical trials. Last, these observations provide the essential framework for the development and testing of new specific targeted therapies for particular glioma subtypes. This review aims to summarize the current literature regarding glioma subclassifications and their clinical relevance in this evolving field.

Transcranial magnetic stimulation for the treatment of epilepsy.

BACKGROUND: Epilepsy is a highly prevalent neurological condition characterized by repeated unprovoked seizures with various etiologies. Although antiepileptic medications produce clinical improvement in most individuals, nearly a third of individuals have drug-resistant epilepsy that carries significant morbidity and mortality. There remains a need for non-invasive and more effective therapies for this population. Transcranial magnetic stimulation (TMS) uses electromagnetic coils to excite or inhibit neurons, with repetitive pulses at low-frequency producing an inhibitory effect that could conceivably reduce cortical excitability associated with epilepsy. OBJECTIVES: To assess the evidence for the use of TMS in individuals with drug-resistant epilepsy compared with other available treatments in reducing seizure frequency, improving quality of life, reducing epileptiform discharges, antiepileptic medication use, and side-effects. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 10 March 2016), ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (ICTRP) up to March 2016. We also searched SCOPUS (1823 to June 2014) as a substitute for Embase (but it is no longer necessary to search SCOPUS, because randomized controlled trials (RCTs) and quasi-RCTs in EMBASE are now included in CENTRAL). SELECTION CRITERIA: Eligible studies were RCTs that were double-blinded, single-blinded or unblinded, and placebo, no treatment, or active controlled, which used repetitive transcranial magnetic stimulation (rTMS) without restriction of frequency, duration, intensity, or setup (focal or vertex treatment) on patients with drug-resistant epilepsy. The search revealed 274 records from the databases, that after selection provided seven full-text relevant studies for inclusion. Of the seven studies included, five were completed studies with published data and included randomized, blinded trials. The total number of participants in the seven trials was 230. DATA COLLECTION AND ANALYSIS: We extracted information from each trial including methodological data; participant demographics including baseline seizure frequency, type of epileptic drugs taken; intervention details and intervention groups for comparison; potential biases; and outcomes and time points, primarily change in seizure frequency or responder rates, as well as quality of life and epileptiform discharges, adverse effects, and changes in medication use. MAIN RESULTS: Two of the seven studies analyzed showed a statistically significant reduction in seizure rate from baseline (72% and 78.9% reduction of seizures per week from the baseline rate, respectively). The other five studies showed no statistically significant difference in seizure frequency following rTMS treatment compared with controls. We were not able to combine the results of the trials in analysis due to differences in the designs of the studies. Four studies evaluated our secondary endpoint of mean number of epileptic discharges, and three of the four showed a statistically significant reduction in discharges. Quality of life was not assessed in any of the studies. Adverse effects were uncommon among the studies and typically involved headache, dizziness, and tinnitus. No significant changes in medication use were found in the trials. AUTHORS' CONCLUSIONS: Overall, we judged the quality of evidence for the primary outcomes of this review to be low. There is evidence that rTMS is safe and not associated with any adverse events, but given the variability in technique and outcome reporting that prevented meta-analysis, the evidence for efficacy of rTMS for seizure reduction is still lacking despite reasonable evidence that it is effective at reducing epileptiform discharges.

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future.

OPINION STATEMENT: High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

Molecular features assisting in diagnosis, surgery, and treatment decision making in low-grade gliomas.

The preferred management of suspected low-grade gliomas (LGGs) has been disputed, and the implications of molecular changes for medical and surgical management of LGGs are important to consider. Current strategies that make use of molecular markers and imaging techniques and therapeutic considerations offer additional options for management of LGGs. Mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes suggest a role for this abnormal metabolic pathway in the pathogenesis and progression of these primary brain tumors. Use of magnetic resonance spectroscopy can provide preoperative detection of IDH-mutated gliomas and affect surgical planning. In addition, IDH1 and IDH2 mutation status may have an effect on surgical resectability of gliomas. The IDH-mutated tumors exhibit better prognosis throughout every grade of glioma, and mutation may be an early genetic event, preceding lineage-specific secondary and tertiary alterations that transform LGGs into secondary glioblastomas. The O6-methylguanine-DNAmethyltransferase (MGMT) promoter methylation and 1p19q codeletion status can predict sensitivity to chemotherapy and radiation in low- and intermediate-grade gliomas. Thus, these recent advances, which have led to a better understanding of how molecular, genetic, and epigenetic alterations influence the pathogenicity of the different histological grades of gliomas, can lead to better prognostication and may lead to specific targeted surgical interventions and medical therapies.

Preadmission beta-blockers are associated with decreased incidence of neurogenic stunned myocardium in aneurysmal subarachnoid hemorrhage.

BACKGROUND: Neurogenic stunned myocardium (NSM) is a frequent complication of aneurysmal subarachnoid hemorrhage (aSAH), with a significant impact on disease course. The presumed cause is catecholamine surge at the time of aneurysm rupture. Beta-blockers, which reduce the impact of the catecholamine surge, may decrease the risk of developing NSM. METHODS: A chart review of 234 consecutive patients admitted to the Oregon Health and Science University Neurosurgery service between March 6, 2008 and June 23, 2010 with a diagnosis of aneurysmal SAH was performed. This group was further subdivided by patients who received echocardiograms on admission, by gender, and by the prehospital administration of ß-blockers. RESULTS: One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed NSM (13.8%). None of the 22 patients taking prehospital ß-blockers developed NSM. Using the Fisher exact test to compare the 2 groups, patients who were administered prehospital ß-blockers were significantly less likely to develop stunning compared to those who were not (P = .04). After correcting for other variables using multiple logistic regression analysis, the previous use of ß-blockers was still found to be significantly associated with a decreased incidence of NSM after SAH (P = .049). There was no significant difference in hospital length of stay, peribleed stroke, vasospasm, or death. Of the 18 patients with stunning, 15 were women, 5 of whom were on estrogen supplementation. The mean peak troponin elevation of women who developed NSM on estrogen supplementation was significantly higher than for those who were not (mean peak troponin 9.97 ± 2.01 mg/dL; P < .001). CONCLUSION: Prehospital ß-blockers are associated with decreased risk of developing NSM in patients with aSAH. Estrogen may play an additional role in shaping the degree of NSM in women.