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Introduction and Objectives: We aimed to assess the outcomes of patients with trigeminal neuralgia (TGN) who underwent Gamma Knife radiosurgery (GKRS)., Materials and Methods: Fifty-three patients with typical TGN underwent GKRS from May 2012 until December 2022. Among these patients, 45 patients who were follow-up for at least 12 months were included in the study. A mean dose of 87.5 Gy (range, 80-90) was administered to the trigeminal nerve. Postoperatively, outcome was considered excellent if the patient was pain- and medication-free., Results: The mean symtpom duration was 9.53 years, and the mean patient age was 59.8 years (range, 34-85). The mean follow-up period was 46.8 months (range, 12-127 months). 46.7% of patients had a history of previous surgical interventions. A single nerve division was affected in 14 patients (31.1%), and multiple divisions were affected in 31 patients (68.9%). The rate of initial pain relief was 80%. Hypoesthesia in the area of trigeminal nerve developed in 30 (66.7%). Twenty patients (44.4%) exhibited excellent results within 72.4 months. Recurrence occurred in 11 patients (24.4%) with 27.6 months., Conclusions: Our results suggest that GKRS is a safe and effective procedure. Thus, it is an attractive first- and second-line treatment choice for TGN., (Copyright © 2024 Sociedad Española de Neurocirugía. Published by Elsevier España, S.L.U. All rights reserved.)

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21 , AZD4625, a clinical development candidate for the treatment of KRAS G12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRAS G12C with an anticipated low clearance and high oral bioavailability profile in humans.

Background: We assessed the safety and efficacy of flow diverter stents (FDSs) in the treatment of recanalized or residual intracranial aneurysms treated endovascularly., Materials & Methods: Patients whose recanalized or residual aneurysms were treated with FDSs in five tertiary hospitals were reviewed retrospectively. The patients' demographic data, aneurysm characteristics, types of previous treatment, and clinical complications, or serious adverse events associated with FDSs, as well as the results of neurological and angiographic follow-up assessments, were recorded., Results: Eighty-six patients (37 males) with 87 aneurysms were included in this study. Eighty (91.9%) aneurysms were in the anterior and seven (8.1%) in the posterior circulation. The initial treatment methods were the primary coiling or balloon remodeling technique in 69 (79.3%) and stent-assisted coiling in 18 (20.7%) aneurysms. The endovascular procedure was successful in all patients. Complications occurred in four patients, for a total complication rate of 4.6%. A technical complication developed in one patient (1.2%). An in-stent thrombosis treated with tirofiban was seen in two cases. Late in-stent stenosis exceeding 50% was treated with balloon angioplasty in one patient. The mean length of follow-up was 21.0 months. The first angiographic follow-up (3-6 months) revealed the complete occlusion of 74 aneurysms (85.1%). While 76 aneurysms (87.4%) were occluded at the last angiographic follow-up (mean: 26.0 months), 11 aneurysms (12.6%) were still filling. Morbimortality was zero., Conclusion: The drawback of endovascular treatment is aneurysmal remnants or recurrences, which is safely and durably amenable to flow diversion.

The RAS-regulated RAF-MEK1/2-ERK1/2 (RAS/MAPK) signaling pathway is a major driver in oncogenesis and is frequently dysregulated in human cancers, primarily by mutations in BRAF or RAS genes. The clinical benefit of inhibitors of this pathway as single agents has only been realized in BRAF -mutant melanoma, with limited effect of single-agent pathway inhibitors in KRAS -mutant tumors. Combined inhibition of multiple nodes within this pathway, such as MEK1/2 and ERK1/2, may be necessary to effectively suppress pathway signaling in KRAS -mutant tumors and achieve meaningful clinical benefit. Here, we report the discovery and characterization of AZD0364, a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and kinase selectivity. In vitro , AZD0364 treatment resulted in inhibition of proximal and distal biomarkers and reduced proliferation in sensitive BRAF -mutant and KRAS -mutant cell lines. In multiple in vivo xenograft models, AZD0364 showed dose- and time-dependent modulation of ERK1/2-dependent signaling biomarkers resulting in tumor regression in sensitive BRAF - and KRAS -mutant xenografts. We demonstrate that AZD0364 in combination with the MEK1/2 inhibitor, selumetinib (AZD6244 and ARRY142886), enhances efficacy in KRAS -mutant preclinical models that are moderately sensitive or resistant to MEK1/2 inhibition. This combination results in deeper and more durable suppression of the RAS/MAPK signaling pathway that is not achievable with single-agent treatment. The AZD0364 and selumetinib combination also results in significant tumor regressions in multiple KRAS -mutant xenograft models. The combination of ERK1/2 and MEK1/2 inhibition thereby represents a viable clinical approach to target KRAS -mutant tumors., (©2020 American Association for Cancer Research.)

Objective: Despite optimal improvement in motor functioning, both short- and long-term studies have reported small but consistent changes in cognitive functioning following STN-DBS in Parkinson's disease (PD). The aim of the present study was to explore whether surgical characteristics were associated with cognitive decline one year following STN-DBS., Methods: We retrospectively analyzed 49 PD patients who underwent bilateral STN-DBS. Cognitive change scores were related to the number of microelectrode recording (MER) trajectories, the STN length as measured by MER, and cortical entry points. Regression analyses were corrected for age at surgery, disease duration, education and preoperative levodopa responsiveness. Patients were then divided into a cognitive and non-cognitive decline group for each neuropsychological test and compared regarding demographic and surgical characteristics., Results: One year postoperatively, significant declines were found in verbal fluency, Stroop Color-Word test and Trail Making Test B (TMT-B). Only changes in TMT-B were associated with the coronal entry point in the right hemisphere. The number of MER trajectories and STN length were not associated with cognitive change scores. When comparing the cognitive decline and non-cognitive decline groups, no significant differences were found in surgical characteristics., Conclusions: The electrode passage through the right prefrontal lobe may contribute to subtle changes in executive function. However, only few patients showed clinically relevant cognitive decline. The use of multiple MER trajectories and a longer STN length were not associated with cognitive decline one year following surgery. From a cognitive point of view, DBS may be considered a relatively safe procedure., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRAS G12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRAS G12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.

The RAS/MAPK pathway is a major driver of oncogenesis and is dysregulated in approximately 30% of human cancers, primarily by mutations in the BRAF or RAS genes. The extracellular-signal-regulated kinases (ERK1 and ERK2) serve as central nodes within this pathway. The feasibility of targeting the RAS/MAPK pathway has been demonstrated by the clinical responses observed through the use of BRAF and MEK inhibitors in BRAF V600E/K metastatic melanoma; however, resistance frequently develops. Importantly, ERK1/2 inhibition may have clinical utility in overcoming acquired resistance to RAF and MEK inhibitors, where RAS/MAPK pathway reactivation has occurred, such as relapsed BRAF V600E/K melanoma. We describe our structure-based design approach leading to the discovery of AZD0364, a potent and selective inhibitor of ERK1 and ERK2. AZD0364 exhibits high cellular potency (IC 50 = 6 nM) as well as excellent physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties and has demonstrated encouraging antitumor activity in preclinical models.

Aim: To investigate the costs of treating the infection with antibiotics only with the risk of surgery when unsuccessful versus immediate removal followed by re-implantation in patients with deep brain stimulation (DBS) hardware infection., Material and Methods: We calculated the costs of the different strategies through a standard costing procedure. A decision model has been applied to establish the average treatment cost per patient representative for a clinical setting where both strategies are employed. Subsequently, a sensitivity analysis has been performed to assess the influence of clinical assumptions regarding the effectiveness of antibiotics treatment on average treatment costs., Results: The costs of treating a case of DBS hardware infection with immediate internal pulse generator (IPG) replacement surgery were ?29,301 compared to ?9499 for successful antibiotic treatment. For antibiotic treatment followed by IPG replacement surgery the total costs were ?38,741. Antibiotic treatment alone was successful in 44% (4/9) of the included cases of DBS infection, resulting in average treatment costs per patient of ?25,745. Trying to resolve DBS hardware infections initially with antibiotics reduced treatment costs by 12.1%., Conclusion: Treatment with antibiotics with the risk of a later removal when unsuccessful was a more valuable strategy in terms of costs when compared to immediate surgical intervention in cases of hardware-related infections in DBS surgeries.

There are a number of small-molecule inhibitors targeting the RAS/RAF/MEK/ERK signaling pathway that have either been approved or are in clinical development for oncology across a range of disease indications. The inhibition of ERK1/2 is of significant current interest, as cell lines with acquired resistance to BRAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition in preclinical models. This article reports on our recent work to identify novel, potent, and selective reversible ERK1/2 inhibitors from a low-molecular-weight, modestly active, and highly promiscuous chemical start point, compound 4. To guide and inform the evolution of this series, inhibitor binding mode information from X-ray crystal structures was critical in the rapid exploration of this template to compound 35, which was active when tested in in vivo antitumor efficacy experiments.

Aim: Failed cranioplasty attempts may lead to numerous complications in a broad spectrum including cosmetic problems, infection, neurological deterioration and even death. Selection of the most appropriate surgical technique for second and further surgical attempts for these patients still remains a debate. We aimed to share our experience and technical pitfalls on management of failed cranioplasty, particularly for patients with large cranial defects., Material and Methods: A retrospective data analysis of cranioplasty cases in our series was performed including the time period between 2002 and 2012. Patients required recurrent cranioplasty were analyzed in detail., Results: Totally, 101 patients underwent cranioplasty for bony defect. Of 101 patients, eleven required a revision surgery due to infection or spontaneous resorption of the bone flap. All patients underwent revision cranioplasty with pre-surgical plaster cast mold technique modified from previous studies and/or tissue expansion technique. Polymethyl-metacrylate (PMMA) was used as substitute for reconstructions. Mean follow-up was 36 months. Two out of eleven cases (18.1%) developed major complications, which led to further revision. At the end, a satisfactory reconstruction was achieved for all patients., Conclusion: Our modified molded plaster cast technique is a safe and cost-effective approach for the revision of failed cranioplasty. We believe that the tissue expanding techniques have also great contribution to achieve successful results.

A collaborative high throughput screen of 1.35 million compounds against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification of a novel series of inhibitors. Elucidation of the bound ligand crystal structure showed that the inhibitors exhibited a novel binding mode in a previously identified allosteric site of IDH1 (R132H). This information guided the optimization of the series yielding submicromolar enzyme inhibitors with promising cellular activity. Encouragingly, one compound from this series was found to induce myeloid differentiation in primary human IDH1 R132H AML cells in vitro.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumor growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels, demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth-inhibitory effects compared with monotherapy alone. Tumor regressions were also seen in a long-term estrogen-deprived breast model, where significant downregulation of ERα protein was observed. AZD9496 bound and downregulated clinically relevant ESR1 mutants in vitro and inhibited tumor growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacologic evidence showed that AZD9496 is an oral, nonsteroidal, selective estrogen receptor antagonist and downregulator in ER(+) breast cells that could provide meaningful benefit to ER(+) breast cancer patients. AZD9496 is currently being evaluated in a phase I clinical trial. Cancer Res; 76(11); 3307-18. ©2016 AACR., (©2016 American Association for Cancer Research.)

Aim: High frequency stimulation of the subthalamic nucleus (STN) is nowadays a widely performed surgery for patients with Parkinson's disease (PD). The field has witnessed a shift from indirect targeting to direct targeting. The question arises whether this change has influenced the final electrode position in STN deep brain stimulation surgery. To address this question, we compared the final electrode positions in atlas-based and magnetic resonance-based targeting methods in our series., Material and Methods: We performed a database review of the surgeries performed in three affiliated centers., Results: We have found that with the shift to direct imaging, three key changes have taken place. The first is that the number of microelectrode recording trajectories has decreased by approximately 1 microelectrode. Secondly, the central trajectory has been chosen as the final position in more patients, and the third change is that direct targeting has improved the laterality of the targeting significantly., Conclusion: Direct targeting has changed routine clinical practice, thereby further refining the surgical approach.

Objectives: Deep brain stimulation is nowadays a frequently performed surgery in patients with movement disorders, intractable epilepsy, and severe psychiatric disorders. The most feared complication of this surgery is an intracerebral hemorrhage due to the electrode placement, either for intraoperative electrophysiology (microelectrode recording) and/or implantation of the final electrode (macroelectrode). Here, we have investigated the risk of developing an intracerebral hemorrhage in our cohort of deep brain stimulation patients over a period of 15 years., Patients and Methods: We have collected demographic data and analyzed the effect of performing surgery with single-electrode versus multiple electrode guided DBS. The effect of using single-dose versus double-dose contrast enhanced MRI to visualize vessels for the electrode trajectory planning has been investigated as well., Results: We have found that the overall calculated risk of an intracerebral hemorrhage in our series was 1.81% per patient, 0.3% per recording electrode and 0.23% per brain insertion. While three out of four patients recovered without neurological deficits, there was one mortality in a patient with cardiovascular comorbidities. Statistical comparisons between the groups of single-electrode versus multiple electrode guided surgery and single-dose gadolinium versus double-dose contrast enhanced MRI revealed no significant differences. In addition, there was no meaningful correlation between the age at surgery and the risk of bleeding., Conclusion: We have found that the risk of developing an intracerebral hemorrhage due to deep brain stimulation surgery is low. The clinical course of the patients with an intracerebral hemorrhage was generally favorable., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The discovery of an orally bioavailable selective estrogen receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced estrogen receptor (ER) positive breast cancer.

Here, we describe an approach to identify novel selective estrogen receptor downregulator (SERD) compounds with improved properties such as oral bioavailability and the potential of increased efficacy compared to currently marketed drug treatments. Previously, methodologies such as Western blotting and transient cell reporter assays have been used to identify and characterize SERD compounds, but such approaches can be limited due to low throughput and sensitivity, respectively. We have used an endogenous cell-imaging strategy that has both the throughput and sensitivity to support a large-scale hit-to-lead program to identify novel compounds. A screening cascade with a suite of assays has been developed to characterize compounds that modulate estrogen receptor α (ERα)-mediated signaling or downregulate ERα levels in cells. Initially, from a focused high-throughput screening, novel ERα binders were identified that could be modified chemically into ERα downregulators. Following this, cellular assays helped determine the mechanism of action of compounds to distinguish between on-target and off-target compounds and differentiate SERDs, selective estrogen receptor modulator (SERM) compounds, and agonist ERα ligands. Data are shown to exemplify the characterization of ERα-mediated signaling inhibitors using a selection of literature compounds and illustrate how this cascade has been used to drive the chemical design of novel SERD compounds., (© 2015 Society for Laboratory Automation and Screening.)

The RAS/RAF/MEK/ERK signaling pathway has been targeted with a number of small molecule inhibitors in oncology clinical development across multiple disease indications. Importantly, cell lines with acquired resistance to B-RAF and MEK inhibitors have been shown to maintain sensitivity to ERK1/2 inhibition by small molecule inhibitors. There are a number of selective, noncovalent ERK1/2 inhibitors reported along with the promiscuous hypothemycin (and related analogues) that act via a covalent mechanism of action. This article reports the identification of multiple series of highly selective covalent ERK1/2 inhibitors informed by structure-based drug design (SBDD). As a starting point for these covalent inhibitors, reported ERK1/2 inhibitors and a chemical series identified via high-throughput screening were exploited. These approaches resulted in the identification of selective covalent tool compounds for potential in vitro and in vivo studies to assess the risks and or benefits of targeting this pathway through such a mechanism of action.

Vertebral artery injury including thrombosis, arteriovenous fistula (AVF), pseudo-aneurysm and hemorrhage may be iatrogenic or due to penetrating or blunt trauma. Although mostly asymptomatic, vertebral artery injury may also present with vertebrobasilar insufficiency findings, cephalgia, radicular pain or myelopathy due to blockade of arterial flow, arterial steal phenomenon and venous hypertension. The gold standard for diagnosis is digital subtraction angiography (DSA). Doppler ultrasonography, magnetic resonance-angiography and computerized tomography-angiography are also helpful. Endovascular treatment is now used more commonly. We present a case with sharp bread knife injury of the vertebral artery that was also complicated with a vertebrojugular fistula and pseudo-aneurysm together with the diagnostic and management options and a review of the current literature.

Flap endonuclease-1 (FEN1) is a highly conserved metallonuclease and is the main human flap endonuclease involved in the recognition and cleavage of single-stranded 5' overhangs from DNA flap structures. The involvement of FEN1 in multiple DNA metabolism pathways and the identification of FEN1 overexpression in a variety of cancers has led to interest in FEN1 as an oncology target. In this article, we describe the development of a 1536-well high-throughput screening assay based on the change in fluorescence polarization of a FEN1 DNA substrate labeled with Atto495 dye. The assay was subsequently used to screen 850 000 compounds from the AstraZeneca compound collection, with a Z' factor of 0.66 ± 0.06. Hits were followed up by IC50 determination in both a concentration-response assay and a technology artifact assay.

Various complications following ventriculoperitoneal (VP) shunting have been reported but transoral protrusion of peritoneal catheter is a very rare situation. This case is the first adult with a transoral VP shunt protrusion in available literature. A 47-year-old female with pseudotumor cerebri admitted after the peritoneal catheter protruded from her mouth during retching. Endoscopic examination showed a catheter inside stomach entered through the anterior surface. The patient was treated via VP shunt extraction and remained stable. Extrusion of peritoneal catheter through vagina, anus, scrotal skin or gastrostomy wound is well-known. However transoral protrusion should be considered as a very rare complication of VP shunting, especially in an adult. We present a rare case of transoral protrusion of a peritoneal catheter 10 years after ventriculo-peritoneal shunting procedure and review of the literature through this article.