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The Nuffield Department of Surgical Sciences’ Research Away Day was held on Thursday 1 October in St Catherine’s College in Oxford. The event aimed to showcase the current research activities in the department.
Patients’ priorities in kidney stone disease
Engaging with patients and the public is essential to design and deliver impactful research. Enhancing the relevance of research and tailoring treatments to align with patients’ preferences can facilitate improved clinical care. We aimed to identify the research, support, and treatment priorities of individuals with kidney stone disease (KSD) using a 25-question survey in inpatient and outpatient urology departments. Forty-four individuals with KSD responded to our survey; 28 (64%) had experienced multiple KSD episodes and 11 reported five or more episodes. Median self-rated quality-of-life (QoL) impact (0=negligible, 10=severe) was 7.00/10.00 [IQR:5.00–9.00],equivalent in individuals with single and recurrent stone episodes. Pain (N=34), haematuria (N=28), and anxiety (N=22) were the primary factors contributing to QoL impact. Participants prioritised research into preventing recurrence, alleviating pain, and slowing stone growth. Over one third desired more information about KSD. Most (N=36) felt “likely” or “very likely” to take medication to reduce their risk of KSD and 25 would commit to life-long therapy. Daily dosing was acceptable to 13 participants if risk of KSD recurrence was reduced by 50%, rising to 34 respondents if risk of recurrence was reduced by 75%. Most respondents (N=44) expressed willingness to have genetic testing to facilitate personalised medicine research. Our findings emphasise symptoms contributing to reduced physical and psychological wellbeing in patients with KSD. We highlight the need for research into developing therapies to prevent stone recurrence, alleviate pain, and slow stone growth, and for educational materials. Responses indicate an appetite for personalised medicine and oral medications in KSD.
Patients’ priorities in kidney stone disease
Engaging with patients and the public is essential to design and deliver impactful research. Enhancing the relevance of research and tailoring treatments to align with patients’ preferences can facilitate improved clinical care. We aimed to identify the research, support, and treatment priorities of individuals with kidney stone disease (KSD) using a 25-question survey in inpatient and outpatient urology departments. Forty-four individuals with KSD responded to our survey; 28 (64%) had experienced multiple KSD episodes and 11 reported five or more episodes. Median self-rated quality-of-life (QoL) impact (0=negligible, 10=severe) was 7.00/10.00 [IQR:5.00–9.00],equivalent in individuals with single and recurrent stone episodes. Pain (N=34), haematuria (N=28), and anxiety (N=22) were the primary factors contributing to QoL impact. Participants prioritised research into preventing recurrence, alleviating pain, and slowing stone growth. Over one third desired more information about KSD. Most (N=36) felt “likely” or “very likely” to take medication to reduce their risk of KSD and 25 would commit to life-long therapy. Daily dosing was acceptable to 13 participants if risk of KSD recurrence was reduced by 50%, rising to 34 respondents if risk of recurrence was reduced by 75%. Most respondents (N=44) expressed willingness to have genetic testing to facilitate personalised medicine research. Our findings emphasise symptoms contributing to reduced physical and psychological wellbeing in patients with KSD. We highlight the need for research into developing therapies to prevent stone recurrence, alleviate pain, and slow stone growth, and for educational materials. Responses indicate an appetite for personalised medicine and oral medications in KSD.
The genetic and metabolic basis of kidney stone disease
Kidney stone disease (KSD) is a common, heritable, frequently recurrent condition affecting approximately 10–20% of people. Patients may be asymptomatic or experience severe pain, haematuria, urinary tract infections, and, in extreme cases, multi-organ failure. KSD and its treatments reduce health-related quality of life and its rising prevalence will cost the National Health Service over £300 million annually in England by 2030. Despite their relevance, the mechanisms underlying stone formation remain poorly understood, limiting effective preventive strategies. In this thesis, I investigate the genetic architecture of KSD to uncover molecular mechanisms and therapeutic targets for the disease. I conduct the largest genetic association studies of KSD to date, integrating combined-sex, and sex-specific analyses, European- and trans-ancestry data, and common and rare genetic variants. These studies identify novel genetic associations with KSD and highlight genes linked to mineral metabolism and renal structural disorders. Using Mendelian randomisation (MR) and colocalisation analyses, I reveal a shared genetic architecture between adiposity and KSD, implicating a causal GIPR missense variant which I propose alters renal tubular osteopontin secretion, affecting risk of stone formation. Drug-target MR analyses suggest that modulating gastric inhibitory polypeptide receptor pathways may reduce KSD risk. To investigate the mechanisms linking mineral metabolism and renal cysts to KSD, I integrate multiomic and chromatin interaction data with MR and colocalisation analyses. I identify three biological pathways contributing to approximately 12–17% of KSD cases: impaired DGKδ-mediated calcium-sensing receptor signalling; increased NaPi-IIa-mediated renal phosphate excretion; and defective 24-α-hydroxylase-mediated 1,25-dihydroxyvitamin D inactivation. I further establish a causal, bidirectional relationship between non-polycystic renal cysts and KSD, implicating TBX2-mediated effects. These findings support a “lithogenic triad” of urine supersaturation, stasis, and tubular epithelial injury in KSD pathogenesis. By integrating multiple analytical approaches with distinct and orthogonal sources of bias , I provide insights into causal mechanisms and therapeutic targets for KSD, laying the foundation for future translational research.
Data from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
<div>Abstract<p>Glioblastoma, the most malignant type of primary brain tumor, is one of the solid cancers where cancer stem cells have been isolated, and studies have suggested resistance of those cells to chemotherapy and radiotherapy. Here, we report the establishment of CSC-enriched cultures derived from human glioblastoma specimens. They grew as neurospheres in serum-free medium with epidermal growth factor and fibroblast growth factor 2, varied in the level of CD133 expression and very efficiently formed highly invasive and/or vascular tumors upon intracerebral implantation into immunodeficient mice. As a novel therapeutic strategy for glioblastoma-derived cancer stem–like cells (GBM-SC), we have tested oncolytic herpes simplex virus (oHSV) vectors. We show that although <i>ICP6</i> (<i>UL39</i>)–deleted mutants kill GBM-SCs as efficiently as wild-type HSV, the deletion of <i>γ34.5</i> significantly attenuated the vectors due to poor replication. However, this was significantly reversed by the additional deletion of <i>α47</i>. Infection with oHSV G47Δ (<i>ICP6<sup>−</sup>, γ34.5<sup>−</sup>, α47<sup>−</sup></i>) not only killed GBM-SCs but also inhibited their self-renewal as evidenced by the inability of viable cells to form secondary tumor spheres. Importantly, despite the highly invasive nature of the intracerebral tumors generated by GBM-SCs, intratumoral injection of G47Δ significantly prolonged survival. These results for the first time show the efficacy of oHSV against human GBM-SCs, and correlate this cytotoxic property with specific oHSV mutations. This is important for designing new oHSV vectors and clinical trials. Moreover, the new glioma models described in this study provide powerful tools for testing experimental therapeutics and studying invasion and angiogenesis. [Cancer Res 2009;69(8):3472–81]</p></div>
Supplementary Legends for Figures 1- 4, Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Legends for Figures 1- 4, Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Legends for Figures 1- 4, Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Supplementary Legends for Figures 1- 4, Table 1 from Human Glioblastoma–Derived Cancer Stem Cells: Establishment of Invasive Glioma Models and Treatment with Oncolytic Herpes Simplex Virus Vectors
Designing a 3D Printed Model of the Skull-Base: A Collaboration Between Clinicians and Industry.
INTRODUCTION: The role of three dimensional (3D) printing in neurosurgical education is becoming increasingly common. Notably, 3D printing can simulate complex anatomical pathways that may be difficult to regularly and accurately reproduce in cadavers. One such example is the course of the facial nerve within the temporal bone and its relation to the labyrinth. This can aid pre-surgical planning and minimise surgical complications. Here we aim to develop a novel anatomically accurate model of the skull base which demonstrates key neuro vascular components and the course of the facial nerve within the temporal bone by developing a 3D printed model of the skull-base that can be used for medical education and pre-surgical planning. MATERIALS AND METHODS: We utilised a combination of Computed Tomography (CT) and angiography scans to reconstruct the skull base and its vascular contents. Neural components were digitally incorporated under the guidance of the Oxford neurosurgical team and the anatomy department. The model was integrated and printed using polymer jetting. RESULTS: The model was successfully printed, with all neurovascular components included. Notably we were able to highlight the intra-temporal course of the facial nerve by creating a bony window within the temporal bone. CONCLUSION: Through a collaboration with industry and a multidisciplinary team, we were able to reproduce the base of the skull from patient neuro-imaging. Our model is both cost-effective, reproducible and can aid both medical students and neurosurgical trainees in their training/education.
Role of the Neuroradiologist and Neurosurgeon in Contouring with the Clinical Oncologist for Stereotactic Radiosurgery.
AIM: To evaluate the value of a multidisciplinary team (MDT), including a neuroradiologist and a neurosurgeon, review of contouring in stereotactic radiosurgery (SRS). MATERIALS AND METHODS: A sequential audit of all patients receiving intracranial SRS at local institution was conducted. Lesions were contoured first by a clinical oncologist, then reviewed/edited by the MDT. The initial contour was compared with the final contour using Jaccard conformity (JCI) and geographical miss indices (GMI). The dosimetric impact of a contouring change was assessed using plan metrics to both original and final contours. RESULTS: In total, 113 patients and 142 lesions treated over 22 months were identified. The mean JCI was 0.92 (0.32-1.00) and 38% needed significant editing (JCI <0.95). The mean GMI was 0.03 (0.0-0.65) and 17% showed significant miss (GMI >0.05). Resection cavities showed more changes, with lower JCI and higher GMI (P < 0.05). There was no significant improvement on JCI or GMI shown over time. The dosimetric analysis indicated a strong association of conformity metrics with planning target volume dose metrics; a 0.1 change in gross tumour volume conformity metric association with a 6-17% change in dose to 95% of the resulting planning target volume. Greater association was seen in the resection cavity, suggesting the geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. The median survival was 20 months; the local relapse-free rate in the treated areas was 0.89 (0.8-0.94) at 40 months; the radionecrosis-free rate at 40 months was 0.9 (0.83-0.95) with a median of 17 months to developing radionecrosis. CONCLUSIONS: This work highlights that MDT contour review adds significant value to SRS and the approach translates into reduced local recurrence rates at the local institution compared with previously published data. No improvement in clinical oncologist contouring over time was shown, indicating that a collaborative approach is needed regardless of the experience of the clinical oncologist. MDT input is recommended in particular for contouring of resection cavities.
Effect of exposure from iPhone 12 on programmable ventriculoperitoneal shunts.
The latest iPhone 12 model has elicited concerns over its interaction with medical devices such as pacemakers due to its integrated MagSafe technology. Historically, programmable ventriculoperitoneal (VP) shunts have been demonstrated to readjust when exposed to magnetic objects. Yet, the presence of interactions between the iPhone 12 and shunts is unknown. In this in-vitro study, we examined the effect on the programming of three VP shunts, Medtronic Strata II, Miethke ProGAV 2.0 and Codman Hakim, when exposed to the iPhone 12 model. We found that all three valves did not re-program when the iPhone was held near or moved in a swiping or rotational motion above the valves. Therefore, the risk of re-programming of these three shunts when exposed to iPhone 12 appears to be low. However, patients should take care until further work is undertaken to examine the complex interplay between programmable VP shunts with magnetic devices.
A surgical protocol for sinogenic brain abscess: the Oxford experience and a review of the literature
Background: Rhinosinusitis-induced brain abscesses are rare but can result in devastating long-term sequalae and mortality; they require a high index of suspicion with early imaging to start early empiric parenteral antibiotic treatment covering aerobes and anaerobes. Methodology: Our study was a retrospective analysis on 32 patients who were treated at Oxford University Hospitals for rhinosinusitis-induced brain abscess between February 2013 and June 2020. Results: Mean age of presentation was 45.83 for adults and 11.14 for children. Subdural collection was the most frequent abscess but 25% of patients had multiple sites of collection; the majority were in the frontal lobe. The most commonly identified pathogens were Streptococcus milleri group and Staphylococcus aureus; 93.75% of the patients were treated with combined Ceftriaxone and Metronidazole for an average of 8 weeks. Conclusions: In our series most patients received also a prompt and aggressive surgical treatment with combined neurosurgical and ENT procedures in the majority; this was especially important in case of subdural empyema, Streptococcus milleri infection and direct intracranial spread of infection. More than half of the patients were treated with a single surgical procedure. Despite aggressive treatment, one third of patients experienced long-term neurological sequelae; there were no deaths.
P14.85 Impact of the neuro-radiologist and neuro-surgeon in contouring with the neuro-oncologist on local relapse rates for brain metastases treated with stereotactic radiosurgery
Abstract BACKGROUND The audit evaluates the value of MDT, including neuro-radiologist and neuro-surgeon, review of contouring carried out by a clinical oncologist in stereotactic radiosurgery (SRS). MATERIAL AND METHODS A sequential audit was conducted of all patients receiving intracranial SRS at our local institution for the first 22 months of a new SRS service. Lesions were contoured first by clinical oncologist then reviewed/edited by the MDT. The initial contour was compared with final contour using Jaccard conformity and geographical miss indices. The dosimetric impact of a contouring change was assessed using plan metrics to both original and final contour. The impact of the contouring review on local relapse, overall survival and radio necrosis rate was evaluated with at least 24 months follow up (24–46 months). RESULTS 113 patients and 142 lesions treated over 22 months were identified. Mean JCI was 0.92 (0.32–1.00) and 38% needed significant editing (JCI<0.95). Mean GMI was 0.03 (0.0–0.65) and 17% showed significant miss (GMI>0.05). Resection cavities showed more changes, with lower JCI and higher GMI (p<0.05). There was no significant improvement on JCI or GMI shown over time. Dosimetric analysis indicated a strong association of conformity metrics with PTV dose metrics; a 0.1 change in GTV conformity metric association with 6–17% change in dose to 95% of resulting PTV. Greater association was seen in resection cavity suggesting the geographical nature of a typical contouring error gives rise to greater potential change in dose. Clinical outcomes compared well with published series. Median survival was 20 months and local relapse free rate in the treated areas of 0.89 (0.8–0.94) at 40 months, and 0.9 (0.83–0.95) radio-necrosis free rate at 40 months with a median 17 months to developing radio-necrosis for those that did. CONCLUSION This work highlights that a MDT contour review adds significant value to SRS and the approach translates into reduced local recurrence rates at our local institution compared with previously published data. Radio-necrosis rates are below 10%. No improvement in clinical oncologist contouring over time was shown indicating a collaborative approach is needed regardless of experience of clinical oncologist. MDT input is recommended in particular in contouring of resection cavities.
Cerebral vascular anatomy and physiology
Knowledge of normal cerebral vascular anatomy and physiology is critical for both recognizing and safely managing a range of neurosurgical conditions through either open or endovascular techniques. In this article we summarize the key features of the arterial supply and venous drainage of the brain along with their main clinical significance.
Endoscopic Endonasal Surgery for Resection of a Pterygopalatine Fossa Malignant Peripheral Nerve Sheath Tumor: 2-Dimensional Operative Video.
The pterygopalatine fossa (PPF) is an inverted, pyramid-shaped space immediately behind the posterior wall of the maxillary sinus, and lesions arising here include juvenile angiofibromas, schwannomas, and, in exceptionally rare cases, malignant peripheral nerve sheath tumors.1,2 Surgical access to the PPF is challenging and has been historically achieved via an open transmaxillary approach associated with facial scaring/deformity as well as potential injury to facial and infraorbital nerve branches.3 We present the case of a 67-year-old woman with facial numbness secondary to a presumed trigeminal schwannoma in the right PPF on magnetic resonance imaging. This surgical video highlights the key stages in performing an endoscopic endonasal excision of a PPF tumor. We start with a wide medial maxillary antrostomy, mobilization of the inferior turbinate, ethmoidectomy, and sphenoidotomy. The posterior wall of the maxillary sinus is then lifted off the anterior aspect of the tumor. The soft tissue attachment medial to the tumor containing the sphenopalatine artery is then cauterized and divided. This is followed by circumferential blunt dissection of the tumor until it is sufficiently mobile to remove in a piecemeal fashion. The PPF is then examined for any residual tumor and any bleeding from the maxillary artery within the fat pad. Hemostasis and reattachment of the inferior turbinate into the lateral nasal wall is demonstrated. The patient did not have any new deficits postoperatively, but histology indicated a malignant peripheral nerve sheath tumor and she underwent postoperative proton beam therapy. Postoperative surveillance magnetic resonance imaging at 14 months showed no tumor recurrence. The patient consented to the procedure in a standard fashion (Video 1).
Reduced decision bias and more rational decision making following ventromedial prefrontal cortex damage.
Human decisions are susceptible to biases, but establishing causal roles of brain areas has proved to be difficult. Here we studied decision biases in 17 people with unilateral medial prefrontal cortex damage and a rare patient with bilateral ventromedial prefrontal cortex (vmPFC) lesions. Participants learned to choose which of two options was most likely to win, and then bet money on the outcome. Thus, good performance required not only selecting the best option, but also the amount to bet. Healthy people were biased by their previous bet, as well as by the unchosen option's value. Unilateral medial prefrontal lesions reduced these biases, leading to more rational decisions. Bilateral vmPFC lesions resulted in more strategic betting, again with less bias from the previous trial, paradoxically improving performance overall. Together, the results suggest that vmPFC normally imposes contextual biases, which in healthy people may actually be suboptimal in some situations.