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A team led by Peter McCulloch, NDS professor and Chair of IDEAL, has examined how surgical research has improved in the last two decades and whether the IDEAL Framework and Recommendations have contributed.
Ten-year outcomes after off-pump versus on-pump coronary artery bypass grafting: Insights from the Arterial Revascularization Trial.
OBJECTIVE: We performed a post hoc analysis of the Arterial Revascularization Trial to compare 10-year outcomes after off-pump versus on-pump surgery. METHODS: Among 3102 patients enrolled, 1252 (40% of total) and 1699 patients received off-pump and on-pump surgery (151 patients were excluded because of other reasons); 2792 patients (95%) completed 10-year follow-up. Propensity matching and mixed-effect Cox model were used to compare long-term outcomes. Interaction term analysis was used to determine whether bilateral internal thoracic artery grafting was a significant effect modifier. RESULTS: One thousand seventy-eight matched pairs were selected for comparison. A total of 27 patients (2.5%) in the off-pump group required conversion to on-pump surgery. The off-pump and on-pump groups received a similar number of grafts (3.2 ± 0.89 vs 3.1 ± 0.8; P = .88). At 10 years, when compared with on-pump, there was no significant difference in death (adjusted hazard ratio for off-pump, 1.1; 95% confidence interval, 0.84-1.4; P = .54) or the composite of death, myocardial infarction, stroke, and repeat revascularization (adjusted hazard ratio, 0.92; 95% confidence interval, 0.72-1.2; P = .47). However, off-pump surgery performed by low volume off-pump surgeons was associated with a significantly lower number of grafts, increased conversion rates, and increased cardiovascular death (hazard ratio, 2.39; 95% confidence interval, 1.28-4.47; P = .006) when compared with on-pump surgery performed by on-pump-only surgeons. CONCLUSIONS: The findings showed that in the Arterial Revascularization Trial, off-pump and on-pump techniques achieved comparable long-term outcomes. However, when off-pump surgery was performed by low-volume surgeons, it was associated with a lower number of grafts, increased conversion, and a higher risk of cardiovascular death.
High-intensity focused ultrasound treatment of unresectable soft tissue sarcoma and desmoid tumours - a systematic review.
AIM: We review the evidence for high-intensity focused ultrasound (HIFU) in the treatment of soft tissue sarcoma (STS) and desmoid tumour (DT). MATERIALS AND METHODS: We searched Embase, Medline, PubMed, and Google Scholar for relevant studies between 2000-2024 using search terms 'high intensity focused ultrasound' and 'sarcoma' or 'chordoma' or 'desmoid'. We extracted data on patient demographics and treatment outcomes. RESULTS: We identified 12 studies pertaining to STS (n=178) and 15 studies pertaining to DT (n=417). These were prospective phase I/II open-label trials and retrospective case series or reports. The commonest adverse effects were skin burns, transient pain, and fever. Less common adverse effects of nerve injury and bowel perforation were depended on anatomic relations of the tumour. The majority of patients treated had unresectable disease that was partially ablated with HIFU for the purpose of local control. There was a high degree of variability in the reporting of outcomes making quantitative analysis challenging. CONCLUSION: The studied papers show that HIFU has a favourable safety profile with a potential role in patients with unresectable STS and DT. HIFU may confer advantages in cases of oligometastatic progression for disease control, complex anatomy including proximity to vital structures, recurrent cases in previously radiotherapy-exposed and/or operated locations with limited other locally-directed treatment options. However, there is limited reporting of the clinically important outcomes of recurrence and survival and further research is required, and this may represent an opportunity for later-phase trials in the UK and worldwide.
Spatial metabolomics informs the use of clinical imaging for improved detection of cribriform prostate cancer.
Cribriform prostate cancer (crPCa) is associated with poor clinical outcomes, yet its accurate detection remains challenging due to the poor sensitivity of standard-of-care diagnostic tools. Here, we use untargeted spatial metabolomics to identify fatty acid biosynthesis as a key metabolic pathway enriched in crPCa epithelium. We also show that imaging tumor lipid metabolism using [1-11C]acetate PET/CT and proton magnetic resonance spectroscopy differentiates cribriform from noncribriform intermediate-risk prostate cancers in two prospective patient cohorts. These findings support the feasibility of using clinical metabolic imaging techniques as adjunctive tools for improving crPCa detection in clinical practice, with prospective studies in larger cohorts warranted to obtain definitive results.
Imaging and intervention for soft tissue tumours in the era of locoregional therapies and immunotherapy.
As part of a multidisciplinary team, clinical radiology plays key roles in the diagnosis, staging and treatment response assessment for soft tissue sarcoma (STS) and desmoid tumours (DTs), typically using a combination of ultrasound and magnetic resonance imaging (MRI) modalities. There is an increasing role for interventional radiology in the treatment of recurrent and oligometastatic disease in these tumour types. This clinical radiology review is aimed primarily at non-specialist cross-sectional consultant radiologists and more junior radiology consultants/specialist trainees with a special interest in musculoskeletal oncology. The existing role of F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and MRI for assessment of treatment response in STS and DT, including the emerging role of whole-body MRI is outlined. Response metrics including Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1), modified RECIST, Positron Emission Tomography Response Criteria in Solid Tumours (PERCIST), immune Response Evaluation Criteria in Solid Tumors, iPERCIST and non-perfused volume ratio are also discussed in context. We introduce the potential role for locoregional therapies (LRTs), including microwave, cryotherapy and therapeutic ultrasound-based treatments as adjunctive treatments for selected cases within the current UK guidelines. We discuss the potential of high intensity focused ultrasound and other LRTs to release sarcoma tumour antigens systemically with the potential to enhance anti-tumour immunity (the 'abscopal' effect). With increasing indications and availability of locoregional therapies (LRTs) and the first indications of immunotherapy for selected subtypes of STS, potential future directions in functional imaging capability for STS and DT are also discussed.
Multidisciplinary evidence-based consensus statements on salvage surgery for recurrent head and neck cancer (International Centre for Recurrent head and neck Cancer).
BACKGROUND: Recurrent head and neck squamous cell carcinomas (rHNSCC) are an understudied subgroup, lacking high quality evidence and thus gold standard management recommendations, resulting in significant variations in practice. The aim of this project was to deliver a national multi-disciplinary expert consensus on patients with rHNSCC managed by curative salvage surgery. METHODS: The AGREEII protocol guided the Delphi process. Best practice statements were developed after literature review on the perioperative management and surgical salvage of major rHNSCC subsites. Members of the International centre for Recurrent head and neck cancer (IREC) network, and other UK based professional stakeholder organisations were invited into an online Delphi study. Participants voted upon statements over three rounds, with items modified in response to vote thresholds and comments. RESULTS: Twenty-eight experts participated including 11 otolaryngologists, 7 oncologists, 9 oral and maxillofacial surgeons, and 1 speech and language therapist. Consensus was achieved on 73 statements, with 29 (39.7%) achieving unanimous (threshold: 100%) and 25 (34.2%) (threshold >90%) agreement. CONCLUSIONS: Salvage surgery for rHNSCC are challenging cases that require intensive multidisciplinary input to achieve cure while balancing impact on function and quality-of-life. In this article, we provide a large series of statements based on UK-wide expert consensus, that will guide clinicians through the complex intra- and perioperative management of patients undergoing surgical salvage.
An intensive weight loss programme with behavioural support for people with type 2 diabetes at risk of eating disorders in England (ARIADNE): a randomised, controlled, non-inferiority trial
Background: There are concerns that low-energy total diet replacement (TDR) programmes could trigger eating disorders, given their focus on weight and rigid dietary rules. We aimed to assess the effect of a TDR programme on eating disorder symptoms in people living with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. Methods: In this randomised, controlled, non-inferiority trial, participants with type 2 diabetes, overweight, and eating disorder symptoms across England were randomly assigned (1:1) to a low-energy TDR programme with formula products and behavioural support delivered remotely, or usual care. In brief, the intervention comprised 12 weeks of low-energy TDR in a nutritionally complete package of soups, shakes, and bars. After the 12 weeks, the intervention continued with stepped food reintroduction (around 8 weeks) based on a low-energy, nutrient-rich diet, followed by weight maintenance advice (around 4 weeks), personalised to an individual participant's circumstances and preferences. Participants allocated to the control group received usual care for their diabetes. The primary outcome was the change in eating disorder symptoms using the Eating Disorders Examination Questionnaire (EDE-Q) global score at 6 months (programme end). Safety was determined by the incidence of cases with high suspicion of a new eating disorder. The primary outcome analysis had an upper non-inferiority margin for EDE-Q of +1 SD (0·72). People with lived experience were involved throughout the trial and provided input on study conceptualisation, protocol development, delivery of the intervention, and intervention materials. The study was registered with ClinicalTrials.gov, NCT05744232. Findings: Between March 8, 2023, and Sept 12, 2023, 56 participants were randomly assigned to the intervention group (28 participants) or control group (28 participants). Participants had a mean age of 49·9 years (SD 8·1). 35 (63%) of 56 participants were women, 20 (36%) were men, and one (2%) was non-binary. 54 (96%) of participants were White and two (4%) were Asian. Participants had a mean BMI of 39·6 kg/m2 (SD 7·8) and a mean EDE-Q global score of 3·3 (0·4). 49 (88%) of 56 participants provided outcome data at 6 months and 45 (80%) at 1 year. At completion of the programme at 6 months, the mean weight loss was –13·9 kg (SD 11·2) in the intervention group and –3·7 kg (7·9) in the control group, with a between-group difference of –10·2 kg (95% CI –14·2 to –6·2). The between-group difference in the EDE-Q score was –0·8 points (–1·4 to –0·3) at 6 months, indicating non-inferiority. At 12 months, weight change was not different between groups, but non-inferiority and superiority in EDE-Q remained. No participants were suspected of having developed an eating disorder. 13 adverse events were documented, of which one, a cholecystectomy, was serious. Interpretation: Participation in a supported TDR programme did not worsen eating disorder symptoms in people with overweight or obesity and type 2 diabetes at high risk of developing an eating disorder. We found no evidence these programmes cause harm and a suggestion of benefit on eating disorder symptoms, independent of weight loss. Funding: Novo Nordisk UK Research Foundation.
A novel synergistic drug combination of a mitogen-activated extracellular signal-regulated kinase inhibitor with [177Lu]Lu-rhPSMA-10.1 for prostate cancer treatment: Results of a preclinical evaluation.
PURPOSE: The prostate-specific membrane antigen (PSMA)-targeted radiohybrid ligand [177Lu]Lu-rhPSMA-10.1 is a promising next-generation radiopharmaceutical therapy in prostate cancer. This preclinical evaluation comprised an in vitro screen of potential novel synergistic drug combinations with [177Lu]Lu-rhPSMA-10.1, and an in vivo efficacy analysis of the lead drug combination in PSMA-expressing prostate cancer xenografts. METHODS: In total, 177 anticancer drugs were screened in a clonogenic survival assay of 22Rv1 cells which used 5-fold serial dilutions of the test drug (≤ 20 μM) to determine the half-maximal inhibitory concentration (IC50), compared to incubations of the test drug plus [177Lu]Lu-rhPSMA-10.1 (15 MBq) after 10 days. A subsequent focused screen assessed the impact of [177Lu]Lu-rhPSMA-10.1 (0-25 MBq/mL) on drug IC50. Synergy scores were determined using the zero interaction potency (ZIP) reference model (ZIP scores >5 % indicate high synergistic potency) and the multidimensional synergy of combinations (MuSyC) platform (log α >0 indicates synergistic potency). Therapeutic efficacy of the lead drug combination was evaluated in vivo: intravenous [177Lu]Lu-rhPSMA-10.1 (30 MBq, single dose) and oral cobimetinib (0.25 mg/day for 21 days) (alone/in combination) were administered to 22Rv1 tumor-bearing NMRI nude mice (eight mice/group plus untreated controls). Tumor volume was measured twice weekly for 69 days (two-way ANOVA and Tukey's multiple comparisons test: data analyzed until three mice/group remained). KaplanMeier Log-rank survival analyses were performed. RESULTS: In vitro screening identified cobimetinib (a mitogen-activated extracellular signal-regulated kinase inhibitor) as a lead candidate for synergistic combination with [177Lu]Lu-rhPSMA-10.1 across a wide concentration range (ZIP score=13 %). MuSyC analysis suggested synergistic efficacy from enhanced potency of both drugs in the combination (both log α>3). Combination treatment significantly suppressed tumor growth in vivo versus untreated controls (from Day 13-30; p<0.01) and [177Lu]Lu-rhPSMA-10.1 (from Day 17-30; p<0.001). Median survival was significantly longer with combination treatment (49 days) versus untreated controls (23 days; p=0.001) and [177Lu]Lu-rhPSMA-10.1 monotherapy (36 days; p=0.002). No major compound-related toxicity for cobimetinib ± [177Lu]Lu-rhPSMA-10.1 was observed. CONCLUSIONS: The combination of cobimetinib and [177Lu]Lu-rhPSMA-10.1 demonstrated enhanced preclinical therapeutic efficacy versus single agents, supporting clinical investigation of this novel drug combination in prostate cancer.
Incidental finding and surgical management of a diaphragmatic macrocystic lymphatic malformation in a child.
Macrocystic lymphatic malformation, previously known as cystic hygroma, is a congenital anomaly and a subtype of lymphatic malformations. The most common location for macrocystic lymphangiomas is the neck, followed by the axilla. On rare occasions, it can be found in other organs and tissues. Our case presented with a large diaphragmatic macrocystic lymphangioma. Our case is about an incidentally discovered right subdiaphragmatic abdominal mass in a normally healthy middle childhood patient. The patient was treated surgically by resection of the mass. Even though the diaphragm is a rare location for cystic hygroma, it should form part of the differential diagnosis for subdiaphragmatic lesions.
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