Velindre Cancer Centre

Chromosomal instability (CIN), a pervasive feature of esophageal adenocarcinoma (EAC), drives tumor aggressiveness and metastasis. CIN stimulates the cGAS–STING pathway, typically linked to antitumor immunity. However, despite the high CIN burden in EAC, the cGAS–STING pathway remains largely intact. To address this paradox, we interrogated multiple esophageal cancer models, finding myeloid-attracting chemokines—with CXCL8 as a prominent hit—as conserved CIN-driven targets in EAC. Using multiplexed immunofluorescence microscopy, we quantified ongoing CIN in human EAC tumors by measuring cGAS-positive micronuclei, validated by whole-genome sequencing. Coupling in situ CIN detection with single-nucleus RNA sequencing and multiplex immunophenotyping of human EAC, we link CIN to tumor-intrinsic innate immune activation, CXCL8 expression, and myeloid cell–mediated immunosuppression. In patients with EAC, CINhigh, myeloid-dominated tumors correlate with poor outcomes and aberrant cGAS–STING signaling. These insights explain the counterintuitive maintenance of cGAS–STING and highlight the disruption of the CIN–cGAS–inflammation axis as a potential therapeutic strategy in EAC.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates were 94% (99% CI 86-98) in the IMPT group versus 97% (82-100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3 to 20·3; 95% CI 0·5-12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group versus 95% (81-99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. Cancer Research UK.

Cardio-oncology remains a speciality dominated by cardiologists despite the importance of doctors from other specialties, such as oncology and haematology, for managing the cardiovascular health of patients living with cancer. A major reason for this is a distinct lack of cardio-oncology training opportunities for the noncardiology trainee. This is because of several factors, including a lack of awareness of cardio-oncology as a specialty. We propose a cardio-oncology training programme that involves early exposure to cardio-oncology as a specialty and provides the noncardiologist with a good understanding of cardiological investigations and treatment in the context of cancer treatment. Future work should elucidate additional barriers to cardio-oncology training as well as identifying programmes that have integrated cross-disciplinary cardio-oncology content to inform future curriculum development. Future work should also focus on establishing pilot cardio-oncology training programmes for the noncardiologist.

BackgroundSeizures are a common consequence of acute hemorrhagic stroke, which has a high morbidity and fatality rate. It is yet unknown how they relate to age, the National Institutes of Health Stroke Scale (NIHSS), the modified Rankin Scale (mRS), and discharge status.MethodsWe conducted a cross-sectional study of 75 patients (aged 16-92 years) with acute hemorrhagic stroke admitted to the Neuropsychiatry Department of Qena University Hospitals, a tertiary care center serving a large catchment area in Upper Egypt. Data were collected over six months, from September 2024 to February 2025. Neurological impairment was assessed using the NIHSS, and functional outcome was measured using the mRS at admission and discharge. Statistical comparisons included paired t-tests and Wilcoxon signed-rank tests. Associations between seizures, age, stroke severity, and outcomes were also analyzed.ResultsSeizures were not correlated with age. During hospitalization, a noteworthy mean improvement in NIHSS (+0.97; t = 10.70 and p < 0.0001; W = 21.50 and p < 0.0001) was noted, suggesting neurological recovery. On the other hand, mRS remained at a median 3 (t = -0.51 and p = 0.6113; W = 275 and p = 0.9173), indicating no discernible change. There was no discernible change in NIHSS or mRS among patients who were released on demand (n = 10). Ten out of the 12 in-hospital fatalities had seizures, and the majority had moderate-to-severe strokes (NIHSS ≥9; mRS ≥3). Patients with very severe strokes (NIHSS 16-17; mRS = 5) and no recovery experienced two non-seizure fatalities. Admission NIHSS (1-17) and mRS (1-5) showed a broad variety of stroke presentations and recovery trajectories.ConclusionThe baseline of stroke severity was the best indicator of a bad prognosis in acute hemorrhagic stroke, and seizure incidence was not age-dependent. Significant neurological recovery was recorded by NIHSS, but short-term functional improvement was not reflected by mRS. These results indicate that seizures are more common in fatal cases but secondary to the total load of strokes, underscoring the prognostic significance of baseline severity.

BackgroundCancers of the oesophagus and stomach are a major cause of morbidity and mortality. Research is crucial to improving outcomes. However, to maximise value and impact, areas of focus should be prioritised in partnership with patients.ObjectiveWe undertook a comprehensive analysis of UK and Ireland patient and healthcare professional (HCP) priorities for research into oesophagogastric cancers across the domains of prevention, diagnosis and staging, treatment, palliative care and survivorship.DesignA scoping exercise sourced research questions from patients and HCPs. These were consolidated and then confirmed by systematic review to represent a true research uncertainty. Research questions were scored on potential impact by an interdisciplinary group of HCPs and prioritised using a weighting derived from a patient survey.ResultsThere were 835 (395 HCP, 440 patient) respondents to the scoping (n=455) and prioritisation (n=380) surveys. Across these, 4295 suggested research uncertainties were consolidated to 92 uncertainties that were prioritised. HCP respondents represented 25 professional groups from community and hospital settings. Patient weighting changed 22.2–46.3% of priority rankings established by HCPs. All domains were represented by the 20 highest priority questions, 5 of which focused on personalising and optimally combining treatment modalities. Two other key themes related to optimising nutrition and improving quality of life during and after treatment, including in patients not cured of their cancer.ConclusionThis work highlights the impact of patient input on HCP-ranked research priorities and provides a robust list of priorities to guide funders, policymakers and researchers to support and undertake impactful research.

Efficacy of immune checkpoint inhibitors in unselected patients with metastatic castration-resistant prostate cancer (mCRPC) is limited. The NEPTUNES study evaluated combination nivolumab and ipilimumab in patients with immunogenic signature-positive (ImS+) mCRPC. This open-label, 2-cohort, phase II trial enrolled patients with ImS+ mCRPC progressing on ≥1 previous line of treatment. ImS+ was defined by (1) mismatch repair deficiency (MMRD); (2) DNA damage repair gene loss; and/or (3) high inflammatory infiltrate (HII). Patients received four doses of nivolumab 1 mg/kg + ipilimumab 3 mg/kg (C1) or nivolumab 3 mg/kg + ipilimumab 1 mg/kg (C2) followed by nivolumab 480 mg once every 4 weeks up to 10 cycles. The primary end point was composite response rate (CRR) assessed radiologically, biochemically, and by reduction of circulating tumor cells. Secondary end points included toxicity, progression-free survival, overall survival, and duration of response. Between May 2018 and June 2022, 35 (C1) and 36 (C2) patients commenced treatment. The CRR in C1 was 14/35 (40%, 90% CI, 26% to 55%) and in C2 was 9/36 (25%, 90% CI, 14% to 40%). The overall CRR was 23/71 (32%, 90% CI, 23% to 43%). Response rates were higher in patients with MMRD (7/10), BRCA2 loss (4/8), and HII ± other ImS+ features (13/30). Duration of response for patients with HII without other ImS+ features, DNA repair gene loss without MMRD, and MMRD was 2.6, 17.3, and 10 months, respectively. Grade 3 to 4 treatment-related adverse events occurred in 22/35 (63%) in C1 and 12/36 (33%) patients in C2. There were no treatment-related deaths. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg is an active treatment in ImS+ pretreated mCRPC. Nivolumab 3 mg/kg + ipilimumab 1 mg/kg has less toxicity but may have lower efficacy. HII is a promising prospectively tested predictive biomarker in prostate cancer that could be integrated into future trials.

Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1·1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011-000144-21), and is still in active follow-up. We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6·8 years (IQR 5·6-8·6) in the no ablation group and 6·6 years (4·8-8·5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97·9% (95% CI 96·1-99·7) in the no ablation group versus 96·3% (93·9-98·7) in the ablation group in the ITT analysis, and 97·9% (96·1-99·7) versus 96·9% (94·7-99·1) in the per-protocol analysis. The 5-year absolute risk difference was 0·5 percentage points (95% CI -2·2 to 3·2, pnon-inferiority=0·033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs. Cancer Research UK.