The Christie School of Oncology: Christie Research Publications Repository
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Gfi1 controls the formation of effector-like CD8(+) T cells during chronic infection and cancer
No full textDuring chronic infection and tumor progression, CD8(+) T cells lose their effector functions and become exhausted. These exhausted CD8(+) T cells are heterogeneous and comprised of progenitors that give rise to effector-like or terminally-exhausted cells. The precise cues and mechanisms directing subset formation are incompletely understood. Here, we show that growth factor independent-1 (Gfi1) is dynamically regulated in exhausted CD8(+) T cells. During chronic LCMV Clone 13 infection, a previously under-described Ly108(+)CX(3)CR1(+) subset expresses low levels of Gfi1 while other established subsets have high expression. Ly108(+)CX(3)CR1(+) cells possess distinct chromatin profiles and represent a transitory subset that develops to effector-like and terminally-exhausted cells, a process dependent on Gfi1. Similarly, Gfi1 in tumor-infiltrating CD8(+) T cells is required for the formation of terminally differentiated cells and endogenous as well as anti-CTLA-induced anti-tumor responses. Taken together, Gfi1 is a key regulator of the subset formation of exhausted CD8(+) T cells
British society of gastroenterology hepatocellular carcinoma guideline review: impact on the frontline
No full textThe British Society of Gastroenterology commissioned an update on the guidelines for management of hepatocellular carcinoma (HCC) in adults at an opportune time. The incidence of and mortality from this cancer is increasing in the UK, as in other Western nations. Several clinical and scientific advances in HCC have been made in the last decade. This article, written on behalf of the HCC-UK committee, provides a commentary on the guidelines, with specific focus on areas of practice change
Clinical presentation and outcomes of sporadic neuroendocrine neoplasms in young adults: International multicentre analysis
No full textAsymptomatic bone metastases: 2024 American Society for Radiation Oncology (ASTRO) education panel
No full textMicroRNA-142 regulates gut associated lymphoid tissues and group 3 innate lymphoid cells
No full textThe transcriptomic signatures that shape responses of innate lymphoid cells (ILCs) have been well characterised, however post-transcriptional mechanisms which regulate their development and activity remain poorly understood. We demonstrate that ILC groups of the intestinal lamina propria express mature forms of microRNA-142 (miR-142), an evolutionarily conserved microRNA family with several non-redundant regulatory roles within the immune system. Germline Mir142 deletion alters intestinal ILC compositions, resulting in the absence of T-bet+ populations and significant defects in the cellularity and phenotypes of ILC3 subsets including CCR6+ LTi-like ILC3s. These effects were associated with decreased pathology in an innate-immune cell driven model of colitis. Furthermore, Mir142- /- mice demonstrate defective development of gut-associated lymphoid tissues, including a complete absence of mature Peyer's patches. Conditional deletion of Mir142 in ILC3s (Rorc Delta Mir142) supported cell-intrinsic roles for these microRNAs in establishing or maintaining cellularity and functions of LTilike ILC3s in intestinal associated tissues. RNAseq analysis revealed several target genes and biological pathways potentially regulated by miR-142 microRNAs in these cells. Finally, lack of Mir142 in ILC3 led to elevated IL-17A production. These data broaden our understanding of immune system roles of miR-142 microRNAs, identifying these molecules as critical post-transcriptional regulators of ILC3s and intestinal mucosal immunity
Rehabilitation for physical frailty in lung transplant candidates: a systematic review
No full textPURPOSE: Physical frailty is prevalent in lung transplant (LTx) candidates and is linked to adverse outcomes preoperatively and postoperatively. Exercise is beneficial in optimizing exercise capacity and quality of life in candidates, but its impact on physical frailty is unknown. METHODS: We prospectively registered and published a protocol (PROSPERO CRD42022363730) before undertaking a systematic review. We searched 4 databases plus trial registries from 1980 to February 2024 for studies of exercise interventions in adults awaiting LTx. Outcomes were measures or surrogate markers of physical frailty. An NIH assessment tool was used to assess study quality, and certainty of evidence was assessed using GRADE. RESULTS: Fifteen studies (664 patients) were included. Interventions were in-person pulmonary rehabilitation, home exercise, and telerehabilitation. Studies included aerobic, resistance, balance, and breathing training. Only 2 studies assessed frailty using a phenotypic measure. Studies demonstrated improvement in some surrogate frailty outcomes including the Short Physical Performance Battery, 5 times sit-to-stand test, and handgrip or muscle strength measures. The study quality was fair or poor; evidence was low or very low certainty for all outcomes due to imprecision and high risk of bias. Uncontrolled study designs and heterogeneity of interventions and outcomes limit conclusions on effectiveness. CONCLUSIONS: Exercise training appears beneficial in modifying surrogate markers of physical frailty before LTx, but conclusions are limited by low or very low certainty evidence. High quality randomized trials are needed to determine the impact of exercise interventions on physical frailty and to develop guidelines for LTx prehabilitation
Corrigendum to 'Artificial intelligence in breast cancer radiotherapy: Insights from the Toolbox Consortium Delphi study' [The Breast, Volume 83 (2025) 104537]
No full textAcute presentations in neoadjuvant chemotherapy/immune checkpoint inhibition for triple negative breast cancer: experiences and impact from real-world data
No full textBACKGROUND: Recent data showed benefit of the addition of immune checkpoint inhibitor (ICI) therapy to cytotoxic chemotherapy in the neoadjuvant setting for patients with early triple negative breast cancer. Acute presentations in patients treated with ICI therapy and combined chemotherapy/ICI therapy can be challenging and have significant resource implications. MATERIALS AND METHODS: A prospective analysis was performed at a specialist oncology hospital in England from December 1, 2022 to December 31, 2024. The primary outcome measure was whether the acute presentation was due to an ICI-related toxicity. Secondary outcome measures were number of inpatient bed days and the proportion of patients with grade ≥3 diarrhoea or transaminases that were diagnosed with ICI-related toxicity. RESULTS: During the study period, 285 patients were treated with neoadjuvant PC-EC/Pembro for triple negative breast cancer with 210 emergency presentations in 168 patients to the acute floor. Fifty-three (25.2 %) patients were diagnosed with an ICI-related toxicity of which 5 were a relapsed/recurrent presentation. One hundred and nine patients (51.9 %) were discharged on the day of presentation. A total of 576 inpatient bed days were used in the management of the cohort. Sixteen (7.6 %) patients had grade 3 diarrhoea at presentation; only 5 (31.3 %) of these were ICI-mediated. Eleven (5.2 %) patients had a grade ≥3 ALT rise at presentation; only 3 (27.2 %) of these were ICI-mediated. CONCLUSION: In triple negative breast cancer being treated in the neoadjuvant setting with chemotherapy/immune checkpoint inhibition only 25.2 % of acute presentations had an ICI-related toxicity driving their attendance. Toxicities in this cohort may require a different approach to those treated with chemotherapy or ICI alone and may necessitate new clinical practice guidance
Epcoritamab monotherapy for relapsed or refractory large B-Cell lymphoma: 3-year follow-up from EPCORE NHL-1
No full textTrastuzumab deruxtecan or ramucirumab plus paclitaxel in gastric cancer
No full textBACKGROUND: On the basis of phase 2 studies, trastuzumab deruxtecan was approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma who had previously received trastuzumab-based therapy. Ramucirumab plus paclitaxel is also a standard second-line treatment option regardless of HER2 status. METHODS: We conducted an international, randomized, phase 3 trial comparing second-line trastuzumab deruxtecan at a dose of 6.4 mg per kilogram of body weight with ramucirumab plus paclitaxel in patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma confirmed on tumor biopsy conducted after the patient had progression while receiving trastuzumab-based therapy. The primary end point was overall survival. Secondary end points included progression-free survival, confirmed objective response (complete or partial response lasting ≥4 weeks), disease control, duration of response, and safety. RESULTS: Among 494 patients who had undergone randomization, overall survival was significantly longer with trastuzumab deruxtecan than with ramucirumab plus paclitaxel (median, 14.7 vs. 11.4 months; hazard ratio for death, 0.70; 95% confidence interval, 0.55 to 0.90; P = 0.004). Significant results were also seen with regard to progression-free survival (hazard ratio for disease progression or death, 0.74; 95% CI, 0.59 to 0.92) and confirmed objective response (in 44.3% of the patients in the trastuzumab deruxtecan group vs. 29.1% of those in the ramucirumab-paclitaxel group). The incidence of drug-related adverse events of any grade was 93.0% with trastuzumab deruxtecan and 91.4% with ramucirumab plus paclitaxel; the incidence of drug-related adverse events of grade 3 or higher was 50.0% and 54.1%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 13.9% of the patients who received trastuzumab deruxtecan (grade 1 or 2 in 33 patients and grade 3 in 1) and in 1.3% of those who received ramucirumab plus paclitaxel (grade 3 in 2 patients and grade 5 in 1). CONCLUSIONS: Trastuzumab deruxtecan led to significantly longer overall survival than ramucirumab plus paclitaxel among patients with HER2-positive metastatic gastric cancer or gastroesophageal junction adenocarcinoma. Adverse events were common in both groups. Events of interstitial lung disease or pneumonitis with trastuzumab deruxtecan, a known risk, were mainly low-grade. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Gastric04 ClinicalTrials.gov number, NCT04704934.)