Niall C. Tebbutt

Oesophageal cancer remains a significant global health burden with poor survival outcomes despite multimodal treatment. Recent advances in magnetic resonance imaging (MRI) have opened opportunities to improve radiotherapy delivery. This review examines the role of MRI and MR-guided radiotherapy (MRgRT) in oesophageal cancer, focusing on applications in staging, treatment planning, and response assessment, with particular emphasis on magnetic resonance linear accelerator (MR-Linac)-based delivery. Compared to computed tomography (CT), MRI offers superior soft-tissue contrast, enabling more accurate tumour delineation and the potential for reduced treatment margins. Real-time MR imaging during treatment can facilitate motion management, while daily adaptive planning can accommodate anatomical changes throughout the treatment course. Functional MRI sequences, including diffusion-weighted and dynamic contrast-enhanced imaging, offer quantitative data for treatment response monitoring. Early clinical and dosimetric studies demonstrate that MRgRT can significantly reduce radiation dose to critical organs while maintaining target coverage. However, clinical evidence for MRgRT in oesophageal cancer is limited to small early-phase studies, with no phase II/III trials demonstrating improvements in survival, toxicity, or patient-reported outcomes. Long-term clinical benefits and cost-effectiveness remain unproven, highlighting the need for prospective outcome-focused studies to define the role for MRgRT within multimodality treatment pathways.

Triple M syndrome is a rare and life‐threatening overlap presentation of myocarditis, myositis and myasthenia gravis, secondary to immune checkpoint inhibition. We report a case of an 80‐year‐old female with metastatic cholangiocarcinoma, presenting with progressive asthenia, ptosis and dysphagia, following completion of six cycles of combination chemotherapy and immunotherapy, durvalumab. Her symptoms emerged 2 weeks after the commencement of maintenance therapy with immune checkpoint inhibitor, durvalumab, and poly(ADP‐ribose) polymerase inhibitor, olaparib. Biochemical investigations were suspicious for myocarditis, myositis and type 2 respiratory failure due to myasthenic crisis. Clinical findings supported the diagnosis of triple M syndrome, and she was treated with high‐dose steroids, intravenous immunoglobulin and supported with non‐invasive ventilation. The patient initially improved; however, her admission was complicated by a fatal retroperitoneal haemorrhage. Our case highlights the need to consider serious immune‐related adverse events and escalate prompt management for overlap syndromes in the context of immunotherapy and poly(ADP‐ribose) polymerase inhibitors. Trial Registration: ClinicalTrials.gov identifier: NCT06441747

Supplementary Figure 1 shows the synergistic effect of trametinib plus panobinostat in CRC cell lines and PDTO's

Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse

Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells

Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies

Supplementary figure 3 shows combining trametinib with different classes of HDAC inhibitors in COLO 201 cells

The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor–induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.