Pain and reward in emergency surgery trials

Locally advanced rectal cancer involves multimodality treatment that combines 5-fluorouracil (5-FU) based chemotherapy, chemoradiation and surgical resection. Total neoadjuvant therapy and radiation (TNT) has shown to induce complete tumor regression in up to 30-40% of patients1 and is associated with improved disease free survival.2 Furthermore, patients who attain a complete response to TNT, may be eligible for organ preserving strategies, offering them the potential to avoid radical resection and its attendant morbidity, including possible low anterior resection syndrome, bowel dysfunction, or permanent stoma formation.2-5 Despite its benefits, response to TNT remains markedly heterogeneous with more than half of patients not attaining a complete clinical response.6 The biological determinants underlying this variability remain an area many researchers are working to define. Identifying mechanisms that underlie variable treatment responses may enable novel strategies to enhance tumor regression and expand organ-preservation opportunities.

Emerging data from our group and others has suggested that the intertumoral microbiome may influence the variability in treatment response.7-9 Anaerobic bacteria, particularly Fusobacterium nucleatum8,10, have been associated with resistance to TNT and poor pathologic regression.11 Importantly, the intratumoral microbiome has shown to be dynamic9,12 and can be influenced by variables such as stress, diet, and therapies.13 Models have demonstrated that exposure to agents such as 5-FU or metronidazole can eradicate fusobacterium nucleatum and when eradicated patients had improved outcome.11,12,14,15

Building on these observations, we developed a phase II clinical trial to quantify intratumoral bacterial populations, particularly anaerobes and evaluate the impact of metronidazole administration on these tumoral bacterial populations. Metronidazole, an imidazole antibiotic, acts as a prodrug that is activated under anaerobic conditions, disrupts bacterial DNA synthesis ad metabolism.16,17 This trial aims to determine if selective depletion of anaerobes can be enhanced by the administration of metronidazole.

PROTECT is a national platform trial designed to deliver multiple multi-centre randomised and non-randomised comparisons in adult surgical patients. Individual trial components will span phase II to phase IV, depending on the specific research question.

The study will be conducted across NHS surgical services and will include patients aged 18 years and over undergoing care within an NHS surgical pathway.

In the complex world of vascular surgery, where “high risk” is basically our love language, one topic continues to spark the debate: the uncomplicated type B aortic dissection. “Uncomplicated” may sound reassuring, but don’t be fooled. In reality, “uncomplicated” may just mean not yet complicating your life. These patients represent the calm before the storm, leaving clinicians to weigh whether it’s better to follow a conservative approach or go in early and do something heroic (and preferably endovascular).

Once upon a time, all type B dissections were approached as ticking time bombs — open surgery, big incisions and lots of drama. Outcomes, however, were far from ideal. As evidence emerged that doing less often yielded better results, the field shifted direction. Medical therapy became the dominant approach; enter the era of “let’s control the blood pressure and hope for the best.” Today, medical therapy — mainly antihypertensives and analgesics — remains the cornerstone for managing uncomplicated type B dissections.

Short-term survival left everyone quite satisfied: in-hospital survival was about 90%. Long-term results, however, were less pleasing. Survival drops to around 79% at five years, with approximately one-third of these initially “uncomplicated” patients eventually requiring intervention – procedures that are technically more challenging in the chronic phase with higher procedural risks. Turns out, “uncomplicated” is more complicated than it sounds.