The effect of dose escalation on gastric toxicity when treating lower oesophageal tumours: a radiobiological investigation

Purpose Using radiobiological modelling to estimate normal tissue toxicity, this study investigates the effects of dose escalation for concurrent chemoradiation therapy (CRT) in lower third oesophageal tumours on the stomach. Methods and materials 10 patients with lower third oesophageal cancer were selected from the SCOPE 1 database (ISCRT47718479) with a mean planning target volume (PTV) of 348 cm3. The original 3D conformal plans (50Gy3D) were compared to newly created RapidArc plans of 50GyRA and 60GyRA, the latter using a simultaneous integrated boost (SIB) technique using a boost volume, PTV2. Dose-volume metrics and estimates of normal tissue complication probability (NTCP) were compared. Results There was a significant increase in NTCP of the stomach wall when moving from the 50GyRA to the 60GyRA plans (11–17 %, Wilcoxon signed rank test, p = 0.01). There was a strong correlation between the NTCP values of the stomach wall and the volume of the stomach wall/PTV 1 and stomach wall/PTV2 overlap structures (R = 0.80 and R = 0.82 respectively) for the 60GyRA plans. Conclusion Radiobiological modelling suggests that increasing the prescribed dose to 60Gy may be associated with a significantly increased risk of toxicity to the stomach. It is recommended that stomach toxicity be closely monitored when treating patients with lower third oesophageal tumours with 60Gy

Defining an ageing-related pathology, disease or syndrome: International Consensus Statement

Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased health span. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand and meet the healthcare, workforce, well-being and socioeconomic needs of ageing populations, whilst supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19, 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥ 70% for approval. The accepted criteria for an ageing-related pathology, disease or syndrome were (1) develops and/or progresses with increasing chronological age; (2) should be associated with, or contribute to, functional decline or an increased susceptibility to functional decline and (3) evidenced by studies in humans. Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes

Syntheses, Structures, and Characterization of Metal Carbonyl Complexes as Photoactive CO Releasing Molecules and their Biological Utility Towards Eradication of Cancer

Carbon monoxide (CO) has recently been shown to elicit various salutary effects in mammalian physiology. This small molecule has shown to exert a multitude of actions, which includes, vasoregulation, inflammation reduction and anti-apoptotic actions in normal cells. Interestingly, in hyperproliferative cells, CO has shown to induce significant pro-apoptotic effects, which can be exploited therapeutically towards cancer eradication. However, the ability to deliver CO in a target-specific manner has been a tantalizingly challenging task. In order to tackle this issue, CO releasing pro-drugs have been developed in order to deliver CO in a more controlled fashion to cellular targets. However, a large number of such pro-drug molecules systemically release CO, a process that can hardly be controlled. We have employed metal carbonyl complexes (MCCs) to deliver CO upon light illumination, which are otherwise stable under dark conditions. The requirement of light of a particular wavelength to trigger CO photorelease from such MCCs is strictly dependent on complex design. The important goal is to develop an ideal MCC where CO release can be initiated upon illumination of lights of biocompatible wavelength range. The series of complexes in Chapter 2 bearing manganese(I), ruthenium(II), and rhenium(I) metal centers elucidates the design principles necessary to enable CO photorelease under certain ranges of light illumination. In such endeavor, the choice of organic ligand frame and co-ligand along with their geometrical placement are critical. The choice of metal also plays an important role in dictating the photo behavior of such complexes. Chapter 3 utilizes the design principles established in chapter 2 and further explores the ligand design and steric features associated with organic ligand frame towards CO photorelease. These characteristics facilitated exceptionally rapid CO release under the control of visible light, thus affording a system ideal for application in certain therapeutic procedure that requires high local concentration of CO. The subject matter of chapter 4 deals with developing a trackable CO delivery system without attenuation of the drug (CO) within the cellular matrices. The design principles for such trackable CO releasing MCC involved rigid ring ligand frames bound to manganese(I) metal center which resulted a “turn on” luminescence, and with a rhenium(I) metal center afforded a “two-tone” theranostic system upon CO delivery. In part 1, such Mn(I) carbonyl complex aided the tracking of CO release event within MDA-MB-231 cancer cells under the control of visible light, while in part 2 the internalization of a luminescent Re(I) complex pro-drug can be followed within biological matrices and a distinct second fluorescence signal is observed when the drug (CO) is released upon illumination. The eventual obstacle towards developing a truly biocompatible CO releasing pro-drug (both sensitivity to visible light and aqueous solubility) is achieved in chapter 5. Two manganese carbonyl complexes incorporating rigid fluorescent α-diimine ligands are reported in this chapter. The inclusion of 1,3,5-triaza-7-phosphaadmantane (PTA) as ancillary ligand confers remarkable water solubility to such complexes. Both of these MCCs exhibit CO release upon low power visible light illumination. Taken together these features, it reasonable to assume that these CO releasing pro drugs have huge potential to find their place in clinic settings as phototherapeutics in near future