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    • The historical paradigm for radiation induced tissue injury

    2018-10-25

    The historical paradigm for radiation-induced tissue injury, which was predicated on indiscriminate clonogenic cell death of rapidly dividing normal cells, has been overturned in favor of a more complex biological cascade (). How, if, and where the oral microbiome contributes to this scheme was the subject of a study reported in this issue of by who prospectively evaluated the relationship between the trajectory of changes in the oral microbiome and oral mucositis in nineteen patients being treated with radiation or concomitant chemoradiation for nasopharyngeal carcinoma (NPC). Thirteen of the studied subjects developed severe mucositis. Differences in the baseline (pre-radiation) oral microbiota were noted between control and NPC subjects: not only was there more similarity in the bacterial communities among healthy patients, but the healthy controls also had a more diverse microflora. Speciation of the oral flora among patients with no or mild mucositis differed from those developing more severe forms of the condition. This observation leads to key questions of its clinical significance: does it represent a means for facilitation of mucositis and is it specific enough to predict the course of mucositis, or do changing bacteria simply reflect the microflora\'s response to other, non-mucositis, but parallel factors? The mucositis puzzle is complicated and consists of multiple pieces which not only fit together, but actively interact. Since the oral microbiome represents only one Tivantinib of the puzzle, other pieces require consideration as, in the context of the Zhu et al. paper, they might provide additional or alternative explanations for the observations noted. The oral microbiome is varied and preferentially colonizes different sites in the mouth (). Consequently, sampling biases or variation might impact how speciation reports differ. This presumes that, if certain species of oral bacteria are more likely to impact mucositis risk and course than others, longitudinal study of high risk sites would be most informative. On the other hand, if, as Zhu et al. conclude, oral bacteria secondarily colonize already ulcerated mucosa, those species capable of sustaining or stimulating a pro-inflammatory response, such as gram negative organisms, could be potential modifiers of mucositis course. While there seems to be little doubt that the flora of patients not being treated for cancer and those who are being treated is different, the question arises as to why. Changes in the oral flora of cancer patients occur in a multifarious local and systemic environment. Even with radiation doses as low as 10Gy, the volume and composition of saliva is altered. The degree of xerostomia, like mucositis, is radiation dose-dependent (). It is possible that the changes in the oral flora noted by Zhu et al. were a consequence of changes in salivary function resulting in less buffering, flushing, and immune function, and a surrogate from cumulative radiation dose. It is also possible that xerostomic changes modified mucosal health making it more susceptible to injury. While this paper focused on the microflora, it is impossible to ignore the intrinsic contribution of the host as an element in mucositis risk. Radiogenomic data strongly suggest a genomic underpinning to individual patient response to radiation with respect to tissue injury (). While these findings are clearly relevant in the case of mucositis, they also raise the likelihood that genomics impact patients\' reactions to specific bacterial species resulting in a lack of uniformity in how individuals respond to colonizing bacteria. For example, while Zhu et al. noted that increases in were associated with the development of severe mucositis, De Ryck et al. contrastingly reported that, in a mucosa co-culture model, markedly enhanced epithelial wound healing (). Host contributions to flora changes are reflected by the substantial body of data demonstrating that neutropenia impacts the oral microbiota and, in particular, predisposes to increases in gram negative organisms. Leukopenia is a recognized side effect of head and neck chemoradiation regimens (). And while not noted by Zhu et al., the finding that concomitant chemoradiation regimens are typically more mucotoxic than those of radiation alone suggests that neutropenia impacts the course of mucositis. The inclusion of such data in future studies would be informative.