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    • Radiotherapy remains the cornerstone of

    2018-10-23

    Radiotherapy remains the cornerstone of treatment for NPC. A systematic literature review reported that OM is one of the most frequent toxicities for HNC, with the mean incidence rate being 80% (Rodriguez-Caballero et al., 2012). Virtually, all patients in this study experienced some degree of mucositis. It has been shown that radiochemotherapy compromises the mouth\'s defense mechanisms and causes distinct shifts in the oral microbiota (Vanhoecke et al., 2015). To analyze these complex changes, patients\' retropharyngeal mucosa was longitudinally sampled in this study using disposable medical sterile swabs, because the mucosal swab sampling, compared to mouthwash, dental plaque and saliva sampling, may more accurately and factually reflect the dynamic changes in mucosal microbiota. Actually, once a pseudomembrane (biofilm) has formed in the oral cavity during treatment, rinsing the mouth out with liquid (mouthwash), although less invasive than mucosal sampling, can only remove planktonic bacteria but not the bacteria living within the biofilm. This may partially explain that the use of topical antimicrobial agents in different forms (solution, lozenge, paste or gel) failed to prevent the occurrence of severe mucositis in many previous experiments (Wijers et al., 2001; Stokman et al., 2003; Donnelly et al., 2003), because microorganisms growing in a biofilm show much greater resistance to antimicrobial agents than their free-living counterparts. It has been shown that chemotherapy was associated with a decrease in intestinal microbial diversity, and that this decrease coincided in time with the development of severe mucositis (van Vliet et al., 2010, 2009). However in this study we did not find any significant changes in bacterial diversity among the non-irradiated samples, RTOG 0 and RTOG 1 (erythema). This suggests therefore that at least the initiation of erythematous lesion may indeed be due to a direct cytotoxic effect of radiation or chemotherapeutic drugs; but not related to an alteration in oral microbiota. Sonis (2009), on the other hand proposed that bacteria, at least quantitatively, could not drive the development of mucosa ulceration, since their work suggests that ulceration preceded the increase in bacterial population, even though its peak severity coincided with peak bacterial loads. This raises a question of whether shifts in bacterial TAPI-1 structure may play a role in the aggravation of ulcers. In our study we found the relative abundance of several Gram-negative bacteria increased significantly as mucositis progressed to peak severity. Most of them were facultative anaerobes and belong to the phylum Proteobacteria, some of which are known opportunistic pathogens capable of causing a wide variety of nosocomial infections and are associated with ulcerative mucosal and/or skin lesions (Zhu et al., 2010; Broniek et al., 2014; Lestin et al., 2008; Song et al., 2011; Soares et al., 2011). Therefore the increase in the proportion of the Gram-negative bacteria that act as “modifiers” may facilitate the aggravation of mucosal inflammation through the activation of host pattern recognition receptors (e.g. TLR, NOD) by bacterial components (e.g. LPS, fimbriae, membrane vesicles, etc.) and the formation of pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 as well as PGE2 and MMPs (Vasconcelos et al., 2016). Surprisingly, only six of our 19 patients in this study experienced mild to moderate mucositis eventually, while the rest developed severe mucositis. This led to the question, as to what differences existed between the mild and severe subgroups with respect to bacterial profile. We found patients from the severe subgroup had a significantly higher abundance of Streptococcus before erythema became visible. This Gram-positive genus consists of approximately 50 species, including species forming a major part of oral commensals and many important human pathogens (Innings et al., 2005). It has been shown that the level of Streptococcus mitis increased significantly in NPC patients after irradiation, and in patients with breast cancer after chemotherapy (Tong et al., 2003; Napenas et al., 2010). This Streptococcus mitis, together with some other oral Streptococci, are mucin-degrading bacteria which play a pivotal role in the breakdown of mucus in the human oral cavity (van der Hoeven and Camp, 1994). When the degradation proceeds, the barrier function of epithelium is compromised, potentially causing pathogen translocation into the lamina propria and subsequent recruitment of inflammatory cells (Deplancke and Gaskins, 2001). Therefore it appears that a higher abundance of Streptococci might predispose patients to oral mucus dysfunction in the very early stage of mucositis, thus potentially disturbing the ecological balance of the oral microenvironment to a greater extent in the severe subgroup prior to erythema arising. From the occurrence of visible erythema to the beginning of severe mucositis (RTOG 3), we found that the patients in the mild subgroup harbored significantly more diverse bacteria and a lower abundance of Actinobacillus than those in the severe category. It is commonly believed that a more diverse oral bacterial community may contribute a lot to the protection of the oral ecosystem from overgrowth of indigenous pathobionts, such as Actinobacillus spp. observed in this study. These species were usually found to serve as both commensals of the oropharynx and opportunistic pathogens often involved in the pathogenesis of meningitis, sinusitis, pleural empyema, bronchopneumonia in patients with their associated underlying diseases (Friis-Moller et al., 2001). Due to its higher abundance shown in the server group and its commensal/pathogen life-style, Actinobacillus spp. may profoundly affect oropharyngeal microbial homeostasis, and be one of associated factors that predispose patients to severe mucositis. Thus, additional research is still needed to determine the species of Actinobacillus and germ-free and gnotobiotic animals can provide invaluable experimental tools for further investigation of host-microbe interactions, since colonization of one or more defined species can be achieved.