New Pathways for Alimentary Mucositis

Alimentary mucositis is a major dose-limiting toxicity associated with anticancer treatment. It is responsible for reducing patient quality of life and represents a significant economic burden in oncology. The pathobiology of alimentary mucositis is extremely complex, and an increased understanding of mechanisms and pathway interactions is required to rationally design improved therapies. This review describes the latest advances in defining mechanisms of alimentary mucositis pathobiology in the context of pathway activation. It focuses particularly on the recent genome-wide analyses of regimen-related mucosal injury and the identification of specific regulatory pathways implicated in mucositis development. This review also discusses the currently known alimentary mucositis risk factors and the development of novel treatments. Suggestions for future research directions have been raised

Allergen-specific T cell quantity in blood is higher in allergic compared to nonallergic individuals

Article deposited according to agreement with BMC, December 6, 2010.YesFunding provided by the Open Access Authors Fund

Systematic Review of Laser and Other Light Therapy for the Management of Oral Mucositis in Cancer Patients

Background The aim of this study was to review the available literature and define clinical practice guidelines for the use of laser and other light therapies for the prevention and treatment of oral mucositis. Methods A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based onthe evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. Results A new recommendation was made for low-level laser (wavelength at 650 nm, power of 40 mW, and each square centimeter treated with the required time to a tissue energy dose of 2 J/cm2 (2 s/point)) for the prevention of oral mucositis in adult patients receiving hematopoietic stem cell transplantation conditioned with high-dose chemotherapy, with or without total body irradiation. A new suggestion was made for low-level laser (wavelength around 632.8 nm) for the prevention of oral mucositis in patients undergoing radiotherapy, without concomitant chemotherapy, for head and neck cancer. No guideline was possible in other populations and for other light sources due to insufficient evidence. Conclusions The increasing evidence in favor of low-level laser therapy allowed for the development of two new guidelines supporting this modality in the populations listed above. Evidence for other populations was also generally encouraging over a range of wavelengths and intensities. However, additional well-designed research is needed to evaluate the efficacy of laser and other light therapies in various cancer treatment settings

The microbiota-gut-brain axis:An emerging therapeutic target in chemotherapy-induced cognitive impairment

Chemotherapy-induced cognitive impairment (CICI) is an ill-defined complication of chemotherapy treatment that places a significant psychosocial burden on survivors of cancer and has a considerable impact on the activities of daily living. CICI pathophysiology has not been clearly defined, with candidate mechanisms relating to both the direct cytotoxicity of chemotherapy drugs on the central nervous system (CNS) and more global, indirect mechanisms such as neuroinflammation and blood brain barrier (BBB) damage. A growing body of research demonstrates that changes to the composition of the gastrointestinal microbiota is an initiating factor in numerous neurocognitive conditions, profoundly influencing both CNS immunity and BBB integrity. Importantly, chemotherapy causes significant disruption to the gastrointestinal microbiota. While microbial disruption is a well-established factor in the development of chemotherapy-induced gastrointestinal toxicities (largely diarrhoea), its role in CICI remains unknown, limiting microbial-based therapeutics or risk prediction strategies. Therefore, this review aims to synthesise and critically evaluate the evidence addressing the microbiota-gut-brain axis as a critical factor influencing the development of CICI

Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis

Background: Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity. Methods: Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Results: Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy. Conclusions: Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.Zhi Yi Ong, Rachel J. Gibson, Joanne M. Bowen, Andrea M. Stringer, Jocelyn M. Darby, Richard M. Logan, Ann S.J. Yeoh, Dorothy M. Keef

Circulating Serum Exosomal miRNAs As Potential Biomarkers for Esophageal Adenocarcinoma

Author version made available in accordance with publisher policy.Abstract Background The poor prognosis and rising incidence of esophageal adenocarcinoma highlight the need for improved detection methods. The potential for circulating microRNAs (miRNAs) as biomarkers in other cancers has been shown, but circulating miRNAs have not been well characterized in esophageal adenocarcinoma. We investigated whether circulating exosomal miRNAs have potential to discriminate individuals with esophageal adenocarcinoma from healthy controls and non-dysplastic Barrett’s esophagus. Methods Seven hundred fifty-eight miRNAs were profiled in serum circulating exosomes from a cohort of 19 healthy controls, 10 individuals with Barrett’s esophagus, and 18 individuals with locally advanced esophageal adenocarcinoma. MiRNA expression was assessed using all possible permutations of miRNA ratios per individual. Four hundred eight miRNA ratios were differentially expressed in individuals with cancer compared to controls and Barrett’s esophagus (Mann-Whitney U test, P<0.05). The 179/408 ratios discriminated esophageal adenocarcinoma from healthy controls and Barrett’s esophagus (linear regression, P0.7, P<0.05). A multi-biomarker panel (RNU6-1/miR- 16-5p, miR-25-3p/miR-320a, let-7e-5p/miR-15b-5p, miR- 30a-5p/miR-324-5p, miR-17-5p/miR-194-5p) demonstrated enhanced specificity and sensitivity (area under ROC=0.99, 95 % CI 0.96–1.0) over single miRNA ratios to distinguish esophageal adenocarcinoma from controls and Barrett’s esophagus. Conclusions This study highlights the potential for serum exosomal miRNAs as biomarkers for the detection of esophageal adenocarcinoma

Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study

Author version made available following 12 month embargo from date of publication (27 March 2015) in accordance with publisher copyright policy.Purpose Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach. Methods Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity. Results Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident. Conclusions This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted

Selective MMP Inhibition, Using AZD3342, to Reduce Gastrointestinal Toxicity and Enhance Chemoefficacy in a Rat Model

BACKGROUND: The common cytotoxic mechanisms that underpin chemoefficacy and toxicity have hampered efforts to deliver effective supportive care interventions, particularly for gastrointestinal (GI) toxicity. Matrix metalloproteinases (MMPs) have been implicated in both tumor growth and GI toxicity, and as such MMP inhibitors present as a novel therapeutic avenue to simultaneously enhance treatment efficacy and reduce toxicity. OBJECTIVES: The aim of this study was to determine the efficacy of an MMP-9/12 inhibitor, AZD3342, on tumor growth and GI toxicity in a rat model. METHODS: Female tumor-bearing Dark Agouti rats (n = 90) were divided into 4 groups: vehicle control; methotrexate (MTX); AZD3342, and MTX + AZD3342. Tumors were measured daily (for 5 days) using digital calipers. GI toxicity was assessed using well-established clinical markers (diarrhea/weight loss), histopathological analysis, and functional assessment of intestinal barrier permeability. RESULTS: AZD3342 delayed the onset of severe diarrhea by 1 day (vs. MTX) but was unable to improve the overall severity of diarrhea. No changes were detected in tissue morphology or intestinal barrier function. AZD3342 alone suppressed tumor growth (p = 0.003 vs. vehicle) but did not enhance the efficacy of MTX. CONCLUSIONS: This study showed partial efficacy of AZD3342 in reducing tumor growth and delaying the onset of severe diarrhea caused by MTX in rats. We suggest further studies be undertaken targeting appropriate scheduling of AZD3342 as well as investigating different cytotoxic therapies that strongly activate MMP signaling

The Koolungar Moorditj Healthy Skin Project: Elder and Community Led Resources Strengthen Aboriginal Voice for Skin Health

In partnership with local Aboriginal Community Controlled Health Organisations, the Elder-led co-designed Koolungar Moorditj Healthy Skin project is guided by principles of reciprocity, capacity building, respect, and community involvement. Through this work, the team of Elders, community members, clinicians and research staff have gained insight into the skin health needs of urban-living Aboriginal koolungar (children); and having identified a lack of targeted and culturally appropriate health literacy and health promotion resources on moorditj (strong) skin, prioritised development of community-created healthy skin resources. Community members self-appointed to Aboriginal Community Advisory Groups (CAG) on Whadjuk (Perth) and Wardandi (Bunbury) boodjar (land/place) provided local leadership and led the development of moorditj skin resources. Over several online and face-to-face meetings facilitated by an Aboriginal project officer, CAG members shared local perspectives and cultural knowledge to develop and inform the messaging, medium, and dissemination of health literacy and health promotion resources for healthy skin. All CAG-created research approaches, resources and materials were presented to the Elder Researchers for discussion, final review, and implementation by the project team. Culturally appropriate moorditj skin resources, designed by community for community, build on knowledge of healthy skin to achieve moorditj skin and moorditj health for urban-living Aboriginal koolungar