Precision Medicine on the Effects of Microbiota on Head–Neck Diseases and Biomarkers Diagnosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Protocol and Registration
2.2. Search Processing
2.3. Eligibility Criteria and Study Selection
2.4. Data Processing
2.5. Data Extraction
2.6. Data Analysis
2.7. PICOS Criteria
2.8. Study Evaluation
3. Results
Study Selection and Characteristic
4. Discussion
4.1. Cancer Diagnosis through Biomarkers
4.2. Microbiota and Head and Neck Cancer
4.3. Microbiota and Cancer Treatment
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AR vs. ARCON | Accelerated radiation with or without carbogen breathing and nicotinamide |
CTLA-4 | Cytotoxic T-lymphocyte associated protein 4 |
dTDP-L-rhamnose | Nucleotide sugar precursor |
GMB | Gut microbiota |
HIF-1 | Hypoxia-inducible factor 1-alpha |
HNC | Head and neck cancer |
HNSCC | Head and neck squamous cell cancer |
HPV | Human papilloma virus |
IL-1 | interleukin-1 |
IL-6 | interleukin-6 |
LB CD2 | Lactobacillus brevis CD2 |
LNs | Lymph nodes |
LPS | Lipopolysaccharides |
LSCC | Laryngeal squamous cell carcinoma |
MB | Microbiota |
miRs | MicroRNAs |
MM | Microbiome |
MMP | Matrix metalloproteinases |
OM | Oral mucositis |
OC-SCC | oral cavity squamous cell carcinoma |
OSCC | Oral squamous cell carcinoma of the oral cavity |
PCR | C-Reactive protein |
PDL1 | Programmed death ligand 1 |
PIMO | Pimonidazole |
PM | Precision medicine |
PML | Premalignant lesions |
RCHT | Radio chemotherapy |
RE | Radiation esophagitis |
ROS | Reactive oxygen species |
RNS | Reactive nitrogen species |
THW | Thyroid hormone withdrawal |
TM | Translational medicine |
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Criteria | Application in the Present Study |
---|---|
Population | Subjects diagnosed with head–neck tumors and potentially malignant lesions |
Intervention | Use of cancer biomarkers. Supplementation with probiotics or prebiotics or symbiotic |
Comparisons | Comparing before and post cancer intervention MB, MM assessment determined by 16 s rRNA sequencing, Mann–Whitney test on cancer biomarkers: fluorodeoxyglucose-positron emission tomography (FDG-PET/CT) scans |
Outcomes | Changes in baseline and end in symptom measurements. Changes in MB composition due to the presence of cancer or after cancer treatments |
Study design | Clinical Trials |
Authors | Study Type | Aim of the Study | Materials and Methods | Results |
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Swartz et al., 2022 [37] | Case-control Study | Tumor hypoxia compromises local control and patient survival. We used a digital, single-cell analysis to compare two hypoxia biomarkers (hypoxia-inducible factor 1-alpha [HIF-1] and pimonidazole [PIMO]) and their effect on outcome in patients with laryngeal cancer who received accelerated radiotherapy with or without carbogen breathing and nicotinamide (AR versus ARCON). | HIF-1 and PIMO immunohistochemical labeling were carried out in successive sections of 44 laryngeal carcinoma patients randomized between AR and ARCON. HIF-1 expression and PIMO-binding were associated in QuPath utilizing digital image analysis. Each biomarker’s high-density regions were automatically identified, and staining overlap was examined. For each biomarker, Kaplan–Meier survival analyses for local control, regional control, and disease-free survival were performed to predict a response advantage of ARCON over AR alone. | In total, 106 tissue pieces from 44 individuals were examined. On the fragment level, a weak but significant positive connection was found between HIF-1 and PIMO positivity, but not at the patient level. The number of high-density staining patches for both biomarkers showed a moderately strong connection (r = 0.705, p = 0.001). The staining overlap was inadequate. ARCON’s response benefit over AR could not be predicted by HIF-1 expression, PIMO-binding, or a combination of the two. |
Nagao et al., 2017 [38] | Randomized Controlled Trial | The goal of this study was to see if there were any variations in baseline p53 and ki67 expression between those who responded and those who did not react to our intervention. A secondary goal was to determine whether there was a link between dietary parameters and clinical responses. | We included all nonsmokers in the experimental group (n = 23) for this biomarker investigation. At the 1-year follow-up, there were four responders and 12 non-responders among the 16 who completed the experiment for one year of supplementation. Following p53 and ki67 immunostaining, the proportion of positive cell nuclei was calculated as the labeling index (LI). | The expression of p53 was higher in the basal layers than in the para-basal layers. Non-responsive subjects had a greater mean para-basal LI of p53 (26.0) than responding subjects (11.2) (p = 0.028). The ki67 LIs in the two groups were not substantially different. |
Ganly et al., 2019 [39] | Case-control Study | The goal of this study was to see if the oral was linked to OC-SCC in nonsmokers with HPV negative. We investigated the oral MMs of HPV-negative nonsmokers with OC-SCC (n = 18), premalignant lesions (n = 8), and healthy controls (n = 12). | Their oral MB was obtained using an oral wash and characterized using 16S rRNA gene sequencing. | In OC-SCC, the periodontal pathogens Fusobacterium, Prevotella, and Alloprevotella were abundant, but commensal Streptococcus was decreased. We divided the oral MM into two categories based on the four species plus a marker genus Veillonella for PML. |
Ganly et al., 2021 [40] | Case-control Study | The goal of this study was to use metagenomic shotgun sequencing to compare the HPV genome in patients with oral cavity squamous cell carcinoma (OCSCC) to normal people. | They gathered 50 OCSCC patients and compared them with a control patient based on age, gender, race, smoking status, and alcohol status. All patients’ DNA was collected from oral wash samples and full genome shotgun sequencing was carried out. The raw sequencing data was cleaned, reads were matched with the human genome (GRCH38), nonhuman reads were detected, and HPV genotypes were determined using HPViewer. The tongue was the most prevalent subsite in 26 (52% of the 50 individuals with OCSCC). Primary resection and neck dissection were performed in all patients. | p16 immunohistochemistry was negative in all but two tumors. In terms of gender, age, race/ethnicity, alcohol use, and cigarette smoking, there were no statistically significant differences between the cases and controls. In the nonhuman DNA readings, there was no statistically significant difference between the cancer samples and the control samples. HPV was found in 5 instances (10%) of OCSCC (genotypes 10, 16, and 98), although only 1 tumor sample (genotype 16) produced enough reads to imply an involvement in the genesis of OCSCC. HPV was found in four healthy people, however each had just 1–2 HPV readings per human genome. HPV genotypes are uncommon in patients with oral cancer. |
Torralba et al., 2021 [41] | Prospective Observational Study | To elucidate the links between the oral MB and cancer virulence factors | They employed 16S rDNA and metagenomic sequencing to evaluate the microbial makeup and functional content of 18 OSCC patients’ tumor tissue, non-tumor tissue, and saliva. | When compared with all other sample categories, the results show a larger number of bacteria from the phyla Fusobacteria, Bacteroidetes, and Firmicutes linked with tumor tissue. Furthermore, saliva metaproteomics indicated a substantial rise in Prevotella in five OSCC patients, whereas Corynebacterium was predominantly related to 10 healthy patients. Finally, we discovered adhesion and virulence factors linked with Streptococcus gordonii as well as recognized oral pathogens belonging to the Fusobacterium genera, which were primarily detected in OSCC tissues. |
Garajei et al., 2023 [42] | Case-control Study | This study compares the expression of the miR-21-5p and miR-429 genes in biopsy samples from patients with OSCC to that of controls. | Tissue samples were collected from 40 people (20 OSCC patients and 20 healthy controls) and analyzed using the Mann–Whitney test to evaluate miR-21-5p and miR-429 expression. | The individuals in the control and sick groups were 47.15 and 53.8 years old, respectively. The Mann–Whitney test revealed significant differences in miR-21-5p (p = 0.0001) and miR-429 (p = 0.0191) expression levels between the two groups (p = 0.05). |
Shah et al., 2022 [43] | A retrospective study of serial FDG-PET/CT scans collected prospectively as part of a phase 2 open-label randomized clinical trial examining neoadjuvant immunotherapy in patients with untreated OCSCC between 2016 and 2019 was performed. | To connect variations in fluoro-[18F]FDG-PET/CT scans with primary tumor pathologic response and immunologic biomarkers in patients with OCSCC undergoing neoadjuvant immunotherapy. | In total, 29 patients with untreated OCSCC (T2, or clinically node positive) from a single academic medical center were randomized 1:1 to receive neoadjuvant therapy with single agent nivolumab or combination nivolumab and ipilimumab, followed by surgery and standard of care adjuvant therapy. FDG-PET/CT scans were performed before (T0) and after (T1) preoperative immunotherapy in this investigation. | There was no relationship between pathologic response and SUVmax change in primary OCSCC between T0 and T1. Thirteen of the 27 subjects had newly FDG-avid ipsilateral LNs at T1, with the majority being pathologically negative. A total of 9 patients experienced radiologic irAEs, the most frequent of which was sarcoid-like LN (7 of 27). There were no relationships between primary OCSCC SUVmax at T0 and CD8+ T-cell number in the main tumor biopsy, and there were no associations between primary OCSCC SUVmax at T1 and CD8+ T-cell number in the original tumor during surgery. |
Hu et al., 2013 [44] | Prospective study | The purpose is to investigate the dynamic core microbiome of oral microbiota in supragingival plaque during head-and-neck radiation. | Dental plaque samples were collected from 8 subjects before and during radiotherapy. | During radiation, 4 phyla and 11 genera were detected, validating the hypothesis of a core microbiome. |
De Sanctis et al., 2019 [45] | Clinical Trial | To evaluate the effect of lactobacillus brevis CD2 (LB CD2) in preventing oral mucositis in patients with head and neck cancers (HNC). | In total, 75 patients were included to receive either LB CD2 lozenges or a mouthwash routine with sodium bicarbonate. | The trial failed to establish the effectiveness of LB CD2 in reducing radiotherapy-induced OM. |
Jiang et al., 2019 [46] | Randomized Controlled Trial | Probiotics will be used to decrease the severity of OM caused by chemoradiotherapy in patients with nasopharyngeal cancer. | During radiotherapy, 99 patients were randomly randomized to receive a probiotic or a placebo. | The gravity of OM was significantly reduced in those who took the probiotic combination. |
Kageyama et al., 2020 [47] | Prospective study | To evaluate the compositional shift of oral microbiota after surgical resection of tongue cancer. | Saliva samples were collected from 25 tongue cancer patients before and after resection of the tongue. Quantitative PCR analysis and 16S ribosomal RNA (rRNA) gene sequencing were used to determine bacterial density and composition. | The surgical resection of the tongue caused a shift in the structure of the salivary microbiota, with an increase in bacterial species from dental plaque, especially periodontal pathogens. |
Xu et al., 2020 [48] | Pilot study | The objective is to examine the relationship between oral bacterial variety and radiation esophagitis in chemoradiotherapy patients with esophageal cancer. | Oral mucosal swabs were obtained from 10 patients who did not have RE, 11 patients who had grade 1 RE, and 10 patients who had grade 2 RE. The diversity of oral bacteria was measured using 16S rRNA gene sequencing. | In patients with esophageal cancer following chemoradiotherapy, a reduction in oral bacterial diversity may be associated with RE. |
Basak et al., 2020 [49] | Randomized Controlled Trial | The purpose of this research is to evaluate the effect of APG-157 on cytokines and microbiota. | APG-157 was given to 13 healthy people and 12 patients with oral cancer. Blood and saliva samples were collected before, 1, 2, 3, and 24 h after therapy. | This study shows that APG-157 is a strategic therapy combined with immunotherapy in cancer. |
Xia et al., 2021 [50] | Randomized Clinical Trial | The purpose is to use Probiotics to prevent radiochemotherapy-induced OM in patients with nasopharyngeal carcinoma. | In total, 77 individuals were chosen and randomly selected to receive either a probiotic cocktail or a placebo. After 7, 14, and 21 days, tongue, blood, fecal, and proximal colon tissue samples were examined. | The improved probiotic cocktail considerably decreases the severity of OM by improving patients’ immune responses and changing the composition of their gut microbiota. |
Niño et al., 2022 [51] | Observational study | To evaluate the effect of the intratumoral microbiome on cancer spatial and cellular heterogeneity. | Spatial profiling and single-cell RNA sequencing are used in situ to identify cellular, molecular, and spacial host-microbe interactions. | Inside a tumor, the microbiota is well structured in microniches with immune and epithelial cell activities that support cancer growth. |
Lin et al., 2022 [52] | Randomized Clinical Trial | To assess the oral-gut microbiota profiles of THW patients and then see if probiotics can help with THW-related problems. | In total, 50 thyroid cancer patients were randomly randomized to receive probiotics or a placebo during thyroidectomy. | Probiotics significantly improved gut and oral microbial diversity and reduced thyroid hormone withdrawal-related problems in thyroid cancer patients prior to radioiodine treatment after thyroidectomy. |
Li et al., 2023 [53] | Observational study | Based on tissue sequencing, this study intends to assess the clinical association of the intratumoral oral microbiome in oral squamous cell cancer. | The oral microbiota was analyzed in 133 OSCC samples to assess its composition compared with healthy patients and also determine its diagnostic and prognostic value. | Differences in bacterial composition have been found between the oral microbiota in OSCC and healthy patients, and only some of these bacteria can be used as diagnostic and prognostic predictors. |
Li, Z. et al., 2021 [54] | Prospective study | To assess the prevalence and distribution of the oral microbiota in oral cancer patients, populations without precancerous lesions, and healthy individuals. To assess the connection between oral cancer incidence and the microbiome of oral bacteria. | In total, 10 patients who had been diagnosed with oral cancer, 10 healthy subjects and 6 patients with oral precancerous lesions were enrolled. Salivary samples were collected from these patients and the microbiome was analyzed | At many species levels, there were significant structural alterations in the oral microbiota of patients with oral cancer, patients with precancerous lesions, and healthy controls. Some metabolic pathways are altered by dysbiosis of the oral microbiota, which has an impact on oral health. |
Chan, J.Y.K. et al., 2022 [55] | Prospective cohort study | The purpose of the study is to understand the correlation between oral microbiome, HPV infection, conventional risk factors, and head and neck squamous cell cancer (HNSCC). | By sequencing 16S rRNA V3-V4 bacterial and HPV L1 sections, respectively, the oral microbiota and HPV infection of tissues of 166 Chinese people were analyzed. the relationship between oral microbiota, HPV and clinical features was analyzed. | It is inferred that dysbiosis of the oral microbiota is involved in the pathogenesis of OSCC. Fusobacterium is involved in improving outcomes of patients with OSCC, especially in patients without traditional risk factors. Understanding how the oral microbiome, HPV infection, and other risk factors for HNSCC interact will be crucial to understanding the pathophysiology of this disease. |
Zuo, H.-J. et al., 2020 [56] | Prospective study | In this study, oral microbial traits and new biomarkers will be assessed for HNC patients, and the relationship between oral microorganisms and HNC-related symptoms will be evaluated prior to surgical intervention. | Overall, 56 patients with HNC and 64 healthy controls were recruited. Salivary samples were taken in order to do 16S rRNA gene sequencing on the microbes. | A decrease in health-related bacteria, such as Peptococcus, and a rise in potentially pathogenic bacteria, such as Capnocytophaga and other LPS-producing bacteria such as Neisseria, were seen in the oral microbiome of HNC patients. Additionally, HNC-related symptoms in conjunction with salivary microorganisms such as Capnocytophaga may be employed as a noninvasive technique for screening, identification, and treatment monitoring of HNC. |
Al-Qadami, G. et al., 2023 [57] | Prospective pilot study | To assess the relationships between a patient’s pre-treatment gut flora and the severity of radiotherapy-induced oral mucositis (OM) and recurrence risk in those with head and neck cancer (HNC). | Patients who were scheduled to receive radiotherapy or chemoradiotherapy for HNC were enrolled in this trial. Before therapy, stool samples were taken, and 16S rRNA gene sequencing was used to analyze the microbial composition. | OM severity and recurrence risk are related to a patient’s gut microbiota makeup at the beginning of therapy. |
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Inchingolo, A.M.; Malcangi, G.; Piras, F.; Palmieri, G.; Settanni, V.; Riccaldo, L.; Morolla, R.; Buongiorno, S.; de Ruvo, E.; Inchingolo, A.D.; et al. Precision Medicine on the Effects of Microbiota on Head–Neck Diseases and Biomarkers Diagnosis. J. Pers. Med. 2023, 13, 933. https://doi.org/10.3390/jpm13060933
Inchingolo AM, Malcangi G, Piras F, Palmieri G, Settanni V, Riccaldo L, Morolla R, Buongiorno S, de Ruvo E, Inchingolo AD, et al. Precision Medicine on the Effects of Microbiota on Head–Neck Diseases and Biomarkers Diagnosis. Journal of Personalized Medicine. 2023; 13(6):933. https://doi.org/10.3390/jpm13060933
Chicago/Turabian StyleInchingolo, Angelo Michele, Giuseppina Malcangi, Fabio Piras, Giulia Palmieri, Vito Settanni, Lilla Riccaldo, Roberta Morolla, Silvio Buongiorno, Elisabetta de Ruvo, Alessio Danilo Inchingolo, and et al. 2023. "Precision Medicine on the Effects of Microbiota on Head–Neck Diseases and Biomarkers Diagnosis" Journal of Personalized Medicine 13, no. 6: 933. https://doi.org/10.3390/jpm13060933