Risk factors for oral mucositis in patients with solid tumorsunder treatment with cetuximab: a retrospective cross-sectional study

Background: This study retrospectively analyzed the risk factors for oral mucositis (OM) during cetuximab treatment. Material and Methods: We screened patients using cetuximab and retrospectively evaluated the presence of OM based on medical records. We collected information from 2 years of evaluations. Patient medical records were reviewed to obtain data on chemotherapy cycle and dose, sex, age, primary tumor, TNM stage, and head and neck radiotherapy (HNR) history. The X2 test and multinomial logistic regression were used for statistical analysis (SPSS 20.0, p < 0.05). Results: Among 1831 patients, OM was showed in 750 in any grade (41%), during cetuximab treatment. Most patients were female (n=944, 51.6%), <70years-old (n=1149, 62.8%), had larynx cancer (n=789, 43.1%) in T4 (n=579, 47.7%), N0 (n=509, 52.6%) stages. Primary tumor surgery was performed in 1476 (80.6%) patients, radiotherapy in 606 (33.1%) patients and cetuximab protocols most used involved up to four cycles (n=1072, 58.5%) of <400mg (n=996, 54.4%) cetuximab doses. Female (OR [odds ratio] = 2.17, CI95% = 1.26-3.75), >70 years-old patients (OR = 16.02, CI95% = 11.99-21.41), with HHNR (OR = 1.84, 1.41-2.40), treated with >4 cycles (OR = 1.52, CI95% = 1.16-2.01) and high doses of cetuximab (OR = 3.80, CI95% = 2.52-5.71) are the greatest risk factors for OM. Conclusions: Since the clinical benefit of cetuximab in the treatment of older patients is limited and there is a high OM, especially in women with head and neck treated with radiotherapy, high doses and a high number of cetuximab cycles must be administered with caution. (AU)

Deficiency in infiltration of CD8/CD3 positive lymphocytes and macrophages plays a role in lip carcinogenesis: an immunohistochemical study.

OBJECTIVE: To evaluate the immunoexpression profile for CD8, CD3, CD20 and CD68 in the process and carcinogenesis of Carcinoma of the vermilion lip. METHODS: Average cell count with positive expression for CD3, CD8, CD20 and CD68. The CD8/CD3 ratio calculated in the region was based on the percentage of positive cells in a total of malignant cells. Kruska-Wallis/Dunn, Mann-Whitney and Spearman correlation tests (SPSS, p < 0.05) were used. RESULTS: In the Aquitic Cheilitis samples, there was an increase in intraepithelial CD8+ and CD68+. In LSCCs, there was an increase in peritumoral and intratumoral CD3+, CD8+, CD20+ and CD68+ cells. In peritumoral LSCC, CD3+ and CD8+ showed a direct correlation (p = 0.004), and CD68+ and CD8+ (p = 0.017). In the intraepithelial region, CD8+ correlated with CD20+ (p = 0.014) and CD68+ (p = 0.013). In the CAs, CD3 (p < 0.001) and CD8 (p = 0.025) correlated intraepithelial and subepithelial. In LSCC CD3+ (p = 0.002), CD8+ (p = 0.001) and CD68+ (p = 0.030) had intra and peritumoral correlation. CONCLUSION: CD68+ is the first interacting cell with the greatest capacity to migrate to the tumor and interact with CD3, CD8 and CD20. Apparently, CD20 affects perineural invasion. LEVEL OF EVIDENCE: Level 2.

Photobiomodulation therapy in the treatment of radiotherapy-related trismus of the head and neck.

This study evaluated photobiomodulation therapy (PBMT) for treatment of trismus in patients undergoing radiotherapy for head and neck cancer (HNC). Sixteen patients, 10 men and 6 women, who had a mouth opening < 35 mm and underwent RT were included. The patients were evaluated daily before and after the PBMT application, measuring mouth opening and performing pain scores for the masticatory muscles using the visual analog scale (VAS). We used the infrared laser (~ 808 nm) extraorally, 0.1 W power, 3 J energy, 30 s (107 J/cm2) per point, applied to temporalis anterior, masseter muscles, and temporomandibular joints (TMJ). An intraoral point was made in the trigonoretromolar region towards the medial pterygoid muscle. The mean mouth opening of the patients increased by more than 7 mm throughout the treatment. The pain scores on the initial days showed an immediate reduction after PBMT on the ipsilateral side in the muscles and TMJ. Throughout PBMT applications, there was a significant reduction in pain scores in all muscles and the TMJ. The radiation dose of all patients was above 40 Gy, which is the threshold dose for the risk of developing trismus. SPSS software was used and adopted a confidence of 95%. The Kolmogorov-Smirnov normality test, Wilcoxon test, and Spearman correlation were performed. PBMT controls muscular pain and reduced mouth opening limitation in HNC during radiotherapy. Further studies are needed to evaluate the preventive capacity of PBMT protocols for RT trismus-related HNC.

Interleukin-17 plays a role in dental pulp inflammation mediated by zoledronic acid: a mechanism unrelated to the Th17 immune response?

OBJECTIVE: To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL). METHODOLOGY: Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-ß). The Kruskal-Wallis/Dunn test was used for statistical analysis. RESULTS: PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-ß immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells. CONCLUSION: ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.

Oral hygiene protocols reduce the severity and incidence of oral mucositis during antineoplastic treatment: a systematic review and meta-analysis of randomized and non-randomized clinical trials.

OBJECTIVE: The objective of this systematic review was to determine whether oral and dental hygiene protocols (DHPs) reduce the incidence and severity of oral mucositis (OM) during antineoplastic treatment. MATERIALS AND METHODS: This PROSPERO-registered systematic review (CRD42021295322) was based on searches of publicly accessible databases, including PubMed, Scopus, Web of Science, LILACS, EBSCOhost, LIVIVO, Embase, and gray literature (Google Scholar, ProQuest, and Energy) until December 2021. Twenty-five articles from these searches and 14 articles retrieved from the references therein were evaluated in this systematic review and meta-analysis. The risk of bias (RoB) was assessed using RoB-2 and ROBINS-I for randomized (RCT) and non-randomized (n-RCT) clinical trials, respectively. A meta-analysis was performed on RCTs and n-RCTs in two subgroups to evaluate oral mouth rinses or DHP. GRADE-pro was used to assess the degree of certainty of the evidence. RESULTS: Of the 3367 articles retrieved, 25 RCTs and 14 n-RCTs involving 2109 and 754 patients, respectively, were included in the analyses. RoB was low for RCTs and moderate-to-very severe for n-RCTs. High heterogeneity and publication RoB were identified. In RCTs, mouth rinses (p = 0.830) and DHP (p = 0.100) did not reduce the incidence of OM. However, mouth rinses strongly reduced the severity of OM (p < 0.001; Cohen's d = - 1.87, 95% confidence interval [CI] = - 2.49 to - 1.24). In non-RCTs, mouth rinses (p < 0.001) and DHP (p < 0.001) reduced the relative risk of OM 0.38 (95% CI = 0.24 to 0.59) and 0.64 (95% CI = 0.53 to 0.70) times, respectively. In addition, DHP strongly reduced OM severity (Cohen's d = - 0.81, 95% CI = - 1.03 to - 0.59). GRADE-pro showed high certainty of OM severity and incidence in RCTs and non-RCTs, respectively, and low (OM incidence in RCTs) to very low (OM severity in non-RCTs) certainty in other outcomes. CONCLUSION: DHPs strongly reduce the severity and moderately reduce the incidence of OM. However, further studies with low heterogeneity are needed to validate these findings.

Interleukin-17 plays a role in dental pulp inflammation mediated by zoledronic acid: a mechanism unrelated to the Th17 immune response?

Abstract Objective To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL). Methodology Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-β). The Kruskal-Wallis/Dunn test was used for statistical analysis. Results PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-β immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells. Conclusion ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.

Celecoxib in the treatment of orofacial pain and discomfort in rats subjected to a dental occlusal interference model.

PURPOSE: To evaluate the effect of a selective cyclooxygenase 2 (COX-2) inhibitor on trigeminal ganglion changes and orofacial discomfort/nociception in rats submitted to an experimental model of dental occlusal interference (DOI). METHODS: Female Wistar rats (180-200 g) were divided into five groups: a sham group (without DOI) (n=15); and four experimental groups with DOI treated daily with 0.1 mL/kg saline (DOI+SAL), 8, 16, or 32 mg/kg celecoxib (DOI+cel -8, -16, -32) (n=30/group). The animals were euthanized after one, three, and seven days. The bilateral trigeminal ganglia were analyzed histomorphometrically (neuron cell body area) and immunohistochemically (COX-2, nuclear factor-kappa B [NFkB], and peroxisome proliferator-activated receptor-y [PPARy]). A bilateral nociception assay of the masseter muscle was performed. The number of bites/scratches, weight, and grimace scale scores were determined daily. One-way/two-way analysis of variance (ANOVA)/Bonferroni post hoc tests were used (P < .05, GraphPad Prism 5.0). RESULTS: DOI+SAL showed a reduction in neuron cell body area bilaterally, whereas DOI+cel-32 exhibited a significative increase in neuron cell body area compared with DOI+SAL group (P < 0.05). The ipsilateral (P=0.007 and P=0.039) and contralateral (P < 0.001 and P=0.005) overexpression of COX-2 and NFkB and downregulation of PPARy (P=0.016 and P < 0.001) occurred in DOI+SAL, but DOI+cel-32 reverted this alteration. DOI+SAL showed increase in isplateral (P < 0.001) and contralateral (P < 0.001) nociception, an increased number of bites (P=0.010), scratches (P < 0.001), and grimace scores (P=0.032). In the group of DOI+cel-32, these parameters were reduced. CONCLUSIONS: Celecoxib attenuated DOI-induced transitory nociception/orofacial discomfort resulting from trigeminal COX-2 overexpression.

Risk factors for oral mucositis during chemotherapy treatmentfor solid tumors: a retrospective STROBE-guided study

Background: This study retrospectively analyzed the risk factors for transchemotherapy oral mucositis (OM).Material and Methods: Before each chemotherapy cycle, patients were routinely evaluated for the presence/severity of OM based on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale for adverse effectsand graded as follows: However, specific conditions such as mucositis are graded on a five-point scale: 0, absenceof mucositis, grade 1 (Asymptomatic or mild), 2 (Presence of pain and moderate ulceration, without interferencewith food intake), 3 (severe pain with interference with food intake) or 4 (Life-threatening with the need for urgentintervention). Information from 2 years of evaluations was collected and patient medical records were reviewed toobtain data on chemotherapy cycle, sex, age, body mass index, body surface area, primary tumor, chemotherapyprotocol, and history of head and neck radiotherapy. The X² test and multinomial logistic regression were used forstatistical analysis (SPSS 20.0, p<0.05).Results: Among 19,000 total evaluations of 3,529 patients during 5.32±4.7 chemotherapy cycles (CT) the prevalence of OM was 6.3% (n=1,195). Chemotherapy duration (p<0.001), female sex (p=0.001), adjuvant intention(p=0.008) and the use of carboplatin (p=0.001), cisplatin (p=0.029), docetaxel (p<0.001) and bevacizumab(p=0.026) independently increased the risk of mucositis. In head and neck tumors, 2018 year (p=0.017), chemotherapy duration (p=0.018), BMI>30 (p=0.008), radiotherapy (p=0.037) and use of carboplatin (p=0.046) andcyclophosphamide (p=0.010) increased this prevalence.Conclusions: Cycles of chemotherapy, sex, cytotoxicity drugs, bevacizumab and head and neck radiotherapy increase the risk of OM in solid tumors. (AU)

Analysis of a Brazilian cross-cultural adaptation of the FACE-Q SFAOS in facial harmonization in dentistry.

The FACE-Q SFAOS is an instrument developed for esthetic facial procedures and has been validated in patients undergoing rhinoplasty. It consists of ten items that assess the current perception of facial appearance regarding symmetry, harmony, proportion, freshness or vitality, and self-perception of appearance; these items are perhaps important to guide demands in orofacial harmonization (OFH). We aimed to validate the FACE-Q SFAOS scale among professionals working with OFH and verify its acceptance for use in clinical practice. Altogether, 25 OFH specialists were included to evaluate the FACE-Q SFAOS scale and the new technology acceptability model (TAM). Internal validity was measured using Cronbach's α coefficient. Both scales were associated with clinical experience and perceived usefulness using Spearman's correlation and Fisher's exact or chi-square tests (SPSS 20.0, p < 0.05). The FACE-Q SFAOS (α = 0.927) and TAM (α = 0.941) scales demonstrated good internal validity, and most professionals demonstrated good acceptance (TAM >70 = 64%). The mean FACE-Q SFAOS and TAM scores were 64.00±17.03 and 74.60±20.66, respectively. Practitioners with more than two years of experience (p=0.032) who believed the scale was useful for lip filler evaluation (p = 0.017) demonstrated greater acceptance. The number of indications on the scale was directly correlated with higher levels of acceptance (p = 0.002, r = 0.594). Thus, the FACE-Q SFAOS scale has good reproducibility and acceptance among OFH specialists; however, acceptability was shown to be dependent on perceived usability.

Analysis of a Brazilian cross-cultural adaptation of the FACE-Q SFAOS in facial harmonization in dentistry

Abstract: The FACE-Q SFAOS is an instrument developed for esthetic facial procedures and has been validated in patients undergoing rhinoplasty. It consists of ten items that assess the current perception of facial appearance regarding symmetry, harmony, proportion, freshness or vitality, and self-perception of appearance; these items are perhaps important to guide demands in orofacial harmonization (OFH). We aimed to validate the FACE-Q SFAOS scale among professionals working with OFH and verify its acceptance for use in clinical practice. Altogether, 25 OFH specialists were included to evaluate the FACE-Q SFAOS scale and the new technology acceptability model (TAM). Internal validity was measured using Cronbach's α coefficient. Both scales were associated with clinical experience and perceived usefulness using Spearman's correlation and Fisher's exact or chi-square tests (SPSS 20.0, p < 0.05). The FACE-Q SFAOS (α = 0.927) and TAM (α = 0.941) scales demonstrated good internal validity, and most professionals demonstrated good acceptance (TAM >70 = 64%). The mean FACE-Q SFAOS and TAM scores were 64.00±17.03 and 74.60±20.66, respectively. Practitioners with more than two years of experience (p=0.032) who believed the scale was useful for lip filler evaluation (p = 0.017) demonstrated greater acceptance. The number of indications on the scale was directly correlated with higher levels of acceptance (p = 0.002, r = 0.594). Thus, the FACE-Q SFAOS scale has good reproducibility and acceptance among OFH specialists; however, acceptability was shown to be dependent on perceived usability.

Prognostic factors on surgically and non-surgically treated oral squamous cell carcinoma: Advances in survival in fifteen years of follow up.

BACKGROUND: Retrospectively to evaluate the influence of radiochemotherapy (RCT) in the treatment of surgically and non-surgically treated Oral Squamous Cell Carcinoma (OSCC). MATERIAL AND METHODS: We analysed 934 patients treated in Hospital Haroldo Juaçaba (2000-2014; 15 years of study) by extraction of data type of cancer, localization of tumour, sex, age, race, education level, risk factors (smoking and alcohol use), year of diagnosis, TNM stage, therapeutic approach, health system used (public or private) and overall survival (OS). Surgically and non-surgically treated OSCC were compared by chi-square and Fisher's exact tests, and their prognostic factors were analysed by log-rank Mantel-Cox plus Cox regression tests (SPSS 20.0, p<0.05). RESULTS: Non-surgically treated OSCC patients had a lower OS than surgically treated OSCC patients (p<0.001), but an increase in OS was shown in both groups. Although the 2010-2014 period (p=0.003), education level (p=0.032), tongue/mouth floor/palate localization (p=0.023) and TNM stage (p<0.05) were important in non-surgically treated OSCC OS, the major prognostic factors were node metastasis (p=0.003) and non-use of RCT (p=0.039) (multivariate analysis). In surgically treated OSCC patients, higher OS was shown in the 2010-2014 period (p<0.001), females (p=0.012), non-drinkers (p=0.011), non-smokers (p=0.009) and those with lower TNM stage (p<0.05), but the major prognostic factor was the 2010-2014 period (p=0.004) (multivariate analysis), which was directly associated with an increase in RCT indication (p<0.001). CONCLUSIONS: The increase in RCT improved the OS in this large cohort of surgically and non-surgically treated OSCC patients. Key words:Mouth neoplasms, neck, radiotherapy, drug therapy, combination.

Distance learning during social seclusion by COVID-19: Improving the quality of life of undergraduate dentistry students.

BACKGROUND: Social isolation is ongoing worldwide with the aim to stem the spread of the novel coronavirus SARS-CoV-2 responsible for the COVID-19 pandemic. However, social isolation leads to significant psycho-emotional changes. This study aimed to assess the effect of distance education (DE) activities implemented due to social isolation, on the quality of life of undergraduate dentistry students. METHOD: An e-questionnaire (Google Forms® ) was administered to identify specific DE activities after social isolation and included the World Health Organization Quality of Life (WHOQOL)-Bref questionnaire. The e-questionnaire was sent 14 days after the initiation of social isolation, remaining available for 48 hours. Cronbach's alpha and the means of the quality-of-life domains were calculated and analysed using the Friedman/Dunn and Spearman's correlation tests. After ranking, chi-squared and Fisher's exact tests plus multinomial logistic regression were performed (SPSS, P < .05). RESULT: There was an excellent internal consistency of WHOQOL-Bref (α = 0.916), and the mean quality of life (0-100) was 70.66 ± 12.61. The psychological domain was the most affected (P < .001). The social domain exhibited the weakest correlation with overall quality of life (P < .001, r = 0.688). The use of the Internet, cell phones and streaming media increased, although all students had DE activities. In the multivariate analysis, attending virtual meetings (P = .028) and performing DE activities in an office/study room (P = .034) were significantly associated with good quality of life. CONCLUSION: Facing social isolation never previously experienced by this generation, undergraduate dentistry students are at risk of reduced quality of life. Therefore, performing DE activities through devices with teacher-student interaction is a key coping tool.