Oral and gastrointestinal mucositis is a toxicity of many forms of radiotherapy and chemotherapy. It has a significant impact on health, quality of life and economic outcomes that are associated with treatment. It also indirectly affects the success of antineoplastic therapy by limiting the ability of patients to tolerate optimal tumoricidal treatment. The complex pathogenesis of mucositis has only recently been appreciated and reflects the dynamic interactions of all of the cell and tissue types that comprise the epithelium and submucosa. The identification of the molecular events that lead to treatment-induced mucosal injury has provided targets for mechanistically based interventions to prevent and treat mucositis.

The pathobiology of mucositis.

Curcumin (diferuloylmethane) is a polyphenol derived from the Curcuma longa plant, commonly known as turmeric. Curcumin has been used extensively in Ayurvedic medicine for centuries, as it is nontoxic and has a variety of therapeutic properties including anti-oxidant, analgesic, anti-inflammatory and antiseptic activity. More recently curcumin has been found to possess anti-cancer activities via its effect on a variety of biological pathways involved in mutagenesis, oncogene expression, cell cycle regulation, apoptosis, tumorigenesis and metastasis. Curcumin has shown anti-proliferative effect in multiple cancers, and is an inhibitor of the transcription factor NF-κB and downstream gene products (including c-myc, Bcl-2, COX-2, NOS, Cyclin D1, TNF-α, interleukins and MMP-9). In addition, curcumin affects a variety of growth factor receptors and cell adhesion molecules involved in tumor growth, angiogenesis and metastasis. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide and treatment protocols include disfiguring surgery, platinum-based chemotherapy and radiation, all of which may result in tremendous patient morbidity. As a result, there is significant interest in developing adjuvant chemotherapies to augment currently available treatment protocols, which may allow decreased side effects and toxicity without compromising therapeutic efficacy. Curcumin is one such potential candidate, and this review presents an overview of the current in vitro and in vivo data supporting its therapeutic activity in head and neck cancer as well as some of the challenges concerning its development as an adjuvant chemotherapeutic agent.

/pdf/curcumin-a-review-of-anti-cancer-properties-and-therapeutic-arkgisjnzq.pdf

Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma

Purpose: To compare directly the effect of intensity-modulated radiotherapy (IMRT) vs. conventional radiotherapy (CRT) on salivary flow and quality of life (QoL) in patients with early-stage nasopharyngeal carcinoma (NPC). Methods and Materials: Fifty-one patients with T2, N0/N1, M0 NPC took part in a randomized controlled clinical study and received IMRT or CRT. Stimulated whole (SWS) and parotid (SPS) saliva flow were measured and Medical Outcomes Short Form 36 (SF-36), European Organization for Research and Treatment of Cancer (EORTC) core quetionnaire, and EORTC head-and-neck module (QLQ-H&N35) were completed at baseline and 2, 6, and 12 months after radiotherapy. Results: Forty-six patients (88%) were in disease remission 12 months after radiotherapy. At 12 months postradiotherapy, 12 (50.0%) and 20 patients (83.3%) in the IMRT group had recovered at least 25% of preradiotherapy SWS and SPS flow respectively, compared with 1 (4.8%) and 2 patients (9.5%), respectively, in the CRT group. Global health scores showed continuous improvement in QoL after both treatments ( p p Conclusions: IMRT was significantly better than CRT in terms of parotid sparing and improved QoL for early-stage disease. The findings support the case for assessment of health-related QoL in relation to head-and-neck cancer using a site-specific approach.

Xerostomia and quality of life after intensity-modulated radiotherapy vs. conventional radiotherapy for early-stage nasopharyngeal carcinoma: initial report on a randomized controlled clinical trial.

Background
This consensus report is concerned with the association between periodontitis and atherosclerotic cardiovascular disease (ACVD). Periodontitis is a chronic multifactorial inflammatory disease caused by microorganisms and characterized by progressive destruction of the tooth supporting apparatus leading to tooth loss; as such, it is a major public health issue.

Aims
This report examined biological plausibility, epidemiology and early results from intervention trials.

Plausibility
Periodontitis leads to entry of bacteria in the blood stream. The bacteria activate the host inflammatory response by multiple mechanisms. The host immune response favors atheroma formation, maturation and exacerbation.

Epidemiology
In longitudinal studies assessing incident cardiovascular events, statistically significant excess risk for ACVD was reported in individuals with periodontitis. This was independent of established cardiovascular risk factors. The amount of the adjusted excess risk varies by type of cardiovascular outcome and across populations by age and gender. Given the high prevalence of periodontitis, even low to moderate excess risk is important from a public health perspective.

Intervention
There is moderate evidence that periodontal treatment: (i) reduces systemic inflammation as evidenced by reduction in C-reactive protein (CRP) and improvement of both clinical and surrogate measures of endothelial function; but (ii) there is no effect on lipid profiles – supporting specificity. Limited evidence shows improvements in coagulation, biomarkers of endothelial cell activation, arterial blood pressure and subclinical atherosclerosis after periodontal therapy. The available evidence is consistent and speaks for a contributory role of periodontitis to ACVD. There are no periodontal intervention studies on primary ACVD prevention and there is only one feasibility study on secondary ACVD prevention.

Conclusions
It was concluded that: (i) there is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease; and (ii) while in vitro, animal and clinical studies do support the interaction and biological mechanism, intervention trials to date are not adequate to draw further conclusions. Well-designed intervention trials on the impact of periodontal treatment on prevention of ACVD hard clinical outcomes are needed.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jcpe.12089

Periodontitis and atherosclerotic cardiovascular disease: consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases.

OBJECTIVE There is growing evidence that periodontitis may affect general health. This study was assigned to explore the robustness of observations that periodontal therapy leads to the improvement of glycemic control in diabetic patients. RESEARCH DESIGN AND METHODS A literature search (until March 2009) was carried out using two databases (MEDLINE and the Cochrane Library) with language restriction to English. Selection of publications was based on 1 ) original investigations, 2 ) controlled periodontal intervention studies where the diabetic control group received no periodontal treatment, and 3 ) study duration of ≥3 months. RESULTS Screening of the initial 639 identified studies and reference checking resulted in five suitable articles. A total of 371 patients were included in this analysis with periodontitis as predictor and the actual absolute change in A1C (ΔA1C) as the outcome. The duration of follow-up was 3–9 months. All studies described a research population of type 2 diabetic patients in whom glycemic control improved after periodontal therapy compared with the control group (range ΔA1C: Δ−1.17 up to Δ−0.05%). The studies in a meta-analysis demonstrated a weighted mean difference of ΔA1C before and after therapy of −0.40% (95% CI −0.77 to −0.04%, P = 0.03) favoring periodontal intervention in type 2 diabetic patients. Nevertheless, this improvement in %A1C must be interpreted with care due to limited robustness as evidenced by heterogeneity among studies (59.5%, P = 0.04). CONCLUSIONS The present meta-analysis suggests that periodontal treatment leads to an improvement of glycemic control in type 2 diabetic patients for at least 3 months.

https://care.diabetesjournals.org/content/diacare/33/2/421.full.pdf

Effect of Periodontal Treatment on Glycemic Control of Diabetic Patients A systematic review and meta-analysis

In addition to anti-tumor effects, ionizing radiation causes damage in normal tissues located in the radiation portals. Oral complications of radiotherapy in the head and neck region are the result of the deleterious effects of radiation on, e.g., salivary glands, oral mucosa, bone, dentition, masticatory musculature, and temporomandibular joints. The clinical consequences of radiotherapy include mucositis, hyposalivation, taste loss, osteoradionecrosis, radiation caries, and trismus. Mucositis and taste loss are reversible consequences that usually subside early post-irradiation, while hyposalivation is normally irreversible. Furthermore, the risk of developing radiation caries and osteoradionecrosis is a life-long threat. All these consequences form a heavy burden for the patients and have a tremendous impact on their quality of life during and after radiotherapy. In this review, the radiation-induced changes in healthy oral tissues and the resulting clinical consequences are discussed.

https://journals.sagepub.com/doi/pdf/10.1177/154411130301400305

Oral Sequelae of Head and Neck Radiotherapy

Background: Currently, a large variety of classifications is used for periodontitis as a risk factor for other diseases. None of these classifications quantifies the amount of inflamed periodontal tissue, while this information is needed to assess the inflammatory burden posed by periodontitis. Aim: To develop a classification of periodontitis that quantifies the amount of inflamed periodontal tissue, which can be easily and broadly applied. Material and Methods: A literature search was conducted to look for a classification of periodontitis that quantified the amount of inflamed periodontal tissue. A classification that quantified the root surface area affected by attachment loss was found. This classification did not quantify the surface area of inflamed periodontal tissue, however. Therefore, an Excel spreadsheet was developed in which the periodontal inflamed surface area (PISA) is calculated using clinical Attachment Level (CAL), recessions and bleeding on probing (BOP). Results: The PISA reflects the surface area of bleeding pocket epithelium in square millimetres. The surface area of bleeding pocket epithelium quantifies the amount of inflamed periodontal tissue. A freely downloadable spreadsheet is available to calculate the PISA. Conclusion: PISA quantifies the inflammatory burden posed by periodontitis and can be easily and broadly applied.

https://www.parsprototo.info/docs/PISA%20quantifying%20inflammatory%20burden.pdf

Periodontal inflamed surface area: quantifying inflammatory burden

It is often assumed that salivary secretion reduces with age. About 25% of the elderly suffer from oral dryness and related complaints. Nevertheless, data on stimulated salivary flow rate in healthy elderly revealed no significant age-related decrease other than a slight decrease of the secretion from the (sero)mucous glands under conditions of minimal or extended stimulation. With regard to salivary gland morphology and composition of saliva, age-related changes have been reported in healthy individuals, too. With increasing age, the number of acini reduces and the amount of fatty and fibrous tissue increases. Moreover, animal studies revealed that the synthesis of proteins is reduced by 60% in advanced years. These data indicate that changes might occur in concentration and/or activity of the organic components of saliva. In human studies, the concentration of sIgA in labial saliva and the concentrations of high-molecular and low-molecular mucins in mucous saliva appeared to be reduced with age. Since sIgA and mucins are important in the immunologic and non-immunologic defense of the oral cavity, both defense systems are reduced in healthy elderly. Analysis of these data suggests that the oral soft tissues may become somewhat more susceptible to environmental factors due to a reduction of the immunological and non-immunological defense systems.

Aging and saliva: a review of the literature.

Background: A dose–response relationship between the amount of inflamed periodontal tissue and HbA1c level, might be indicative for a causal association between periodontitis and type 2 diabetes. Aim: To assess a dose–response relationship between the periodontal inflamed surface area (PISA), as a measure of the amount of inflamed periodontal tissue, and HbA1c levels in type 2 diabetics. Material and Methods: Forty consecutive dentate type 2 diabetics attending their general practitioner for regular check-up, underwent full-mouth probing pocket depth and bleeding on probing assessment. From these data PISA was calculated. HbA1c levels were retrieved from patients’ medical files. The dose–response relationship between PISA and HbA1c levels was assessed using multiple linear regression analyses, controlling for factors that might influence PISA or HbA1c levels. Results: The higher the PISA of type 2 diabetics was, the higher their HbA1c levels were. On a group level, an increase of PISA with 333 mm 2 was associated with a 1.0 percentage point increase of HbA1c, independent of the influence of other factors. Conclusion: On a group level, there is a dose–response relationship between PISA and HbA1c in type 2 diabetics. This might be an indication of a causal relationship between type 2 diabetes and periodontitis.

/pdf/dose-response-relationship-between-periodontal-inflamed-42sb8sudcu.pdf

Dose–response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics

Objective To evaluate the responsiveness of the EULAR Sjogren9s Syndrome Patient Reported Index (ESSPRI) and EULAR Sjogren9s Syndrome Disease Activity Index (ESSDAI) in patients with primary Sjogren9s syndrome (pSS) treated with rituximab. Methods Twenty-eight patients with pSS treated with rituximab (1000 mg) infusions on days 1 and 15 were included in the study. Data were collected prospectively at baseline and 16, 24, 36, 48 and 60 weeks after treatment. Internal responsiveness was assessed using standardised response means (SRM) and effect sizes (ES). SRM and ES 0.8 were interpreted as small, moderate and large, respectively. External responsiveness was assessed using Spearman correlation coefficients. Results Median (range) ESSPRI and ESSDAI scores at baseline were 6.7 (0.3–9.0) and 8 (2–18), respectively. Both indices improved significantly after treatment. SRM and ES values for ESSPRI and ESSDAI were ≥0.8 at week 16 and decreased afterwards, and were larger for ESSDAI than for ESSPRI. SRM and ES values for patient9s and physician9s global disease activity (GDA) and rheumatoid factor broadly followed the pattern of those of ESSPRI and ESSDAI. SRM and ES for stimulated whole salivary flow were small at all time points. At baseline and for most change scores, moderate to good correlations were found between ESSPRI and patient9s GDA and between ESSDAI and physician9s GDA. Poor association was found between ESSPRI and ESSDAI. Conclusions ESSPRI and ESSDAI are sensitive measures of change in disease activity after therapeutic intervention, which supports the usefulness of these indices for future clinical trials in patients with pSS. The responsiveness of ESSDAI was greater than that of ESSPRI.

https://ard.bmj.com/content/annrheumdis/71/8/1297.full.pdf

F.K.L. Spijkervet

Papers

Oral Sequelae of Head and Neck Radiotherapy

Periodontal inflamed surface area: quantifying inflammatory burden

Aging and saliva: a review of the literature.

Dose–response relationship between periodontal inflamed surface area and HbA1c in type 2 Diabetics

Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjögren's syndrome treated with rituximab