Salivary Gland Hypofunction and/or Xerostomia Induced by Nonsurgical Cancer Therapies: ISOO/MASCC/ASCO Guideline.

PURPOSE: To provide evidence-based recommendations for prevention and management of salivary gland hypofunction and xerostomia induced by nonsurgical cancer therapies. METHODS: Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and ASCO convened a multidisciplinary Expert Panel to evaluate the evidence and formulate recommendations. PubMed, EMBASE, and Cochrane Library were searched for randomized controlled trials published between January 2009 and June 2020. The guideline also incorporated two previous systematic reviews conducted by MASCC/ISOO, which included studies published from 1990 through 2008. RESULTS: A total of 58 publications were identified: 46 addressed preventive interventions and 12 addressed therapeutic interventions. A majority of the evidence focused on the setting of radiation therapy for head and neck cancer. For the prevention of salivary gland hypofunction and/or xerostomia in patients with head and neck cancer, there is high-quality evidence for tissue-sparing radiation modalities. Evidence is weaker or insufficient for other interventions. For the management of salivary gland hypofunction and/or xerostomia, intermediate-quality evidence supports the use of topical mucosal lubricants, saliva substitutes, and agents that stimulate the salivary reflex. RECOMMENDATIONS: For patients who receive radiation therapy for head and neck cancer, tissue-sparing radiation modalities should be used when possible to reduce the risk of salivary gland hypofunction and xerostomia. Other risk-reducing interventions that may be offered during radiation therapy for head and neck cancer include bethanechol and acupuncture. For patients who develop salivary gland hypofunction and/or xerostomia, interventions include topical mucosal lubricants, saliva substitutes, and sugar-free lozenges or chewing gum. For patients with head and neck cancer, oral pilocarpine and oral cevimeline, acupuncture, or transcutaneous electrostimulation may be offered after radiation therapy.Additional information can be found at www.asco.org/supportive-care-guidelines.

Effectiveness of Transcutaneous Electrical Nerve Stimulation Therapy on whole Salivary Flow in Patients with Xerostomia and Healthy Adults

ABSTRACT Objective: To evaluate and compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) therapy on whole salivary flow in patients with xerostomia and healthy adults. Material and Methods: Thirty subjects with a history of xerostomia and subjects withunstimulated salivary flow equal to or less than 0.5 ml in 5 min were included in the study group, and 30 healthy subjects were included in the control group. Low forced spitting unstimulated saliva was collected for five minutes in a test tube fitted with a funnel. Then electrode pads of the TENS unit were applied bilaterally on skin overlying the parotid glands and at optimal intensity, stimulated saliva was collected for 5 minutes with the same method in a separate graduated test tube. The salivary flow rate (per minute) was calculated by dividing the amount of collected saliva (volume in mL) by the duration of collection period (5 minutes) and the salivary flow rates prior and after electrostimulation were compared for both groups. The Student's t-test (unpaired and paired) was performed for group-wise comparisons. Results: In study group, the mean unstimulated salivary flow rate was 0.07 ± 0.01 mL/min. There was an 85.71% increase in salivary flow (0.13 ± 0.03 mL/min) during the TENS application and the difference was highly significant (p<0.001). In control group, the mean unstimulated salivary flow rate was 0.37 ± 0.07 mL/min. There was a 21.62% increase in salivary flow (0.45 ± 0.07 mL/min) during the TENS application and the difference was highly significant (p<0.001). An increase in mean salivary flow rate both in males and females after TENS application in both groups (p<0.001) was noted. The difference between unstimulated, stimulated and mean difference in salivary flow rate between males and females was notstatistically significant in both groups (p<0.05). Conclusion: TENS can be an effective therapy in increasing whole salivary flow rates in patients with xerostomia.

Traditional Herbal Medicine Mediated Regulations during Head and Neck Carcinogenesis.

Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. It is well recognized that environmental challenges such as smoking, viral infection and alcohol consumption are key factors underlying HNSCC pathogenesis. Other than major clinical interventions (e.g., surgical resection, chemical and radiotherapy) that have been routinely practiced over years, adjuvant anticancer agents from Traditional Herbal Medicine (THM) are proposed, either alone or together with conventional therapies, to be experimentally effective for improving treatment efficacy in different cancers including HNSCCs. At a cellular and molecular basis, THM extracts could modulate different malignant indices via distinct signaling pathways and provide better control in HNSCC malignancy and its clinical complications such as radiotherapy-induced xerostomia/oral mucositis. In this article, we aim to systemically review the impacts of THM in regulating HNSCC tumorous identities and its potential perspective for clinical use.

[Effects of Oral Gargling with Aroma Solution in Psychiatric Inpatients: A Non-Randomized Controlled Trial].

PURPOSE: The purpose of this study was to examine the effects of oral gargling with an aromatic solution on xerostomia, objective oral status, and oral health-related quality of life in psychiatric inpatients. METHODS: A nonequivalent control group with a non-synchronized design was used in this study. The experimental group (n=34) received oral gargling with an aroma solution, while the control group (n=33) gargled with 0.9% normal saline. Dependent variables were measured at pre-, post-, and follow-up test. Data were analyzed using an χ²-test, Fisher's exact probability test, t-tests, and repeated measures ANOVA using SPSS/WIN v.21.0. RESULTS: After the intervention, significant differences were revealed in xerostomia (F=15.30, p <.001), objective oral status (F=38.44, p <.001), and oral health-related quality of life (F=62.70, p <.001) with an interaction effect between group and time. CONCLUSION: These findings indicate that gargling with an aroma solution is more effective than 0.9% normal saline for the oral health of psychiatric inpatients. Therefore gargling with an aroma can be safely recommended as a brief, economical, and positive intervention in clinical settings.

Low-level laser therapy with 850 nm recovers salivary function via membrane redistribution of aquaporin 5 by reducing intracellular Ca2+ overload and ER stress during hyperglycemia.

The overall goal is to study the effect of low-level laser therapy (LLLT) on membrane distribution of major water channel protein aquaporin 5 (AQP5) in salivary gland during hyperglycemia. Par C10 cells treated with high glucose (50 mM) showed a reduced membrane distribution of AQP5. The functional expression of AQP5 was downregulated due to intracellular Ca2+ overload and ER stress. This reduction in AQP5 expression impairs water permeability and therefore results in hypo-salivation. A reduced salivary flow was also observed in streptozotocin (STZ)-induced diabetic mice model and the expression of AQP5 and phospho-AQP5 was downregulated. Low-level laser treatment with 850 nm (30 mW, 10 min = 18 J/cm2) reduced ER stress and recovered AQP5 membrane distribution via serine phosphorylation in the cells. In the STZ-induced diabetic mouse, LLLT with 850 nm (60 J/cm2) increased salivary flow and upregulated of AQP5 and p-AQP5. ER stress was also reduced via downregulation of caspase 12 and CHOP. In silico analysis confirmed that the serine 156 is one of the most favorable phosphorylation sites of AQP5 and may contribute to the stability of the protein. Therefore, this study suggests high glucose inhibits phosphorylation-dependent AQP5 membrane distribution. High glucose induces intracellular Ca2+ overload and ER stress that disrupt AQP5 functional expression. Low-level laser therapy with 850 nm improves salivary function by increasing AQP5 membrane distribution in hyperglycemia-induced hyposalivation.

Dietary nitrate protects submandibular gland from hyposalivation in ovariectomized rats via suppressing cell apoptosis.

Xerostomia, a major oral symptom of menopause, is a subjective feeling of dry mouth associated with oral pain and difficulties in deglutition and speech, which significantly reduces patient's quality of life. Dietary nitrate, which can be converted to nitric oxide, has multiple physiological functions in the body, including antioxidant activity and vasodilatation; however, its protective effect against xerostomia remains poorly understood. The present study aimed to evaluate the effects of dietary nitrate on estrogen deficiency-induced xerostomia. We established an ovariectomized (OVX) rat model, which included five groups: sham-operated, OVX, OVX + 0.4 mM nitrate, OVX + 2 mM nitrate, and OVX + 4 mM nitrate (n = 6). After ovariectomy, animals in the nitrate treatment groups received appropriate amounts of sodium nitrate dissolved in distilled water for 3 months. The results showed that nitrate treatment reduced body weight and water intake, and increased serum nitrate and nitrite levels. Furthermore, nitrate uptake increased saliva secretion as evidenced by saliva flow rates and aquaporin 5 expression, and alleviated histological lesions as evidenced by reduction of the fibrotic area and cell atrophy in the salivary glands. Although protective effects of nitrate against estrogen deficiency-induced xerostomia were observed at all doses, treatment with 2 mM nitrate was more effective than that with 0.4 mM and 4 mM nitrate. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase-3 expression analyses showed that nitrate also protected cells from apoptosis, possibly through upregulation of Cu-Zn superoxide dismutase (Cu-Zn SOD) known to inhibit oxidative stress-related apoptosis. Our findings indicate that nitrate could improve functional activity of the salivary glands in OVX rats by suppressing apoptosis and upregulating Cu-Zn SOD expression, suggesting that dietary nitrate may potentially prevent hyposalivation in menopausal women.

Retrograde ductal administration of the adenovirus-mediated NDRG2 gene leads to improved sialaden hypofunction in estrogen-deficient rats.

One of the most common oral manifestations of menopause is xerostomia. Oral dryness can profoundly affect quality of life and interfere with basic daily functions, such as chewing, deglutition, and speaking. Although the feeling of oral dryness can be ameliorated after estrogen supplementation, the side effects of estrogen greatly restrict its application. We previously found that N-myc downstream-regulated gene 2 (NDRG2) is involved in estrogen-mediated ion and fluid transport in a cell-based model. In the present study, we used an ovariectomized rat model to mimic xerostomia in menopausal women and constructed two adenovirus vectors bearing NDRG2 to validate their therapeutic potential. Ovariectomized rats exhibited severe sialaden hypofunction, including decreased saliva secretion and ion reabsorption as well as increased water intake. Immunohistochemistry revealed that the expression of NDRG2 and Na(+) reabsorption-related Na(+)/K(+)-ATPase and epithelial sodium channels (EnaC) decreased in ovariectomized rat salivary glands. We further showed that the localized delivery of NDRG2 improved the dysfunction of Na(+) and Cl(-) reabsorption. In addition, the saliva flow rate and water drinking recovered to normal. This study elucidates the mechanism of estrogen deficiency-mediated xerostomia or sialaden hypofunction and provides a promising strategy for therapeutic intervention.

Root bark extracts of Juncus effusus and Paeonia suffruticosa protect salivary gland acinar cells from apoptotic cell death induced by cis-platinum (II) diammine dichloride.

Cis-platinum (II) diammine dichloride (CDDP) is a platinum-based anticancer agent, and is often used for chemotherapy for malignant tumors, albeit CDDP has serious side-effects, including xerostomia (dry mouth). Since patients with xerostomia have reduced quality of life, it is urgent and important to identify nontoxic and natural agents capable of reducing the adverse effect of chemotherapy on salivary gland function. Therefore, we commenced an institutional collaborative project in which candidates of herbal extracts were selected from more than 400 bioactive herbal products for their potential therapeutic effects not only on xerostomia, but also on oral diseases. In the present study, we report on two Chinese medical herbal extracts from the root barks of Juncus effusus and Paeonia suffruticosa. The two extracts showed a protective effect in NS-SV-Ac cells from the cytotoxicity and apoptosis caused by CDDP. The effect was dependent on the p53 pathway, protein kinase B/Akt 1 and mitochondrial apoptosis-related proteins (i.e. Bcl-2 and Bax), but was not dependent on nuclear factor κB. Notably, the apoptosis-protective effect of the extracts was not observed in adenocystic carcinoma cell lines. Although these extracts have been utilized in traditional Chinese medicine for hundreds of years, there are no reports to our knowledge, on their therapeutic effects on xerostomia. Thus, in the present study, we elucidated the potency of these herbal extracts as novel candidates for xerostomia to improve the quality of life of patients undergoing chemotherapy.

Established and novel approaches for the management of hyposalivation and xerostomia.

Hyposalivation, often symptomatically manifested as xerostomia (dry mouth sensation) may indicate the presence of altered salivary gland function and places patients at a higher risk for oral complications. Diverse symptoms and consequences have been associated with hyposalivation, such as difficulties with speaking, swallowing and tasting and a significant increase in dental caries and other oral infections. Although hyposalivation may be caused by a variety of conditions (head and neck radiotherapy, Sjogren's syndrome, medications, etc.), its hallmark symptom, xerostomia, is common to all such disorders, and varies only in intensity. Therefore, treatment is generally non-specific, and similar therapeutic approaches are used in all cases. In the present paper, available palliative oral care in the form of saliva substitutes, such as mouthwashes or gels, is detailed. Also salivary flow stimulants, such as certain pharmaceutical or gustatory preparations, acupuncture and electrostimulation are reviewed. Finally, other approaches, currently under investigation, such as biological and gene therapies, are discussed. The degree of evidence of the best known methods and their intended use are analyzed.

[Adverse drug effects in the oral region]. / Legemiddelbivirkninger i munnhulen.

Syphilis was previously termed "the great imitator" because so many of the signs and symptoms are indistinguishable from those of other diseases. This role has been taken over by drugs, and this also applies to adverse drug reactions in the oral region. Accordingly, a careful drug history, including identification of any prescription, over-the-counter, or herbal medicines used, may give an important clue to the differential diagnosis of oral diseases when the aetiology is not apparent. Virtually all drugs have the potential to cause oral adverse reactions, but some have a greater ability to do so than others. Among the numerous adverse oral manifestations are xerostomia, taste disturbances and ulceration. The reactions are often non-specific, but they may mimic specific disease states such as erythema multiforme, lichen planus and pemphigus. Drug-induced gingival hyperplasia is an example of a quite characteristic and easily recognisable oral side effect. This article briefly describes some of the presentations and mechanisms of oral manifestations of drug therapy and the drugs that most commonly are responsible. Just like approved pharmaceuticals, herbal medicines are also associated with adverse oral manifestations. Finally we comment on some of the more recent reports on osteonecrosis of the jaws associated with the use of bisphosphonates.

Effects of honey consumption on enamel microhardness in normal versus xerostomic patients.

The aim was to investigate the effect of honey on the microhardness of enamel in normal and xerostomic patients. Normal subjects and patients who were xerostomic after neck irradiation, wearing prosthetic appliances with slabs of human enamel inserted, were asked to consume a single teaspoonful of pure honey, pH 3.9. Measurements of the saliva pH were taken before, during and after a 5 min exposure to the honey. The pH of the honey-saliva mixtures decreased significantly from about 6 to 4 in both groups, returning to the baseline pH after the mixture was swallowed. The initial microhardness of the surface of the enamel slabs decreased significantly after consumption of a teaspoonful of the honey in the subjects with a regular saliva flow, whereas in the irradiated dry-mouth patients, no enamel microhardness decrease occurred. The supposed solubility-reducing factor present in honey which, according to the literature remains active in the absence of saliva, but will be inactivated by salivary enzymes, gives some support to the hypothesis that honey is less cariogenic in dry-mouth subjects. The absence of adequate controls in the present study prevents the investigation of how specific this effect is to honey.

Parotid gland biopsy for investigation of xerostomia.

A technique is described for biopsy of the parotid salivary gland under local anaesthesia, which has been undertaken for a series of 59 patients who presented with suspected inflammatory exocrinopathy. The procedure is reliable and is associated with negligible postoperative discomfort. The advantages of the technique suggest that parotid gland biopsy is an acceptable alternative to conventional lower lip biopsy of minor salivary glands in the investigation of xerostomia.

Patients with primary Sjögren's syndrome treated for two months with evening primrose oil.

Twenty-four female and 4 male patients, all fulfilling the Copenhagen criteria for primary Sjögren's syndrome (primary SS), were treated for 8 weeks with evening primrose oil (Efamol). Efamol is a seed oil which consists primarily of the n-6 essential fatty acids (EFA): cis-linoleic acid and gammalinolenic acid (GLA). The investigation was carried out as a randomized, double-blind, placebo-controlled, cross-over trial in order to determine whether long-term treatment of patients with primary SS with Efamol would improve the ocular and oral clinical status, and whether the levels of EFA in plasma and erythrocytes increase during Efamol treatment. The objective ocular status, evaluated by a combined ocular score, including the results from Schirmer-I test, break-up time and van Bijsterveld score, improved significantly during Efamol treatment when compared with Efamol start-values (p less than 0.05), but not when compared with placebo values (p less than 0.2). The GLA metabolite and prostaglandin-E1 (PGE1) precursor dihomogammalinolenic acid (20: 3n6, DGLA) increased both in plasma (p less than 0.001) and in erythrocytes (p less than 0.001) during treatment with Efamol. No correlations between objective ocular and oral status and DGLA values in plasma or erythrocytes were found.