Immediate effects of photobiomodulation on saliva production. / Efeitos imediatos da fotobiomodulação na produção de saliva.

PURPOSE: To verify the immediate effects of photobiomodulation on the production of salivary flow and the correlation of demographic, anthropometric and medication use data. METHODS: The study included 100 healthy individuals, aged between 18 and 76 years (mean 27.2 years), randomly split into an experimental group and a placebo group. Assessments of anthropometric measurements, self-perception of saliva production and sialometry were performed. Next, LASER irradiation was carried out at an infrared wavelength (808 nanometers) with 100 milliwatts (mw) of power at five intraoral points: on the sublingual glands and bilaterally on the submandibular and parotid glands, at doses of 9, 18 and 24 joules (J). Sialometry was repeated after each application. The control group received the same procedures with placebo equipment. RESULTS: There was a statistical association in the self-perception of reduced saliva in the experimental group for the 24J dose and in sialometry and in the reduction in salivary flow for the 18J and 24J doses and an increase to 9J, in both groups. There was no association when comparing the experimental and placebo groups. Multiple multinomial regression analysis revealed that the reduction or increase in salivary flow is independent of demographic, anthropometric and medication use variables. CONCLUSION: The bioinhibitory action of photobiomodulation on healthy salivary glands occurred at a dose of 18J and 24J, while the biostimulant action happened at a dose of 9J, regardless of demographic, anthropometric variables and medication use. The self-perception of reduced salivary flow occurred at 24J.

OBJETIVO: Verificar os efeitos imediatos da fotobiomodulação na produção do fluxo salivar e a correlação dos dados demográficos, antropométricos e de uso de medicamentos. MÉTODO: Participaram do estudo 100 indivíduos saudáveis, com idade entre 18 e 76 anos (média 27,2 anos), divididos de forma randomizada em grupo experimental e grupo placebo. Foram realizadas as avaliações das medidas antropométricas, autopercepção da produção de saliva e a sialometria. Na sequência, realizou-se a irradiação do LASER no comprimento de onda infravermelho (808 nanômetros) com 100 miliwatts (mw) de potência em cinco pontos intraorais: nas glândulas sublingual e bilateralmente nas submandibulares e parótidas, nas doses 9, 18 e 24 joules (J). A sialometria foi repetida após cada aplicação. O grupo controle recebeu os mesmos procedimentos com equipamento placebo. RESULTADOS: Houve associação estatística na autopercepção de redução da saliva no grupo experimental para a dose de 24J e na sialometria e na redução do fluxo salivar para as doses 18J e 24J e aumento para 9J, em ambos os grupos. Não houve associação quando comparado entre os grupos experimental e placebo. A análise de regressão multinomial múltipla revelou que a redução ou o aumento do fluxo salivar independe das variáveis demográficas, antropométricas e uso de medicamentos. CONCLUSÃO: A ação bioinibitória da fotobiomodulação sobre as glândulas salivares saudáveis ocorreu em dose de 18J e 24J, já ação bioestimulante na dose 9J, independe das variáveis demográficas, antropométricas e uso de medicamentos. A autopercepção da redução do fluxo salivar ocorreu em 24J.

Evaluation of photobiomodulation in the salivary production of patients with hyposalivation induced by antihypertensive drugs - A blind, randomized, controlled clinical trial.

BACKGROUND: Arterial hypertension is a systemic condition that affects about 35% of the world population. The drugs that are used for its control can produce hyposalivation. This work evaluated the effect of photobiomodulation on salivary flow rate, salivary pH, total protein concentration, and calcium concentration in individuals using antihypertensive medications. MATERIAL AND METHODS: 41 subjects were randomly allocated in one of two groups: control (placebo) and photobiomodulation. The subjects had their salivary glands (20 sites) irradiated with a laser emitting at 808 nm, 4J/site once a week for 4 weeks and had their salivary flow measured before and after the whole treatment. RESULTS: The intragroup analysis (before and after treatment) shows a significant difference for both non-stimulated and stimulated salivary flow in the photobiomodulation group (p = 0.0007 and p = 0.0001, respectively). Comparing the placebo with the photobiomodulation group, significant differences were found for both non-stimulated (p = 0.0441) and stimulated salivary flow (p = 0.0441) after the treatment. No significant differences were found in pH, total protein concentration, calcium concentration. CONCLUSION: Despite the usage of drugs that influence the nervous system and typically result in a reduction of saliva production, photobiomodulation demonstrated a remarkable ability to enhance saliva production by a significant 75%.

Short-term and bystander effects of radiation on murine submandibular glands.

Many patients treated for head and neck cancers experience salivary gland hypofunction due to radiation damage. Understanding the mechanisms of cellular damage induced by radiation treatment is important in order to design methods of radioprotection. In addition, it is crucial to recognize the indirect effects of irradiation and the systemic responses that may alter saliva secretion. In this study, radiation was delivered to murine submandibular glands (SMGs) bilaterally, using a 137Cs gamma ray irradiator, or unilaterally, using a small-animal radiation research platform (SARRP). Analysis at 3, 24 and 48 h showed dynamic changes in mRNA and protein expression in SMGs irradiated bilaterally. Unilateral irradiation using the SARRP caused similar changes in the irradiated SMGs, as well as significant off-target, bystander effects in the non-irradiated contralateral SMGs.

Topical Xerostomia Treatment with Hyaluronate Sheets Containing Pilocarpine.

Sjogren's syndrome and radiation therapy for head and neck cancers are often accompanied by xerostomia. Oral pilocarpine (PCP) to treat xerostomia produces systemic side effects, such as runny nose and lacrimation. To improve the therapeutic efficacy of PCP and reduce the aforementioned side effects, we developed a topical delivery system for PCP using freeze-dried sheets of hyaluronic acid (HA). The advantages of HA sheets over conventional oral formulations were examined through in vivo pharmacokinetic and pharmacodynamic studies after their application to oral tissues and salivary glands. The concentration of PCP in the submucosal tissue of the oral cavity was determined using the microdialysis (MD) method after buccal application of HA sheets containing PCP to hamsters. The concentration of PCP in the MD outflow was quite low after gastric administration, whereas the PCP concentration in plasma was high. In contrast, after buccal application of HA sheets containing PCP, the concentration of the drug in the MD outflow increased, despite the negligible concentration in plasma. These findings indicated that both enhancement of saliva secretion and the avoidance of systemic side effects could be achieved through buccal administration of PCP-loaded HA sheets. In addition, the pharmacodynamic study showed that when compared with intravenous and gastric administration, salivary application of HA sheets containing PCP resulted in similar volumes of saliva secretion and reduced lacrimal secretions. In conclusion, freeze-dried HA sheets allow for the development of a novel buccal delivery system with enhanced therapeutic efficacy and safety to treat xerostomia.

Oral health-related quality of life in oral cancer patients: systematic review and meta-analysis.

Aim: The purpose of this meta-analysis was to evaluate the impact of oral health on quality of life in oral cancer patients (OCPs). Methods: PubMed, Scopus and Web of Science databases were searched for publications on oral health-related quality of life (OHRQoL) in OCP and the information was extracted according to the PRISMA guidelines. A random effect model was used to obtain the pooled standard mean differences of Oral Health Impact Profile (OHIP)-14 questionnaire responses in meta-analysis. Results: total of 12 research papers were analyzed and revealed poor OHRQoL in OCPs (standard mean difference: 2.53; 95% CI: 1.55-3.50; p < 0.00001) compared with healthy individuals due to the effects of oncotherapy. Moreover, OHRQoL deteriorated with combinations of different treatment modalities. Conclusion: Oral health and oncotherapy can affect the quality of life in OCPs.

The effect of radiotherapy on taste sensation in head and neck cancer patients - a prospective study.

BACKGROUND: One of the main side effects of head and neck (H&N) radiation therapy (RT) is alteration in taste sensation. It causes significant morbidity and has a major effect on quality of life (QoL). The aim of this study was to prospectively define the effect of RT on taste sensation (general, and four basic tastes) and correlate these findings with changes in saliva secretion and QoL questionnaires. METHODS: Patients with H&N cancer treated with RT, in which the oral cavity was expected to receive a mean dose of 30 Gray (Gy). Patients were evaluated by Whole-Saliva Sialometry, validated Taste Strips and European Organization for Research and Treatment of Cancer H&N QoL questionnaires prior to RT (T0), mid-point of radiotherapy dose (T1), at the end of radiotherapy (T2) and 1 (T3), 3 (T4) and 12 months (T5) after completion of treatment course. RESULTS: Twenty-eight patients were recruited, and 21 patients completed study procedures and were analyzed. Median age was 66 years (range 18-90). The most common tumor site was the oral cavity. The median prescribed radiation dose to the high dose volume was 66 (range 60-70). The median mean and max dose to the oral cavity were 25.1 (range 14-69) and 64.9 (range 30-70), respectively. There was a significant decrease in overall taste sensation between T0 and T1 and T2. With specific tastes, there were significant decreases in sensation of sweet and salty, a trend with bitter and no change with sour. All returned to baseline at T3 and onwards. There was no significant correlation between the max or mean dose to the oral cavity and overall taste sensation or between doses to different areas of the tongue and overall or specific tastes. At T0 there was a significant positive correlation between overall taste sensation and whole-saliva sialometry, and at T1 and T2 there were strong trends. There were significant declines in QoL scores during RT. CONCLUSIONS: We found a significant immediate reduction in taste sensation due to RT in H&N cancer patients with taste recovery 1 month after treatment completion. There were strong trends to a correlation with saliva production that requires further exploration.

Evaluation of photobiomodulation in salivary production of patients with xerostomy induced by anti-hypertensive drugs: Study protocol clinical trial (SPIRIT compliant).

INTRODUCTION: Hypertension (systemic arterial hypertension [SAH]) is a systemic condition that affects about 30% of the world population, according to data from the World Health Organization (WHO). Drugs used to control this disease have the potential to induce xerostomia, an oral condition in which the decrease of the salivary flow is observed and whose presence leads to the increase of the index of caries, periodontal disease, loss of the teeth, dysgeusia, difficulty of mastication, dysphagia, bad breath and oral burning and impairment of prothesis installed in the buccal cavity, including retention of removable and total dentures. METHODS: This is a randomized, placebo-controlled, blind clinical protocol that aims to analyze the impact of phobiomodulation (PBM) on salivary glands of patients with antihypertensive drug induced xerostomia. Patients will be divided into 2 groups: G1: older adults with xerostomia induced by antihypertensive drugs and treatment with PBM (n = 30); G2: placebo PBM (n = 30). The irradiation will be made using a diode laser emitting at 808 nm with 100 mW and 40 seconds of exposure per site at the salivary glands. Twenty sites will be irradiated weekly for 4 weeks. Non-stimulated and stimulated salivary flow will be analyzed before and after the treatment. RESULTS: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. CONCLUSION: This protocol will determine the effectiveness of photodynamic therapy regarding the reduction of xerostomia in older adults using antihypertensive drugs. TRIAL REGISTRATION: Clinicaltrials.gov - NCT03632096.

Diffusion-weighted imaging as a follow-up modality for evaluation of major salivary gland function in nasopharyngeal carcinoma patients: a preliminary study.

PURPOSE: To investigate the value of diffusion-weighted imaging (DWI) in assessing dynamic changes of major salivary gland function during follow-up post radiotherapy (RT) in nasopharyngeal carcinoma (NPC) patients. MATERIALS AND METHODS: 31 consecutive patients with pathologically confirmed NPC scheduled for RT underwent six routine follow-up MRI examinations including DWI sequence prior to (pre-RT) and 1, 3, 6, 9, and 12 months post RT. Mean apparent diffusion coefficient (ADC) values of bilateral parotid glands (PGs) and submandibular glands (SMGs) were measured. Objective measurement of salivary flow rate (SFR) under unstimulated (uSFR) and stimulated conditions (sSFR) as well as subjective xerostomia assessment according to a patient-rated questionnaire were conducted before each MRI. Variance analysis was used to evaluate dynamic changes of ADC, SFR and xerostomia questionnaire summary scores (XQ-sum) at different timepoints and the correlation between ADC and XQ-sum. Pearson's correlation test was used to evaluate the correlations between pre- and post-RT changes of ADC (ΔADC) and SFR (ΔSFR) or mean RT dose. RESULTS: At each timepoint, ADCs of PGs were significantly lower than of SMGs, uSFR was significantly lower than sSFR. For both PGs and SMGs, ADCpost-RT were all higher than ADCpre-RT, with significant differences. ADC1m-post-RT initially increased and changed little to ADC3m-post-RT, ADC6m-post-RT, ADC9m-post-RT, and ADC12m-post-RT, then gradually declined over time. The dynamic change trends of SFR were negatively paralleled to those of ADC, while that of XQ-sum was similar. Dose-response relationships were detected between salivary gland mean RT dose and ΔADC. In PGs, negative correlations between ΔsSFR9m-post-RT and ΔADC9m-post-RT, and ΔsSFR12m-post-RT and ΔADC12m-post-RT were detected. In SMGs, negative correlations between ΔsSFR12m-post-RT and ΔADC12m-post-RT, and ΔuSFR12m-post-RT and ΔADC12m-post-RT were also detected. The ADCs of patients with severe subjective xerostomia were significantly higher, while patients with moderate subjective xerostomia presented a tendency toward higher ADCs compared to those with mild xerostomia from 6 to 12 months post RT. CONCLUSION: As part of routine follow-up MRI in NPC patients, DWI might be a promising modality for follow-up assessing the dynamic changes of major salivary gland function and might be more powerful in the late post-RT period.

Transcutaneous Electrical Nerve Stimulation (TENS) on hyposalivation induced by radiotherapy in the head and neck region: a preliminary study. / Efeito agudo da Transcutaneous Electric Nerve Stimulation (TENS) sobre a hipossalivação induzida pela radioterapia na região de cabeça e pescoço: um estudo preliminar.

PURPOSE: To verify the acute effect of electrostimulation on the salivary flow of patients with hyposalivation. METHODS: Uncontrolled clinical trial evaluating 15 patients with hyposalivation induced by radiotherapy (RT) used for head and neck cancer treatment. Mean age of the patients was 56.8 ± 6.46 years. Males outnumbered females (73%). Transcutaneous Electrical Nerve Stimulation (TENS) was adjusted with 50Hz of frequency and 250µs of pulse width. Intensity was adjusted over a 20-minute period according to maximum tolerance. The electrodes were attached bilaterally on the region of the salivary glands. Evaluation of the salivary flow was performed through sialometry before and immediately after application of TENS. RESULTS: The most prevalent region for RT was the oropharynx (80.0% of cases). The mean dose used in RT was 64.6 ± 7.27 Gy. After TENS, salivary flow increased significantly (p = 0.0051) from 0.05 (0.00; 0.40) mL/min to 0.10 (0.07: 0.40) mL/min. The response to TENS was directly correlated with the intensity of the tolerated electric current (r = 0.553; p = 0.032) and the dose used in RT (r = -0.514; p = 0.050). CONCLUSION: TENS was able to increase the salivary flow rate of patients with RT-induced hyposalivation.

OBJETIVO: Verificar o efeito agudo da eletroestimulação sobre o fluxo salivar de pacientes com hipossalivação. MÉTODO: Ensaio clínico não controlado que avaliou o efeito de uma única aplicação da Transcutaneous Electric Nerve Stimulation (TENS) sobre o fluxo salivar de 15 pacientes com hipossalivação induzida por radioterapia (RT), utilizada no tratamento de câncer de cabeça e pescoço. A média de idade dos pacientes foi de 56,8 ± 6,46 anos e o gênero masculino foi predominante (73%). A TENS foi programada com 50Hz de frequência, 250µs de largura de pulso e a intensidade foi ajustada ao longo dos 20 minutos conforme máxima tolerância. Os eletrodos foram fixados bilateralmente sobre a região das glândulas salivares. A avaliação do fluxo salivar foi realizada por meio de sialometria estimulada, antes e imediatamente após a aplicação da TENS. RESULTADOS: Em 80% dos casos, o tratamento oncológico incluiu quimioterapia. A RT foi aplicada em 80% dos casos na região e orofaringe, com intensidade média de 64,6 ± 7,27 Gy. Após a TENS, o fluxo salivar aumentou significativamente (p = 0,0051), passando de 0,05 (0,00; 0,40) mL/min para 0,10 (0,07;0,40) mL/min. A resposta à TENS foi diretamente correlacionada à intensidade da corrente elétrica tolerada (r = 0,553; p = 0,032) e à dose utilizada na RT (r = -0,514; p = 0,050). CONCLUSÃO: A TENS aumentou significativamente o fluxo salivar de pacientes com hipossalivação induzida pela RT.

Persistent disruption of lateral junctional complexes and actin cytoskeleton in parotid salivary glands following radiation treatment.

Xerostomia and hyposalivation are debilitating side effects for patients treated with ionizing radiation for head and neck cancer. Despite technological advances, collateral damage to the salivary glands remains a significant problem for patients and severely diminishes their quality of life. During the wound healing process, restoration of junctional contacts is necessary to maintain polarity, structural integrity, and orientation cues for secretion. However, little is known about whether these structural molecules are impacted following radiation damage and more importantly, during tissue restoration. We evaluated changes in adherens junctions and cytoskeletal regulators in an injury model where mice were irradiated with 5 Gy and a restoration model where mice injected postradiation with insulin-like growth factor 1 (IGF1) are capable of restoring salivary function. Using coimmunoprecipitation, there is a decrease in epithelial (E)-cadherin bound to ß-catenin following damage that is restored to untreated levels with IGF1. Via its adaptor proteins, ß-catenin links the cadherins to the cytoskeleton and part of this regulation is mediated through Rho-associated coiled-coil containing kinase (ROCK) signaling. In our radiation model, filamentous (F)-actin organization is fragmented, and there is an induction of ROCK activity. However, a ROCK inhibitor, Y-27632, prevents E-cadherin/ß-catenin dissociation following radiation treatment. These findings illustrate that radiation induces a ROCK-dependent disruption of the cadherin-catenin complex and alters F-actin organization at stages of damage when hyposalivation is observed. Understanding the regulation of these components will be critical in the discovery of therapeutics that have the potential to restore function in polarized epithelium.

Safety and Efficacy of Mesenchymal Stem Cells for Radiation-Induced Xerostomia: A Randomized, Placebo-Controlled Phase 1/2 Trial (MESRIX).

BACKGROUND: Salivary gland hypofunction and xerostomia are major complications to head and neck radiotherapy. This trial assessed the safety and efficacy of adipose tissue-derived mesenchymal stem cell (ASC) therapy for radiation-induced xerostomia. PATIENT AND METHODS: This randomized, placebo-controlled phase 1/2 trial included 30 patients, randomized in a 1:1 ratio to receive ultrasound-guided transplantation of ASCs or placebo to the submandibular glands. Patients had previously received radiotherapy for a T1-2, N0-2A, human papillomavirus-positive, oropharyngeal squamous cell carcinoma. The primary outcome was the change in unstimulated whole salivary flow rate, measured before and after the intervention. All assessments were performed one month prior (baseline) and one and four months following ASC or placebo administration. RESULTS: No adverse events were detected. Unstimulated whole salivary flow rates significantly increased in the ASC-arm at one (33%; P = .048) and four months (50%; P = .003), but not in the placebo-arm (P = .6 and P = .8), compared to baseline. The ASC-arm symptom scores significantly decreased on the xerostomia and VAS questionnaires, in the domains of thirst (-22%, P = .035) and difficulties in eating solid foods (-2%, P = .008) after four months compared to baseline. The ASC-arm showed significantly improved salivary gland functions of inorganic element secretion and absorption, at baseline and four months, compared to the placebo-arm. Core-needle biopsies showed increases in serous gland tissue and decreases in adipose and connective tissues in the ASC-arm compared to the placebo-arm (P = .04 and P = .02, respectively). MRIs showed no significant differences between groups in gland size or intensity (P < .05). CONCLUSIONS: ASC therapy for radiation-induced hypofunction and xerostomia was safe and significantly improved salivary gland functions and patient-reported outcomes. These results should encourage further exploratory and confirmatory trials.

A novel method to evaluate salivary flow rates of head and neck cancer patients after radiotherapy: a pilot study / Um novo método para avaliar as taxas de fluxo salivar em pacientes com câncer de cabeça e pescoço após radioterapia: estudo piloto

Abstract Introduction The procedure used to evaluate salivary flow rate is called sialometry. It can be performed through several techniques, but none appears to be really efficient for post-radiotherapy patients. Objective To adequate sialometry tests for head and neck cancer patients submitted to radiotherapy. Methods 22 xerostomic patients post-radiotherapy (total radiation dose ranging from 60 to 70 Gy) were included in this study. Ten patients were evaluated using sialometries originally proposed by the Radiation Therapy Oncology Group and twelve were assessed by our modified methods. Unstimulated and stimulated sialometries were performed and the results were classified according a grading scale and compared between both groups. Results There was no statistically significant difference between the salivary evaluations of both groups (p = 0.4487 and p = 0.5615). Also, most of these rates were classified as very low and low. Conclusion This novel method seems to be suitable for patients submitted to radiotherapy.

Resumo Introdução O procedimento utilizado para avaliar a taxa de fluxo salivar é denominado sialometria. Pode ser realizado por meio de várias técnicas, mas nenhuma parece ser realmente eficiente para pacientes pós-radioterapia. Objetivo Adaptar sialometrias para pacientes com câncer de cabeça e pescoço submetidos à radioterapia. Método 22 pacientes xerostômicos pós-radioterapia (dose de radiação total variando de 60-70 Gy) foram incluídos neste estudo. Dez pacientes foram avaliados utilizando sialometrias originalmente propostas pelo Radiation Therapy Oncology Group e doze foram avaliados por nossos métodos modificados. Sialometrias não estimuladas e estimuladas foram conduzidas e os resultados foram classificados de acordo com uma escala de graduação e comparados entre os dois grupos. Resultados Não houve diferença estatisticamente significante entre as avaliações salivares de ambos os grupos (p = 0,4487 e p = 0,5615). Além disso, a maioria dessas taxas foi classificada como muito baixa e baixa. Conclusão Esse novo método parece ser adequado para pacientes submetidos à radioterapia.

[Radiation-associated changes in salivation of patients with cancer of maxillofacial region]. / Radioindutsirovannye izmeneniia sliunootdeleniia u patsientov so zlokachestvennymi novoobrazovaniiami cheliustno-litsevoi oblasti.

The radiation has an antitumor effect and causes radiation reactions and damage to surrounding tissues within the framework of combined antitumor treatment of patients with cancer of maxillofacial region. It also has an irreversible effect on the production of saliva by large and small salivary glands, and this must be taken into account when planning radiation therapy for this group of patients.

A novel method to evaluate salivary flow rates of head and neck cancer patients after radiotherapy: a pilot study.

INTRODUCTION: The procedure used to evaluate salivary flow rate is called sialometry. It can be performed through several techniques, but none appears to be really efficient for post-radiotherapy patients. OBJECTIVE: To adequate sialometry tests for head and neck cancer patients submitted to radiotherapy. METHODS: 22 xerostomic patients post-radiotherapy (total radiation dose ranging from 60 to 70Gy) were included in this study. Ten patients were evaluated using sialometries originally proposed by the Radiation Therapy Oncology Group and twelve were assessed by our modified methods. Unstimulated and stimulated sialometries were performed and the results were classified according a grading scale and compared between both groups. RESULTS: There was no statistically significant difference between the salivary evaluations of both groups (p=0.4487 and p=0.5615). Also, most of these rates were classified as very low and low. CONCLUSION: This novel method seems to be suitable for patients submitted to radiotherapy.

Different Protocols of Photobiomodulation Therapy of Hyposalivation.

OBJECTIVE: Photobiomodulation (PBM) therapy has proved to be effective for a wide range of oral pathologies including oral dryness, but the literature still lacks reports of clinical trials and protocols. The purpose of our study was to evaluate the effects of different wavelengths of PBM on salivation in patients suffering from hyposalivation aiming at determination of optimal treatment protocol. MATERIALS AND METHODS: This study included 30 patients whose major salivary glands were treated with low-intensity diode laser BTL2000 (Medical Technologies, s.r.o., Czech Republic) during 10 consecutive days. Patients were randomly assigned into two groups, each of 15 patients, and treated with PBM of 830 nm and PBM of 685 nm, respectively. The whole unstimulated and stimulated saliva quantities were measured each day during 10 days, before and after laser treatment, and at 10th day after treatment was ended. RESULTS: Results have shown that the laser treatment significantly improves salivation (p < 0.0001) in both groups after 10 days treatment. The salivation also remains improved 10 days after the end of treatment. The patients treated with PBM of 830 nm have had continuously higher values of quantity of saliva. CONCLUSIONS: Our results have shown that both laser wavelengths were effective in increasing salivary flow rate, and the improvement in salivation was statistically significant. The effect of treatment could be observed 10 days after the completion of treatment, thus providing evidence not only of stimulative effect but also indicating regenerative potential of PBM therapy.

Optimal timing and frequency of bone marrow soup therapy for functional restoration of salivary glands injured by single-dose or fractionated irradiation.

Injections of bone marrow (BM) cell extract, known as 'BM soup', were previously reported to mitigate ionizing radiation (IR) injury to salivary glands (SGs). However, the optimal starting time and frequency to maintain BM soup therapeutic efficacy remains unknown. This study tested the optimal starting time and frequency of BM soup injections in mice radiated with either a single dose or a fractionated dose. First, BM soup treatment was started at 1, 3 or 7 weeks post-IR; positive (non-IR) and negative (IR) control mice received injections of saline (vehicle control). Second, BM soup-treated mice received injections at different frequencies (1, 2, 3 and 5 weekly injections). Third, a 'fractionated-dose radiation' model to injure mouse SGs was developed (5 Gy × 5 days) and compared with the single high dose radiation model. All mice (n = 65) were followed for 16 weeks post-IR. The results showed that starting injections of BM soup between 1 and 3 weeks mitigated the effect of IR-induced injury to SGs and improved the restoration of salivary function. Although the therapeutic effect of BM soup lessens after 8 weeks, it can be sustained by increasing the frequency of weekly injections. Moreover, both single-dose and fractionated-dose radiation models are efficient and comparable in inducing SG injury and BM soup treatments are effective in restoring salivary function in both radiation models. In conclusion, starting injections of BM soup within 3 weeks post-radiation, with 5 weekly injections, maintains 90-100% of saliva flow in radiated mice.

Efeito agudo da Transcutaneous Electric Nerve Stimulation (TENS) sobre a hipossalivação induzida pela radioterapia na região de cabeça e pescoço: um estudo preliminar / Transcutaneous Electrical Nerve Stimulation (TENS) on hyposalivation induced by radiotherapy in the head and neck region: a preliminary study

RESUMO Objetivo Verificar o efeito agudo da eletroestimulação sobre o fluxo salivar de pacientes com hipossalivação. Método Ensaio clínico não controlado que avaliou o efeito de uma única aplicação da Transcutaneous Electric Nerve Stimulation (TENS) sobre o fluxo salivar de 15 pacientes com hipossalivação induzida por radioterapia (RT), utilizada no tratamento de câncer de cabeça e pescoço. A média de idade dos pacientes foi de 56,8 ± 6,46 anos e o gênero masculino foi predominante (73%). A TENS foi programada com 50Hz de frequência, 250μs de largura de pulso e a intensidade foi ajustada ao longo dos 20 minutos conforme máxima tolerância. Os eletrodos foram fixados bilateralmente sobre a região das glândulas salivares. A avaliação do fluxo salivar foi realizada por meio de sialometria estimulada, antes e imediatamente após a aplicação da TENS. Resultados Em 80% dos casos, o tratamento oncológico incluiu quimioterapia. A RT foi aplicada em 80% dos casos na região e orofaringe, com intensidade média de 64,6 ± 7,27 Gy. Após a TENS, o fluxo salivar aumentou significativamente (p = 0,0051), passando de 0,05 (0,00; 0,40) mL/min para 0,10 (0,07;0,40) mL/min. A resposta à TENS foi diretamente correlacionada à intensidade da corrente elétrica tolerada (r = 0,553; p = 0,032) e à dose utilizada na RT (r = -0,514; p = 0,050). Conclusão A TENS aumentou significativamente o fluxo salivar de pacientes com hipossalivação induzida pela RT.

ABSTRACT Purpose To verify the acute effect of electrostimulation on the salivary flow of patients with hyposalivation. Methods Uncontrolled clinical trial evaluating 15 patients with hyposalivation induced by radiotherapy (RT) used for head and neck cancer treatment. Mean age of the patients was 56.8 ± 6.46 years. Males outnumbered females (73%). Transcutaneous Electrical Nerve Stimulation (TENS) was adjusted with 50Hz of frequency and 250μs of pulse width. Intensity was adjusted over a 20-minute period according to maximum tolerance. The electrodes were attached bilaterally on the region of the salivary glands. Evaluation of the salivary flow was performed through sialometry before and immediately after application of TENS. Results The most prevalent region for RT was the oropharynx (80.0% of cases). The mean dose used in RT was 64.6 ± 7.27 Gy. After TENS, salivary flow increased significantly (p = 0.0051) from 0.05 (0.00; 0.40) mL/min to 0.10 (0.07: 0.40) mL/min. The response to TENS was directly correlated with the intensity of the tolerated electric current (r = 0.553; p = 0.032) and the dose used in RT (r = -0.514; p = 0.050). Conclusion TENS was able to increase the salivary flow rate of patients with RT-induced hyposalivation.

Common oral complications of head and neck cancer radiation therapy: mucositis, infections, saliva change, fibrosis, sensory dysfunctions, dental caries, periodontal disease, and osteoradionecrosis.

Patients undergoing radiation therapy for the head and neck are susceptible to a significant and often abrupt deterioration in their oral health. The oral morbidities of radiation therapy include but are not limited to an increased susceptibility to dental caries and periodontal disease. They also include profound and often permanent functional and sensory changes involving the oral soft tissue. These changes range from oral mucositis experienced during and soon after treatment, mucosal opportunistic infections, neurosensory disorders, and tissue fibrosis. Many of the oral soft tissue changes following radiation therapy are difficult challenges to the patients and their caregivers and require life-long strategies to alleviate their deleterious effect on basic life functions and on the quality of life. We discuss the presentation, prognosis, and management strategies of the dental structure and oral soft tissue morbidities resulting from the administration of therapeutic radiation in head and neck patient. A case for a collaborative and integrated multidisciplinary approach to the management of these patients is made, with specific recommendation to include knowledgeable and experienced oral health care professionals in the treatment team.

Pharmacological interventions for preventing dry mouth and salivary gland dysfunction following radiotherapy.

BACKGROUND: Salivary gland dysfunction is an 'umbrella' term for the presence of either xerostomia (subjective sensation of dryness), or salivary gland hypofunction (reduction in saliva production). It is a predictable side effect of radiotherapy to the head and neck region, and is associated with a significant impairment of quality of life. A wide range of pharmacological interventions, with varying mechanisms of action, have been used for the prevention of radiation-induced salivary gland dysfunction. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of radiation-induced salivary gland dysfunction. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 14 September 2016); the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 14 September 2016); MEDLINE Ovid (1946 to 14 September 2016); Embase Ovid (1980 to 14 September 2016); CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 14 September 2016); LILACS BIREME Virtual Health Library (Latin American and Caribbean Health Science Information database; 1982 to 14 September 2016); Zetoc Conference Proceedings (1993 to 14 September 2016); and OpenGrey (1997 to 14 September 2016). We searched the US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: We included randomised controlled trials, irrespective of their language of publication or publication status. Trials included participants of all ages, ethnic origin and gender, scheduled to receive radiotherapy on its own or in addition to chemotherapy to the head and neck region. Participants could be outpatients or inpatients. We included trials comparing any pharmacological agent regimen, prescribed prophylactically for salivary gland dysfunction prior to or during radiotherapy, with placebo, no intervention or an alternative pharmacological intervention. Comparisons of radiation techniques were excluded. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 39 studies that randomised 3520 participants; the number of participants analysed varied by outcome and time point. The studies were ordered into 14 separate comparisons with meta-analysis only being possible in three of those.We found low-quality evidence to show that amifostine, when compared to a placebo or no treatment control, might reduce the risk of moderate to severe xerostomia (grade 2 or higher on a 0 to 4 scale) at the end of radiotherapy (risk ratio (RR) 0.35, 95% confidence interval (CI) 0.19 to 0.67; P = 0.001, 3 studies, 119 participants), and up to three months after radiotherapy (RR 0.66, 95% CI 0.48 to 0.92; P = 0.01, 5 studies, 687 participants), but there is insufficient evidence that the effect is sustained up to 12 months after radiotherapy (RR 0.70, 95% CI 0.40 to 1.23; P = 0.21, 7 studies, 682 participants). We found very low-quality evidence that amifostine increased unstimulated salivary flow rate up to 12 months after radiotherapy, both in terms of mg of saliva per 5 minutes (mean difference (MD) 0.32, 95% CI 0.09 to 0.55; P = 0.006, 1 study, 27 participants), and incidence of producing greater than 0.1 g of saliva over 5 minutes (RR 1.45, 95% CI 1.13 to 1.86; P = 0.004, 1 study, 175 participants). However, there was insufficient evidence to show a difference when looking at stimulated salivary flow rates. There was insufficient (very low-quality) evidence to show that amifostine compromised the effects of cancer treatment when looking at survival measures. There was some very low-quality evidence of a small benefit for amifostine in terms of quality of life (10-point scale) at 12 months after radiotherapy (MD 0.70, 95% CI 0.20 to 1.20; P = 0.006, 1 study, 180 participants), but insufficient evidence at the end of and up to three months postradiotherapy. A further study showed no evidence of a difference at 6, 12, 18 and 24 months postradiotherapy. There was low-quality evidence that amifostine is associated with increases in: vomiting (RR 4.90, 95% CI 2.87 to 8.38; P < 0.00001, 5 studies, 601 participants); hypotension (RR 9.20, 95% CI 2.84 to 29.83; P = 0.0002, 3 studies, 376 participants); nausea (RR 2.60, 95% CI 1.81 to 3.74; P < 0.00001, 4 studies, 556 participants); and allergic response (RR 7.51, 95% CI 1.40 to 40.39; P = 0.02, 3 studies, 524 participants).We found insufficient evidence (that was of very low quality) to determine whether or not pilocarpine performed better or worse than a placebo or no treatment control for the outcomes: xerostomia, salivary flow rate, survival, and quality of life. There was some low-quality evidence that pilocarpine was associated with an increase in sweating (RR 2.98, 95% CI 1.43 to 6.22; P = 0.004, 5 studies, 389 participants).We found insufficient evidence to determine whether or not palifermin performed better or worse than placebo for: xerostomia (low quality); survival (moderate quality); and any adverse effects.There was also insufficient evidence to determine the effects of the following interventions: biperiden plus pilocarpine, Chinese medicines, bethanechol, artificial saliva, selenium, antiseptic mouthrinse, antimicrobial lozenge, polaprezinc, azulene rinse, and Venalot Depot (coumarin plus troxerutin). AUTHORS' CONCLUSIONS: There is some low-quality evidence to suggest that amifostine prevents the feeling of dry mouth in people receiving radiotherapy to the head and neck (with or without chemotherapy) in the short- (end of radiotherapy) to medium-term (three months postradiotherapy). However, it is less clear whether or not this effect is sustained to 12 months postradiotherapy. The benefits of amifostine should be weighed against its high cost and side effects. There was insufficient evidence to show that any other intervention is beneficial.

Interventions for the management of radiotherapy-induced xerostomia and hyposalivation: A systematic review and meta-analysis.

INTRODUCTION: Salivary gland hypofunction is a common and permanent adverse effect of radiotherapy to the head and neck. Randomised trials of available treatment modalities have produced unclear results and offer little reliable guidance for clinicians to inform evidence-based therapy. We have undertaken this systematic review and meta-analysis to estimate the effectiveness of available interventions for radiotherapy-induced xerostomia and hyposalivation. METHODS: We searched MEDLINE, Cochrane Central, EMBASE, AMED, and CINAHL database through July 2016 for randomised controlled trials comparing any topical or systemic intervention to active and/or non-active controls for the treatment of radiotherapy-induced xerostomia. The results of clinically and statistically homogenous studies were pooled and meta-analyzed. RESULTS: 1732 patients from twenty studies were included in the systematic review. Interventions included systemic or topical pilocarpine, systemic cevimeline, saliva substitutes/mouthcare systems, hyperthermic humidification, acupuncture, acupuncture-like transcutaneous electrical nerve stimulation, low-level laser therapy and herbal medicine. Results from the meta-analysis, which included six studies, suggest that both cevimeline and pilocarpine can reduce xerostomia symptoms and increase salivary flow compared to placebo, although some aspects of the relevant effect size, duration of the benefit, and clinical meaningfulness remain unclear. With regard to interventions not included in the meta-analysis, we found no evidence, or very weak evidence, that they can reduce xerostomia symptoms or increase salivary flow in this population. CONCLUSIONS: Pilocarpine and cevimeline should represent the first line of therapy in head and neck cancer survivors with radiotherapy-induced xerostomia and hyposalivation. The use of other treatment modalities cannot be supported on the basis of current evidence.