Radiation Sialadenitis Research Articles

Nicotinamide mitigates radiation injury in submandibular gland by protecting mitochondrial structure and functions.

Radiation damage to salivary gland is inevitable in head and neck cancer patients receiving radiotherapy. Safe and effective treatments for protecting salivary glands from radiation are still unavailable. Mitochondrial damage is a critical mechanism in irradiated salivary gland; however, treatment targeting mitochondria has not received much attention. Nicotinamide is a key component of the mitochondrial metabolism. Here, we investigated the effects and underlying mechanisms of nicotinamide on protecting irradiated submandibular gland. Submandibular gland cells and tissues were randomly divided into four groups: control, nicotinamide alone, radiation alone, and radiation with nicotinamide pretreatment. Cell viability was detected by PrestoBlue cell viability reagent. Histopathological alterations were observed with HE staining. Pilocarpine-stimulated saliva was measured from Wharton's duct. Cell apoptosis was determined by flow cytometry and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Nicotinamide phosphoribosyl transferase was examined with immunofluorescence. The levels of nicotinamide adenine dinucleotide, mitochondrial membrane potential, and adenosine triphosphate were measured with the relevant kits. The mitochondrial ultrastructure was observed under transmission electron microscopy. Nicotinamide significantly mitigated radiation damage both in vitro and in vivo. Also, nicotinamide improved saliva secretion and reduced radiation-induced apoptosis in irradiated submandibular glands. Moreover, nicotinamide improved nicotinamide phosphoribosyl transferase and the levels of nicotinamide adenine dinucleotide/adenosine triphosphate and mitochondrial membrane potential, all of which were decreased by radiation in submandibular gland cells. Importantly, nicotinamide protected the mitochondrial ultrastructure from radiation. These findings demonstrate that nicotinamide alleviates radiation damage in submandibular gland by replenishing nicotinamide adenine dinucleotide and maintaining mitochondrial function and ultrastructure, suggesting that nicotinamide could be used as a prospective radioprotectant for preventing radiation sialadenitis.

The underlying mechanisms and strategies of DNA damage and repair in radiation sialadenitis.

Radiation therapy is a critical strategy for the treatment of malignant tumors. X-ray external radiation has been successfully used to treat head and neck cancer. On the other hand, 131 I internal radiation has been effective in managing differentiated thyroid cancer. However, these therapies cause radiation damage to salivary glands. Radiation sialadenitis is the most common complication associated with radiotherapy applied to the head and neck and it severely affects patients' quality of life. Since DNA is the main intracellular target of radiation, and the integrity of the DNA structure is critical to genomic stability and the cellular survival of salivary glands, regulating radiation-induced DNA damage offers great promise in preventing and managing radiation sialadenitis. In this review, we summarize recent progress in DNA damage and repair in irradiated salivary glands.

Dual Roles of Nicotinamide Phosphoribosyltransferase as a Promising Target for Cancer Radiotherapy.

Nicotinamide phosphoribosyltransferase (NAMPT) is the key rate-limiting enzyme in the regulation of nicotinamide adenine dinucleotide (NAD) biosynthesis, and its activity is critical for the replenishment of NAD level as well as cell survival or death. As one of the most important components in the electron transport chain of complex I in mitochondrion, sustained supply of NAD is essential to the maintenance of energy metabolism both in normal and cancer cells. Recent research showed that X-ray radiation sharply downregulated the expression of NAMPT, which may be the main cause of radiation damage in salivary gland. Consistently, upregulation of NAMPT by phenylephrine restored the function and tissue structure of salivary gland, indicating the cytoprotective role of NAMPT in preventing radiation damage in normal tissues of patients with head and neck cancer during radiotherapy. On the other hand, NAMPT downregulation and NAD depletion could induce cell death in oral squamous cell cancer, suggesting that a combination of NAMPT inhibitor and radiotherapy presents a promising therapeutic strategy for cancer treatment. Based on our and other's studies, NAMPT may have dual roles in cancer radiotherapy: the upregulation of NAMPT could serve to suppress radiotherapy complications such as radiation sialadenitis, and combination regimens that involve NAMPT inhibitors may enhance efficacy of radiotherapy for cancer treatment.

Nerve growth factor protects salivary glands from irradiation-induced damage

AimsRadiotherapy has become a basic treatment modality for head and neck cancer. However, radiotherapy results in inevitable side effects, particularly radiation sialadenitis, that significantly impairs quality of life. A previous study indicated that nerve growth factor (NGF) has a radio-protective effect, but the mechanism was not determined in salivary glands. In this study, we explored the functional role and mechanism regarding how NGF protects salivary glands against IR-induced damage. Main methodsHuman salivary gland (HSG) cells and C57BL/6 mice were selected to establish an IR-induced salivary gland damage model in vitro and in vivo. Recombinant NGF protein and NGF siRNA and over-expression plasmids were applied to manipulate NGF expression in vitro. AAV-NGF was retrogradely perfused into the submandibular gland (SMG) through the SMG duct to manipulate NGF expression in vitro. Small-molecule inhibitors and siRNAs were applied to inhibit AKT and JNK. Western blotting, quantitative PCR, flow cytometry and histology assays were performed to analyse the functional role and mechanism of NGF. Key findingsOur study demonstrated that NGF expression was upregulated following radiotherapy both in human HSG cells and mouse SMG tissues. NGF could reduce IR-induced HSG cell apoptosis, and AAV-mediated gene therapy could restore the salivary flow rate and protect the salivary gland against IR-induced apoptosis in vivo. Mechanistically, NGF protects salivary glands from IR-induced apoptosis by de-phosphorylating JNK kinase rather than promoting AKT phosphorylation. SignificanceThe current study findings indicated that the modulation of the NGF pathway might prevent IR-induced salivary hypo-function.

Phenylephrine alleviates 131I damage in submandibular gland through promoting endogenous stem cell regeneration via lissencephaly-1 upregulation

Thyroid cancer is the most common endocrine malignancy. 131I ablation therapy is an effective treatment for patients with differentiated thyroid cancer (DTC) but frequently causes radiation damage in salivary glands (SGs). Stem cell-based regenerative therapy has been found to reduce radiation sialadenitis. We hypothesize that microtubule motor-regulating protein lissencephaly-1 (LIS1) may be a key stem cell regulator responsible for its efficacy and that upregulating LIS1 would decrease131I-induced radiation sialadenitis. Here, we report that LIS1 was reduced by 131I in submandibular glands (SMGs) of rats, using both proteomic analysis and Western blot approach. Moreover, the levels of LIS1-Sca-1 and LIS1-SOX2 were downregulated by 131I together with the decrease of LIS1. In contrast, phenylephrine pretreatment enhanced LIS1 and improved the co-expressions and co-localizations of LIS1-Sca-1 and LIS1-SOX2 in 131I-irradiated SMGs. Since Sca-1 and SOX2 are the established stem cell biomarkers in salivary gland, our findings demonstrate that LIS1 may be a potential target for regulating stem cell maintenance in irradiated SGs. Importantly, phenylephrine may have the ability to promote endogenous stem cell regeneration in SMGs via upregulating the LIS1/Sca-1 and LIS1/SOX2 signaling pathways, suggesting that phenylephrine application before 131I ablation therapy may provide a practical and effective way to prevent radiation sialadenitis for DTC patients.

Phenylephrine Alleviates 131I Radiation Damage in Submandibular Gland Through Maintaining Mitochondrial Homeostasis

The impairment of the salivary glands is a permanent side effect of 131I ablation therapy for patients with differentiated thyroid cancer. Effective and safe treatments for protecting the salivary glands against 131I are currently not available. Mitochondria are susceptible to ionizing radiation, but alterations after 131I exposure are unknown. Here, we investigated the mechanisms of 131I damage in submandibular glands (SMGs) and evaluated the cytoprotective effect of phenylephrine (PE) against mitochondrial radiation damage. Rats were randomly divided into 4 groups: control, PE alone, 131I alone, and 131I with PE pretreatment. The mitochondrial structure of SMGs was observed under transmission electron microscopy. Apoptosis was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. Cytochrome c, cleaved-caspase 3, SIRT1, NAMPT, and PGC-1α protein levels were determined with Western blot and immunohistochemistry. Levels of mitochondrial membrane potential, nicotinamide adenine dinucleotide (NAD), and adenosine triphosphate (ATP) were measured with relevant kits. After exposing rat SMGs to 131I, the mitochondrial membrane structures were destroyed, the mitochondrial membrane potential decreased, the release of cytochrome c increased, and cleaved-caspase 3 and cell apoptosis were activated. Moreover, the expression of SIRT1, NAMPT, and PGC-1α was downregulated, and the levels of NAD and ATP decreased. In contrast, PE alleviated the 131I-induced mitochondrial damages and upregulated the expression of SIRT1/NAMPT/PGC-1α and the levels of NAD and ATP. These findings demonstrate that 131I impairs the salivary glands via the downregulation of SIRT1/NAMPT/PGC-1α signal pathways, which disturbs mitochondrial homeostasis. PE alleviated the 131I damage in SMGs at the mitochondrial level, suggesting that PE could be used as a potential radioprotector for patients with differentiated thyroid cancer with radiation sialadenitis.

Initial clinical experience performing sialendoscopy for salivary gland protection in patients undergoing 225Ac-PSMA-617 RLT.

The main side effect of prostate-specific membrane antigen targeting alpha therapy (PSMA TAT) is dry mouth syndrome. Inflammation of the salivary glands and consequent reduced salivary function have been reported in patients after radioiodine therapy. The beneficial effects of sialendoscopy on radiation-induced inflammation in tissue are well known. Thus sialendoscopy with dilatation, saline irrigation and steroid injections (prednisolone) was performed before and after 225Ac-PSMA-617 TAT to reduce inflammatory effects in the salivary glands and to improve or prevent xerostomia. Eleven men with metastatic castration-resistant prostate cancer (mean age 68.5years, range 58-80years) underwent sialendoscopy, dilatation, saline irrigation and steroid injection of both submandibular and both parotid glands before or after every cycle of 225Ac-PSMA-617 TAT. Sialendoscopy and steroid injection were performed by a senior ENT physician. Quality of life was evaluated using two health-related quality of life (HRQOL) questionnaires, the Xerostomia Questionnaire (XQ) and the Xerostomia Inventory (XI) before and 3months after the intervention. In all 11 patients both parotid and both submandibular glands were affected by radiation sialadenitis and sialendoscopy was performed. The patients experienced no complications after sialendoscopy, and showed a significant improvement in HRQOL as measured using the XQ and XI. After sialendoscopy the XQ score decreased significantly from 77.7 ± 13.6 to 42.7 ± 14.8 (p = 0.003) and the XI score decreased from 44.5 ± 6.9 to 25.8 ± 12.8 (p = 0.003). Due to the limited number of patients we only report tendencies. Sialendoscopy with dilatation, saline irrigation and steroid injection had beneficial effects on salivary gland function and HRQOL in patients undergoing 225Ac-PSMA-617 RLT. However, even with sialadenoscopic support after multiple cycles of TAT, salivary gland function was reduced and xerostomia was present. Therefore, not only inflammation but also the direct effect of radiation is a putative cause of dry mouth. Further research is necessary to determine the main side effects of PSMA TAT.

Comparison of 30 mCi and 50 mCi I-131 doses for ablation of thyroid remnant in papillary thyroid cancer patients

ABSTRACT Purpose of the study: To compare efficacy of thyroid remnant ablation using 30 mCi or 50 mCi 131-I in papillary thyroid cancer patients. Materials and methods: Five hundred and fifteen consecutive patients with Tumor-Node-Metastasis (TNM) stages T1-T3 N1/N0/NX receiving either 30 mCi or 50 mCi I-131 were analyzed for the effectiveness of remnant ablation using rhTSH-stimulated serum thyroglobulin. One hundred and five consecutive patients receiving 100 mCi I-131 were analyzed for the incidence of radiation thyroiditis and sialadenitis. Results and conclusions: Doses of 30 mCi and 50 mCi were equally effective for low- and moderate-risk disease but 30 mCi was less effective for T1T2NX disease, and 50 mCi was less effective for T3 compared to T1T2 disease. Low dose radiation hypersensitivity or unknown more extensive disease may have accounted for observed differences. Radiation thyroiditis and sialadenitis were more common in a comparison series of 100 mCi dose compared to 30 mCi, but not more common than in 50 mCi doses.

Diagnostic Utility of Acoustic Structure Quantification for Evaluation of Radiation Sialadenitis after Radioactive Iodine Therapy

Acoustic structure quantification (ASQ) software was used to analyze statistical information on acquired echo signals, to determine the ability of ASQ to distinguish normal salivary glands of asymptomatic patients from glands of patients with radiation sialadenitis (RS) after radioactive iodine therapy. The ASQ values of 192 salivary glands were compared by multinomial logistic regression analysis, and receiver operating characteristic curves were constructed. Between-observer agreement was assessed by calculating the intra-class correlation coefficient. The mean ASQ values of patients with chronic RS or asymptomatic patients who had undergone radioactive iodine therapy were greater than those of patients with normal glands (p < 0.001). The ratio was associated with the highest odds ratio in patients with chronic RS compared with normal patients. Diagnostic performance was moderate; the intra-class correlation coefficient between observers was very good. ASQ can objectively differentiate RS-affected tissue from normal salivary tissue and is thus valuable for clinically diagnosing RS after radioactive iodine therapy.

Nicotinamide Phosphoribosyltransferase Upregulation by Phenylephrine Reduces Radiation Injury in Submandibular Gland

Radiation therapy for head and neck cancer commonly leads to radiation sialadenitis. Emerging evidence has indicated that phenylephrine pretreatment reduces radiosensitivity in the salivary gland; however, the underlying cytoprotective mechanism remains unclear. Nicotinamide phosphoribosyltransferase (NAMPT) is not only a key enzyme for the nicotinamide adenine dinucleotide salvage pathway, but also a cytokine participating in cell survival, metabolism, and longevity, with a broad effect on cellular functions in physiology and pathology. However, the regulatory events of NAMPT in response to the irradiated salivary gland are unknown. The cell viability of primary cultured submandibular gland cells was determined using the PrestoBlue assay. NAMPT expression was measured using reverse transcriptase polymerase chain reaction and Western blotting invitro and invivo. Silent information regulator 1 (SIRT1) and phosphorylated Akt protein levels were examined by Western blotting. The cellular locations of NAMPT and SIRT1 were detected by immunohistochemistry. NAMPT promoter activity was assessed using the luciferase reporter gene assay. NAMPT was mainly distributed in the cytoplasm of granular convoluted tubule cells and ductal cells in normal submandibular glands. mRNA and protein expression of NAMPT was downregulated after radiation but upregulated with phenylephrine pretreatment both invivo and invitro. Moreover, the protein expression of phosphorylated Akt and SIRT1 was decreased in irradiated glands, and phenylephrine pretreatment restored the expression of both. SIRT1 was mainly located in the cell nucleus and cytoplasm in the normal submandibular gland. Phenylephrine dramatically enhanced the expression of SIRT1, which was significantly reduced by radiation. Furthermore, phenylephrine induced a marked increase of NAMPT promoter activity. These findings reveal the regulatory mechanisms of NAMPT expression, which help to understand the mechanism of the cytoprotective role of phenylephrine on irradiated tissues.

Retraction note: Radiation sialadenitis induced by high-dose radioactive iodine therapy.

Radioactive iodine ((131)I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, (131)I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with (131)I-induced sialadenitis that is unresponsive to medical treatment.

Iodide mumps: a case report of complicated radioactive iodine causing sialadenitis

Radiation sialadenitis is an uncommon adverse reaction to radioactive iodide therapy. Sialadenitis due to radiation exposure has a dose-related damage that can follow an acute or chronic inflammatory nature. We present a case of a patient who developed radiation sialadenitis after radioactive iodide therapy for papillary thyroid cancer resulting in severe parotid swelling and swelling, which resulted in an emergency department visit and had complete resolution with conservative management.

RETRACTED ARTICLE: Radiation sialadenitis induced by high-dose radioactive iodine therapy.

Radioactive iodine ((131)I) is accumulated in the thyroid tissue and plays an important role in the treatment of differentiated papillary and follicular cancers after thyroidectomy. Simultaneously, (131)I is concentrated in the salivary glands and secreted into the saliva. Dose-related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, candidiasis, and neoplasia. Prevention of (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration. Recently interventional sialoendoscopy has been introduced an effective tool for the management of patients with (131)I-induced sialadenitis that is unresponsive to medical treatment.

Reducing the Incidence of 131I-Induced Sialadenitis: The Role of Pilocarpine

The goal of this study was to reduce the salivary symptoms of pain and xerostomia caused by 131I therapy for papillary and follicular thyroid carcinoma. In a single-blind controlled prospective study of 60 patients, we investigated whether pilocarpine, 5 mg orally every 8 h for 1 wk after 131I therapy, would reduce salivary symptoms. All patients received 8 mg of dexamethasone and 100 mg of dolasetron mesylate orally 2 h before therapy and every 12 h for another 5 doses after 131I ingestion. In addition, for a week after therapy all drank 2,400 mL of nondairy liquid per day and had sugar-free gum or candy in their mouths at all times when awake for a week and, for the first 3 nights, every 3 h after retiring. All brushed their mouths out every 3 h while awake and also for the first 3 nights after 131I therapy. Symptoms and signs were followed by frequent telephone calls over the first week and every 8-12 wk thereafter, a physical examination within the first 10 d after therapy, and a clinic visit 6-8 mo after therapy. Statistical comparisons were by chi2 analysis. The 2 patient groups were not statistically different in age, sex, type of thyroid cancer, or 131I activity administered (P > 0.05). There were no statistical differences between the groups in the prevalence of sialadenitis, stomatitis, xerostomia, or dysgeusia over the next 6 mo (P > 0.05). Under the conditions of the study, pilocarpine did not reduce the occurrence of radiation sialadenitis or stomatitis. The occurrence, however, was lower than had previously been reported in the literature, possibly because of the concurrent stringent application of physiologic sialogogues (candy, gum, fluids), dexamethasone, and dolasetron mesylate, a serotonin receptor antagonist.

Radioactive iodine and the salivary glands.

Radioactive iodine ((131)I) targets the thyroid gland and has been proven to play an effective role in the treatment of differentiated papillary and follicular cancers. Simultaneously, this radioisotope hones in on the salivary glands where it is concentrated and secreted into the saliva. Dose related damage to the salivary parenchyma results from the (131)I irradiation. Salivary gland swelling and pain, usually involving the parotid, can be seen. The symptoms may develop immediately after a therapeutic dose of (131)I and/or months later and progress in intensity with time. In conjunction with the radiation sialadenitis, secondary complications reported include xerostomia, taste alterations, infection, increases in caries, facial nerve involvement, stomatitis, candidiasis, and neoplasia. Prevention of the (131)I sialadenitis may involve the use of sialogogic agents to hasten the transit time of the radioactive iodine through the salivary glands. However, studies are not available to delineate the efficacy of this approach. Recently, amifostine has been advocated to prevent the effects of irradiation. Treatment of the varied complications that may develop encompass numerous approaches and include gland massage, sialogogic agents, duct probing, antibiotics, mouthwashes, good oral hygiene, and adequate hydration.

Diagnostic accuracy of salivary scintigraphic indices in xerostomic populations.

Three decades of work to enhance the diagnostic accuracy of salivary scintigraphy have generated various plausible decision criteria. This study evaluates four commonly cited numeric indices in studies of xerostomic populations and how accurately they identify Sjögren's syndrome, chronic sialadenitis, radiation sialadenitis, and drug effects and distinguish each from the other. Stimulated dynamic salivary scintigraphy was performed on 295 xerostomic patients and on 31 controls. The nonparametric area under the receiver operating characteristic curves expressed the diagnostic accuracy of the following scintigraphic indices: the parotid:submandibular ratio of unstimulated glandular activity, the peak:baseline uptake ratio, its time of occurrence, and the stimulated excretion fraction. The stimulated excretion fraction distinguished Sjögren's syndrome and radiation sialadenitis from healthy states with respective accuracies of 0.78 and 0.90. The maximum diagnostic payoff in Sjögren's syndrome occurred at a cutoff of 73%, yielding a 73% rate of test sensitivity and a 73% rate of specificity. The other three indices were not useful. Even the stimulated excretion fraction performed indifferently or poorly in most other diagnostic tasks. In the scintigraphic examination of xerostomic and healthy populations, an acceptable diagnostic utility of the stimulated excretion fraction was evident only in Sjögren's syndrome and radiation sialadenitis. When presented with differential diagnostic alternatives not involving radiation sialadenitis, none of the four numeric indices performed acceptably.