Experimental Animal Model Systems for Understanding Salivary Secretory Disorders.

Salivary secretory disorders are life-disrupting pathologic conditions with a high prevalence, especially in the geriatric population. Both patients and clinicians frequently feel helpless and get frustrated by the currently available therapeutic strategies, which consist mainly of palliative managements. Accordingly, to unravel the underlying mechanisms and to develop effective and curative strategies, several animal models have been developed and introduced. Experimental findings from these models have contributed to answer biological and biomedical questions. This review aims to provide various methodological considerations used for the examination of pathological fundamentals in salivary disorders using animal models and to summarize the obtained findings. The information provided in this review could provide plausible solutions for overcoming salivary disorders and also suggest purpose-specific experimental animal systems.

Dynamics of Salivary Gland AQP5 under Normal and Pathologic Conditions.

AQP5 plays an important role in the salivary gland function. The mRNA and protein for aquaporin 5 (AQP5) are expressed in the acini from embryonic days E13-16 and E17-18, respectively and for entire postnatal days. Ligation-reopening of main excretory duct induces changes in the AQP5 level which would give an insight for mechanism of regeneration/self-duplication of acinar cells. The AQP5 level in the submandibular gland (SMG) decreases by chorda tympani denervation (CTD) via activation autophagosome, suggesting that its level in the SMG under normal condition is maintained by parasympathetic nerve. Isoproterenol (IPR), a ß-adrenergic agonist, raised the levels of membrane AQP5 protein and its mRNA in the parotid gland (PG), suggesting coupling of the AQP5 dynamic and amylase secretion-restoration cycle. In the PG, lipopolysaccharide (LPS) is shown to activate mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalings and potentially downregulate AQP5 expression via cross coupling of activator protein-1 (AP-1) and NF-κB. In most species, Ser-156 and Thr-259 of AQP5 are experimentally phosphorylated, which is enhanced by cAMP analogues and forskolin. cAMP-dependent phosphorylation of AQP5 does not seem to be markedly involved in regulation of its intracellular trafficking but seems to play a role in its constitutive expression and lateral diffusion in the cell membrane. Additionally, Ser-156 phosphorylation may be important for cancer development.

Diagnostic value of acustic radiation force impulse imaging in the assessment of salivary gland involvement in primary Sjögren's sydrome.

AIMS: The aim of this study is to investigate the diagnostic value of Acoustic Radiation Force Impulse (ARFI) imaging in the assessment of salivary gland involvement in primary Sjögren's syndrome (pSS). MATERIAL AND METHODS: Twenty five patients with pSS and 25 healthy volunteers were included. First, echostructures and the thickness of the submandibular and parotid glands were evaluated by B-mode ultrasonography. Then, ARFI imaging with Virtual Touch Quantification® was performed. Ten independent shear wave velocity measurements were taken from each gland. Finally, the mean shear wavevelocity (SWV) values were calculated, and used for further analysis. RESULTS: The mean SWV values of parotid and submandibular glands were significantly higher in the pSS patients than in the healthy control group (p<0.001). The cut-off of SWV values were calculated to be 1.98 m/s for submandibular glands, and 1.93 m/s for parotid glands. In pSS patients, the mean SWV values of parotid glands were higher than those of the submandibular glands (p<0.001) and no statistically significant relationships between symptom duration or the degree of xerostomia and mean SWV values of parotid and submandibularglands were found (all p>0.005). CONCLUSIONS: Our findings indicate that ARFI imaging may provide a non-invasive, simple and fast means of assessment of glandular impairment as an alternative test when other salivary gland tests are inconclusive or cannot be performed. ARFI may be a valuable adjunct for the clinical diagnosis of pSS.

Radioactive iodine: An unappreciated threat to salivary gland function.

Thyroid cancer is an endocrine malignancy whose prevalence is increasing in the United States. Nearly 57,000 new cases of thyroid cancer are estimated to be diagnosed in 2017. The standard of care for differentiated thyroid cancer is thyroidectomy followed by ablation of thyroid remnants with high-dose radioactive iodine (131 I). Apart from thyroid glands, 131 I accumulates in cells of salivary glands and compromises its function. Xerostomia is, therefore, a frequent and often persistent complaint of patients. Despite adoption of standard preventive measures, parenchymal damage and chronic salivary dysfunction are observed in a substantial number of patients. Saliva is important for oral homeostasis, and its reduction increases the risk of oral morbidity. As differentiated thyroid cancer patients have an excellent survival rate, preservation of salivary gland function carries added significance. A focus on treatments that preserve or restore long-term salivary flow can significantly improve the quality of life of thyroid cancer survivors.

Salivary gland disease in Sjögren's syndrome: sialoadenitis to lymphoma.

Although the cause and molecular pathways of Sjögren's syndrome are still unknown, basic, clinical, and translational science have started to identify linkages to other known processes. With the advent of newer, more sensitive, and more accurate chemokine, cytokine, and genetic analysis, the molecular progression of the disease may be understood. The modern technology of sialoendoscopy to treat obstructive sialoadenitis from mucous plugging, and the addition of rituximab to current chemotherapy, have allowed patients with Sjögren's syndrome to have a better quality of life and, if they develop lymphomatous changes, a significant increase in their disease remission and survival rate.

Chronic inflammation in the pancreas and salivary glands--lessons from similarities and differences in pathophysiology and treatment modalities.

The pancreas and salivary glands have similar anatomical structures and physiological functions producing bicarbonate-rich fluid containing digestive enzymes and other components to be delivered into the gut. Despite these similarities, the two organs are also different in numerous respects, especially regarding the inflammatory diseases affecting them. This article will summarize the pathophysiology and current and potential pharmacological treatments of chronic inflammatory diseases such as chronic pancreatitis, autoimmune pancreatitis, Sjögren's syndrome and irradiation-induced salivary gland atrophy. Despite the differences, in both organs the inflammatory process is accompanied by epithelial tissue destruction and fibrosis. Both in pancreatic and in salivary research, an important task is to stop or even reverse this process. The utilization of stem/progenitor cell populations previously identified in these organs and the application of mesenchymal stem cells are very promising for such regenerative purposes. In addition, gene therapy and tissue engineering research progressively advance and have already yielded clinically beneficial preliminary results for salivary gland diseases. For the hard-to-access, hard-to-regenerate pancreas these developments may also offer new solutions, especially since salivary and pancreatic progenitors are very similar in characteristics and may be mutually useful to regenerate the respective other organ as well. These novel developments could be of great significance and may bring new hope for patients since currently used therapeutic protocols in salivary and in pancreatic chronic inflammatory diseases offer primarily symptomatic treatments and limited beneficial outcome.

Salivary and lacrimal gland dysfunction after remnant ablation with radioactive iodine in patients with differentiated thyroid carcinoma prepared with recombinant human thyrotropin.

BACKGROUND: One of the adverse effects of radioactive iodine (¹³¹I) treatment in patients with thyroid cancer is damage to the salivary and lacrimal glands. In almost all studies evaluating salivary and lacrimal gland dysfunction, the patients received ¹³¹I after levothyroxine (L-T4) withdrawal. Since the biokinetics of ¹³¹I after recombinant human thyrotropin (rhTSH) is not the same as in hypothyroidism, studies need to evaluate ¹³¹I-induced salivary and lacrimal toxicity after preparation with rhTSH. This prospective study investigated the occurrence of salivary and lacrimal damage after ablation with ¹³¹I using this preparation. METHODS: One hundred forty-eight patients who had a total thyroidectomy were included in the study. The subjects were evaluated after thyroidectomy during L-T4 use to exclude those who already showed symptoms or had a history of ocular or oral disease. Symptoms were investigated 12 and 18 months after ablation. In patients who had persistent symptoms, specific tests were performed to confirm glandular dysfunction and to rule out other causes. RESULTS: Twelve months after ablation, symptoms of salivary or lacrimal dysfunction were observed in 10 (6.7%) patients, including oral symptoms in 8 (5.4%) and ocular symptoms in 6 (4%). Eighteen months after ¹³¹I, symptoms persisted in eight (5.4%) patients, including oral symptoms in seven (4.7%) and ocular symptoms in five (3.4%). In all of the patients, glandular dysfunction was confirmed by specific tests and other causes were ruled out. No symptoms were seen in the patients who received a low ¹³¹I dose (30 mCi). In the patients who received high ¹³¹I doses (100 or 150 mCi), symptoms were noted 12 months after ¹³¹I in 10 patients (9.2%), and 18 months after ¹³¹I in 8 patients (7.4%). CONCLUSIONS: Apparently, the rates of salivary and lacrimal damage were lower than those reported in prospective studies that used similar ¹³¹I activities, but these studies were performed in patients who were hypothyroid at the time of ¹³¹I ablation. Further studies are needed to compare radiotoxicity between patients prepared for ¹³¹I ablation with rhTSH and those prepared for ¹³¹I ablation with L-T4 withdrawal.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Xerostomia and salivary hypofunction in vulnerable elders: prevalence and etiology.

OBJECTIVE: The goal of this article is to review existing research on the prevalence and etiology of dry mouth in the vulnerable elders and identify knowledge gaps. STUDY DESIGN: Vulnerable elders (VE) are persons aged >65 years who have any or all of the following: limited mobility, limited resources, or complex health status. A systematic search was conducted of PubMed sources from 1989 to May 2010. Evidence was evaluated on the prevalence and etiology of xerostomia and salivary gland hypofunction (SGH) in VE. RESULTS: The search identified 1,422 publications. The inclusion/exclusion criteria yielded 348 articles, 80 of which are cited herein. CONCLUSIONS: Research has showed a high prevalence of xerostomia and SGH in VE. Common etiologies include medications, poor general health, female gender, and age. Gaps still exist in the evaluation of dry mouth in VE. Nonetheless, oral dryness will remain an important health issue as life expectancy increases.

Diagnosis and gland-preserving minimally invasive therapy for Wharton's duct stenoses.

OBJECTIVES/HYPOTHESIS: The management of stenoses of Wharton's duct has so far been little investigated or systematized. The development of minimally invasive treatment methods, including sialendoscopy, has made preservation of gland function possible. STUDY DESIGN: Retrospective study in a tertiary referral center. METHODS: A total of 153 stenoses of the submandibular duct were diagnosed and treated in 138 patients. Ultrasound and sialendoscopy were the first-choice diagnostic measures. A total of 62.7% of the stenoses were located in the distal, 11.1% in the middle segment, and 18.3% in the proximal to posthilar duct. Diffuse stenoses were observed in 7.8% of the cases. Sialendoscopy-assisted intraductal cortisone administration, interventional sialendoscopy, and transoral ductal surgery were the treatment options. The mean period between treatment and data collection was 52.5 months. RESULTS: Fibrotic stenoses were diagnosed in 88.3% and bilateral involvement in 8.6% of the cases. Distal stenoses were treated predominantly by ductal incision (79.2%). Stenoses of the midsubmandibular duct were treated conservatively in 29.4% or with sialendoscopy or ductal incision in 35.3% of cases each. Proximal up to posthilar stenoses could be dilated by interventional sialendoscopy in 82.2%. In 25% of all diffuse stenoses, glandular resection was carried out, representing 2.6% of all stenoses. Glandular function was preserved in 97.8% of cases. CONCLUSIONS: Stenoses of the submandibular duct can be treated using minimally invasive procedures and with preservation of glandular function with a high success rate. Ductal incision procedures are the most important measure, but sialendoscopy becomes more important the more centrally the stenosis is located.

Prevention of radiation-induced salivary hypofunction following hKGF gene delivery to murine submandibular glands.

PURPOSE: Salivary glands are significantly affected when head and neck cancer patients are treated by radiation. We evaluated the effect of human keratinocyte growth factor (hKGF) gene transfer to murine salivary glands on the prevention of radiation-induced salivary hypofunction. EXPERIMENTAL DESIGN: A hybrid serotype 5 adenoviral vector encoding hKGF (AdLTR(2)EF1α-hKGF) was constructed. Female C3H mice, 8 weeks old, were irradiated by single (15 Gy) or fractionated (6 Gy for 5 days) doses to induce salivary hypofunction. AdLTR(2)EF1α-hKGF or AdControl was administered (10(8) - 10(10) particles per gland) to both submandibular glands (SG) by retrograde ductal instillation before irradiation (IR). Salivary flow was measured following pilocarpine stimulation. Human KGF levels were measured by ELISA. SG cell proliferation was measured with bromodeoxyuridine labeling. Endothelial and progenitor or stem cells in SGs were measured by flow cytometry. The effect of SG hKGF production on squamous cell carcinoma (SCC VII) tumor growth was assessed. RESULTS: In 3 separate single-dose IR experiments, salivary flow rates of mice administered the AdLTR(2)EF1α-hKGF vector were not significantly different from nonirradiated control mice (P > 0.05). Similarly, in 3 separate fractionated IR experiments, the hKGF-expressing vector prevented salivary hypofunction dramatically. Transgenic hKGF protein was found at high levels in serum and SG extracts. AdLTR(2)EF1α-hKGF-treated mice showed increased cell proliferation and numbers of endothelial cells, compared with mice treated with AdControl. hKGF gene transfer had no effect on SCC VII tumor growth ± radiation. CONCLUSIONS: hKGF gene transfer prevents salivary hypofunction caused by either single or fractionated radiation dosing in mice. The findings suggest a potential clinical application.

Mucus extravasation and retention phenomena: a 24-year study.

BACKGROUND: Mucoceles are benign lesions related to the minor salivary glands and their respective ducts frequently affecting oral structures which are generally asymptomatic. Mucoceles are generally characterized by swollen nodular lesions preferentially located on the lower lip and differ from the so-called ranulas, which are lesions located on the floor of the mouth and related to the sublingual or submandibular glands. METHODS: The objective of the present study was to analyze data such as age, gender, race and site of the lesion of 173 mucocele cases diagnosed at the Discipline of Stomatology, São José dos Campos Dental School, UNESP, over a period of 24 years (April 1980 to February 2003). RESULTS: Of the 173 cases analyzed, 104 (60.12%) were females and 69 (39.88%) were males. Age ranged from 4 to 70 years (mean +/- SD: 17 +/- 9.53) and most patients were in the second decade of life (n = 86, 49.42%); white (n = 124, 71.68%). The lower lip was the site most frequently affected by the lesions (n = 135, 78.03%), whereas the lowest prevalence was observed for the soft palate, buccal mucosa, and lingual frenum. CONCLUSION: In this study, mucoceles predominated in white female subjects in the second decade of life, with the lower lip being the most frequently affected site.

Extracellular matrix and growth factors in salivary gland development.

The interstitial extracellular matrix (ECM) and epithelial-cell associated basement membrane (BM) play critical roles in the morphogenesis and differentiation of developing salivary glands. Early studies used ex vivo organ culture and tissue recombination methods to identify the importance of the ECM in organ development. Incorporation of transgenic mice and molecular tools has facilitated progress in our understanding of the mechanisms by which ECM proteins influence SMG development. Recent work has identified alterations in the ECM, BM, and associated proteins in salivary gland diseases, including Sjögren's syndrome and salivary gland cancers, but the significance of such changes is not known. Understanding the basic mechanisms controlling morphogenesis and differentiation in mammalian organ development is the first step towards understanding pathogenesis. Molecular characterization of the function of the ECM and BM in cellular processes is critical for future development of therapeutic approaches in regenerative medicine and tissue engineering. Here we provide a historical overview of experiments defining the functions of the ECM, ECM receptors, and associated molecules in salivary gland development. We include a discussion of the function of ECM-associated proteases and major growth factor signaling components that are in some way regulated by the ECM or associated molecules. We conclude with a discussion of defects in ECM and BM occurring in salivary gland pathologies and speculation on future areas of research pertaining to further understanding of the function of the ECM in the salivary gland.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life.

PURPOSE: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. RESULTS: The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. CONCLUSIONS: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

A single centre retrospective analysis of AECG classification criteria for primary Sjogren's syndrome based on 112 minor salivary gland biopsies in a Japanese population.

OBJECTIVE: To assess the usefulness and performance of the American European Consensus Group (AECG) criteria based on minor salivary gland biopsy (MSGB) in Japanese patients with primary SS. METHODS: Among 208 MSGB cases, we retrospectively selected 112 subjects who satisfied the complete set of AECG classification criteria. Of the 112 subjects studied, 63 primary SS patients and 49 non-SS group subjects were classified according to the AECG criteria. The contribution of subjective and objective components was statistically analysed. RESULTS: Sex, dry eye, Saxon test, Schirmer's test, anti-SSA/Ro antibody, MSGB grading and sialography statistically contributed to the diagnosis. Multiple logistic regression analysis showed that positive MSGB [odds ratio (OR) 105; 95% CI 13, 849), positive anti-SSA/Ro antibody (OR 96; 95% CI 10, 923), a positive Saxon test (OR 46; 95% CI, 6, 340) and the existence of dry eye (OR 8, 95% CI 2, 43) were associated with the diagnosis of primary SS. Among the components of the AECG criteria, MSGB and anti-SSA/Ro antibody were very strong contributors. Furthermore, the abnormal-finding positive rate in sialography significantly correlated with MSGB grading (P-value for trend = 0.0006), although other subjective and objective components were not associated with MSGB grading. CONCLUSION: The usefulness of the AECG criteria for Japanese primary SS patients was confirmed.

Conditional overexpression of TGF-beta1 disrupts mouse salivary gland development and function.

Transforming growth factor-beta (TGF-beta) signaling is known to affect salivary gland physiology by influencing branching morphogenesis, regulating ECM deposition, and controlling immune homeostasis. To study the role of TGF-beta1 in the salivary gland, we created a transgenic mouse (beta1(glo)) that conditionally overexpresses active TGF-beta1 upon genomic recombination by Cre recombinase. beta1(glo) mice were bred with an MMTV (mouse mammary tumor virus)-Cre (MC) transgenic line that expresses the Cre recombinase predominantly in the secretory cells of both the mammary and salivary glands. Although most of the double positive (beta1(glo)/MC) pups die either in utero or just after birth, clear defects in salivary gland morphogenesis such as reduced branching and increased mesenchyme could be seen. Those beta1(glo)/MC mice that survived into adulthood, however, had hyposalivation due to salivary gland fibrosis and acinar atrophy. Increased TGF-beta signaling was observed in the salivary gland with elevated phosphorylation of Smad2 and concomitant increase in ECM deposition. In particular, aberrant TGF-beta1 overexpression caused salivary gland hypofunction in this mouse model because of the replacement of normal glandular parenchyma with interstitial fibrous tissue. These results further implicate TGF-beta in pathological cases of salivary gland inflammation and fibrosis that occur with chronic infections in the glands or with the autoimmune disease, Sjögren's syndrome, or with radiation therapy given to head-and-neck cancer patients.

Modern management and pathophysiology of ranula: literature review.

BACKGROUND: There is a lack of consensus about the appropriate treatment of ranula. The objective of the present investigation was to produce a scientific basis for treatment. METHODS: A review of the relevant literature is interpreted in the light of improved knowledge about the local anatomy and the pathophysiology of the salivary glands. RESULTS: The oral and plunging ranulas are cystic extravasation mucoceles that arise from the sublingual gland and usually from a torn duct of Rivinus. The sublingual gland is a spontaneous secretor and the salivary flow is resistant to obstruction, which is caused by fibrosis induced by the extravasation. The submandibular gland is not a spontaneous secretor, is less resistant, and does not give rise to ranulas. CONCLUSIONS: Effective treatment is removal of the involved unit of the sublingual gland or inducing sufficient fibrosis to seal the leak through which the mucus extravasates.

Dispersed donor salivary gland cells are widely distributed in the recipient gland when infused up the ductal tree.

The salivary glands often are severely and permanently damaged by therapeutic irradiation for cancer of the head and neck. The markedly reduced quantity and quality of saliva results in greatly increased susceptibility to dental caries and infection of the oral mucosa and alveolar bone. Recently, subcapsular injection of cultured mouse salivary gland cells has achieved a significant degree of regeneration in a previously irradiated mouse salivary gland; however, the recovery was limited to one lobule. We describe here a method for delivering donor rat salivary gland cells via the main duct that distributes several thousand cells throughout the recipient rat's salivary gland. The donated cells exhibited the cytodifferentiation of the structures in which they lodged, i.e., acini, granular convoluted tubules, and the several types of ducts. This method may facilitate the simultaneous functional recovery of almost all of the lobules of irradiated rat salivary glands.

Salivary gland functional recovery after sialendoscopy.

OBJECTIVES/HYPOTHESIS: To date, there has been no report on the salivary gland functional outcomes after sialendoscopic surgery. The purpose of this study is to evaluate salivary gland functional recovery after sialendoscopic management of obstructive salivary gland disease. STUDY DESIGN: A prospective, self-control study. METHODS: The present study was undertaken among patients scheduled for sialendoscopic surgery with unilateral salivary ductal obstructions. Glandular function was quantitatively assessed with the use of sialometry and scintigraphy preoperatively and at least 3 months postoperatively. RESULTS: A consecutive series of 17 patients were followed for 14 +/- 8 months. Sialendoscopic procedures included removal of calculi in 15 cases and dilatation of stenosis in two cases. All patients were free of symptoms during follow-up. Before surgery, there was a significant decline in the resting and stimulated saliva flow rate, uptake index, and excretion fraction of the obstructive glands compared with the contralateral normal glands. Postoperatively, although the degrees of functional recovery varied in individuals, statistical analysis revealed that the glandular function increased significantly in the affected glands and had no differences when compared to the contralateral glands. CONCLUSIONS: These data provide a unique functional assessment after sialendoscopic surgery. Our results demonstrate that sialendoscopy is an organ-preserving surgical approach which can achieve satisfactory functional recovery in the management of salivary ductal obstructions.

Oral pilocarpine (5mg t.i.d.) used for xerostomia causes adverse effects in Japanese.

OBJECTIVE: To evaluate Japanese tolerability to pilocarpine of 5 mg t.i.d. METHODS: From January 2006 to July 2006, 39 patients with xerostomia received 5 mg t.i.d. pilocarpine for at least for 12 weeks unless they had experienced unacceptable adverse effects. All patients received radiotherapy that included the parotid glands in the radiation field >50 Gy. The body weights of the patients ranged from 42 to 73 kg (median 60 kg). RESULTS: Thirty-six of the 39 patients were evaluable. The tolerated rate was only 47%. Of the 25 patients whose body weights were less than 65 kg, the tolerated rate was 36%, whereas the rate of the 11 patients whose body weights were 65 kg or above was 72% (p=0.050). The most common adverse effect was sweating with an incidence of 64%. Response rate, which was defined as the total number of patients with an increase of at least 25 mm from the baseline in the VAS score divided by the number of maintaining patients among those who started pilocarpine after more than 4 months from the start of radiotherapy, was 40% at 12 weeks (n=15). CONCLUSION: For Japanese, 5mg t.i.d. pilocarpine caused a high incidence of unacceptable adverse effects. A lower dose of pilocarpine needs to be considered.