Optimum dose range for the amelioration of long term radiation-induced hyposalivation using prophylactic pilocarpine treatment.

BACKGROUND: To determine dose and time dependency of pilocarpine pre-treatment protection from late damage after unilateral irradiation of the rat parotid gland. METHODS AND MATERIALS: The right parotid gland of saline (1mg/ml) or pilocarpine (4 mg/kg) pre-treated rats was irradiated with 10, 15 and 20 Gy. Saliva was collected from the irradiated and shielded parotid before, 30, 60, 120 and 240 days after irradiation. The number of acinar cells/gland was determined 30, 120 and 240 days after irradiation by histological examination. RESULTS: Pilocarpine pre-treated rats, protection of parotid gland function was seen in the early-intermediate phase (0-120 days) after 15 Gy and in the late phase (>120 days) after 10 and 15 Gy. Although no protection was observed after 20 Gy, a stimulatory effect of pilocarpine on the non-irradiated gland resulted in a significant increase in total saliva secretion. The increase in function after pilocarpine treatment was paralleled by a significant increase in the number of acinar cells in both the irradiated and shielded glands. CONCLUSIONS: Pre-irradiation treatment with pilocarpine induces compensatory response, at lower doses, in the irradiated and at higher doses in the non-irradiated gland reducing late damage, due to stimulation of unirradiated or surviving cells to divide.     

Comparison of radiosensitivity of rat parotid and submandibular glands after different radiation schedules.

BACKGROUND AND PURPOSE: To investigate the radiosensitivity of rat parotid and submandibular gland functioning after local single dose, conventional fractionated and accelerated fractionated irradiation. METHODS: The salivary glands of male albino Wistar rats were locally irradiated with a single dose (15 Gy) or a calculated (alpha/beta; 9.6) biological effective dose of fractionated irradiation equal to this, viz. conventional fractionation (32 Gy in 16 fractions of 2 Gy/day, five times/week) or accelerated fractionation (32 Gy in 16 fractions of 2 Gy, two fractions/day). Parotid and submandibular/sublingual saliva samples were collected by means of miniaturized Lashley cups before and up to 240 days after irradiation. Salivary flow rate, lag phase and amylase secretion were used as parameters for the assessment of salivary gland function. At the end of the experiments the animals were sacrificed and the glands processed for histopathological examination. RESULTS: Up to 120 days after irradiation no differences were observed between the glands or between the different irradiation schedules. Beyond 120 days, however, the parotid gland performed better in flow rate and lag phase after fractionated irradiation, when compared to the submandibular gland. The observed differences in function corresponded with the observed late histopathological changes. The parotid gland contained more acinar cells and had a higher gland weight. No differences were observed between both fractionation schedules on each gland. CONCLUSIONS: The main observation from this study is the higher radiosensitivity of the submandibular gland compared to the parotid gland for late effects after fractionated irradiation. This may have implications for the treatment planning in case of radiotherapy for head and neck cancer.     

Structural and functional characteristics of irradiation damage to parotid glands in the miniature pig

PURPOSE: To evaluate the effects of a solitary megadose protocol of ionizing radiation (IR) on the structure and function of the miniature pig (minipig) parotid gland. METHODS AND MATERIALS: Fourteen minipigs were subjected to either 15 or 20 Gy to one parotid gland with a linear accelerator, whereas another four minipigs served as non-IR controls. Salivary flow rates and salivary chemistries were measured pre-IR and 4 and 16 weeks post-IR. A quantitative assessment of gland weight and acinar area and detailed serum chemistry and hematologic analyses were also performed. RESULTS: Parotid flow rates decreased by approximately 50% either with 20 Gy at 4 weeks, or 15 Gy at 16 weeks post-IR. In the 20 Gy group, salivary flow rates were reduced by approximately 80% at 16 weeks post-IR. A significant decrease in salivary calcium and amylase and an increase of salivary potassium levels were found in both IR groups. There were also transient alterations in serum chemistry and hematology parameters post-IR. Parotid gland weights were significantly decreased (-50%) in the 15 and 20 Gy groups at 4 and 16 weeks post-IR. Additionally, the acinar cell area in glands of both IR groups was significantly reduced from that in control glands at both the 4 and 16 weeks time points. CONCLUSION: Structural changes in salivary gland parenchyma occurred relatively early after IR, whereas the alterations in salivary output were relatively delayed. Further, reductions in salivary flow were not proportional to acinar cell area loss. Together, these findings suggest that nonparenchymal IR damage likely contributes to IR-induced salivary hypofunction.     

On the mechanism of salivary gland radiosensitivity

PURPOSE: To contribute to the understanding of the enigmatic radiosensitivity of the salivary glands by analysis of appropriate literature, especially with respect to mechanisms of action of early radiation damage, and to supply information on the possibilities of amelioration of radiation damage to the salivary glands after radiotherapy of head-and-neck cancer. METHODS AND MATERIALS: Selected published data on the mechanism of salivary gland radiosensitivity and radioprotection were studied and analyzed. RESULTS: From a classical point of view, the salivary glands should not respond as rapidly to radiation as they appear to do. Next to the suggestion of massive apoptosis, the leakage of granules and subsequent lysis of acinar cells was suggested to be responsible for the acute radiation-induced function loss of the salivary glands. The main problem with these hypotheses is that recently performed assays show no cell loss during the first days after irradiation, while saliva flow is dramatically diminished. The water secretion is selectively hampered during the first days after single-dose irradiation. Literature is discussed that shows that the compromised cells suffer selective radiation damage to the plasma membrane, disturbing signal transduction primarily affecting watery secretion. Although the cellular composition of the submandibular gland and the parotid gland are different, the damage response is very alike. The acute radiation-induced function loss in both salivary glands can be ameliorated by prophylactic treatment with specific receptor agonists. CONCLUSIONS: The most probable mechanism of action, explaining the enigmatic high radiosensitivity for early effects, is selective radiation damage to the plasma membrane of the secretory cells, disturbing muscarinic receptor stimulated watery secretion. Later damage is mainly due to classical mitotic cell death of progenitor cells, leading to a hampered replacement capacity of the gland for secretory cells, but is also caused by damage to the extracellular environment, preventing proper cell functioning.     

Increase in mast cells and hyaluronic acid correlates to radiation-induced damage and loss of serous acinar cells in salivary glands: the parotid and submandibular glands differ in radiation sensitivity.

The detailed mechanisms which can explain the inherent radiosensitivity of salivary glands remain to be elucidated. Although DNA is the most plausible critical target for the lethal effects of irradiation, interactions with other constituents, such as cell membrane and neuropeptides, have been suggested to cause important physiological changes. Moreover, mast cells seem to be closely linked to radiation-induced pneumonitis. Therefore, in the present study the effects of fractionated irradiation on salivary glands have been assessed with special regard to the appearance of mast cells and its correlation with damage to gland parenchyma. Sprague-Dawley strain rats were unilaterally irradiated to the head and neck with the salivary glands within the radiation field. The irradiation was delivered once daily for 5 days to a total dose of 20, 35 and 45 Gy. The contralateral parotid and submandibular glands served as intra-animal controls and parallel analysis of glands was performed 2, 4, 10 or 180 days following the last radiation treatment. Morphological analysis revealed no obvious changes up to 10 days after the irradiation. At 180 days a radiation dose-dependent loss of gland parenchyma was seen, especially with regard to serious acinar cells in parotid gland and acinar cells and serous CGT (convoluted granular tubule) cells in the submandibular gland. These changes displayed a close correlation with a concomitant dose-dependent enhanced density of mast cells and staining for hyaluronic acid. This cell population seems to conform with the features of the connective tissue mast cell type. The parotid seems to be more sensitive to irradiation than the submandibular gland. Thus, the present results further strengthen the role of and the potential interaction of mast cells with radiation-induced tissue injury and alterations in normal tissue integrity.     

鼻中隔涎腺腺泡细胞癌1例

涎腺腺泡细胞癌是一种临床上少见的低度恶性肿瘤,多发生于腮腺、颌下腺、舌下腺及小唾液腺等涎腺。发生于鼻中隔的极为罕见,本文报道一例近期发现的位于鼻中隔的涎腺腺泡细胞癌。     

Changes in serum and salivary amylase during radiotherapy for head and neck cancer: a comparison of conventionally fractionated radiotherapy with CHART.

The changes in serum amylase that occur when radiotherapy is given in the treatment of head and neck cancer has been studied in 41 patients, 29 treated by CHART and 12 by conventionally fractionated radiotherapy. The peak rise in serum amylase following the start of treatment is seen earlier and is greater in the patients receiving continuous hyperfractionated accelerated radiotherapy (CHART). The serum amylase returns to normal earlier in the CHART patients so that the area under the curve is the same for both groups. The difference probably reflects the more rapid delivery of treatment to the patients receiving CHART. A close correlation between the peak rise in serum amylase and the amount of parotid tissue in the treatment volume is demonstrated. For six patients the total amount of amylase secreted by the parotid gland during CHART was measured and found to decline rapidly within a few days of the start of radiotherapy. The rise in serum amylase that results from the irradiation of salivary tissue provides a unique biochemical measure of an early radiation effect in a normal tissue. This probably reflects the interphase cell death of serous salivary cells. Although these immediate changes are of considerable interest they may not relate to the late effects of radiation on salivary gland function.     

Preservation of the rat parotid gland function after radiation by prophylactic pilocarpine treatment: radiation dose dependency and compensatory mechanisms.

PURPOSE: To study the ability of a prophylactic pilocarpine administration to preserve the rat parotid gland function after unilateral irradiation with graded doses of X-rays. METHODS: The right parotid gland of male albino Wistar rats was irradiated with single doses of X-rays (10-30 Gy, at 1.5 Gy min(-1)). Pilocarpine (4 mg/kg) was administered intraperitoneally, 1 hour prior to irradiation. Saliva samples of both left and right parotid gland were collected by means of miniaturized Lashley cups 4 days before and 3, 7, 10, and 30 days after irradiation. The parotid salivary flow rate (microl/min) was used as a parameter for the assessment of parotid gland function. RESULTS: Our data confirm that a single prophylactic treatment of pilocarpine can attenuate radiation-induced loss of gland function. Surprisingly, the effect of pilocarpine was not restricted to the irradiated gland only. Pilocarpine also enhanced the flow rate in the contralateral, nonirradiated gland. The latter effect was found for all doses above 10 Gy and became apparent around 7 days after the radiation treatment. The effectiveness of pilocarpine to attenuate function loss in the irradiated gland decreased with increasing dose and was lost after single doses of 30 Gy. CONCLUSIONS: Our data provide direct evidence that increasing the compensatory potential of the nondamaged gland, at least in part, underlies the "radioprotective effect" of pilocarpine in case of unilateral radiation. The ability of pilocarpine to ameliorate the early radiation-induced impairment of the parotid gland function in the irradiated gland may therefore be dependent on the remaining number of functional cells, and thus on the volume of the gland that lies within the radiation portal.     

Recurrent malignant salivary gland neoplasms

Recurrent salivary gland malignancies present difficult therapeutic decisions and poor prognosis in many instances, and treatment becomes of a palliative nature only. As many of the salivary gland malignancies we see are of the recurrent type, the following study was done to determine the efficacy of a vigorous attempt at retreatment. During the period January 1, 1960, through December 31, 1984, 352 patients with major and minor salivary gland tumors were evaluated at our institution. There were 149 benign lesions and 203 patients with malignant tumors. Of these, 99 patients had recurrent and metastatic tumors that had been treated initially elsewhere. Thirty-three of these patients were able to be treated with curative intent: surgery, 21; surgery plus radiation, 9; radiation therapy alone, 2; and radiation plus chemotherapy, 1. The 5 year survival with no evidence of disease was achieved in three patients with surgery alone and two patients with surgery plus radiation therapy. The group of five patients was comprised of two patients with adenoid cystic carcinomas of the parotid, one with intermediate grade mucoepidermoid carcinoma of the parotid, one, sebaceous cell carcinoma of the parotid, and one, adenoid cystic carcinoma of an accessory salivary gland. The results of this study serve to re-emphasize the relative poor yield of attempts at retreatment of loco-regional recurrence of salivary gland tumors.