The Effect of Resveratrol on Radioiodine Therapy-Associated Lacrimal Gland Damage.

PURPOSE: We have evaluated the potential radioprotective, antioxidant and anti-apoptotic effects of resveratrol (RSV) against high-dose radioactive iodine (RAI) therapy associated damage of the lacrimal glands by biochemical, histopathological and immunohistochemical methods. MATERIALS AND METHODS: Thirty Wistar-albino rats were randomly divided into three groups; the control group received no treatment or medication, the RAI group received RAI but no medication and the RSV group received oral RAI and intraperitoneal RSV. RSV was started at day one, before RAI administration, and continued for 8 days. Bilateral intraorbital (IG), extraorbital (EG), and Harderian (HG) lacrimal glands were evaluated in all rats for histopathological, immunohistochemical, tissue cytokine and oxidant and antioxidant level assessment. RESULTS: RSV group restored inflammation, fibrosis, vacuolization, change in nucleus characteristics, lipofuscin-like accumulation and cellular morphologic patterns were statistically significant in all lacrimal gland types, compared to the RAI group (p < .05 for all variables). Similarly, elevated Caspase-3 and TUNEL levels in the RAI group were significantly alleviated in the RSV group in all lacrimal gland types (p < .05 for all variables). RAI administration significantly elevated TNF-α, IL-6, NF-кb levels, and decreased IL-10 levels (p < .05 for all parameters) whereas TOS levels significantly increased and TAS levels were significantly decreased. However, RSV significantly diminished TNF-α, IL-6, IL-4, and NF-кb levels. Furthermore, RSV significantly decreased TOS and increased TAS levels (p < .05 for all variables). CONCLUSIONS: We conclude that with its anti-cancer effect as well as its antioxidant effect RSV has protected the histopathological pattern of the lacrimal glands from the damage, decreased inflammation in histopathologic assessments, and decreased tissue cytokine levels, apoptosis and DNA fragmentation on the lacrimal glands after RAI.

Examining Absorbed Doses of Indigenously Developed 177Lu-PSMA-617 in Metastatic Castration-Resistant Prostate Cancer Patients at Baseline and During Course of Peptide Receptor Radioligand Therapy.

Aim: The objective of this study was to estimate the absorbed doses to the normal organs and tumor lesions in metastatic castration-resistant prostate cancer (mCRPC) patients treated with indigenously developed 177Lu-PSMA-617 that could establish optimal treatment protocol with minimum risk to the dose-limiting organs. Furthermore, attempt was also made to compare radiation absorbed doses for normal organs and tumor lesions in subsequent cycles of 177Lu-PSMA-617 peptide receptor radioligand therapy (PRLT) in the same group of patients during the course of treatment. Methods: A total of 30 patients of proven mCRPC were enrolled for this prospective study. These patients received up to 5 cycles of treatment with 177Lu-PSMA-617 PRLT (1 cycle for 13 patients, 2 cycles for 9 patients, 3 cycles for 3 patients, and 5 cycles for 5 patients), at 11-12-week intervals between the two successive therapies. The patients underwent postadministration whole-body scintigraphy at five time points: 0.5 (prevoid), 2, 12, 24, and 72/96 h (postvoid). From time-activity curves generated by drawing regions of interests on the images, number of disintegrations was determined. Tumor masses were estimated from pretherapeutic 68Ga-PSMA-11 positron emission tomography-computed tomography images. Absorbed doses for organs and tumors were calculated using OLINDA 2.0 software. Results: The average activity of 177Lu-PSMA-617 (mean ± SD) administered per patient per cycle was 4.94 ± 0.45 GBq. The mean absorbed organ doses (mean ± SD) from first therapy cycle in Gy/GBq were as follows: kidneys 0.52 ± 0.16, spleen 0.17 ± 0.07, liver 0.08 ± 0.05, salivary glands 0.53 ± 0.30, lacrimal glands 1.45 ± 0.85, nasal mucosa membrane 0.46 ± 0.19, urinary bladder 0.23 ± 0.02, and bone marrow 0.04 ± 0.03. The mean effective dose for whole body from first therapy cycle was 0.05 ± 0.03 Sv/GBq. Among all the normal organs, lacrimal glands received the highest absorbed dose. The median dose for all lesions, bone lesions, lymph nodes, primary site, liver lesion, lung lesion, and soft tissue deposit from first therapy cycle was determined to be 4.17, 4.23, 3.96, 4.36, 10.27, 0.78, and 4.68 Gy/GBq respectively. Absorbed doses received by the normal organs in five consecutive cycles follow three different trends, (a) for kidneys, salivary glands, and nasal mucous membrane, absorbed doses increased from first therapy cycle to second therapy cycle and then slowly decreased in subsequently therapy cycles; (b) for spleen, liver, and lacrimal glands, absorbed doses decreased with the successive therapy cycles; and (c) in case of bone marrow, bladder, and whole body, mean absorbed dose almost remained constant in each therapy cycle. Absorbed doses to the lesions gradually decreased with increase of the number of therapy cycles. Conclusions: The organ and tumor absorbed doses of 177Lu-PSMA-617 in mCRPC patients were found to be comparable to the data reported in the literature. The highest absorbed organ dose was observed in lacrimal glands and being a dose limiting organ, a cumulative activity up to 32.5 GBq (878 mCi) of 177Lu-PSMA-617 in 4-5 therapy cycles appears safe and feasible to achieve full therapeutic window.

Radioprotective effect of montelukast sodium in rat lacrimal glands after radioiodine treatment.

PURPOSE: The aim of this study was to evaluate the morphological changes of rat lacrimal glands at the third month following radioiodine (RAI) treatment and the radioprotective effect of montelukast (ML) sodium against RAI-related lacrimal gland damage. METHODS: Fifty female Wistar Albino rats were divided into three groups. The control group (n=10) consisted of rats with no intervention. RAI group (n=20) consisted of rats treated with oral (131)I (111 MBq). The ML group (n=20) consisted of rats treated with intraperitoneal 10mg/kg/day ML sodium, starting three days before and continuing for one week after oral RAI administration. Intraorbital (IG), extraorbital (EG) and Harderian glands (HG) were removed bilaterally after three months. RESULTS: The existence of acinar atrophy, acinar fibrosis, abnormal cell lines, peripheral basophilia, cell size variation and decrease in amount of cytoplasm was significantly more common in the RAI-rat treated group than in the ML group, in each of the glands. The ML-treated group had less-frequent cell shape variation in EG (P=0.001) and HG (P=0.027), cell size variation in IG (P<0.001) and HG (P=0.01), ductal pathology in EG (P<0.001) and HG (P<0.001) and lipofuscin accumulation in EG (P=0.001) and in HG (P=0.01) than the RAI-treated group. CONCLUSIONS: RAI treatment seems to cause morphological damage to rat lacrimal glands, and ML sodium effectively protects against damage to lacrimal glands.

The effect of high-dose radioiodine treatment on lacrimal gland function in patients with differentiated thyroid carcinoma.

PURPOSE: There are a limited number of case reports confirming the radioiodine (I-131) presence in tears and only a few case reports of lacrimal gland dysfunction after I-131 therapy. This study was designed to clarify whether lacrimal gland function can be affected by I-131 therapy. MATERIALS AND METHODS: We studied 100 eyes of 50 patients who had received high doses of I-131 for treatment of differentiated thyroid carcinoma and 100 eyes of 50 age- and sex-matched control individuals without a history of interfering conditions. The exposed group was studied at least 3 months after their last I-131 therapy. Dry eye symptoms and Schirmer test values (wetting level in millimeters per 5 minutes) of an exposed group were compared with those of an unexposed group. RESULTS: Fifty-one percent of the exposed eyes and 50% of the unexposed ones revealed at least 1 of the dry eye symptoms. There was no significant difference in symptoms between 2 groups, except for burning sensation and eye redness, which were significantly higher in the exposed eyes. A lower Schirmer test value was noted in the exposed group, 14.5 +/- 10.8 mm, when compared with that in controls, 18.2 +/- 11.0 mm (P = 0.016), and the relative risk of an abnormal Schirmer test in exposed cases to control group was 1.78 +/- 0.62. Correlation coefficient analysis showed no significant relationship between Schirmer test values and cumulative doses of administered I-131. CONCLUSIONS: Reduction in the tear secretion from lacrimal glands is seen after high-dose I-131 therapy; however, their symptoms are no greater than an unexposed population.

Expression of sodium iodide symporter in the lacrimal drainage system: implication for the mechanism underlying nasolacrimal duct obstruction in I(131)-treated patients.

PURPOSE: Nasolacrimal outflow obstruction has been associated with high-dose (>150 mCi) radioactive iodine (I(131)) treatment. Commonly used for thyroid cancer treatment, I(131) is effectively transported in the targeted tissue by the Na(+)/I symporter (NIS). We hypothesized that NIS is expressed in the lacrimal sac and nasolacrimal duct and that active accumulation of I(131) is responsible for the clinical observations seen in these patients. METHODS: Reverse transcriptase-polymerase chain reaction and immunohistochemical analyses were used to evaluate NIS expression in both archived and fresh human tissues RESULTS: Reverse transcriptase-polymerase chain reaction analysis showed that NIS mRNA is present in the lacrimal sac. Immunohistochemical analysis indicated that NIS protein is expressed in the stratified columnar epithelial cells of the lacrimal sac and nasolacrimal duct. NIS protein was undetectable in the lacrimal gland, Wolfring and Krause glands, conjunctiva, canaliculus, and nasal mucosa. NIS-expressing columnar epithelial cells were absent and fibrosis was evident in the lacrimal sacs from I(131)-treated patients undergoing dacryocystorhinostomy. CONCLUSIONS: NIS is present in the lacrimal sac and nasolacrimal duct of humans, correlating to the anatomic areas of clinical obstruction that develop in patients treated with greater than 150 mCi of I(131). This suggests that NIS may be the vector of radiation-induced injury to the lacrimal system. To our knowledge, this is the first report of any ion transporter in the nasolacrimal outflow system and raises new questions as to the role the lacrimal sac plays in the modification of tears and in lacrimal outflow pathology.

Long-term impairment of the lacrimal glands after radioiodine therapy: a cross-sectional study.

Impairment of the lacrimal glands after external radiation has been well documented, but there are only a few reports on the effects of radioiodine therapy on the lacrimal glands. Long-term effects of high-dose radioiodine therapy on tear secretion have not previously been studied. We investigated 175 eyes of 88 patients with a history of radioiodine therapy for thyroid carcinoma (68 females, 20 males; mean age 55+/-16 years, range 17-81 years) and compared them with a sex- and age-matched control group ( n=39). All patients had been given at least 2.96 GBq iodine-131 (maximal administered activity 22.3 GBq (131)I). An ophthalmological investigation was performed 64+/-71 months (range 3-317 months) after initial radioiodine therapy by a single ophthalmologist. Lacrimal gland function was evaluated with three different function tests. External eye morphology was considered, and detailed ophthalmological history-taking was performed. Patients with factors known to affect lacrimal gland function (contact lenses, autoimmune disorders, history of additional radiation exposure) were excluded from the study. A total of 81 patients (92%) had at least one abnormal function test indicating impaired lacrimal gland function. Schirmer's tear test was decreased (<10 mm/5 min) in 47 of the 88 patients and definitely abnormal (<5 mm/5 min) in 35 patients. A tear film break-up time of <10 s was found in 78 patients, and 62 patients had a definitely abnormal break-up time of <5 s. The lacrimal lipid layer was impaired in 43 patients. The function tests were all significantly altered in the study group as compared with the controls ( P<0.005, P<0.001, P<0.001, respectively). Both subjective symptoms of dry eye ( P<0.01) and changes in the external eye morphology ( P<0.001) were significantly more prevalent in the study group. Our findings suggest that in the majority of patients, lacrimal gland function may be permanently impaired after high-dose radioiodine therapy. All three layers of the tear film are involved and there is a pronounced long-term effect on the tear film stability.

Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy.

UNLABELLED: Salivary gland dysfunction has been described in patients undergoing radioiodine therapy but associated lacrimal gland dysfunction (sicca syndrome) has never been reported. We conducted a prospective cohort study with follow-up for up to 3 y in a tertiary care university center to determine the prevalence of sicca syndrome in patients after high-dose radioiodine treatment. METHODS: From January 1990 to December 1995, all patients undergoing radioiodine therapy (n = 79) with a standard dose of 925 MBq to 18.5 GBq (25-500 mCi) were interviewed using a standardized questionnaire to determine subjective ocular and oral dryness and were examined for objective lacrimal and salivary gland dysfunction. RESULTS: After radioiodine treatment, 32.9% of the patients reported subjective xerostomia and 25.3% reported subjective xerophthalmia in the first year of follow-up. Xerostomia persisted to the second year of follow-up in 20.3% of cases and was still present >3 y after the last dose of radioiodine in 15.2% of cases. Xerophthalmia persisted to the second year of follow-up in 17.7% of cases and was still present in the third year of follow-up in 13.9% of cases. Severe xerostomia occurred in 4 patients. Reduced salivary and lacrimal gland function was documented in 40 (50.6%) and 14 (17.7%) of the 79 cases, respectively, in the first year of follow-up. Objective xerostomia persisted in 13.9% of cases to the second year of follow-up and was still present in all patients >3 y after the last radioiodine application. Keratoconjunctivitis sicca persisted in 11 patients (13.9%) to the second year of follow-up but was only present in 6 patients (7.6%) >3 y after the last radioiodine application. Additionally, 28/79 patients (35.4%) who had a normal salivary gland scintigraphy previously showed reduced salivary gland function in the third year of follow-up. No significant dependence on cumulative treatment was found for objective xerostomia or xerophthalmia, but doses >11.1 GBq (300 mCi) were related to stage 3 dysfunction on salivary gland scintigraphy. CONCLUSION: Salivary and lacrimal gland dysfunction (sicca syndrome) is relatively frequent after radioiodine therapy. In most cases this is a transient side effect, but in some patients it may persist for a long period or appear late.