ABSTRACT
BACKGROUND AND PURPOSE: Recently, a comprehensive xerostomia prediction model was published, based on baseline xerostomia, mean dose to parotid glands (PG) and submandibular glands (SMG). Previously, PET imaging biomarkers (IBMs) of PG were shown to improve xerostomia prediction. Therefore, this study aimed to explore the potential improvement of the additional PET-IBMs from both PG and SMG to the recent comprehensive xerostomia prediction model (i.e., the reference model). MATERIALS AND METHODS: Totally, 540 head and neck cancer patients were split into training and validation cohorts. PET-IBMs from the PG and SMG, were selected using bootstrapped forward selection based on the reference model. The IBMs from both the PG and SMG with the highest selection frequency were added to the reference model, resulting in a PG-IBM model and a SMG-IBM model which were combined into a composite model. Model performance was assessed using the area under the curve (AUC). Likelihood ratio test compared the predictive performance between the reference model and models including IBMs. RESULTS: The final selected PET-IBMs were 90th percentile of the PG SUV and total energy of the SMG SUV. The additional two PET-IBMs in the composite model improved the predictive performance of the reference model significantly. The AUC of the reference model and the composite model were 0.67 and 0.69 in the training cohort, and 0.71 and 0.73 in the validation cohort, respectively. CONCLUSION: The composite model including two additional PET-IBMs from PG and SMG improved the predictive performance of the reference xerostomia model significantly, facilitating a more personalized prediction approach.
Subject(s)
Fluorodeoxyglucose F18 , Head and Neck Neoplasms , Positron-Emission Tomography , Xerostomia , Humans , Head and Neck Neoplasms/diagnostic imaging , Female , Male , Middle Aged , Xerostomia/diagnostic imaging , Xerostomia/etiology , Positron-Emission Tomography/methods , Radiopharmaceuticals , Aged , Adult , Submandibular Gland/diagnostic imaging , Parotid Gland/diagnostic imaging , Salivary Glands/diagnostic imagingABSTRACT
BACKGROUND: This study aimed to investigate the homogeneity of the major salivary glands in multiple sclerosis (MS) patients using ultrasonography (USG), assess DMFT indices, measure resting salivary flow rates, and compare these values with healthy individuals. METHODS: In this study, 20 individuals diagnosed with Relapsing-Remitting Multiple Sclerosis (RRMS) (mean age 36.15 ± 8.51) and 20 systemically healthy individuals (mean age 35.7 ± 9.22) were included. Oral and radiologic examinations were performed in all individuals. The parotid and submandibular salivary glands were examined using USG, and their homogeneity was assessed based on the scoring system recommended by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) study group. Resting salivary flow rates and DMFT indices were measured, and the obtained data were subjected to statistical analysis. RESULTS: The parotid glands exhibited more heterogeneity on USG within the MS patient group than the control group, with a statistically significant difference between the two groups (p = 0.015). A statistically significant correlation was observed in total homogeneity values between the patient and control groups (p = 0.021). Furthermore, the MS patient group exhibited higher DMFT indices and lower salivary flow rates than the control group. The difference between the DMFT indices and salivary flow rate between the patient groups was statistically significant (p = 0.004 and p = 0.002 respectively). CONCLUSIONS: The parenchyma of the major salivary glands in MS patients exhibited decreased homogeneity than the healthy controls. Additionally, the MS group showed a decrease in salivary flow rate and an increase in the DMFT index. Autonomic dysfunction and medications used for MS are thought to cause salivary gland hypofunction and dry mouth. It can be interpreted that hyposalivation and motor skill losses in MS patients lead to an increase in DMFT index.
Subject(s)
Multiple Sclerosis , Sjogren's Syndrome , Xerostomia , Humans , Adult , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/complications , Salivary Glands/diagnostic imaging , Xerostomia/diagnostic imaging , Xerostomia/etiology , Parotid Gland/diagnostic imaging , Ultrasonography/adverse effects , Sjogren's Syndrome/complicationsABSTRACT
OBJECTIVE: To assess the construct validity of the novel Outcome Measures in Rheumatology (OMERACT) ultrasound (US) semiquantitative scoring system for morphological lesions in major salivary glands by comparing it with magnetic resonance imaging (MRI) and unstimulated whole salivary flow rates (U-WSFRs) in patients with primary Sjögren syndrome (pSS). METHODS: Nine sonographers applied the OMERACT 0-3 grayscale scoring system for parotid (PGs) and submandibular glands (SMGs) in 11 patients with pSS who also had MRIs performed. These were evaluated by 2 radiologists using a semiquantitative 0-3 scoring system for morphological lesions. The agreement between US and MRI and the association between U-WSFRs and imaging structural lesions was determined. A score ≥ 2 for both US and MRI was defined as gland pathology. RESULTS: The prevalence of US morphological lesions in 11 patients with a score ≥ 2 was 58% for PGs and 76% for SMGs, and 46% and 41% for PGs and SMGs, respectively, for MRI. The agreement between OMERACT US scores and MRI scores was 73-91% (median 82%) in the right PG and 73-91% (median 91%) in the left PG, 55-91% (median 55%) in the right SMG and 55-82% (median 55%) in the left SMG. When relations between the presence of hyposalivation and an US score ≥ 2 were examined, agreement was 91-100% (median 83%) in both PGs and 55-91% (median 67%) in both SMGs. CONCLUSION: There is moderate to strong agreement between the OMERACT US and MRI scores for major salivary glands in patients with pSS. Similar agreement ratios were observed between the higher OMERACT US scores and presence of hyposalivation.
Subject(s)
Sjogren's Syndrome , Xerostomia , Humans , Sjogren's Syndrome/diagnostic imaging , Salivary Glands/diagnostic imaging , Ultrasonography , Xerostomia/diagnostic imaging , Magnetic Resonance ImagingABSTRACT
BACKGROUND: The aim of this study was to measure functional changes in parotid glands using mid-treatment FDG-PET/CT and correlate early imaging changes to subsequent xerostomia in mucosal head and neck squamous cell carcinoma patients undergoing radiotherapy. MATERIALS AND METHODS: 56 patients from two prospective imaging biomarker studies underwent FDG-PET/CT at baseline and during radiotherapy (week 3). Both parotid glands were volumetrically delineated at each time point. PET parameter SUVmedian were calculated for ipsilateral and contralateral parotid glands. Absolute and relative change (Δ) in SUVmedian were correlated to moderate-severe xerostomia (CTCAE grade ≥ 2) at 6 months. Four predictive models were subsequently created using multivariate logistic regression using clinical and radiotherapy planning parameters. Model performance was calculated using ROC analysis and compared using Akaike information criterion (AIC) RESULTS: 29 patients (51.8%) developed grade ≥ 2 xerostomia. Compared to baseline, there was an increase in SUVmedian at week 3 in ipsilateral (8.4%) and contralateral (5.5%) parotid glands. Increase in ipsilateral parotid Δ SUVmedian (p = 0.04) and contralateral mean parotid dose (p = 0.04) were correlated to xerostomia. The reference 'clinical' model correlated to xerostomia (AUC 0.667, AIC 70.9). Addition of ipsilateral parotid Δ SUVmedian to the clinical model resulted in the highest correlation to xerostomia (AUC 0.777, AIC 65.4). CONCLUSION: Our study shows functional changes occurring in the parotid gland early during radiotherapy. We demonstrate that integration of baseline and mid-treatment FDG-PET/CT changes in the parotid gland with clinical factors has the potential to improve xerostomia risk prediction which could be utilised for personalised head and neck radiotherapy.
Subject(s)
Head and Neck Neoplasms , Radiation Injuries , Xerostomia , Humans , Fluorodeoxyglucose F18 , Radiotherapy Dosage , Parotid Gland/diagnostic imaging , Parotid Gland/pathology , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/pathology , Prospective Studies , Positron Emission Tomography Computed Tomography , Xerostomia/diagnostic imaging , Xerostomia/etiology , Xerostomia/pathology , Radiation Injuries/pathology , Positron-Emission TomographyABSTRACT
The incidence of head and neck cancers (HNC) is rising worldwide especially with HPV-related oropharynx squamous cell carcinoma. The standard of care for the majority of patients with locally advanced pharyngeal disease is curative-intent radiotherapy (RT) with or without concurrent chemotherapy. RT-related toxicities remain a concern due to the close proximity of critical structures to the tumour, with xerostomia inflicting the most quality-of-life burden. Thus, there is a paradigm shift towards research exploring the use of imaging biomarkers in predicting treatment outcomes. Diffusion-weighted imaging (DWI) is a functional MRI feature of interest, as it quantifies cellular changes through computation of apparent diffusion coefficient (ADC) values. DWI has been used in differentiating HNC lesions from benign tissues, and ADC analyses can be done to evaluate tumour responses to RT. It is also useful in healthy tissues to identify the heterogeneity and physiological changes of salivary glands to better understand the inter-individual differences in xerostomia severity. Additionally, DWI is utilised in irradiated salivary glands to produce ADC changes that correlate to clinical xerostomia. The implementation of DWI into multi-modal imaging can help form prognostic models that identify patients at risk of severe xerostomia, and thus guide timely interventions to mitigate these toxicities.
Subject(s)
Head and Neck Neoplasms , Radiation Injuries , Xerostomia , Humans , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/complications , Xerostomia/diagnostic imaging , Xerostomia/etiology , Salivary Glands , Diffusion Magnetic Resonance Imaging/methods , Magnetic Resonance Imaging , Radiation Injuries/etiology , Radiation Injuries/complicationsABSTRACT
BACKGROUND AND PURPOSE: Previously, PET image biomarkers (PET-IBMs) - the 90th percentile standardized uptake value (P90-SUV) and the Mean SUV (Mean-SUV) of the contralateral parotid gland (cPG) - were identified as predictors for late-xerostomia following head and neck cancer (HNC) radiotherapy. The aim of the current study was to assess in an independent validation cohort whether these pre-treatment PET-IBM can improve late-xerostomia prediction compared to the prediction with baseline xerostomia and mean cPG dose alone. MATERIALS AND METHODS: The prediction endpoint was patient-rated moderate-to-severe xerostomia at 12 months after radiotherapy. The PET-IBMs were extracted from pre-treatment 18 F-FDG PET images. The performance of the model (base model) with baseline xerostomia and mean cPG dose alone and models with additionally P90-SUV or Mean-SUV were tested in the current independent validation cohort. Specifically, model discrimination (area under the curve: AUC) and calibration (calibration plot) were evaluated. RESULTS: The current validation cohort consisted of 137 patients of which 40% developed moderate-to-severe xerostomia at 12 months. Both the PET-P90 model (AUC:PET-P90 = 0.71) and the PET-Mean model (AUC: PET-Mean = 0.70) performed well in the current validation cohort. Moreover, their performance were improved compared to the base model (AUC:base model= 0.68). The calibration plots showed a good fit of the prediction to the actual rates for all tested models. CONCLUSION: PET-IBMs showed an improved prediction of late-xerostomia when added to the base model in this validation cohort. This contributed to the published hypothesis that PET-IBMs include individualized information and can serve as a pre-treatment risk factor for late-xerostomia.
Subject(s)
Head and Neck Neoplasms , Xerostomia , Humans , Fluorodeoxyglucose F18 , Xerostomia/diagnostic imaging , Xerostomia/etiology , Head and Neck Neoplasms/radiotherapy , Biomarkers , Parotid Gland , Positron-Emission TomographyABSTRACT
Xerostomia is a common side effect of radiation therapy (RT) in patients with head and neck cancer. However, limited information is available on the temporal dynamics of parenchymal and vascular changes in salivary glands following RT. To address this gap in knowledge, we conducted experimental studies in mice employing ultrasound (US) with coregistered photoacoustic imaging (PAI) to noninvasively assess the early and late changes in salivary gland size, structure, vascularity, and oxygenation dynamics following RT. Multiparametric US-PAI of salivary glands was performed in immune-deficient and immune-competent mice before and after RT along with correlative sialometry and ex vivo histologic-immunohistochemical validation. US revealed reduction in gland volume and an early increase in vascular resistance postradiation. This was accompanied by a reduction in glandular oxygen consumption on PAI. Imaging data correlated strongly with salivary secretion and histologic evidence of acinar damage. The magnitude and kinetics of radiation response were impacted by host immune status, with immunodeficient mice showing early and more pronounced vascular injury and DNA damage response compared to immunocompetent animals. Our findings demonstrate the ability of noninvasive US-PAI to monitor dynamic changes in salivary gland hemodynamics following radiation and highlight the impact of the host immune status on salivary gland radiation injury.
Subject(s)
Head and Neck Neoplasms , Radiation Injuries , Vascular System Injuries , Xerostomia , Animals , Mice , Salivary Glands/diagnostic imaging , Salivary Glands/radiation effects , Xerostomia/diagnostic imaging , Xerostomia/etiology , Parotid GlandABSTRACT
BACKGROUND AND PURPOSE: Xerostomia remains a common side effect of radiotherapy (RT) for patients with head and neck (H&N) cancer despite advancements in treatment planning and delivery. Secretory salivary gland cells express the prostate-specific membrane antigen (PSMA), and show significant uptake on PET scans using 68Ga/18F-PSMA-ligands. We aimed to objectively quantify the dose-response of salivary glands to RT using PSMA PET. METHODS AND MATERIALS: 28H&N cancer patients received RT with 70 Gy in 35 fractions over 7 weeks. PSMA PET/CT was acquired at baseline (BL), during treatment (DT) and at 1-&6-months post-treatment (PT1M/PT6M). Dose, BL- PT1M- and PT6M-SUV were extracted for every voxel inside each parotid (PG) and submandibular (SMG) gland. The PT1M/6M data was analysed using a generalised linear mixed effects model.Patient-reported xerostomia and DT-PSMA loss was also analysed. RESULTS: Dose had a relative effect on BL SUV. For a population average gland (BL-SUV of 10), every 1 Gy increment, decreased the PT1M/PT6M-SUV by 1.6 %/1.6 % for PGs and by 0.9 %/1.8 % for SMGs. TD50 of the population curves was 26.5/31.3 Gy for PGs, and 22.9/27.8 Gy for SMGs at PT1M /PT6M. PSMA loss correlated well with patient-reported xerostomia at DT/PT1M (Spearman's ρ = -0.64, -0.50). CONCLUSION: A strong relationship was demonstrated between radiation dose and loss of secretory cells in salivary glands derived using PSMA PET/CT. The population curve could potentially be used as a dose planning objective, by maximising the predicted post-treatment SUV. BL scans could be used to further tailor this to individual patients.
Subject(s)
Head and Neck Neoplasms , Xerostomia , Male , Humans , Positron Emission Tomography Computed Tomography , Salivary Glands/diagnostic imaging , Xerostomia/diagnostic imaging , Xerostomia/etiology , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/radiotherapy , Head and Neck Neoplasms/metabolism , Positron-Emission TomographyABSTRACT
INTRODUCTION: This study examined whether time-activity curves (TAC) can be used to differentiate between patients with and without Sjögren's syndrome using SPECT/CT. METHODS: Thirteen xerostomia patients (5 with Sjögren's syndrome and 8 without Sjögren's syndrome) underwent SPECT/CT. Salivary gland secretion data were digitally observed, producing separate time-activity curves (TAC) for the submandibular glands and parotid glands using SPECT/CT. The salivary gland secretion fraction was defined as A (before stimulation test [counts/frame]) divided by B (after stimulation test [counts/frame]). The A/B ratios of patients with Sjögren's syndrome and those without Sjögren's syndrome were compared using the Mann-Whitney U test for nonparametric data. RESULTS: The A/B ratio of parotid glands with Sjögren's syndrome (1.3 ± 0.2) was significantly lower than for those without Sjögren's syndrome (2.7 ± 0.7). The A/B ratio of submandibular glands with Sjögren's syndrome (1.3 ± 0.4) is significantly lower than for those without Sjögren's syndrome (1.8 ± 0.6). CONCLUSION: The TAC for the submandibular glands and parotid glands using SPECT/CT may be useful for the objective and quantitative diagnosis of Sjögren's syndrome.
Subject(s)
Sjogren's Syndrome , Xerostomia , Humans , Parotid Gland/diagnostic imaging , Pilot Projects , Salivary Glands/diagnostic imaging , Sjogren's Syndrome/complications , Sjogren's Syndrome/diagnostic imaging , Submandibular Gland/diagnostic imaging , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed , Xerostomia/diagnostic imaging , Xerostomia/etiologyABSTRACT
Scrub typhus is an acute febrile illness caused by the intracellular pathogen Orientia tsutsugamushi. The clinical features include fever, myalgia, lymphadenopathy, and dry mouth. However, no studies have assessed the symptom of dry mouth in patients with scrub typhus. We investigated the pattern of salivary scintigraphy during the acute febrile state and compared it with any changes after treatment. Fourteen patients underwent both pre- and post-treatment salivary scintigraphy. Imaging analysis was conducted using radioactivity in the oral cavity, parotid glands, and submandibular glands. During the acute phase, the radioactivity in the oral cavity markedly decreased, while that in the parotid and submandibular glands was preserved. After treatment, radioactivity in the oral cavity showed a significant increase at 20-min, 40-min, and after wash-out. The ejection fraction (%) of the parotid glands also increased after treatment. In contrast, the radioactivity levels of the parotid and submandibular glands were not statistically different after treatment. Salivary scintigraphy indicated that insufficient saliva excretion from the salivary glands into the oral cavity was one reason for the dry mouth reported by patients with scrub typhus. In the future, salivary scintigraphy imaging could contribute to the evaluation of dry mouth in patients with scrub typhus.
Subject(s)
Parotid Gland/diagnostic imaging , Radionuclide Imaging/methods , Saliva , Scrub Typhus/complications , Submandibular Gland/diagnostic imaging , Xerostomia/diagnostic imaging , Aged , Female , Humans , Male , Middle Aged , Xerostomia/etiologyABSTRACT
The clinical features of xerostomia induced by immune checkpoint inhibitors (ICI) are similar to those of Sjögren's syndrome (SS), whereas the immunohistological and serological features are known to differ from those of SS. However, the radiologic imaging features of salivary glands are not yet well known. We report a case of a 56-year-old male patient diagnosed with ICI-induced xerostomia. The patient underwent various imaging examinations to investigate the condition of the salivary glands, which indicated the following: (1) less specific findings on contrast-enhanced computed tomography, (2) mixed with intermediate and low signal intensity on both T1-weighted and fat-suppressed T2-weighted magnetic resonance imaging and poor "salt and pepper" appearance on magnetic resonance sialography, and (3) multiple ovoid hypoechoic areas with hyperechoic bands without acute sialadenitis on ultrasound. These radiologic imaging findings suggested remarkable lymphocyte infiltration, which could be a characteristic of ICI-induced xerostomia.
Subject(s)
Sjogren's Syndrome , Xerostomia , Humans , Immune Checkpoint Inhibitors , Male , Middle Aged , Salivary Glands/diagnostic imaging , Sjogren's Syndrome/diagnostic imaging , Ultrasonography , Xerostomia/chemically induced , Xerostomia/diagnostic imagingABSTRACT
The response of the major salivary glands, the parotid glands, to radiation dose is patient-specific. This study was designed to investigate whether parotid gland changes seen in weekly CT during treatment, quantified by delta-radiomics features (Δfeatures), could improve the prediction of moderate-to-severe xerostomia at 12 months after radiotherapy (Xer12m). Parotid gland Δfeatures were extracted from in total 68 planning and 340 weekly CTs, representing geometric, intensity and texture characteristics. Bootstrapped forward variable selection was performed to identify the best predictors of Xer12m. The predictive contribution of the resulting Δfeatures to a pre-treatment reference model, based on contralateral parotid gland mean dose and baseline xerostomia scores (Xerbaseline) only, was evaluated. Xer12m was reported by 26 (38%) of the 68 patients included. The most predictive Δfeature was the contralateral parotid gland surface change, which was significantly associated with Xer12m for all weeks (p < 0.04), but performed best for week 3 (ΔPG-surfacew3; p < 0.001). Moreover, ∆PG-surfacew3 showed a significant predictive contribution in addition to the pre-treatment reference model (likelihood-ratio test; p = 0.003), resulting in a significantly better model performance (AUCtrain = 0.92; AUCtest = 0.93) compared to that of the pre-treatment model (AUCtrain = 0.82; AUCtest = 0.82). These results suggest that mid-treatment parotid gland changes substantially improve the prediction of late radiation-induced xerostomia.
Subject(s)
Head and Neck Neoplasms , Parotid Gland/diagnostic imaging , Radiation Injuries/diagnostic imaging , Tomography, X-Ray Computed , Xerostomia , Adolescent , Adult , Aged , Female , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/radiotherapy , Humans , Male , Middle Aged , Predictive Value of Tests , Radiotherapy Dosage , Xerostomia/diagnostic imaging , Xerostomia/etiologyABSTRACT
PURPOSE: To analyze baseline CT/MR-based image features of salivary glands to predict radiation-induced xerostomia 3-months after head-and-neck cancer (HNC) radiotherapy. METHODS: A retrospective analysis was performed on 266 HNC patients who were treated using radiotherapy at our institution between 2009 and 2018. CT and T1 post-contrast MR images along with NCI-CTCAE xerostomia grade (3-month follow-up) were prospectively collected at our institution. CT and MR images were registered on which parotid/submandibular glands were contoured. Image features were extracted for ipsilateral/contralateral parotid and submandibular glands relative to the location of the primary tumor. Dose-volume-histogram (DVH) parameters were also acquired. Features were pre-selected based on Spearman correlation before modelling by examining the correlation with xerostomia (p < 0.05). A shrinkage regression analysis of the pre-selected features was performed using LASSO. The internal validity of the variable selection was estimated by repeating the entire variable selection procedure using a leave-one-out-cross-validation. The most frequently selected variables were considered in the final model. A generalized linear regression with repeated ten-fold cross-validation was developed to predict radiation-induced xerostomia at 3-months after radiotherapy. This model was tested in an independent dataset (n = 50) of patients who were treated at the same institution in 2017-2018. We compared the prediction performances under eight conditions (DVH-only, CT-only, MR-only, CT + MR, DVH + CT, DVH + CT + MR, Clinical+CT + MR, and Clinical+DVH + CT + MR) using the area under the receiver operating characteristic curve (ROC-AUC). RESULTS: Among extracted features, 7 CT, 5 MR, and 2 DVH features were selected. The internal cohort (n = 216) ROC-AUC values for DVH, CT, MR, and Clinical+DVH + CT + MR features were 0.73 ± 0.01, 0.69 ± 0.01, 0.70 ± 0.01, and 0.79 ± 0.01, respectively. The validation cohort (n = 50) ROC-AUC values for DVH, CT, MR, and Clinical+DVH + CT + MR features were 0.63, 0.57, 0.66, and 0.68, respectively. The DVH-ROC was not significantly different than the CT-ROC (p = 0.8) or MR-ROC (p = 0.4). However, the CT + MR-ROC was significantly different than the CT-ROC (p = 0.03), but not the Clinical+DVH + CT + MR model (p = 0.5). CONCLUSION: Our results suggest that baseline CT and MR image features may reflect baseline salivary gland function and potential risk for radiation injury. The integration of baseline image features into prediction models has the potential to improve xerostomia risk stratification with the ultimate goal of truly personalized HNC radiotherapy.
Subject(s)
Head and Neck Neoplasms/radiotherapy , Magnetic Resonance Imaging/methods , Parotid Gland/pathology , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Intensity-Modulated/adverse effects , Submandibular Gland/pathology , Tomography, X-Ray Computed/methods , Xerostomia/diagnosis , Female , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Humans , Image Processing, Computer-Assisted/methods , Male , Middle Aged , Organs at Risk/radiation effects , Parotid Gland/diagnostic imaging , Parotid Gland/radiation effects , Prognosis , Radiotherapy Dosage , Retrospective Studies , Submandibular Gland/diagnostic imaging , Submandibular Gland/radiation effects , Xerostomia/diagnostic imaging , Xerostomia/etiologyABSTRACT
BACKGROUND: Salivary gland dysfunction is one of the main clinical features of Sjögren's syndrome (SS), manifested by xerostomia with subsequent complications and well-established effects on the person's quality of life. OBJECTIVES: To determine firstly whether selected tests of salivary gland function and structure, unstimulated whole salivary flow rate (UWSFR), parotid flow rate (PFR), clinical oral dryness score (CODS) and ultrasound score (USS), can discriminate SS from non-SS sicca patients and secondly whether these tests can differentiate between patients in different subgroups of SS. METHOD: Unstimulated whole salivary flow rate, PFR, CODS and USS were determined in 244 patients comprised of SS patients (n = 118), SS patients at higher risk of lymphoma (n = 30) or with lymphoma (n = 26), and non-SS sicca disease controls (n = 70). RESULTS: All assessments showed a significant difference between the overall SS group and the disease control group, attributed mainly to the lymphoma subgroups of SS (p < 0.0001 for all parameters). There was a significant correlation (Spearman r = 0.7, p value <0.0001) and 87.3% agreement between USS and the histology focus scores of 119 patients. CONCLUSION: The results suggest that salivary gland tests including USS can aid in differentiating between SS and non-SS dry mouth, especially the subgroups of SS with lymphoma or at higher risk of developing lymphoma.
Subject(s)
Parotid Gland/diagnostic imaging , Salivary Glands/diagnostic imaging , Sjogren's Syndrome/complications , Xerostomia/etiology , Humans , Lymphoma/complications , Predictive Value of Tests , Quality of Life , Ultrasonography , Xerostomia/diagnostic imagingABSTRACT
PURPOSE: To determine whether serial cone beam computed tomography (CBCT) images taken during head and neck radiation therapy (HNR) can improve chronic xerostomia prediction. METHODS AND MATERIALS: In a retrospective analysis, parotid glands (PGs) were delineated on daily kV CBCT images using deformable image registration for 119 HNR patients (60 or 70 Gy in 2 Gy fractions over 6 or 7 weeks). Deformable image registration accuracy for a subset of deformed contours was quantified using the Dice similarity coefficient and mean distance to agreement in comparison with manually drawn contours. Average weekly changes in CBCT-measured mean Hounsfield unit intensity and volume were calculated for each PG relative to week 1. Dose-volume histogram statistics were extracted from each plan, and interactions among dose, volume, and intensity were investigated. Univariable analysis and penalized logistic regression were used to analyze association with observer-rated xerostomia at 1 year after HNR. Models including CBCT delta imaging features were compared with clinical and dose-volume histogram-only models using area under the receiver operating characteristic curve (AUC) for grade ≥1 and grade ≥2 xerostomia prediction. RESULTS: All patients experienced end-treatment PG volume reduction with mean (range) ipsilateral and contralateral PG shrinkage of 19.6% (0.9%-58.4%) and 17.7% (4.4%-56.3%), respectively. Midtreatment volume change was highly correlated with mean PG dose (r = -0.318, P < 1e-6). Incidence of grade ≥1 and grade ≥2 xerostomia was 65% and 16%, respectively. For grade ≥1 xerostomia prediction, the delta-imaging model had an AUC of 0.719 (95% confidence interval [CI], 0.603-0.830), compared with 0.709 (95% CI, 0.603-0.815) for the dose/clinical model. For grade ≥2 xerostomia prediction, the dose/clinical model had an AUC of 0.692 (95% CI, 0.615-0.770), and the addition of contralateral PG changes modestly improved predictive performance, with an AUC of 0.776 (0.643-0.912). CONCLUSIONS: The rate of CBCT-measured PG image feature changes improves prediction over dose alone for chronic xerostomia prediction. Analysis of CBCT images acquired for treatment positioning may provide an inexpensive monitoring system to support toxicity-reducing adaptive radiation therapy.
Subject(s)
Head and Neck Neoplasms/radiotherapy , Parotid Gland/diagnostic imaging , Xerostomia/etiology , Aged , Biomarkers , Chronic Disease , Cone-Beam Computed Tomography/methods , Dose-Response Relationship, Radiation , Female , Humans , Logistic Models , Male , Middle Aged , Parotid Gland/pathology , Radiotherapy Dosage , Retrospective Studies , Xerostomia/diagnostic imagingABSTRACT
PURPOSE: To investigate radiation-induced changes of computed tomography (CT) textures in parotid glands (PG) to predict acute xerostomia during radiotherapy (RT) for head and neck cancer (HNC). METHODS AND MATERIALS: Daily or fraction kilovoltage CTs acquired using diagnostic CT scanners (eg, in-room CTs) during intensity-modulated RT for 59 HNC patients at 3 institutions were analyzed. The PG contours were generated on selected daily/fraction CTs. A series of histogram-based texture features, including the mean CT number (MCTN) in Hounsfield units, volume, standard deviation, skewness, kurtosis, and entropy for PGs were calculated for each fraction. Correlations between the changes of the texture features, radiation dose, and observed acute xerostomia were analyzed. A classifier model and the incurred CT-based xerostomia score (CTXS) were introduced to predict xerostomia based on combined changes of MCTN and volume of PGs. The t test and Spearman and Pearson correlation tests were used in the analyses. RESULTS: Substantial changes in various CT texture features of PGs were observed during RT delivery. The changes of PG MCTN or volume are not strongly correlated with the observed xerostomia grades if they are considered separately. The CTXS showed a significant correlation to the observed xerostomia grades (r = 0.71, P < .00001). The CTXS-based classifier can predict the xerostomia severity with a success rate ranging from 79% to 98%. The xerostomia severity at the end of treatment can be predicted based on the CTXS determined at the fifth week with a precision and sensitivity of 100%. CONCLUSION: Significant changes in the CT histogram features of the parotid glands were observed during RT of HNC. A practical method of using the changes of MCTN and volume of PGs is proposed to predict radiation-induced acute xerostomia, which may be used to help design adaptive treatment.
Subject(s)
Head and Neck Neoplasms/radiotherapy , Parotid Gland/diagnostic imaging , Radiation Injuries/etiology , Radiotherapy, Intensity-Modulated/adverse effects , Tomography, X-Ray Computed/methods , Xerostomia/etiology , Acute Disease , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Radiotherapy Dosage , Xerostomia/diagnostic imagingABSTRACT
Hyposalivation is commonly observed in the autoimmune reaction of Sjögren's syndrome or following radiation injury to the major salivary glands. In these cases, questions remain regarding disease pathogenesis and effective interventions. An optimized technique that allows functional assessment of the salivary glands is invaluable for investigating exocrine gland biology, dysfunction, and therapeutics. Here, we present a step by step approach to performing pilocarpine stimulated saliva secretion, including tracheostomy and the dissection of the three major murine salivary glands. We also detail the appropriate murine head and neck anatomy accessed during these techniques. This approach is scalable, allowing for multiple mice to be processed simultaneously, thus improving the efficiency of the work flow. We aim to improve the reproducibility of these methods, each of which has further applications within the field. In addition to saliva collection, we discuss metrics for quantifying and normalizing functional capacity of these tissues. Representative data are included from submandibular glands with depressed salivary gland function 2 weeks following fractionated radiation (4 doses of 6.85 Gy).
Subject(s)
Pilocarpine/therapeutic use , Salivary Glands/diagnostic imaging , Xerostomia/diagnostic imaging , Animals , Dose Fractionation, Radiation , Female , Humans , Male , Mice , Mice, Inbred C57BL , Pilocarpine/pharmacology , Xerostomia/radiotherapyABSTRACT
Xerostomia induced by radiotherapy is a common toxicity for head and neck carcinoma patients. In this study, the deformable image registration of planning computed tomography (CT) and weekly cone-beam CT (CBCT) was used to override the Hounsfield unit value of CBCT, and the modified CBCT was introduced to estimate the radiation dose delivered during the course of treatment. Herein, the beams from each patient's treatment plan were applied to the modified CBCT to construct the weekly delivered dose. Then, weekly doses were summed together to obtain the accumulated dose. A total of 42 parotid glands (PGs) of 21 nasopharyngeal carcinoma patients were analyzed. Doses delivered to the parotid glands significantly increased compared with the planning doses. V20 , V30 , V40 , Dmean , and D50 increased by 11.3%, 28.6%, 44.4%, 9.5%, and 8.4% respectively. Of the 21 patients included in the study, eight developed xerostomia and the remaining 13 did not. Both planning and delivered PG Dmean for all patients exceeded tolerance (26 Gy). Among the 21 patients, the planning dose and delivered dose of Dmean were 30.6 Gy and 33.6 Gy, respectively, for patients with xerostomia, and 26.3 Gy and 28.0 Gy, respectively, for patients without xerostomia. The D50 of the planning and delivered dose for patients was below tolerance (30 Gy). The results demonstrated that the p-value of V20 , V30 , D50 , and Dmean difference of the delivery dose between patients with xerostomia and patients without xerostomia was less than 0.05. However, for the planning dose, the significant dosimetric difference between the two groups only existed in D50 and Dmean . Xerostomia is closely related to V20 , V30 , D50 , and Dmean .
Subject(s)
Carcinoma/radiotherapy , Cone-Beam Computed Tomography/methods , Nasopharyngeal Neoplasms/radiotherapy , Parotid Gland/pathology , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy, Intensity-Modulated/adverse effects , Xerostomia/etiology , Adolescent , Adult , Aged , Carcinoma/diagnostic imaging , Female , Follow-Up Studies , Humans , Image Processing, Computer-Assisted/methods , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/diagnostic imaging , Organs at Risk/radiation effects , Parotid Gland/radiation effects , Prognosis , Radiotherapy Dosage , Retrospective Studies , Xerostomia/diagnostic imaging , Xerostomia/pathology , Young AdultABSTRACT
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.
Subject(s)
Mesenchymal Stem Cell Transplantation/adverse effects , Radiation Injuries/therapy , Safety , Xerostomia/etiology , Xerostomia/therapy , Adipose Tissue/cytology , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Placebos , Salivary Glands/diagnostic imaging , Salivary Glands/physiopathology , Salivary Glands/radiation effects , Salivation/radiation effects , Xerostomia/diagnostic imagingABSTRACT
BACKGROUND: Salivary gland hypofunction and xerostomia are major complications following radiotherapy for head and neck cancer and may lead to debilitating oral disorders and impaired quality of life. Currently, only symptomatic treatment is available. However, mesenchymal stem cell (MSC) therapy has shown promising results in preclinical studies. Objectives are to assess safety and efficacy in a first-in-man trial on adipose-derived MSC therapy (ASC) for radiation-induced xerostomia. METHODS: This is a single-center, phase I/II, randomized, placebo-controlled, double-blinded clinical trial. A total of 30 patients are randomized in a 1:1 ratio to receive ultrasound-guided, administered ASC or placebo to the submandibular glands. The primary outcome is change in unstimulated whole salivary flow rate. The secondary outcomes are safety, efficacy, change in quality of life, qualitative and quantitative measurements of saliva, as well as submandibular gland size, vascularization, fibrosis, and secretory tissue evaluation based on contrast-induced magnetic resonance imaging (MRI) and core-needle samples. The assessments are performed at baseline (1 month prior to treatment) and 1 and 4 months following investigational intervention. DISCUSSION: The trial is the first attempt to evaluate the safety and efficacy of adipose-derived MSCs (ASCs) in patients with radiation-induced xerostomia. The results may provide evidence for the effectiveness of ASC in patients with salivary gland hypofunction and xerostomia and deliver valuable information for the design of subsequent trials. TRIAL REGISTRATION: EudraCT, Identifier: 2014-004349-29. Registered on 1 April 2015. ClinicalTrials.gov, Identifier: NCT02513238 . First received on 2 July 2015. The trial is prospectively registered.