Proton- compared to X-irradiation leads to more acinar atrophy and greater hyposalivation accompanied by a differential cytokine response.

Proton therapy gives less dose to healthy tissue compared to conventional X-ray therapy, but systematic comparisons of normal tissue responses are lacking. The aim of this study was to investigate late tissue responses in the salivary glands following proton- or X-irradiation of the head and neck in mice. Moreover, we aimed at investigating molecular responses by monitoring the cytokine levels in serum and saliva. Female C57BL/6J mice underwent local fractionated irradiation with protons or X-rays to the maximally tolerated acute level. Saliva and serum were collected before and at different time points after irradiation to assess salivary gland function and cytokine expression. To study late responses in the major salivary glands, histological analyses were performed on tissues collected at day 105 after onset of irradiation. Saliva volume after proton and X-irradiation was significantly lower than for controls and remained reduced at all time points after irradiation. Protons caused reduced saliva production and fewer acinar cells in the submandibular glands compared to X-rays at day 105. X-rays induced a stronger inflammatory cytokine response in saliva compared to protons. This work supports previous preclinical findings and indicate that the relative biological effectiveness of protons in normal tissue might be higher than the commonly used value of 1.1.

A single dose of radiation elicits comparable acute salivary gland injury to fractionated radiation.

The salivary glands are often damaged during head and neck cancer radiotherapy. This results in chronic dry mouth, which adversely affects quality of life and for which there is no long-term cure. Mouse models of salivary gland injury are routinely used in regenerative research. However, there is no clear consensus on the radiation regime required to cause injury. Here, we analysed three regimes of γ-irradiation of the submandibular salivary gland. Transcriptional analysis, immunofluorescence and flow cytometry was used to profile DNA damage, gland architecture and immune cell changes 3 days after single doses of 10 or 15 Gy or three doses of 5 Gy. Irrespective of the regime, radiation induced comparable levels of DNA damage, cell cycle arrest, loss of glandular architecture, increased pro-inflammatory cytokines and a reduction in tissue-resident macrophages, relative to those observed in non-irradiated submandibular glands. Given these data, coupled with the fact that repeated anaesthetic can negatively affect animal welfare and interfere with saliva secretion, we conclude that a single dose of 10 Gy irradiation is the most refined method of inducing acute salivary gland injury in a mouse model.

The Mechanism of 540 nm Green Light in Promoting Salivary Secretion.

Background: Although low-level laser therapy (LLLT) is a widely used noninvasive treatment because of photobiomodulation effects, its application for xerostomia remained uncertain. Tight junctions (TJs), mainly composed of claudins, occludin, and ZO family members, are crucial structures that determine material transport through paracellular pathway in salivary gland epithelial cells. This work aimed to investigate whether LLLT affected salivary secretion through epithelial TJs. Methods: Transepithelial electrical resistance (TER) measurement and paracellular permeability assay were applied to evaluate paracellular permeability in submandibular gland (SMG)-C6 cells after irradiation with 540 nm green light. Immunofluorescence and western blot were used to detect the expression of TJ proteins. Quantitative phosphoproteomics were performed to explore possible intracellular signals. Results: We found that irradiation with 540 nm green light significantly decreased TER values while increased paracellular transport in SMG-C6 cells. 540 nm green light-induced redistribution of claudin-1, -3, and -4, but not occludin or ZO-1. Moreover, above phenomena were abolished by preincubation with capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. Notably, irradiation with 540 nm green light on the skin covering the whole submandibular gland regions promoted salivary secretion and attenuated lymphocytic infiltration in 21-week-old non-obese diabetic mice (n = 5 per group), a xerostomia animal model for Sjögren's syndrome. Through in-depth bioinformatics analysis and expression verification, ERK1/2 and EphA2 served as potential canonical and noncanonical signals underlying 540 nm green light. Conclusions: Our findings uncovered the novel therapeutic effects of 540 nm green light on xerostomia through regulation on the expression and distribution of TJs.

Tert-expressing cells contribute to salivary gland homeostasis and tissue regeneration after radiation therapy.

Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (TertHigh) cell population located in the ductal region of the adult SMG. These TertHigh cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. TertHigh cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of "cell cycling" and "oxidative stress response" pathways in TertHigh cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of TertHigh cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

Diagnosis and Treatment of Radioactive Iodine-Induced Sialadenitis: A 10-Year Endoscopic Experience.

OBJECTIVES: The aim of this study was to explore the endoscopic characteristics of radioactive iodine-induced sialadenitis (RAIS), and to evaluate the treatment outcomes of endoscopic intervention for RAIS. STUDY DESIGN: Retrospective case series. METHODS: Eighty-two consecutive patients (11 males and 71 females) diagnosed as RAIS from Nov. 2012 to Sep. 2023 were retrospectively included. All patients underwent endoscopic exploration and intervention of the affected glands. The endoscopic features were collected, and treatment outcomes were followed-up and evaluated through post to pre-operative comparisons of gland status. RESULTS: Overall, endoscopic procedures were undertaken for 162 parotid glands (PGs) and 62 submandibular glands (SMGs). Endoscopy showed severe lumen stricture (49.3%) and ductal atresia (23.5%) in PGs, as well as severe stenosis of the anterior duct and ectasia of the proximal duct (59.7%) in SMGs. During a median six months' follow-up, the treatment outcomes of PGs were evaluated as "improvement" in 23.4%，"lesion maintenance" in 45.1% and "lesion aggravation" in 31.5% of the glands. As for SMGs, the treatment outcomes were scored as "improvement"in 29.0%，"lesion maintenance"in 54.8%, and"lesion aggravation"in 16.1% of the glands. No significant differences of treatment outcomes were found relative to RAI treatment sessions and cumulative dosage. CONCLUSION: RAIS is characteristic of severe lumen stricture and ductal atresia in PGs, and stenosis of the distal duct and ectasia of the proximal duct in SMGs. Endoscopy can alleviate clinical symptoms of RAIS and help to preserve the gland function. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:4506-4513, 2024.

Radiation-induced Xerostomia is Related to Stem Cell Dose-dependent Reduction of Saliva Production.

PURPOSE: Previous studies have shown that the mean dose to the parotid gland stem cell rich regions (Dmean,SCR) is the strongest dosimetric predictor for the risk of patient-reported daytime xerostomia. This study aimed to test whether the relationship between patient-reported xerostomia and Dmean,SCR is explained by a dose-dependent reduction of saliva production. METHODS AND MATERIALS: In 570 patients with head and neck cancer treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual (FLOWSMSL) glands, and patient-reported daytime (XERDAY) and nighttime (XERNIGHT) xerostomia were prospectively measured before, at 6 months, and 12 months after RT. Using linear mixed effect models, the relationship of the mean dose to the parotid glands (Dmean,par), Dmean,SCR, non-SCR parotid gland tissue (Dmean,non-SCR), submandibular glands (Dmean,sub), and oral cavity (Dmean,oral) with salivary flow and xerostomia was analyzed while correcting for known confounders. RESULTS: Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (P ≤ .03), while Dmean,non-SCR did not affect FLOWPAR (P ≥ .11). To illustrate, increasing Dmean,SCR by 10 Gy at a fixed Dmean,non-SCR reduced FLOWPAR by 0.02 mL/min (25%) after RT. However, if the opposite happened, no change in FLOWPAR was observed (0.00 mL/min [4%]). As expected, Dmean,sub was significantly associated with FLOWSMSL (P < .001). For example, increasing Dmean,sub by 10 Gy reduced FLOWSMSL by 0.07 mL/min (26%) after RT. Xerostomia scores were also affected by dose to the salivary glands. Dmean,SCR and Dmean,oral were associated with higher XERDAY scores (P ≤ .05), while Dmean,sub increased XERNIGHT scores (P = .01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores by 2.13 points (5%) after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores by 2.20 points (6%) after RT. Salivary flow was not only associated with radiation dose, but also with xerostomia scores in line with the salivary glands' functions; ie, FLOWPAR only influenced XERDAY (P < .001, 10.92 points lower XERDAY per 1 mL/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (P ≤ .004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 mL/min saliva). Therefore, the observed relationships between dose and xerostomia were corrected for salivary flow. As hypothesized, Dmean,SCR only increased XERDAY scores via reducing FLOWPAR, whereas the effects of Dmean,oral on XERDAY and Dmean,sub on XERNIGHT were independent of salivary flow. CONCLUSIONS: Higher SCR region dose reduced parotid gland saliva production, subsequently resulting in higher daytime xerostomia scores. Consequently, this study supports the clinical implementation of stem cell sparing RT to preserve salivary flow with the aim of reducing the risk of xerostomia.

Assessment of Dimensional Changes in Submandibular Glands in Head-Neck Radiotherapy Patients by Ultrasonography.

OBJECTIVES: The present study investigated the dimensional changes in the submandibular glands following radiotherapy using ultrasonography. METHODS: Twenty-three patients planned to receive head-neck radiotherapy were included in this study. The anteroposterior, superoinferior, mediolateral length, and volumes of 46 submandibular glands were measured by ultrasonography at 3 different time periods (before radiotherapy and in the second and sixth months after the radiotherapy onset) and evaluated in terms of dimensional changes and the effect of the radiation dose on these changes. The data were statistically analyzed using repeated measures analysis of variance (ANOVA) and 2-factor repeated measures ANOVA. RESULTS: Before radiotherapy and in the second and sixth months after the radiotherapy onset, mean anteroposterior length of the submandibular glands was 32.39 ± 4.55, 30.38 ± 4.80, and 31.50 ± 3.68 mm, respectively; mean superoinferior length was 9.96 ± 1.54, 8.76 ± 1.26, and 9.08 ± 1.01 mm, respectively; mean mediolateral length was 24.66 ± 3.77, 22.03 ± 3.73, and 21.76 ± 4.01 mm, respectively; and mean volume was 4.21 ± 1.01, 3.08 ± 0.77, and 3.32 ± 0.63 cm3 , respectively. Moreover, there were significant differences in the anteroposterior (P < .01), superoinferior (P < .001), and mediolateral lengths (P < .001), as well as the volumes (P < .001) of the submandibular glands measured at the 3 different time periods. CONCLUSION: In the second and sixth months after the radiotherapy onset, the sizes of the submandibular glands were markedly reduced, but it partially recovered to normal as more time elapsed after radiotherapy.

Possible radioprotection of submandibular glands in gamma-irradiated rats using kaempferol: a histopathological and immunohistochemical study.

BACKGROUND AND PURPOSE: Salivary gland damage remains a problem despite advances in radiotherapy schedules for head and neck cancer. Kaempferol, a natural flavonoid, found in several fruits and vegetables, is a good antioxidant. This study was designed to evaluate the possible protective effects of kaempferol on submandibular glands (SMGs) of rats exposed to fractionated gamma irradiation. MATERIALS AND METHODS: Twenty-four male adult Wistar albino rats were included in this study and assigned to three groups (n = 8). Rats in group K received kaempferol orally in five doses at a dose of 10 mg/kg/2 days for 10 days. Meanwhile, rats in group R were subjected to fractionated whole-body gamma irradiation at a dose of 2 Gy/5 days/week for 2 weeks (20 Gy), and the KR group received kaempferol as group K and then was subjected to a fractionated whole-body gamma irradiation as group R. SMG samples were collected on days 1 and 7 after the last radiation session; and processed for histopathological and immunohistochemical investigations. RESULTS: The SMGs of group R showed focal atrophy and degeneration. Acini showed vacuolization and had pyknotic hyperchromatic nuclei. Striated ducts degenerated, shrunken, and were surrounded by empty spaces. The percentage of areas covered by cyclooxygenase-2 (COX-2) significantly increased, whereas the percentage of areas covered by proliferating cell nuclear antigen (PCNA) significantly decreased compared with those in group K. Cotreatment with kaempferol (group KR) partially preserved normal gland architecture where acinar vacuolation and degeneration were almost absent; however, some ducts degenerated. A significant decrease in the percentage of areas covered by COX-2 and a significant increase in the percentage of areas covered by PCNA were observed compared with those in group R. CONCLUSIONS: Kaempferol has a possible radioprotective effect on the SMGs of rats exposed to fractionated gamma irradiation.

Short-term and bystander effects of radiation on murine submandibular glands.

Many patients treated for head and neck cancers experience salivary gland hypofunction due to radiation damage. Understanding the mechanisms of cellular damage induced by radiation treatment is important in order to design methods of radioprotection. In addition, it is crucial to recognize the indirect effects of irradiation and the systemic responses that may alter saliva secretion. In this study, radiation was delivered to murine submandibular glands (SMGs) bilaterally, using a 137Cs gamma ray irradiator, or unilaterally, using a small-animal radiation research platform (SARRP). Analysis at 3, 24 and 48 h showed dynamic changes in mRNA and protein expression in SMGs irradiated bilaterally. Unilateral irradiation using the SARRP caused similar changes in the irradiated SMGs, as well as significant off-target, bystander effects in the non-irradiated contralateral SMGs.

SPM Receptor Expression and Localization in Irradiated Salivary Glands.

Radiation therapy-mediated salivary gland destruction is characterized by increased inflammatory cell infiltration and fibrosis, both of which ultimately lead to salivary gland hypofunction. However, current treatments (e.g., artificial saliva and sialagogues) only promote temporary relief of symptoms. As such, developing alternative measures against radiation damage is critical for restoring salivary gland structure and function. One promising option for managing radiation therapy-mediated damage in salivary glands is by activation of specialized proresolving lipid mediator receptors due to their demonstrated role in resolution of inflammation and fibrosis in many tissues. Nonetheless, little is known about the presence and function of these receptors in healthy and/or irradiated salivary glands. Therefore, the goal of this study was to detect whether these specialized proresolving lipid mediator receptors are expressed in healthy salivary glands and, if so, if they are maintained after radiation therapy-mediated damage. Our results indicate that specialized proresolving lipid mediator receptors are heterogeneously expressed in inflammatory as well as in acinar and ductal cells within human submandibular glands and that their expression persists after radiation therapy. These findings suggest that epithelial cells as well as resident immune cells represent potential targets for modulation of resolution of inflammation and fibrosis in irradiated salivary glands.

Dental pulp stem cell-derived small extracellular vesicle in irradiation-induced senescence.

Small extracellular vesicles (sEV) facilitate signaling molecule transfer among cells. We examined the therapeutic efficacy of human dental pulp stem cell-derived sEV (hDPSC-sEV) against cellular senescence in an irradiated-submandibular gland mouse model. Seven-week-old mice were exposed to 25 Gy radiation and randomly assigned to control, phosphate-buffered saline (PBS), or hDPSC-sEV groups. At 18 days post-irradiation, saliva production was measured; histological and reverse transcription-quantitative PCR analyses of the submandibular glands were performed. The salivary flow rate did not differ significantly between the PBS and hDPSC-sEV groups. AQP5-expressing acinar cell numbers and AQP5 expression levels in the submandibular glands were higher in the hDPSC-sEV group than in the other groups. Furthermore, compared with non-irradiated mice, mice in the 25 Gy + PBS group showed a high senescence-associated-ß-galactosidase-positive cell number and upregulated senescence-related gene (p16INK4a, p19Arf, p21) and senescence-associated secretory phenotypic factor (MMP3, IL-6, PAI-1, NF-κB, and TGF-ß) expression, all of which were downregulated in the hDPSC-sEV group. Superoxide dismutase levels were lower in the PBS group than in the hDPSC-sEV group. In summary, hDPSC-sEV reduced inflammatory cytokine and senescence-related gene expression and reversed oxidative stress in submandibular cells, thereby preventing irradiation-induced cellular senescence. Based on these results, we hope to contribute to the development of innovative treatment methods for salivary gland dysfunction that develops after radiotherapy for head and neck cancer.

Sialographic Analysis of Radioiodine-Associated Chronic Sialadenitis.

OBJECTIVES/HYPOTHESIS: To apply a novel sialography classification system to identify parotid and submandibular ductal findings following I-131 therapy and to assess correlates to dose and duration of symptoms. STUDY DESIGN: Retrospective single-center case series. METHODS: Patients who underwent sialography between February 2008 and February 2019 after previously receiving I-131 treatment were identified via a retrospective chart review. Their sialograms were systematically evaluated and scored by applying the Iowa parotid sialogram scale to also include submandibular gland analysis. RESULTS: From 337 sialograms, 30 (five submandibular, 25 parotid) underwent analysis. Ductal stenosis was identified in all sialograms and was graded as moderate (>50%-75%) in 7/30 cases and severe (>75%) in 15/30 cases. The distal (main) duct was narrowed in 23/30 cases. No association was identified between degree of ductal stenosis and I-131 dose (P = .39), age (P = .81), or time from I-131 therapy to sialogram (P = .97). CONCLUSIONS: The Iowa parotid sialogram scale was successfully applied to report abnormalities of the parotid and submandibular ductal system. The most common manifestation of I-131-associated sialadenitis was a severe stenosis within the distal salivary duct. No statistically significant association was found between degree of ductal stenosis and dose of I-131, age, or duration of symptoms. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1450-E1456, 2021.

Long-Term Maintenance of Acinar Cells in Human Submandibular Glands After Radiation Therapy.

PURPOSE: In a combined retrospective and prospective study, human salivary glands were investigated after radiation treatment for head and neck cancers. The aim was to assess acinar cell loss and morphologic changes after radiation therapy and to determine whether irradiated salivary glands have regenerative potential. METHODS AND MATERIALS: Irradiated human submandibular and parotid salivary glands were collected from 16 patients at a range of time intervals after completion of radiation therapy (RT). Control samples were collected from 14 patients who had not received radiation treatments. Tissue sections were analyzed using immunohistochemistry to stain for molecular markers. RESULTS: Human submandibular and parotid glands isolated less than 1 year after RT showed a near complete loss of acinar cells. However, acinar units expressing functional secretory markers were observed in all samples isolated at later intervals after RT. Significantly lower acinar cell numbers and increased fibrosis were found in glands treated with combined radiation and chemotherapy, in comparison to glands treated with RT alone. Irradiated samples showed increased staining for duct cell keratin markers, as well as many cells coexpressing acinar- and duct cell-specific markers, in comparison to nonirradiated control samples. CONCLUSIONS: After RT, acinar cell clusters are maintained in human submandibular glands for years. The surviving acinar cells retain proliferative potential, although significant regeneration does not occur. Persistent DNA damage, increased fibrosis, and altered cell identity suggest mechanisms that may impair regeneration.

Early effect of laser irradiation in signaling pathways of diabetic rat submandibular salivary glands.

Low-power laser irradiation (LPLI) is clinically used to modulate inflammation, proliferation and apoptosis. However, its molecular mechanisms are still not fully understood. This study aimed to describe the effects of LPLI upon inflammatory, apoptotic and proliferation markers in submandibular salivary glands (SMGs) in an experimental model of chronic disorder, 24h after one time irradiation. Diabetes was induced in rats by the injection of streptozotocin. After 29 days, these animals were treated with LPLI in the SMG area, and euthanized 24h after this irradiation. Treatment with LPLI significantly decreased diabetes-induced high mobility group box 1 (HMGB1) and tumor necrosis factor alpha (TNF-α) expression, while enhancing the activation of the transcriptional factor cAMP response element binding (CREB) protein. LPLI also reduced the expression of bax, a mitochondrial apoptotic marker, favoring the cell survival. These findings suggest that LPLI can hamper the state of chronic inflammation and favor homeostasis in diabetic rats SMGs.

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

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

[What is the impact of IMRT of nasopharyngeal carcinomas on glandular structures?] / Quel impact de la RCMI des carcinomes nasopharyngés sur les structures glandulaires ?

PURPOSE: The aim of this work is to evaluate the anatomical changes of the glandular structures during the NPC IMRT and to study their dosimetric impacts. PATIENTS AND METHODS: Twenty patients receiving IMRT for NPC were included. For each patient, a second dosimetric CT was performed at a dose of 38Gy, which was fused with the initial planning dosimetric CT. We calculated the volume percent change, the positional and dosimetric variation between the 2 scanners for the glandular structures (parotid, submaxillary, thyroid and pituitary). RESULTS: We observed a decrease in the volume of right and left parotids (-27.9% and -27.54%). It was correlated with the initial dose planned at its level. For the sub maxillary glands, the decrease was -36.1% on the right and -27.28% on the left. The value of reduction of the thyroid gland was -18.01%. A medial supra-millimeter migration of 2 and 1.15mm was found for right and left parotid glands respectively, correlated with GTV N reduction volume. We found a significant increase in mean doses for the parotid glands. It was 1.8±2.3Gy for the right and 1.5±2.7Gy for the left. For the right sub maxillary gland, the increase was about 0.35±2Gy and 3.79±5.2Gy for the thyroid. CONCLUSION: The modifications observed for glandular structures during NPC IMRT can explain the different toxicities caused by radiation. It seems also that a careful adaptation of the treatment plan should be considered during therapy.

Functional outcomes of the modified submandibular gland transfer procedure.

OBJECTIVES: Treatment for advanced head and neck cancers typically includes surgery followed by radiation therapy (RT). Radiation-induced xerostomia is a common sequela of these treatments. The modified submandibular gland transfer (M-SGT) procedure was developed to decrease xerostomia in the treatment of oral cavity cancer by sparing one submandibular gland (SMG) from radiation. This study's objectives were to: 1) elucidate the radiation-sparing capacity of the M-SGT, and 2) study the xerostomia-reducing potential of the M-SGT based on the University of Washington Quality-of-Life Questionnaire (UW-QOL). METHODS: Radiation therapy treatment plans were reviewed for all patients treated with surgery and RT who had a M-SGT at the University of Alberta Hospital during the study period. Outcomes included: 1) radiation dose received by the transferred SMG within the periparotid area compared to the submandibular triangle (ST), and 2) patient-reported saliva scores on the UW-QOL compared to historical controls without a gland transfer. RESULTS: Twenty-two patients were included. The mean radiation dose received by the transferred SMG was 29.00 grays (Gy) (standard deviation 14.59 Gy), thus reducing the mean radiation dose to the SMG by a statistically significant 18.34 Gy (confidence interval 95% (13.37, 23.32), P < 0.01) compared to the ST and below the D50 of the SMG (34 Gy). Sixty-five percent of patients rated their saliva as normal or mildly reduced on the UW-QOL as compared to 16% of controls (P = 0.01). CONCLUSION: The M-SGT technique is successful at reducing the radiation dose sustained by the SMG during adjuvant treatment and provides a significant improvement in xerostomia-related functional outcomes as compared to historical controls not receiving a gland transfer. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:925-929, 2020.

Reducing Xerostomia by Comprehensive Protection of Salivary Glands in Intensity-Modulated Radiation Therapy with Helical Tomotherapy Technique for Head-and-Neck Cancer Patients: A Prospective Observational Study.

OBJECTIVE: This study aimed to analyze the effects of comprehensive protection of bilateral parotid glands (PG-T), contralateral submandibular gland (cSMG), and accessory salivary glands in the oral cavity (OC) by helical tomotherapy for head-and-neck cancer patients. METHODS: Totally 175 patients with histologically confirmed head-and-neck cancer treated with helical tomotherapy were recruited. The doses delivered to PG-T, cSMG, and OC were constrained to be as low as possible in treatment planning. The saliva flow rates and xerostomia questionnaire were evaluated. Correlation between xerostomia and other clinical factors were assessed using univariate and multivariate models. The impact of salivary gland dose on locoregional (LR) recurrence was assessed by Cox analysis. ROC curve was used to determine the threshold of mean dose for each gland. RESULTS: The median follow-up was 25 (19-36) months. The OC mean dose, PG-T mean dose, cSMG mean dose, age, clinical stage (II and III versus IV), and both unstimulated and stimulated saliva flow rates were significantly correlated with xerostomia. The OC mean dose, cSMG mean dose, age, and clinical stage were predictors of xerostomia after adjusting PG-T mean dose, and unstimulated and stimulated saliva flow rates. Xerostomia was significantly decreased when the mean doses of PG-T, cSMG, and OC were kept below 29.12Gy, 29.29Gy, and 31.44Gy, respectively. At 18 months after radiation therapy, early LR recurrence rate was only 4%. CONCLUSION: Comprehensive protection of salivary glands minimized xerostomia in head-and-neck cancer patients treated by helical tomotherapy, without increasing early LR recurrence risk.

Targeted Intervention to Improve the Quality of Head and Neck Radiation Therapy Treatment Planning in the Netherlands: Short and Long-Term Impact.

PURPOSE: To benchmark and improve, through means of a targeted intervention, the quality of intensity modulated radiation therapy treatment planning for locally advanced head and neck cancer (HNC) in the Netherlands. The short and long-term impact of this intervention was assessed. METHODS AND MATERIALS: A delineated computed tomography-scan of an oropharynx HNC case was sent to all 15 Dutch radiation therapy centers treating HNC. Aims for planning target volume and organ-at-risk (OAR) dosimetry were established by consensus. Each center generated a treatment plan. In a targeted intervention, OAR sparing of all plans was discussed, and centers with the best OAR sparing shared their planning strategies. Impact of the intervention was assessed by (1) short-term (half a year after intervention) replanning of the original case and (2) long-term (1 and 3 years after intervention) planning of new cases. RESULTS: Benchmarking revealed substantial difference in OAR doses. Initial mean doses were 22 Gy (range, 15-31 Gy), 35 Gy (18-49 Gy), and 37 Gy (20-46 Gy) for the contralateral parotid gland, contralateral submandibular gland, and combined swallowing structures, respectively. Replanning after targeted intervention significantly reduced mean doses and variation, but clinically relevant differences still remained: 18 Gy (14-22 Gy), 28 Gy (17-45 Gy), and 29 Gy (18-39 Gy), respectively. One and 3 years later the variation remained stable. CONCLUSIONS: Despite many years of HNC intensity modulated radiation therapy experience, initial treatment plans showed surprisingly large variations. The simple targeted intervention used in this analysis improved OAR sparing, and its impact was durable; however, fairly large dose differences still continue to exist. Additional work is needed to understand these variations and to minimize them. A national radiation oncology platform can be instrumental for developing and maintaining high-quality planning protocols.

Predicting acute radiation induced xerostomia in head and neck Cancer using MR and CT Radiomics of parotid and submandibular glands.

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.