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In pigs, nitrate supplements can protect salivary glands from the damage caused by radiation therapy to the head and neck.In pigs, nitrate supplements can protect salivary glands from the damage caused by radiation therapy to the head and neck.

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.

Xerostomia is a common consequence of radiotherapy in head and neck cancer. The objective was to compare the regional radiation dose distribution in patients that developed xerostomia within 6 months of radiotherapy and those recovered from xerostomia within 18 months post-radiotherapy. We developed a feature generation pipeline to extract dose volume histogram features from geometrically defined ipsilateral/contralateral parotid glands, submandibular glands, and oral cavity surrogates for each patient. Permutation tests with multiple comparisons were performed to assess the dose difference between injury vs. non-injury and recovery vs. non-recovery. Ridge logistic regression models were applied to predict injury and recovery using clinical features along with dose features (D10-D90) of the subvolumes extracted from oral cavity and salivary gland contours + 3 mm peripheral shell. Model performances were assessed by the area under the receiver operating characteristic curve (AUC) using nested cross-validation. We found that different regional dose/volume metrics patterns exist for injury vs. recovery. Compared to injury, recovery has increased importance to the subvolumes receiving lower dose. Within the subvolumes, injury tends to have increased importance towards D10 from D90. This suggests that different threshold for xerostomia injury and recovery. Injury is induced by the subvolumes receiving higher dose, and the ability to recover can be preserved by further reducing the dose to subvolumes receiving lower dose.

This is a prospective, rigorous inquiry into the systemic immune effects of standard adjuvant chemoradiotherapy, for WHO grade 4, glioblastoma. The purpose is to identify peripheral immunologic effects never yet reported in key immune populations, including myeloid-derived suppressor cells, which are critical to the immune suppressive environment of glioblastoma. We hypothesize that harmful immune-supportive white blood cells, myeloid derived suppressor cells, expand in response to conventionally fractionated radiotherapy with concurrent temozolomide, essentially promoting systemic immunity similar what is seen in chronic diseases like diabetes and heart disease. 16 patients were enrolled in a single-institution, observational, immune surveillance study where peripheral blood was collected and interrogated by flow cytometry and RNAseq. Tumor tissue from baseline assessment was analyzed with spatial proteomics to link peripheral blood findings to baseline tissue characteristics. We identified an increase in myeloid-derived suppressor cells during the final week of a six-week treatment of chemoradiotherapy in peripheral blood of patients that were not alive at two years after diagnosis compared to those who were living. This was also associated with a decrease in CD8 T lymphocytes that produced IFNγ, the potent anti-tumor cytokine. These data suggest that, as in chronic inflammatory disease, systemic immunity is impaired following delivery of adjuvant chemoradiotherapy. Finally, baseline investigation of myeloid cells within tumor tissue did not differ between survival groups, indicating immune surveillance of peripheral blood during adjuvant therapy may be a critical missing link to educate our understanding of the immune effects of standard of care therapy for glioblastoma.

Social determinants of health (SDOH) such as lack of basic resources, housing, transportation, and social isolation play an important role for patients on the cancer care continuum. Health systems' current technological solutions for identifying and managing patients' SDOH data largely focus on information recorded in the electronic health record by providers, which is often inaccessible to patients to contribute to or modify. We developed and tested a patient-centric SDOH screening tool designed for use on patients' personal mobile phone that preserves patient privacy and confidentiality, collects information about the unmet social needs of patients with cancer, and communicates them to the provider. We interviewed 22 patients with cancer, oncologists, and social workers associated with a US-based comprehensive cancer center to better understand how patients' SDOH information is collected and reported. After triangulating data obtained from thematic analysis of interviews, an environmental scan, and a literature search of validated tools to collect SDOH data, we developed an SDOH screening tool mobile app and conducted a pilot study of 16 dyadic pairs of patients and cancer care team members at the same cancer center. We collected patient SDOH data using 36 survey items covering 7 SDOH domains and used validated scales and follow-up interviews to assess the app's usability and acceptability among patients and cancer care team members. Formative interviews with patients and care team members revealed that transportation, financial challenges, food insecurity, and low health literacy were common SDOH challenges and that a mobile app that collected those data, shared those data with care team members, and offered supportive resources could be useful and valuable. In the pilot study, 25% (4/16) of app-using patients reported having at least one of the abovementioned social needs; the most common social need was social isolation (7/16, 44%). Patients rated the mobile app as easy to use, accurately capturing their SDOH, and preserving their privacy but suggested that the app could be more helpful by connecting patients to actual resources. Providers reported high acceptability and usability of the app. Use of a brief, patient-centric, mobile app-based SDOH screening tool can effectively capture SDOH of patients with cancer for care team members in a way that preserves patient privacy and that is acceptable and usable for patients and care team members. However, only collecting SDOH information is not sufficient; usefulness can be increased by connecting patients directly to resources to address their unmet social needs.

Radiation oncologists have focused on the pharyngeal constrictors as the primary muscles of concern for dysphagia. However, our prior investigations have demonstrated that radiation dose to the geniohyoid rather than the constrictor muscles was more closely related to penetration aspiration scores (PAS). We examined the relationship between (1) radiation dose and swallowing temporal kinematics, and (2) between PAS and swallowing kinematics in these patients. Videofluoroscopic swallowing studies of 41 patients following radiation therapy for oropharyngeal cancer were analyzed for thin liquid boluses. Timing measures included duration of laryngeal vestibule closure (DLVC), duration to maximum hyoid elevation (DTMHE), duration to cricopharyngeal opening (DTCPO), and pharyngeal transit time (PTT). PAS was extracted for each swallow and considered normal if ≤2. As minimum and mean dose to the geniohyoid increased, DTMHE, DTCPO, and PTT increased. Worse PA scores were most strongly correlated with radiation dose received by geniohyoid ( r  = 0.445, p  < 0.0001). Mean DLVC varied according to PAS group (normal PAS mean = 0.67 s, abnormal PAS mean = 0.13 s; p  < 0.001). Similarly, DTCPO was significantly different based upon PAS (normal PAS mean = 0.22 s, abnormal PAS mean = 0.37 s, p  = 0.016). As PAS increased, DTPCO and PTT increased ( r  = 0.208, p  = 0.04; r  = 0.204, p  = 0.043). A negative correlation was noted between PAS and DLVC ( r  = −0.375, p  = 0.001). Higher doses of radiation to the geniohyoid muscles are associated with increased severity of dysphagia as measured through both kinematics and PAS. Consideration of dose to the geniohyoid should be considered when planning radiation.

Base of tongue (BOT) is a difficult subsite to examine clinically and radiographically. Yet, anatomic delineation of the primary tumor site, its extension to adjacent sites or across midline, and endophytic vs. exophytic extent are important characteristics for staging and treatment planning. We hypothesized that ultrasound could be used to visualize and describe BOT tumors. Transcervical ultrasound was performed using a standardized protocol in cases and controls. Cases had suspected or confirmed BOT malignancy. Controls were healthy individuals without known malignancy. 100% of BOT tumors were visualized. On ultrasound BOT tumors were hypoechoic (90.9%) with irregular margins (95.5%). Ultrasound could be used to characterize adjacent site involvement, midline extent, and endophytic extent, and visualize the lingual artery. No tumors were suspected for controls. Ultrasonography can be used to transcervically visualize BOT tumors and provides clinically relevant characteristics that may not otherwise be appreciable.

Salivary glands are common organs at risk in both head and neck external beam radiotherapy (EBRT) and radiopharmaceutical therapy (RPT), but incidences of xerostomia in RPT are inconsistent with the EBRT Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) limits. In EBRT, salivary glands are usually assumed to be parallel organs, with QUANTEC guidelines based on Dmean, but this is known to be a gross over-simplification of the full complexity of the underlying functional organization. The goal of this work is to combine machine learning of EBRT dose–outcome data with stylized small-scale RPT dosimetry to discover more reliable normal tissue complication probability (NTCP) models of xerostomia across both modalities. A retrospective cohort of 211 EBRT patients was analyzed using a custom-designed in-house machine learning workflow. From this, a hierarchy of three models of increasing complexity was trained, evaluated for performance and generalization, and coupled with stylized small-scale salivary gland dosimetry to assess the influence of model complexity on the predicted NTCP for plausible patterns of RPT dose nonuniformity. The three models in the hierarchy (A, B, C), in increasing order of complexity, associate xerostomia with the following: the mean dose to the whole contralateral parotid (model A), the mean dose to a ductally localized region (model B) and a serial interaction dose term between two ductal sub-compartments (model C). While the difference between the three models for EBRT p-values and AUCs is rather marginal, for physiologically driven ductal dose distributions in RPT, the predicted reduction in TD50 can be as large as a factor of 10. These results provide hints towards a plausible reconciliation of the observed inconsistency of xerostomia in RPT with EBRT dose limits.

Epidermal growth factor receptor (EGFR) inhibitors have shown only modest clinical activity when used as single agents to treat cancers. They decrease tumor cell expression of hypoxia-inducible factor 1-alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). Hypothesizing that this might normalize tumor vasculature, we examined the effects of the EGFR inhibitor erlotinib on tumor vascular function, tumor microenvironment (TME) and chemotherapy and radiotherapy sensitivity. Erlotinib treatment of human tumor cells in vitro and mice bearing xenografts in vivo led to decreased HIF-1alpha and VEGF expression. Treatment altered xenograft vessel morphology assessed by confocal microscopy (following tomato lectin injection) and decreased vessel permeability (measured by Evan's blue extravasation), suggesting vascular normalization. Erlotinib increased tumor blood flow measured by Power Doppler ultrasound and decreased hypoxia measured by EF5 immunohistochemistry and tumor O(2) saturation measured by optical spectroscopy. Predicting that these changes would improve drug delivery and increase response to chemotherapy and radiation, we performed tumor regrowth studies in nude mice with xenografts treated with erlotinib and either radiotherapy or the chemotherapeutic agent cisplatin. Erlotinib therapy followed by cisplatin led to synergistic inhibition of tumor growth compared with either treatment by itself (p<0.001). Treatment with erlotinib before cisplatin led to greater tumor growth inhibition than did treatment with cisplatin before erlotinib (p = 0.006). Erlotinib followed by radiation inhibited tumor regrowth to a greater degree than did radiation alone, although the interaction between erlotinib and radiation was not synergistic. EGFR inhibitors have shown clinical benefit when used in combination with conventional cytotoxic therapy. Our studies show that targeting tumor cells with EGFR inhibitors may modulate the TME via vascular normalization to increase response to chemotherapy and radiotherapy. These studies suggest ways to assess the response of tumors to EGFR inhibition using non-invasive imaging of the TME.