Radiation-induced xerostomia is related to stem cell dose-dependent reduction of saliva production.

BACKGROUND AND 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. MATERIAL/METHODS: In 570 head and neck cancer patients treated with definitive radiation therapy (RT), flow from the parotid (FLOWPAR) and submandibular/sublingual glands (FLOWSMSL) and patient-reported daytime (XERDAY) and nighttime xerostomia (XERNIGHT) were prospectively measured before, and at 6 and 12 months after RT. Using linear mixed effect models, the relations of 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 were analyzed while correcting for known confounders. RESULTS: Dmean,SCR proved to be responsible for the effect of Dmean,par on FLOWPAR (p≤0.03), while Dmean,non-SCR did not affect FLOWPAR (p≥0.11). To illustrate, increasing Dmean,SCR by 10 Gy at fixed Dmean,non-SCR, reduced FLOWPAR by 0.02 (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<0.001). For example, increasing Dmean,sub by 10 Gy, reduced FLOWSMSL with 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≤0.05), while Dmean,sub increased XERNIGHT scores (p=0.01). For example, an increase of 10 Gy in Dmean,SCR raised XERDAY scores with 2.13 (5%) points after RT, while an additional 10 Gy in Dmean,subs increased XERNIGHT scores with 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, i.e., FLOWPAR only influenced XERDAY (p<0.001, 10.92 points lower XERDAY per 1 ml/min saliva), while FLOWSMSL affected XERDAY and XERNIGHT (p≤0.004, 6.69 and 5.74 points lower XERDAY and XERNIGHT, respectively, per 1 ml/min saliva). Therefore, the observed relations 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 of Dmean,sub on XERNIGHT were independent of salivary flow. CONCLUSION: 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.

Proton therapy induces a local microglial neuroimmune response.

BACKGROUND AND PURPOSE: Although proton therapy is increasingly being used in the treatment of paediatric and adult brain tumours, there are still uncertainties surrounding the biological effect of protons on the normal brain. Microglia, the brain-resident macrophages, have been shown to play a role in the development of radiation-induced neurotoxicity. However, their molecular and hence functional response to proton irradiation remains unknown. This study investigates the effect of protons on microglia by comparing the effect of photons and protons as well as the influence of age and different irradiated volumes. MATERIALS AND METHODS: Rats were irradiated with 14 Gy to the whole brain with photons (X-rays), plateau protons, spread-out Bragg peak (SOBP) protons or to 50 % anterior, or 50 % posterior brain sub-volumes with plateau protons. RNA sequencing, validation of microglial priming gene expression using qPCR and high-content imaging analysis of microglial morphology were performed in the cortex at 12 weeks post irradiation. RESULTS: Photons and plateau protons induced a shared transcriptomic response associated with neuroinflammation. This response was associated with a similar microglial priming gene expression signature and distribution of microglial morphologies. Expression of the priming gene signature was less pronounced in juvenile rats compared to adults and slightly increased in rats irradiated with SOBP protons. High-precision partial brain irradiation with protons induced a local microglial priming response and morphological changes. CONCLUSION: Overall, our data indicate that the brain responds in a similar manner to photons and plateau protons with a shared local upregulation of microglial priming-associated genes, potentially enhancing the immune response to subsequent inflammatory challenges.

Prediction of Radiation-Induced Parotid Gland-Related Xerostomia in Patients With Head and Neck Cancer: Regeneration-Weighted Dose.

PURPOSE: Despite improvements to treatment, patients with head and neck cancer (HNC) still experience radiation-induced xerostomia due to salivary gland damage. The stem cells of the parotid gland (PG), concentrated in the gland's main ducts (stem cell rich [SCR] region), play a critical role in the PG's response to radiation. Treatment optimization requires a dose metric that properly accounts for the relative contributions of dose to this SCR region and the PG's remainder (non-SCR region) to the risk of xerostomia in normal tissue complication probability (NTCP) models for xerostomia. MATERIALS AND METHODS: Treatment and toxicity data of 1013 prospectively followed patients with HNC treated with definitive radiation therapy (RT) were used. The regeneration-weighted dose, enabling accounting for the hypothesized different effects of dose to the SCR and non-SCR region on the risk of xerostomia, was defined as Dreg PG = Dmean SCR region + r × Dmean non-SCR region, where Dreg is the regeneration-weighted dose, Dmean is the mean dose, and r is the weighting factor. Considering the different volumes of these regions, r > 3.6 in Dreg PG demonstrates an enhanced effect of the SCR region. The most predictive value of r was estimated in 102 patients of a previously published trial testing stem cell sparing RT. For each endpoint, Dreg PG, dose to other organs, and clinical factors were used to develop NTCP models using multivariable logistic regression analysis in 663 patients. The models were validated in 350 patients. RESULTS: Dose to the contralateral PG was associated with daytime, eating-related, and physician-rated grade ≥2 xerostomia. Consequently, r was estimated and found to be smaller than 3.6 for most PG function-related endpoints. Therefore, the contribution of Dmean SCR region to the risk of xerostomia was larger than predicted by Dmean PG. Other frequently selected predictors were pretreatment xerostomia and Dmean oral cavity. The validation showed good discrimination and calibration. CONCLUSIONS: Tools for clinical implementation of stem cell sparing RT were developed: regeneration-weighted dose to the parotid gland that accounted for regional differences in radiosensitivity within the gland and NTCP models that included this new dose metric and other prognostic factors.

Physics Considerations for Evaluation of Dose for Dose-Response Models of Pediatric Late Effects From Radiation Therapy.

PURPOSE: We describe the methods used to estimate the accuracy of dosimetric data found in literature sources used to construct the Pediatric Normal Tissue Effects in the Clinic (PENTEC) dose-response models, summarize these findings of each organ-specific task force, describe some of the dosimetric challenges and the extent to which these efforts affected the final modeling results, and provide guidance on the interpretation of the dose-response results given the various dosimetric uncertainties. METHODS AND MATERIALS: Each of the PENTEC task force medical physicists reviewed all the journal articles used for dose-response modeling to identify, categorize, and quantify dosimetric uncertainties. These uncertainties fell into 6 broad categories. A uniform nomenclature was developed for describing the "dosimetric quality" of the articles used in the PENTEC reviews. Among the multidisciplinary experts in the PENTEC effort, the medical physicists were charged with the dosimetric evaluation, as they are most expert in this subject. RESULTS: The percentage dosimetric uncertainty was estimated for each late effect endpoint for all PENTEC organ reports. Twelve specific sources of dose uncertainty were identified related to the 6 broad categories. The most common reason for organ dose uncertainty was that prescribed dose rather than organ dose was reported. Percentage dose uncertainties ranged from 5% to 200%. Systematic uncertainties were used to correct the dose component of the models. Random uncertainties were also described in each report and in some cases used to modify dose axis error bars. In addition, the potential effects of dose binning were described. CONCLUSIONS: PENTEC reports are designed to provide guidance to radiation oncologists and treatment planners for organ dose constraints. It is critical that these dose constraint recommendations are as accurate as possible, acknowledging the large error bars for many. Achieving this accuracy is important as it enables clinicians to better balance target dose coverage with risk of late effects. Evidence-based dose constraints for pediatric patients have been lacking and, in this regard, PENTEC fills an important unmet need. One must be aware of the limitations of our recommendations, and that for some organ systems, large uncertainties exist in the dose-response model because of clinical endpoint uncertainty, dosimetric uncertainty, or both.

Radiation-induced cardiac side-effects: The lung as target for interacting damage and intervention.

Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated. The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable.

Late cardiac toxicity of neo-adjuvant chemoradiation in esophageal cancer survivors: A prospective cross-sectional pilot study.

PURPOSE: Although cure rates in esophageal cancer (EC) have improved since the introduction of neoadjuvant chemoradiation (nCRT), evidence for treatment-related cardiac toxicity is growing, of which the exact mechanisms remain unknown. The primary objective of this study was to identify (subclinical) cardiac dysfunction in EC patients after nCRT followed by surgical resection as compared to surgery alone. MATERIALS AND METHODS: EC survivors followed for 5-15 years after curative resection with (n = 20) or without (n = 20) nCRT were enrolled in this prospective cross-sectional pilot study. All patients underwent several clinical and diagnostic tests in order to objectify (sub)clinical cardiac toxicity including cardiac CT and MRI, echocardiography, ECG, 6-minutes walking test, physical examination and EORTC questionnaires. RESULTS: We found an increased rate of myocardial fibrosis (Linear late gadolinium enhancement (LGE) 4 vs. 1; p = 0.13; mean extracellular volume (ECV) 28.4 vs. 24.0; p < 0.01), atrial fibrillation (AF) (6 vs. 2; p = 0.07) and conduction changes in ECG among patients treated with nCRT as compared to those treated with surgery alone. The results suggested an impact on quality of life in terms of worse role functioning for this patient group (95.0 vs. 88.8; p = 0.03). CONCLUSION: Based on our analyses we hypothesize that in EC patients, radiation-induced myocardial fibrosis plays a central role in cardiac toxicity leading to AF, conduction changes and ultimately to decreased role functioning. The results emphasize the need to verify these findings in larger cohorts of patients.

Parotid Gland Stem Cell Sparing Radiation Therapy for Patients With Head and Neck Cancer: A Double-Blind Randomized Controlled Trial.

PURPOSE: Radiation therapy for head and neck cancer frequently leads to salivary gland damage and subsequent xerostomia. The radiation response of the parotid glands of rats, mice, and patients critically depends on dose to parotid gland stem cells, mainly located in the gland's main ducts (stem cell rich [SCR] region). Therefore, this double-blind randomized controlled trial aimed to test the hypothesis that parotid gland stem cell sparing radiation therapy preserves parotid gland function better than currently used whole parotid gland sparing radiation therapy. METHODS AND MATERIALS: Patients with head and neck cancer (n = 102) treated with definitive radiation therapy were randomized between standard parotid-sparing and stem cell sparing (SCS) techniques. The primary endpoint was >75% reduction in parotid gland saliva production compared with pretreatment production (FLOW12M). Secondary endpoints were several aspects of xerostomia 12 months after treatment. RESULTS: Fifty-four patients were assigned to the standard arm and 48 to the SCS arm. Only dose to the SCR regions (contralateral 16 and 11 Gy [P = .004] and ipsilateral 26 and 16 Gy [P = .001] in the standard and SCS arm, respectively) and pretreatment patient-rated daytime xerostomia (35% and 13% [P = .01] in the standard and SCS arm, respectively) differed significantly between the arms. In the SCS arm, 1 patient (2.8%) experienced FLOW12M compared with 2 (4.9%) in the standard arm (P = 1.00). However, a trend toward better relative parotid gland salivary function in favor of SCS radiation therapy was shown. Moreover, multivariable analysis showed that mean contralateral SCR region dose was the strongest dosimetric predictor for moderate-to-severe patient-rated daytime xerostomia and grade ≥2 physician-rated xerostomia, the latter including reported alteration in diet. CONCLUSIONS: No significantly better parotid function was observed in SCS radiation therapy. However, additional multivariable analysis showed that dose to the SCR region was more predictive of the development of parotid gland function-related xerostomia endpoints than dose to the entire parotid gland.

Salivary and Dental Complications in Childhood Cancer Survivors Treated With Radiation Therapy to the Head and Neck: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) Comprehensive Review.

PURPOSE: Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children. MATERIALS & METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. RESULTS: Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT. CONCLUSIONS: This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses <20 Gy in patients <4 years old.

Radiation-Induced Myocardial Fibrosis in Long-Term Esophageal Cancer Survivors.

PURPOSE: Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC). METHODS AND MATERIALS: Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis. RESULTS: Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 ± 8.1 (nCRT) and 122 ± 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups. CONCLUSIONS: Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis.

Regional Responses in Radiation-Induced Normal Tissue Damage.

Normal tissue side effects remain a major concern in radiotherapy. The improved precision of radiation dose delivery of recent technological developments in radiotherapy has the potential to reduce the radiation dose to organ regions that contribute the most to the development of side effects. This review discusses the contribution of regional variation in radiation responses in several organs. In the brain, various regions were found to contribute to radiation-induced neurocognitive dysfunction. In the parotid gland, the region containing the major ducts was found to be critical in hyposalivation. The heart and lung were each found to exhibit regional responses while also mutually affecting each other's response to radiation. Sub-structures critical for the development of side effects were identified in the pancreas and bladder. The presence of these regional responses is based on a non-uniform distribution of target cells or sub-structures critical for organ function. These characteristics are common to most organs in the body and we therefore hypothesize that regional responses in radiation-induced normal tissue damage may be a shared occurrence. Further investigations will offer new opportunities to reduce normal tissue side effects of radiotherapy using modern and high-precision technologies.

Combining Clinical and Dosimetric Features in a PBS Proton Therapy Cohort to Develop a NTCP Model for Radiation-Induced Optic Neuropathy.

PURPOSE: Radiation-induced optic neuropathy (RION) is a rare, yet severe complication following radiation therapy for brain, head and neck, or skull-base tumors. Although several risk factors, such as age, metabolic syndrome, and delivered dose, have been identified, we aimed at expanding the understanding of the mechanisms of interplay regarding dosimetry and patient variables leading to the onset of RION with a focus on proton therapy. METHODS AND MATERIALS: In this retrospective study, we have investigated proton-specific risk factors by comparing common phenomenological normal tissue complication probability models with a multivariate analysis that includes clinical features on a cohort of patients with skull-base and head and neck cancer treated with pencil beam scanning. RESULTS: Although predictive power of the Lyman-Kutcher-Burman and Poisson models was limited for this data set, the addition of clinical variables such as age, tumor involvement, hypertension, or sex remarkably increased model performance. CONCLUSIONS: Based on our assessment, the maximum dose in the optical apparatus is confirmed the most intuitive risk factor. However, above a certain dose threshold, clinical patient characteristics are the deciding factors for the onset of RION. We observed a tendency toward a volume effect that, if confirmed, would imply a benefit for high precision radiation therapy techniques such as proton therapy for the treatment of patients with high clinical risk for RION.

Mouse parotid salivary gland organoids for the in vitro study of stem cell radiation response.

OBJECTIVE: Hyposalivation-related xerostomia is an irreversible, untreatable, and frequent condition after radiotherapy for head and neck cancer. Stem cell therapy is an attractive option of treatment, but demands knowledge of stem cell functioning. Therefore, we aimed to develop a murine parotid gland organoid model to explore radiation response of stem cells in vitro. MATERIALS AND METHODS: Single cells derived from murine parotid gland organoids were passaged in Matrigel with defined medium to assess self-renewal and differentiation potential. Single cells were irradiated and plated in a 3D clonogenic stem cell survival assay to assess submandibular and parotid gland radiation response. RESULTS: Single cells derived from parotid gland organoids were able to extensively self-renew and differentiate into all major tissue cell types, indicating the presence of potential stem cells. FACS selection for known salivary gland stem cell markers CD24/CD29 did not further enrich for stem cells. The parotid gland organoid-derived stem cells displayed radiation dose-response curves similar to the submandibular gland. CONCLUSIONS: Murine parotid gland organoids harbor stem cells with long-term expansion and differentiation potential. This model is useful for mechanistic studies of stem cell radiation response and suggests similar radiosensitivity for the parotid and submandibular gland organoids.

Prevention and treatment of radiotherapy-induced side effects.

Radiotherapy remains a mainstay of cancer treatment, being used in roughly 50% of patients. The precision with which the radiation dose can be delivered is rapidly improving. This precision allows the more accurate targeting of radiation dose to the tumor and reduces the amount of surrounding normal tissue exposed. Although this often reduces the unwanted side effects of radiotherapy, we still need to further improve patients' quality of life and to escalate radiation doses to tumors when necessary. High-precision radiotherapy forces one to choose which organ or functional organ substructures should be spared. To be able to make such choices, we urgently need to better understand the molecular and physiological mechanisms of normal tissue responses to radiotherapy. Currently, oversimplified approaches using constraints on mean doses, and irradiated volumes of normal tissues are used to plan treatments with minimized risk of radiation side effects. In this review, we discuss the responses of three different normal tissues to radiotherapy: the salivary glands, cardiopulmonary system, and brain. We show that although they may share very similar local cellular processes, they respond very differently through organ-specific, nonlocal mechanisms. We also discuss how a better knowledge of these mechanisms can be used to treat or to prevent the effects of radiotherapy on normal tissue and to optimize radiotherapy delivery.

Can we safely reduce the radiation dose to the heart while compromising the dose to the lungs in oesophageal cancer patients?

PURPOSE: The aim of this study was to evaluate which clinical and treatment-related factors are associated with heart and lung toxicity in oesophageal cancer patients treated with chemoradiation (CRT). The secondary objective was to analyse whether these toxicities are associated with overall survival (OS). MATERIALS AND METHODS: The study population consisted of a retrospective cohort of 216 oesophageal cancer patients treated with curative CRT. Clinical and treatment related factors were analysed for OS and new pulmonary and cardiac events by multivariable regression analyses. The effect of these toxicities on OS was assessed by Kaplan Meyer analyses. RESULTS: Multivariable analysis revealed that pulmonary toxicity was best predicted by the mean lung dose. Cardiac complications were diverse; the most frequently occurring complication was pericardial effusion. Several cardiac dose parameters correlated with this endpoint. Patients developing radiation pneumonitis had significantly worse OS than patients without radiation pneumonitis, while no difference was observed in OS between patients with and without pericardial effusion. OS was best predicted by the V45 of the lung and tumour stage. None of the cardiac dose parameters predicted OS in multivariable analyses. CONCLUSION: Cardiac dose volume parameters predicted the risk of pericardial effusion and pulmonary dose volume parameters predicted the risk of radiation pneumonitis. However, in this patient cohort, pulmonary DVH parameters (V45) were more important for OS than cardiac DVH parameters. These results suggest that reducing the cardiac dose at the expense of the dose to the lungs might not always be a good strategy in oesophageal cancer patients.

The Acute and Early Effects of Whole-Brain Irradiation on Glial Activation, Brain Metabolism, and Behavior: a Positron Emission Tomography Study.

PURPOSE: Radiotherapy is a frequently applied treatment modality for brain tumors. Concomitant irradiation of normal brain tissue can induce various physiological responses. The aim of this study was to investigate whether acute and early-delayed effects of brain irradiation on glial activation and brain metabolism can be detected with positron emission tomography (PET) and whether these effects are correlated with behavioral changes. PROCEDURES: Rats underwent 0-, 10-, or 25-Gy whole-brain irradiation. At 3 and 31 days post irradiation, 1-(2-chlorophenyl)-N-[11C]methyl-(1-methylpropyl)-3-isoquinoline carboxamide ([11C]PK11195) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) PET scans were acquired to detect changes in glial activation (neuroinflammation) and glucose metabolism, respectively. The open-field test (OFT) was performed on days 6 and 27 to assess behavioral changes. RESULTS: Twenty-five-gray-irradiated rats showed higher [11C]PK11195 uptake in most brain regions than controls on day 3 (striatum, hypothalamus, accumbens, septum p < 0.05), although some brain regions had lower uptake (cerebellum, parietal association/retrosplenial visual cortex, frontal association/motor cortex, somatosensory cortex, p < 0.05). On day 31, several brain regions in 25-Gy-irradiated rats still showed significantly higher [11C]PK11195 uptake than controls and 10-Gy-irradiated group (p < 0.05). Within-group analysis showed that [11C]PK11195 uptake in individual brain regions of 25-Gy treated rats remained stable or slightly increased between days 3 and 31. In contrast, a significant reduction (p < 0.05) in tracer uptake between days 3 and 31 was found in all brain areas of controls and 10-Gy-irradiated animals. Moreover, 10-Gy treatment led to a significantly higher [18F]FDG uptake on day 3 (p < 0.05). [18F]FDG uptake decreased between days 3 and 31 in all groups; no significant differences between groups were observed anymore on day 31, except for increased uptake in the hypothalamus in the 10-Gy group. The OFT did not show any significant differences between groups. CONCLUSIONS: Non-invasive PET imaging indicated that brain irradiation induces neuroinflammation and a metabolic flare, without causing acute or early-delayed behavioral changes.

In vitro biological response of cancer and normal tissue cells to proton irradiation not affected by an added magnetic field.

To optimize beam delivery and conformality of proton therapy, MRI integration has been proposed. Therefore, we investigated if proton irradiation in a magnetic field would change biological responses. Our data in cancer cell lines and stem cell-derived organoid models suggest that a magnetic field does not modify the biological response.

Cardiac Function After Radiation Therapy for Breast Cancer.

PURPOSE: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT). METHODS AND MATERIALS: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function. RESULTS: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint. CONCLUSIONS: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.