CD103+ regulatory T cells underlie resistance to radio-immunotherapy and impair CD8+ T cell activation in glioblastoma.

Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.

Study protocol: PreOperative Brain Irradiation in Glioblastoma (POBIG) - A phase I trial.

Background: Glioblastoma is a high-grade aggressive neoplasm whose outcomes have not changed in decades. In the current treatment pathway, tumour growth continues and remains untreated for several weeks post-diagnosis. Intensified upfront therapy could target otherwise untreated tumour cells and improve the treatment outcome. POBIG will evaluate the safety and feasibility of single-fraction preoperative radiotherapy for newly diagnosed glioblastoma, assessed by the maximum tolerated dose (MTD) and maximum tolerated irradiation volume (MTIV). Methods: POBIG is an open-label, dual-centre phase I dose and volume escalation trial that has received ethical approval. Patients with a new radiological diagnosis of glioblastoma will be screened for eligibility. This is deemed sufficient due to the high accuracy of imaging and to avoid treatment delay. Eligible patients will receive a single fraction of preoperative radiotherapy ranging from 6 to 14 Gy followed by their standard of care treatment comprising maximal safe resection and postoperative chemoradiotherapy (60 Gy/30 fr) with concurrent and adjuvant temozolomide). Preoperative radiotherapy will be directed to the part of the tumour that is highest risk for remaining as postoperative residual disease (hot spot). Part of the tumour will remain unirradiated (cold spot) and sampled separately for diagnostic purposes. Dose/volume escalation will be guided by a Continual Reassessment Method (CRM) model. Translational opportunities will be afforded through comparison of irradiated and unirradiated primary glioblastoma tissue. Discussion: POBIG will help establish the role of radiotherapy in preoperative modalities for glioblastoma. Trial registration: NCT03582514 (clinicaltrials.gov).

Visualising spatial heterogeneity in glioblastoma using imaging habitats.

Glioblastoma is a high-grade aggressive neoplasm characterised by significant intra-tumoral spatial heterogeneity. Personalising therapy for this tumour requires non-invasive tools to visualise its heterogeneity to monitor treatment response on a regional level. To date, efforts to characterise glioblastoma's imaging features and heterogeneity have focussed on individual imaging biomarkers, or high-throughput radiomic approaches that consider a vast number of imaging variables across the tumour as a whole. Habitat imaging is a novel approach to cancer imaging that identifies tumour regions or 'habitats' based on shared imaging characteristics, usually defined using multiple imaging biomarkers. Habitat imaging reflects the evolution of imaging biomarkers and offers spatially preserved assessment of tumour physiological processes such perfusion and cellularity. This allows for regional assessment of treatment response to facilitate personalised therapy. In this review, we explore different methodologies to derive imaging habitats in glioblastoma, strategies to overcome its technical challenges, contrast experiences to other cancers, and describe potential clinical applications.

Re-purposing the pro-senescence properties of doxorubicin to introduce immunotherapy in breast cancer brain metastasis.

An increasing number of breast cancer patients develop brain metastases (BM). Standard-of-care treatments are largely inefficient, and breast cancer brain metastasis (BCBM) patients are considered untreatable. Immunotherapies are not successfully employed in BCBM, in part because breast cancer is a "cold" tumor and also because the brain tissue has a unique immune landscape. Here, we generate and characterize immunocompetent models of BCBM derived from PyMT and Neu mammary tumors to test how harnessing the pro-senescence properties of doxorubicin can be used to prime the specific immune BCBM microenvironment. We reveal that BCBM senescent cells, induced by doxorubicin, trigger the recruitment of PD1-expressing T cells to the brain. Importantly, we demonstrate that induction of senescence with doxorubicin improves the efficacy of immunotherapy with anti-PD1 in BCBM in a CD8 T cell-dependent manner, thereby providing an optimized strategy to introduce immune-based treatments in this lethal disease. In addition, our BCBM models can be used for pre-clinical testing of other therapeutic strategies in the future.

Rapid early progression (REP) of glioblastoma is an independent negative prognostic factor: Results from a systematic review and meta-analysis.

Background: In patients with newly diagnosed glioblastoma, rapid early progression (REP) refers to tumor regrowth between surgery and postoperative chemoradiotherapy. This systematic review and meta-analysis appraised previously published data on REP to better characterize and understand it. Methods: Systematic searches of MEDLINE, EMBASE and the Cochrane database from inception to October 21, 2021. Studies describing the incidence of REP-tumor growth between the postoperative MRI scan and pre-radiotherapy MRI scan in newly diagnosed glioblastoma were included. The primary outcome was REP incidence. Results: From 1590 search results, 9 studies were included with 716 patients. The median age was 56.9 years (IQR 54.0-58.8 y). There was a male predominance with a median male-to-female ratio of 1.4 (IQR 1.1-1.5). The median number of days between MRI scans was 34 days (IQR 18-45 days). The mean incidence rate of REP was 45.9% (range 19.3%-72.0%) and significantly lower in studies employing functional imaging to define REP (P < .001). REP/non-REP groups were comparable with respect to age (P = .99), gender (P = .33) and time between scans (P = .81). REP was associated with shortened overall survival (HR 1.78, 95% CI 1.30-2.43, P < .001), shortened progression-free survival (HR 1.78, 95% CI 1.30-2.43, P < .001), subtotal resection (OR 6.96, 95% CI 4.51-10.73, P < .001) and IDH wild-type versus mutant tumors (OR 0.20, 95% CI 0.02-0.38, P = .03). MGMT promoter methylation was not associated with REP (OR 1.29, 95% CI 0.72-2.28, P = .39). Conclusions: REP occurs in almost half of patients with newly diagnosed glioblastoma and has a strongly negative prognostic effect. Future studies should investigate its biology and effective treatment strategies.

Protocol for live-cell imaging during Tumor Treating Fields treatment with Inovitro Live.

Tumor Treating Fields (TTFields) are an FDA-approved anticancer treatment using alternating electric fields. Here, we present a protocol to perform live-cell imaging (LCI) of cells during TTFields treatment with the Inovitro LiveTM system. The setup we describe dissipates TTFields-related heat production and can be used in conjunction with any LCI-compatible microscope setup. This approach will enable further elucidation of TTFields' mechanism of action at the molecular level and facilitate the development of promising combination strategies.

Estimating the percentage of patients who might benefit from proton beam therapy instead of X-ray radiotherapy.

OBJECTIVES: High-energy Proton Beam Therapy (PBT) commenced in England in 2018 and NHS England commissions PBT for 1.5% of patients receiving radical radiotherapy. We sought expert opinion on the level of provision. METHODS: Invitations were sent to 41 colleagues working in PBT, most at one UK centre, to contribute by completing a spreadsheet. 39 responded: 23 (59%) completed the spreadsheet; 16 (41%) declined, arguing that clinical outcome data are lacking, but joined six additional site-specialist oncologists for two consensus meetings. The spreadsheet was pre-populated with incidence data from Cancer Research UK and radiotherapy use data from the National Cancer Registration and Analysis Service. 'Mechanisms of Benefit' of reduced growth impairment, reduced toxicity, dose escalation and reduced second cancer risk were examined. RESULTS: The most reliable figure for percentage of radical radiotherapy patients likely to benefit from PBT was that agreed by 95% of the 23 respondents at 4.3%, slightly larger than current provision. The median was 15% (range 4-92%) and consensus median 13%. The biggest estimated potential benefit was from reducing toxicity, median benefit to 15% (range 4-92%), followed by dose escalation median 3% (range 0 to 47%); consensus values were 12 and 3%. Reduced growth impairment and reduced second cancer risk were calculated to benefit 0.5% and 0.1%. CONCLUSIONS: The most secure estimate of percentage benefit was 4.3% but insufficient clinical outcome data exist for confident estimates. The study supports the NHS approach of using the evidence base and developing it through randomised trials, non-randomised studies and outcomes tracking. ADVANCES IN KNOWLEDGE: Less is known about the percentage of patients who may benefit from PBT than is generally acknowledged. Expert opinion varies widely. Insufficient clinical outcome data exist to provide robust estimates. Considerable further work is needed to address this, including international collaboration; much is already underway but will take time to provide mature data.

Early Therapeutic Interventions for Newly Diagnosed Glioblastoma: Rationale and Review of the Literature.

PURPOSE OF REVIEW: Glioblastoma is the commonest primary brain cancer in adults whose outcomes are amongst the worst of any cancer. The current treatment pathway comprises surgery and postoperative chemoradiotherapy though unresectable diffusely infiltrative tumour cells remain untreated for several weeks post-diagnosis. Intratumoural heterogeneity combined with increased hypoxia in the postoperative tumour microenvironment potentially decreases the efficacy of adjuvant interventions and fails to prevent early postoperative regrowth, called rapid early progression (REP). In this review, we discuss the clinical implications and biological foundations of post-surgery REP. Subsequently, clinical interventions potentially targeting this phenomenon are reviewed systematically. RECENT FINDINGS: Early interventions include early systemic chemotherapy, neoadjuvant immunotherapy, local therapies delivered during surgery (including Gliadel wafers, nanoparticles and stem cell therapy) and several radiotherapy techniques. We critically appraise and compare these strategies in terms of their efficacy, toxicity, challenges and potential to prolong survival. Finally, we discuss the most promising strategies that could benefit future glioblastoma patients. There is biological rationale to suggest that early interventions could improve the outcome of glioblastoma patients and they should be investigated in future trials.

Preoperative Stereotactic Radiosurgery for Glioblastoma.

Glioblastoma is a devastating primary brain tumor with a median overall survival of approximately 15 months despite the use of optimal modern therapy. While GBM has been studied for decades, modern therapies have allowed for a reduction in treatment-related toxicities, while the prognosis has largely been unchanged. Adjuvant stereotactic radiosurgery (SRS) was previously studied in GBM; however, the results were disappointing. SRS is a highly conformal radiation technique that permits the delivery of high doses of ionizing radiation in 1-5 sessions while largely sparing surrounding healthy tissues. Furthermore, studies have shown that the delivery of ablative doses of ionizing radiation within the central nervous system is associated with enhanced anti-tumor immunity. While SRS is commonly used in the definitive and adjuvant settings for other CNS malignancies, its role in the preoperative setting has become a topic of great interest due to the potential for reduced treatment volumes due to the treatment of an intact tumor, and a lower risk of nodular leptomeningeal disease and radiation necrosis. While early reports of SRS in the adjuvant setting for glioblastoma were disappointing, its role in the preoperative setting and its impact on the anti-tumor adaptive immune response is largely unknown. In this review, we provide an overview of GBM, discuss the potential role of preoperative SRS, and discuss the possible immunogenic effects of this therapy.

The impact of anatomical changes during photon or proton based radiation treatment on tumor dose in glioblastoma dose escalation trials.

PURPOSE/OBJECTIVE: Most dose-escalation trials in glioblastoma patients integrate the escalated dose throughout the standard course by targeting a specific subvolume. We hypothesize that anatomical changes during irradiation may affect the dose coverage of this subvolume for both proton- and photon-based radiotherapy. MATERIAL AND METHODS: For 24 glioblastoma patients a photon- and proton-based dose escalation treatment plan (of 75 Gy/30 fr) was simulated on the dedicated radiotherapy planning MRI obtained before treatment. The escalated dose was planned to cover the resection cavity and/or contrast enhancing lesion on the T1w post-gadolinium MRI sequence. To analyze the effect of anatomical changes during treatment, we evaluated on an additional MRI that was obtained during treatment the changes of the dose distribution on this specific high dose region. RESULTS: The median time between the planning MRI and additional MRI was 26 days (range 16-37 days). The median time between the planning MRI and start of radiotherapy was relatively short (7 days, range 3-11 days). In 3 patients (12.5%) changes were observed which resulted in a substantial deterioration of both the photon and proton treatment plans. All these patients underwent a subtotal resection, and a decrease in dose coverage of more than 5% and 10% was observed for the photon- and proton-based treatment plans, respectively. CONCLUSION: Our study showed that only for a limited number of patients anatomical changes during photon or proton based radiotherapy resulted in a potentially clinically relevant underdosage in the subvolume. Therefore, volume changes during treatment are unlikely to be responsible for the negative outcome of dose-escalation studies.

PSMA-11-PET/CT versus choline-PET/CT to guide stereotactic ablative radiotherapy for androgen deprivation therapy deferral in patients with oligometastatic prostate cancer.

BACKGROUND: In patients with oligometastatic recurrent prostate cancer, standard treatment is androgen deprivation therapy (ADT). However, ADT has many potential side effects that may result in impaired quality of life. Early identification to select patients suitable for stereotactic ablative radiotherapy (SABR) is of utmost importance to prevent or delay start of ADT and its side effects. Because Prostate-Specific Membrane Antigen-11-Positron Emission Tomography (PSMA-11-PET) has a higher sensitivity than choline-PET, we hypothesise that PSMA-11-PET based SABR results in longer response duration and subsequent longer delay in starting ADT than choline-PET. METHODS: Patients with oligometastatic (≤4 metastases) recurrent prostate cancer (with no local recurrence) based on PSMA-11-PET or choline-PET treated with SABR from January 2012 until December 2017 were included. Primary endpoint was ADT-free survival. Secondary endpoints were Prostate Specific Antigen (PSA) response after SABR and time to PSA rise after SABR. RESULTS: Fifty patients (n = 40 PSMA-11-PET and n = 10 choline-PET) with in total 72 lesions were included. Median follow-up was 24.3 months. PSMA-11-PET enabled eligibility of patients with lower PSA levels than choline-PET (median 1.8 versus 4.2 ng/mL, p = 0.03). The PSMA-11-PET group had a significant longer PSA response duration (median 34.0 months (95% confidence interval (CI), 16.0-52.0) versus 14.7 months (95% CI 4.7-24.7), p = 0.004) with a subsequent longer ADT-free survival (median 32.7 months (95% CI, 20.8-44.5) versus 14.9 months (95% CI, 5.7-24.1), p = 0.01). CONCLUSIONS: With PSMA-11-PET we are able to select patients with oligometastatic recurrent prostate cancer suitable for SABR in an earlier disease stage at lower PSA levels. PSMA-11-PET guided SABR resulted in a significant longer response duration and ADT-free survival compared with choline-PET and can therefore prevent or delay ADT related side effects.

[Treatment options for patients with brain metastases: The choice of treatment demands special attention]. / Behandelopties voor patiënten met hersenmetastasen.

The incidence and survival of patients with brain metastases is increasing which stresses the importance of treatment decisions regarding local control and toxicity. Unfortunately, the literature (that usually forms the backbone of treatment guidelines) encompasses mostly retrospective analysis of a wide variety of cancers and clinical presentations, and only limited data of the intracranial effects of novel systemic agents is available. The extrapolation of the literature to the individual patient should therefore be done with caution. For example, until more reliable prediction models are available, treatment guidelines should better avoid categorization of patients according to cut-off values (e.g. tumor size or number of metastases) to prevent suboptimal treatment decisions. For each patient the multidisciplinary team has to take all the individual factors that determine the prognosis into account and discuss the best options regarding symptomatology, local control and toxicity. This approach secures a tailored and optimised treatment strategy for every patient.

The role of alexithymia and empathy on radiation therapists' professional quality of life.

BACKGROUND AND PURPOSE: Physical and mental well-being are crucial for oncology professionals as they affect performance at work. Personality traits, as alexithymia and empathy, may influence professional quality of life. Alexithymia involves diminished skills in emotion processing and awareness. Empathy is pertinent to the ability to understand another's 'state of mind/emotion'. The PROject on Burn-Out in RadiatioN Oncology (PRO BONO) investigates professional quality of life amongst radiation oncology professionals, exploring the role of alexithymia and empathy. The present study reports on data pertinent to radiation therapists (RTTs). MATERIAL AND METHODS: An online survey targeted ESTRO members. Participants were asked to fill out 3 questionnaires for alexithymia, empathy and professional quality of life: (a) Toronto Alexithymia Scale (TAS-20); (b) Interpersonal Reactivity Index (IRI); (c) Professional Quality of Life Scale (ProQoL). The present analysis focuses on RTTS to evaluate compassion satisfaction (CS), secondary traumatic stress (STS) and Burnout and their correlation with alexithymia and empathy, using generalized linear modeling. Covariates found significant at univariate linear regression analysis were included in the multivariate linear regression model. RESULTS: A total of 399 RTTs completed all questionnaires. The final model for the burnout scale of ProQoL found, as significal predictors, the TAS-20 total score (ß = 0.46, p < 0 0.001), and the individual's perception of being valued by supervisor (ß = -0.29, p < 0.001). With respect to CS, the final model included TAS-20 total score (ß = -0.33, p < 0.001), the Empatic Concern domain (ß = 0.23, p < 0.001) of the IRI questionnaire and the individual's perception of being valued by colleagues (ß = 0.22, p < 0.001). CONCLUSIONS: Alexithymia increased the likelyhood to experience burnout and negatively affected the professional quality of life amongst RTTs working in oncology. Empathy resulted in higher professional fulfillment together with collegaues' appreciation. These results may be used to benchmark preventing strategies and implement organization-direct and/or individual-directed interventions.

Professional quality of life and burnout amongst radiation oncologists: The impact of alexithymia and empathy.

BACKGROUND AND PURPOSE: Different factors may influence the professional quality of life of oncology professionals. Among them, personality traits, as alexithymia and empathy, are underinvestigated. Alexithymia is about deficits in emotion processing and awareness. Empathy is the ability to understand another's 'state of mind'/emotion. The PROject on BurnOut in RadiatioN Oncology (PRO BONO) assesses professional quality of life, including burnout, in the field of radiation oncology and investigates alexithymia and empathy as contributing factors. MATERIAL AND METHODS: An online survey was conducted amongst ESTRO members. Participants completed 3 validated questionnaires for alexithymia, empathy and professional quality of life: (a) Toronto Alexithymia Scale; (b) Interpersonal Reactivity Index; (c) Professional Quality of Life Scale. The present analysis, focusing on radiation/clinical oncologists, evaluates Compassion Satisfaction (CS), Secondary Traumatic Stress (STS) and Burnout and correlates them with alexithymia and empathy (empathic concern, perspective taking and personal distress) with generalized linear modeling. Significant covariates on univariate linear regression analysis were included in the multivariate linear regression model. RESULTS: A total of 825 radiation oncologists completed all questionnaires. A higher level of alexithymia was associated to decreased CS (ß: -0.101; SE: 0.018; p < 0.001), increased STS (ß: 0.228; SE: 0.018; p < 0.001) and burnout (ß: 0.177; SE: 0.016; p < 0.001). A higher empathic concern was significantly associated to increased CS (ß: 0.1.287; SE: 0.305; p = 0.001), STS (ß: 0.114; SE: 0.296; p < 0.001), with no effect on burnout. Personal distress was associated to decreased CS (ß: -1.423; SE: 0.275; p < 0.001), increased STS (ß: 1.871; SE: 0.283; p < 0.001) and burnout (ß: 1.504; SE: 0.245; p < 0.001). CONCLUSIONS: Alexithymic personality trait increased burnout risk, with less professional satisfaction. Empathic concern was associated to increased stress, without leading to burnout, resulting in higher professional fulfillment. These results may be used to benchmark preventing strategies, such as work-hour restrictions, peer support, debriefing sessions, and leadership initiatives for professionals at risk.

Correction: Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.

[This corrects the article DOI: 10.18632/oncotarget.20936.].

Professional quality of life and burnout among medical physicists working in radiation oncology: The role of alexithymia and empathy.

BACKGROUND AND PURPOSE: The professional quality of life of radiation oncology professionals can be influenced by different contributing factors, including personality traits. Alexithymia involves deficits in emotion processing and awareness. Empathy is the ability to understand another's 'state of mind/emotion'. We investigated professional quality of life, including burnout, in radiation oncology, exploring the role of alexithymia and empathy and targeting the population of medical physicists (MPs), since this professional category is usually underrepresented in surveys exploring professional well-being in radiation oncology and MPs may experience professional distress given the increasing complexity of multimodal cancer care. MATERIAL AND METHODS: An online survey was addressed to ESTRO members. Participants filled out three questionnaires to evaluate alexithymia, empathy and professional quality of life: a) Toronto Alexithymia Scale (TAS-20); b) Interpersonal Reactivity Index (IRI); c) Professional Quality of Life Scale (ProQoL). Professional quality of life as per ProQoL was considered as dependent variable. The three domains of the ProQoL, namely compassion satisfaction (CS), secondary traumatic stress (STS) and burnout were correlated with alexithymia (as per TAS-20) and empathy (as per IRI with three subcategories: empathic concern, perspective taking and personal distress) and demographic/professional characteristics as independent variables. Generalized linear modeling was used. Significant covariates on univariate linear regression analysis were included in the multivariate linear regression model. RESULTS: A total of 308 medical physicists completed all questionnaires. Alexithymia as per TAS-20 was correlated to decreased CS (ß = -0.25, p < 0 0.001), increased likelihood for STS (ß = 0.26, p < 0 0.001) and burnout (ß = 0.47, p < 0 0.001). With respect to empathy, the 'Empatic Concern' subscale of the IRI was found to be a significant predictor for increased CS (ß = 0.19, p = 0 0.001) and increased STS (ß = 0.19, p < 0 0.001), without significant correlation with burnout. The individual's perception of being valued by own's supervisor was correlated to increased CS (ß = 0.23, p < 0.001), and decreased burnout (ß = -0.29, p < 0.001). CONCLUSIONS: Alexithymic personality trait increased the likelihood to develop burnout, with less professional satisfaction amongst MPs working in radiation oncology. Empathy results in higher professional fulfilment. These results may be used to benchmark preventing strategies, including peer support, debriefing sessions, leadership initiatives and work-load limitation strategies.

Predicting and implications of target volume changes of brain metastases during fractionated stereotactic radiosurgery.

OBJECTIVE: To study the impact of target volume changes in brain metastases during fractionated stereotactic radiosurgery (fSRS) and identify patients that benefit from MRI guidance. MATERIAL AND METHODS: For 15 patients (18 lesions) receiving fSRS only (fSRSonly) and 19 patients (20 lesions) receiving fSRS postoperatively (fSRSpostop), a treatment planning MRI (MR0) and repeated MRI during treatment (MR1) were acquired. The impact of target volume changes on the target coverage was analyzed by evaluating the planned dose distribution (based on MR0) on the planning target volume (PTV) during treatment as defined on MR1. The predictive value of target volume changes before treatment (using the diagnostic MRI (MRD)) was studied to identify patients that experienced the largest changes during treatment. RESULTS: Target volume changes during fSRS did result in large declines of the PTV dose coverage up to -34.8% (median = 3.2%) for fSRSonly patients. For fSRSpostop the variation and declines were smaller (median PTV dose coverage change = -0.5% (-4.5% to 1.9%)). Target volumes changes did also impact the minimum dose in the PTV (fSRSonly; -2.7 Gy (-16.5 to 2.3 Gy), fSRSpostop; -0.4 Gy (-4.2 to 2.5 Gy)). Changes in target volume before treatment (i.e. seen between the MRD and MR0) predicted which patients experienced the largest dose coverage declines during treatment. CONCLUSION: Target volume changes in brain metastases during fSRS can result in worsening of the target dose coverage. Patients benefiting the most from a repeated MRI during treatment could be identified before treatment.

Evaluation of acute esophageal radiation-induced damage using magnetic resonance imaging: a feasibility study in mice.

BACKGROUND: Thoracic and head and neck cancer radiation therapy (RT) can cause damage to nearby healthy organs such as the esophagus, causing acute radiation-induced esophageal damage (ARIED). A non-invasive method to detect and monitor ARIED can facilitate optimizing RT to avoid ARIED while improving local tumor control. Current clinical guidelines are limited to scoring the esophageal damage based on the symptoms of patients. Magnetic resonance imaging (MRI) is a non-invasive imaging modality that may potentially visualize radiation-induced organ damage. We investigated the feasibility of using T2-weighted MRI to detect and monitor ARIED using a two-phased study in mice. METHODS: The first phase aimed to establish the optimal dose level at which ARIED is inducible and to determine the time points where ARIED is detectable. Twenty four mice received a single dose delivery of 20 and 40 Gy at proximal and distal spots of 10.0 mm (in diameter) on the esophagus. Mice underwent MRI and histopathology analysis with esophageal resection at two, three, and 4 weeks post-irradiation, or earlier in case mice had to be euthanized due to humane endpoints. In the second phase, 32 mice received a 40 Gy single dose and were studied at two, three, and 7 days post-irradiation. We detected ARIED as a change in signal intensity of the MRI images. We measured the width of the hyperintense area around the esophagus in all mice that underwent MRI prior to and after irradiation. We conducted a blind qualitative comparison between MRI findings and histopathology as the gold standard. RESULTS/CONCLUSIONS: A dose of 40 Gy was needed to induce substantial ARIED. MRI detected ARIED as high signal intensity, visible from 2 days post-irradiation. Quantitative MRI analysis showed that the hyperintense area around the esophagus with severe ARIED was 1.41 mm wider than with no damage and MRI-only mice. The overall sensitivity and specificity were 56 and 43% respectively to detect any form of ARIED. However, in this study MRI correctly detected 100% of severe ARIED cases. Our two-phased preclinical study showed that MRI has the potential to detect ARIED as a change in signal intensity and width of enhancement around the esophagus.

Optical coherence tomography to detect acute esophageal radiation-induced damage in mice: A validation study.

Radiation therapy for patients with non-small-cell lung cancer is hampered by acute radiation-induced toxicity in the esophagus. This study aims to validate that optical coherence tomography (OCT), a minimally invasive imaging technique with high resolution (~10 µm), is able to visualize and monitor acute radiation-induced esophageal damage (ARIED) in mice. We compare our findings with histopathology as the gold standard. Irradiated mice receive a single dose of 40 Gy at proximal and distal spots of the esophagus of 10.0 mm in diameter. We scan mice using OCT at two, three, and seven days post-irradiation. In OCT analysis, we define ARIED as a presence of distorted esophageal layering, change in backscattering signal properties, or change in the esophageal wall thickness. The average esophageal wall thickness is 0.53 mm larger on OCT when ARIED is present based on histopathology. The overall sensitivity and specificity of OCT to detect ARIED compared to histopathology are 94% and 47%, respectively. However, the overall sensitivity of OCT to assess ARIED is 100% seven days post-irradiation. We validate the capability of OCT to detect ARIED induced by high doses in mice. Nevertheless, clinical studies are required to assess the potential role of OCT to visualize ARIED in humans.

Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors.

The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and PARP inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identify radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells in vitro and in vivo. In contrast to the radioresistance caused by HR restoration through BRCA1 reconstitution, HR restoration by 53BP1 pathway inactivation further increases radiosensitivity. This highlights the relevance of this pathway for the repair of radiotherapy-induced damage. Moreover, our data show that BRCA1-mutated tumors that acquire drug resistance due to BRCA1-independent HR restoration can be targeted by radiotherapy. SIGNIFICANCE: These findings uncover radiosensitivity as a novel, therapeutically viable vulnerability of BRCA1-deficient mouse mammary cells that have acquired drug resistance due to the loss of the 53BP1 pathway.