Shifting the Immune-Suppressive to Predominant Immune-Stimulatory Radiation Effects by SBRT-PArtial Tumor Irradiation Targeting HYpoxic Segment (SBRT-PATHY)

Radiation-induced immune-mediated abscopal effects (AE) of conventional radiotherapy are very rare. Whole-tumor irradiation leads to lymphopenia due to killing of immune cells in the tumor microenvironment, resulting in immunosuppression and weak abscopal potential. This limitation may be overcome by partial tumor irradiation sparing the peritumoral immune-environment, and consequent shifting of immune-suppressive to immune-stimulatory effect. This would improve the radiation-directed tumor cell killing, adding to it a component of immune-mediated killing. Our preclinical findings showed that the high-single-dose irradiation of hypoxic tumor cells generates a stronger bystander effect (BE) and AE than the normoxic cells, suggesting their higher “immunogenic potential”. This led to the development of a novel Stereotactic Body RadioTherapy (SBRT)-based PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) for induction of the immune-mediated BE and AE. Encouraging SBRT-PATHY-clinical outcomes, together with immunohistochemical and gene-expression analyses of surgically removed abscopal-tumor sites, suggested that delivery of the high-dose radiation to the partial (hypoxic) tumor volume, with optimal timing based on the homeostatic fluctuation of the immune response and sparing the peritumoral immune-environment, would significantly enhance the immune-mediated anti-tumor effects. This review discusses the current evidence on the safety and efficacy of SBRT-PATHY in the treatment of unresectable hypoxic bulky tumors and its bystander and abscopal immunomodulatory potential.

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Targeted Radiotherapy: Microgray Doses and the Bystander Effect

Dose-Response ◽

10.2203/dose-response.07-002.mairs ◽

2007 ◽

Vol 5 (3) ◽

pp. dose-response.0 ◽

Cited By ~ 22

Author(s):

Robert J. Mairs ◽

Natasha E. Fullerton ◽

Michael R. Zalutsky ◽

Marie Boyd

Keyword(s):

Indirect Effects ◽

Bystander Effect ◽

High Dose ◽

Protective Effects ◽

Survival Fraction ◽

Bystander Effects ◽

High Let ◽

Radiation Induced ◽

Clonogenic Cell ◽

Dose Dependent

Indirect effects may contribute to the efficacy of radiotherapy by sterilizing malignant cells that are not directly irradiated. However, little is known of the influence of indirect effects in targeted radionuclide treatment. We compared γ-radiation-induced bystander effects with those resulting from exposure to three radiohaloanalogues of meta-iodobenzylguanidine (MIBG): [131I]MIBG (low linear energy transfer (LET) β-emitter), [123I]MIBG (high LET Auger electron emitter), and meta-[211At]astatobenzylguanidine ([211At]MABG) (high LET α-emitter). Cells exposed to media from γ-irradiated cells exhibited a dose-dependent reduction in survival fraction at low dosage and a plateau in cell kill at > 2 Gy. Cells treated with media from [131I]MIBG demonstrated a dose-response relationship with respect to clonogenic cell death and no annihilation of this effect at high radiopharmaceutical dosage. In contrast, cells receiving media from cultures treated with [211At]MABG or [123I]MIBG exhibited dose-dependent toxicity at low dose but elimination of cytotoxicity with increasing radiation dose (i.e. U-shaped survival curves). Therefore radionuclides emitting high LET radiation may elicit toxic or protective effects on neighboring untargeted cells at low and high dose respectively. We conclude that radiopharmaceutical-induced bystander effects may depend on LET and be distinct from those elicited by conventional radiotherapy.

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The radiation-induced bystander effect: evidence and significance

Human & Experimental Toxicology ◽

10.1191/0960327104ht418oa ◽

2004 ◽

Vol 23 (2) ◽

pp. 61-65 ◽

Cited By ~ 91

Author(s):

Edouard I Azzam ◽

John B Little

Keyword(s):

Ionizing Radiation ◽

Radiation Exposure ◽

Low Dose ◽

Bystander Effect ◽

Current Knowledge ◽

Biological Effects ◽

High Dose ◽

Adaptive Responses ◽

Radiation Induced

A multitude of biological effects observed over the past two decades in various in vivo and in vitro cell culture experiments have indicated that low dose/low fluence ionizing radiation has significantly different biological responses than high dose radiation. Exposure of cell populations to very low fluences of particles or incorporated radionuclides results in significant biological effects occurring in both the irradiated and nonirradiated cells in the population. Cells recipient of growth medium from irradiated cultures can also respond to the radiation exposure. This phenomenon, termed the ‘bystander response’, has been postulated to impact both the estimation of risks of exposure to ionizing radiation and radiotherapy. Amplification of radiation-induced cyto-toxic and genotoxic effects by the bystander effect is in contrast to the observations of adaptive responses, which are generally induced following exposure to low dose, low linear energy transfer radiation and which tend to attenuate radiation-induced damage. In this article, the evidence for existence of radiation-induced bystander effects and our current knowledge of the biochemical and molecular events involved in mediating these effects are described. Potential similarities between factors that mediate the radiation-induced bystander and adaptive responses are highlighted.

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Radiation-Induced Reactions in The Liver — Modulation of Radiation Effects by Lifestyle-Related Factors —

International Journal of Molecular Sciences ◽

10.3390/ijms19123855 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3855 ◽

Cited By ~ 4

Author(s):

Tetsuo Nakajima ◽

Yasuharu Ninomiya ◽

Mitsuru Nenoi

Keyword(s):

Radiation Effects ◽

Animal Experiments ◽

High Dose ◽

Acute Effects ◽

Related Factors ◽

Dose Irradiation ◽

Important Concern ◽

Radiation Induced ◽

Effects Of Radiation ◽

High Calorie

Radiation has a wide variety of effects on the liver. Fibrosis is a concern in medical fields as one of the acute effects of high-dose irradiation, such as with cancer radiotherapies. Cancer is also an important concern following exposure to radiation. The liver has an active metabolism and reacts to radiations. In addition, effects are modulated by many environmental factors, such as high-calorie foods or alcohol beverages. Adaptations to other environmental conditions could also influence the effects of radiation. Reactions to radiation may not be optimally regulated under conditions modulated by the environment, possibly leading to dysregulation, disease or cancer. Here, we introduce some reactions to ionizing radiation in the liver, as demonstrated primarily in animal experiments. In addition, modulation of radiation-induced effects in the liver due to factors such as obesity, alcohol drinking, or supplements derived from foods are reviewed. Perspectives on medical applications by modulations of radiation effects are also discussed.

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Non-Targeted Radiation Effects in Radiotherapy &Roles of Radiation-Induced Genomic Instability and of the Bystander Effect in Cancer Cure by Radiotherapy

Acta Oncologica ◽

10.1080/02841860152708260 ◽

2001 ◽

Vol 40 (8) ◽

pp. 976-980 ◽

Cited By ~ 7

Author(s):

Klaus-Rüdiger Trott

Keyword(s):

Genomic Instability ◽

Radiation Effects ◽

Bystander Effect ◽

Radiation Induced

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Bilateral dysthyroid compressive optic neuropathy responsive to teprotumumab

European Journal of Ophthalmology ◽

10.1177/1120672121991042 ◽

2021 ◽

pp. 112067212199104

Author(s):

Catherine J Hwang ◽

Erin E Nichols ◽

Brian H Chon ◽

Julian D Perry

Keyword(s):

Side Effects ◽

Optic Neuropathy ◽

Surgical Decompression ◽

Thyroid Eye Disease ◽

Eye Disease ◽

High Dose ◽

Compressive Optic Neuropathy ◽

Traditional Management ◽

Immune Mediated ◽

Orbital Radiation

Thyroid eye disease is an auto-immune mediated orbitopathy which can cause dysthyroid compressive optic neuropathy. Traditional management of active thyroid eye disease includes temporizing high-dose steroids, orbital radiation and surgical decompression, which each possess significant limitations and/or side effects. Teprotumumab is an IGF-IR inhibitor recently FDA-approved for active thyroid eye disease. The authors report reversal of bilateral dysthyroid compressive optic neuropathy managed medically utilizing teprotumumab.

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Nonepileptic Myoclonus in COVID-19: Case Report

The Neurohospitalist ◽

10.1177/19418744211004315 ◽

2021 ◽

pp. 194187442110043

Author(s):

Henly Hewan ◽

Annie Yang ◽

Aparna Vaddiparti ◽

Benison Keung

Keyword(s):

Case Report ◽

Critically Ill ◽

Recovery Phase ◽

Critically Ill Patient ◽

High Dose ◽

The Novel ◽

Neurological Manifestations ◽

Immune Mediated ◽

Novel Coronavirus ◽

Post Infectious

In late 2019, the novel coronavirus, SARS-CoV-2, and the disease it causes, COVID-19, was identified. Since then many different neurological manifestations of COVID-19 have been well reported. Movement abnormalities have been rarely described. We report here a critically ill patient with COVID-19 who developed generalized myoclonus during the recovery phase of the infection. Myoclonus was associated with cyclical fevers and decreased alertness. Movements were refractory to conventional anti-epileptic therapies. There was concern that myoclonus could be part of a post-infectious immune-mediated syndrome. The patient improved fully with a 4-day course of high-dose steroids. Our experience highlights a rare, generalized myoclonus syndrome associated with COVID-19 that may be immune-mediated and is responsive to treatment.

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Impact of [18F]FDG-PET and [18F]FLT-PET-Parameters in Patients with Suspected Relapse of Irradiated Lung Cancer

Diagnostics ◽

10.3390/diagnostics11020279 ◽

2021 ◽

Vol 11 (2) ◽

pp. 279

Author(s):

Tine N. Christensen ◽

Seppo W. Langer ◽

Gitte Persson ◽

Klaus Richter Larsen ◽

Annemarie G. Amtoft ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Fdg Pet ◽

Tumor Volume ◽

High Dose ◽

Flt Pet ◽

Pet Ct ◽

Radiation Induced ◽

Fdg Pet Ct ◽

Induced Changes

Radiation-induced changes may cause a non-malignant high 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-uptake. The 3′-deoxy-3′-[18F]fluorothymidine (FLT)-PET/CT performs better in the differential diagnosis of inflammatory changes and lung lesions with a higher specificity than FDG-PET/CT. We investigated the association between post-radiotherapy FDG-PET-parameters, FLT-PET-parameters, and outcome. Sixty-one patients suspected for having a relapse after definitive radiotherapy for lung cancer were included. All the patients had FDG-PET/CT and FLT-PET/CT. FDG-PET- and FLT-PET-parameters were collected from within the irradiated high-dose volume (HDV) and from recurrent pulmonary lesions. For associations between PET-parameters and relapse status, respectively, the overall survival was analyzed. Thirty patients had a relapse, of these, 16 patients had a relapse within the HDV. FDG-SUVmax and FLT-SUVmax were higher in relapsed HDVs compared with non-relapsed HDVs (median FDG-SUVmax: 12.8 vs. 4.2; p < 0.001; median FLT-SUVmax 3.9 vs. 2.2; p < 0.001). A relapse within HDV had higher FDG-SUVpeak (median FDG-SUVpeak: 7.1 vs. 3.5; p = 0.014) and was larger (median metabolic tumor volume (MTV50%): 2.5 vs. 0.7; 0.014) than the relapsed lesions outside of HDV. The proliferative tumor volume (PTV50%) was prognostic for the overall survival (hazard ratio: 1.07 pr cm3 [1.01–1.13]; p = 0.014) in the univariate analysis, but not in the multivariate analysis. FDG-SUVmax and FLT-SUVmax may be helpful tools for differentiating the relapse from radiation-induced changes, however, they should not be used definitively for relapse detection.

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Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

Dose-Response ◽

10.1177/1559325820982166 ◽

2021 ◽

Vol 19 (1) ◽

pp. 155932582098216

Author(s):

Bing Wang ◽

Kaoru Tanaka ◽

Takanori Katsube ◽

Kouichi Maruyama ◽

Yasuharu Ninomiya ◽

...

Keyword(s):

Dietary Restriction ◽

High Dose ◽

Cancer Treatments ◽

Hematopoietic Stem ◽

Beneficial Effects ◽

Radiation Induced ◽

Potential Strategy ◽

Higher Doses

Radioadaptive response (RAR) describes a phenomenon in a variety of in vitro and in vivo systems that a low-dose of priming ionizing radiation (IR) reduces detrimental effects of a subsequent challenge IR at higher doses. Among in vivo investigations, studies using the mouse RAR model (Yonezawa Effect) showed that RAR could significantly extenuate high-dose IR-induced detrimental effects such as decrease of hematopoietic stem cells and progenitor cells, acute radiation hematopoietic syndrome, genotoxicity and genomic instability. Meanwhile, it has been demonstrated that diet intervention has a great impact on health, and dietary restriction shows beneficial effects on numerous diseases in animal models. In this work, by using the mouse RAR model and mild dietary restriction (MDR), we confirmed that combination of RAR and MDR could more efficiently reduce radiogenotoxic damage without significant change of the RAR phenotype. These findings suggested that MDR may share some common pathways with RAR to activate mechanisms consequently resulting in suppression of genotoxicity. As MDR could also increase resistance to chemotherapy and radiotherapy in normal cells, we propose that combination of MDR, RAR, and other cancer treatments (i.e., chemotherapy and radiotherapy) represent a potential strategy to increase the treatment efficacy and prevent IR risk in humans.

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