Normal Tissue Toxicity Research Articles

Evaluation of Radiosensitive Effect of Tolmetin in Radiotherapy on Human Colonic Carcinoma Cell Line HT-29

Background: Radiotherapy is one of the cancer treatment methods. Although radioresistance and normal tissue toxicity limit the radiation therapy in certain anatomical locations, using some substances can be useful to increase radiosensitivity on cancer cells without cytotoxicity effect on normal cells. Objective: This study aimed to evaluate the radiosensitizing effect of tolmetin in radiotherapy treatment on human colon cancer cell line HT-29. Methods In this study, human colon cancer cells HT-29 in different groups were irradiated with 4 Gy x-ray, and tolmetin was administered in different concentrations (75, 100, and 150 μM). Then, the groups were compared with each other and with the control group by Micronucleus Assay (MN) and Nuclear Division Index (NDI). NDI investigated the cytotoxicity, and MN indicated the genotoxicity. Results: In the group receiving radiation, micronuclei increased significantly compared to the control group. In the group receiving tolmetin with a concentration of 75 and 100 μM, the number of micronuclei also increased compared to the control group. In all groups treated with tolmetin that also received radiation, a significant increase in micronuclei was observed, which was more noticeable at concentrations of 100 and 150 μM. At the same time, tolmetin at the studied concentrations did not change the NDI index. Conclusion: The present study demonstrates that tolmetin has a radiosensitizing effect on HT-29 colon cancer cells, which depends on the tolmetin concentration. In addition, tolmetin has no cytotoxic effect on this cell line.

The Role of Intracellular Trafficking of Notch Receptors in Ligand-Independent Notch Activation.

Aberrant Notch signaling has been found in a broad range of human malignancies. Consequently, small molecule inhibitors and antibodies targeting Notch signaling in human cancers have been developed and tested; however, these have failed due to limited anti-tumor efficacy because of dose-limiting toxicities in normal tissues. Therefore, there is an unmet need to discover novel regulators of malignant Notch signaling, which do not affect Notch signaling in healthy tissues. This review provides a comprehensive overview of the current knowledge on the role of intracellular trafficking in ligand-independent Notch receptor activation, the possible mechanisms involved, and possible therapeutic opportunities for inhibitors of intracellular trafficking in Notch targeting.

Evaluating predictive factors for toxicities experienced by head & neck cancer patients undergoing radiotherapy

PurposeThe purpose of this study was to evaluate if HPV status serves as an independent predictor of early and late dysphagia outcomes when considered alongside standard patient characteristics and dose metrics for head and neck cancer patients treated with radiotherapy.Methods and materialsThe age, sex, smoking history, cancer type (oropharyngeal vs non-oropharyngeal), HPV status, and early and late dysphagia outcomes were obtained for 99 retrospective head and neck cancer patients treated at our clinic with radiotherapy. Additionally for each patient, the mean radiation dose to the pharynx, superior/middle/inferior pharyngeal constrictor muscles, and cricopharyngeus was calculated. The predictive power of these clinical characteristics and radiation metrics was evaluated using chi-square tests for categorical variables and t-tests for continuous variables. Then multi-variate logistic models were built for each outcome using a single dose metric at a time, and either HPV status, cancer type, or both. Multi-variate models were built using both top-down and bottom-up technique to establish the most predictive independent covariates.ResultsIn the univariate analysis for early dysphagia, cancer type (p = 0.04) and four dose metrics (p ≤ 0.02) were significantly associated with outcome, while for late dysphagia, only cancer type (p = 0.04) was associated with outcome. In the multivariate analysis for early dysphagia, cancer type, smoking history, and mean dose to the five structures were consistently selected as covariates. For late dysphagia, either HPV status or cancer type was selected in each model and the mean dose to the cricopharyngeus was selected in one model.ConclusionWhile HPV is a known contributing factor for tumor prognosis in oropharyngeal cancers, its role in normal tissue toxicities for head and neck cancers has not previously been evaluated. Our results indicate having an oropharyngeal cancer may increase a patient’s risk of high-grade early and late dysphagia while HPV status was seldom selected.

A self-amplified nanocatalytic system for achieving \u201c1\u2009+\u20091\u2009+\u20091\u2009>\u20093\u201d chemodynamic therapy on triple negative breast cancer

BackgroundChemodynamic therapy (CDT), employing Fenton or Fenton-like catalysts to convert hydrogen peroxide (H2O2) into toxic hydroxyl radicals (·OH) to kill cancer cells, holds great promise in tumor therapy due to its high selectivity. However, the therapeutic effect is significantly limited by insufficient intracellular H2O2 level in tumor cells. Fortunately, β-Lapachone (Lapa) that can exert H2O2-supplementing functionality under the catalysis of nicotinamide adenine dinucleotide (phosphate) NAD(P)H: quinone oxidoreductase-1 (NQO1) enzyme offers a new idea to solve this problem. However, extensive DNA damage caused by high levels of reactive oxygen species can trigger the “hyperactivation” of poly(ADP-ribose) polymerase (PARP), which results in the severe interruption of H2O2 supply and further the reduced efficacy of CDT. Herein, we report a self-amplified nanocatalytic system (ZIF67/Ola/Lapa) to co-deliver the PARP inhibitor Olaparib (Ola) and NQO1-bioactivatable drug Lapa for sustainable H2O2 production and augmented CDT (“1 + 1 + 1 > 3”).ResultsThe effective inhibition of PARP by Ola can synergize Lapa to enhance H2O2 formation due to the continuous NQO1 redox cycling. In turn, the high levels of H2O2 further react with Co2+ to produce the highly toxic ·OH by Fenton-like reaction, dramatically improving CDT. Both in vitro and in vivo studies demonstrate the excellent antitumor activity of ZIF67/Ola/Lapa in NQO1 overexpressed MDA-MB-231 tumor cells. Importantly, the nanocomposite presents minimal systemic toxicity in normal tissues due to the low NQO1 expression.ConclusionsThis design of nanocatalytic system offers a new paradigm for combing PARP inhibitor, NQO1-bioactivatable drug and Fenton-reagents to obtain sustained H2O2 generation for tumor-specific self-amplified CDT.Graphic

Co-targeting TGF-β and PD-L1 with radiation therapy: The Goldilocks principle

In the current issue of Cancer Cell, Lan et al.1 demonstrate that a bifunctional fusion protein targeting TGF-β and PD-L1 can synergize with radiation therapy to simultaneously augment tumor control and reduce normal tissue toxicity.

Model Selection for the Preclinical Development of New Drug–Radiotherapy Combinations

Radiotherapy plays an essential role in the treatment of more than half of all patients with cancer. In recent decades, advances in devices that deliver radiation and the development of treatment planning software have helped radiotherapy attain precise tumour targeting with minimal toxicity to surrounding tissues. Simultaneously, as more targeted drug therapies are being brought into the market, there has been significant interest in improving cure rates for cancer by adding drugs to radiotherapy to widen the therapeutic window, the difference between normal tissue toxicity and treatment efficacy. The development of new combination therapies will require judicious adaptation of preclinical models that are routinely used for traditional drug discovery. Here we highlight the strengths and weaknesses of each of these preclinical models and discuss how they can be used optimally to identify new and clinically beneficial drug–radiotherapy combinations.

Monte Carlo simulations of photodynamic therapy in human blood model.

This study aims to simulate a therapeutic plan for a normal human blood model under various patho-physiological conditions, such as the development of leukemia/blood diseases, by means of Monte Carlo multilayered simulation. The photosensitizing compound selectively accumulates in the target cells. A superficial treatment of a blood sample was performed at different ratios of oxygen saturation ([Formula: see text]) under the concentration ([Formula: see text] = 30µM) effect of merocyanine 540 (MC540) in the blood irradiation. This was done under the application of visible light of wavelength ~ [Formula: see text] at an exposure time ~ 60s. The dose of photodynamic therapy (PDT) was evaluated for the biological damage, leading to necrosis and blood damage during the treatment. In addition, the effect of PDT treatment response in the blood is related to hemoglobin oxygen saturation, resulting in an excellent relationship between the changes caused by the treatment in the blood at a peculiar oxygen saturation rate (for the highest response: [Formula: see text] 50%) and a light dose (LD) of 3.83 [Formula: see text] above the minimal toxicity of normal tissues. The photodynamic dose is related to the depth of necrosis and the time of treatment for the achievement of the LD delivery at the PDT of blood.

Increased incidence of gastrointestinal toxicity in canine cancer patients treated with concurrent abdominal radiation therapy and toceranib phosphate.

Receptor tyrosine kinase inhibitors (TKIs) are used to treat human and canine cancers and may be combined with radiation therapy (RT) to enhance tumor control due their anticancer and antiangiogenic effects; however, recent case reports have emerged describing incidences of gastrointestinal toxicity when antiangiogenic therapies are combined with hypofractionated radiotherapy in human cancer patients. We evaluated the incidence of gastrointestinal (GI) toxicity in dogs receiving concurrent hypofractionated abdominal RT and the TKI toceranib (TOC) compared to those receiving abdominal RT alone, TOC alone, or concurrent non-abdominal RT and TOC. Medical records of canine cancer patients were retrospectively reviewed and identified dogs were included in the following treatment categories: dogs which received RT to a portion of the abdomen and concurrent TOC (n = 19), abdominal RT alone (n-29), TOC alone (n = 20), or non-abdominal RT plus TOC (n = 9). Toxicities were graded using the Veterinary Cooperative Oncology Group - Common Terminology Criteria for Adverse Events criteria and compared to published data on TOC-associated GI toxicity. Patients receiving TOC while undergoing abdominal RT had significantly increased rates of any grade of diarrhea (p = 0.002), hyporexia (p = 0.0045), and vomiting (p = 0.003), as well as severe hyporexia (p = 0.003) when compared across the treatment groups. This retrospective study reveals significantly increased incidences of GI toxicity when abdominal RT is combined with TOC in canine patients. These findings are in-line with the clinical concerns reported for increased normal tissue toxicity in human patients when antiangiogenics are combined with RT.

Comparison of FLASH Proton Entrance and the Spread-Out Bragg Peak Dose Regions in the Sparing of Mouse Intestinal Crypts and in a Pancreatic Tumor Model.

Simple SummaryFLASH radiotherapy is a treatment technique of interest that involves radiation delivered at ultra-high dose rates >100 times faster than traditional radiation therapy, which has been shown to spare radiation damage to normal tissue but maintain tumor control capabilities. Proton therapy uses spread-out proton Bragg peaks to reduce radiation dose to normal tissue by directing the highest dose of radiation to the tumor volume. In this study, irradiation of the whole abdomen of mice was performed with proton beams at FLASH dose rates in order to investigate the normal tissue sparing capabilities of the spread-out Bragg peak compared to the entrance region of the proton depth dose curve.Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.

Quantitative Bioluminescence Tomography-Guided Conformal Irradiation for Preclinical Radiation Research

Purpose:Widely used cone beam computed tomography (CBCT)-guided irradiators in preclinical radiation research are limited to localize soft tissue target because of low imaging contrast. Knowledge of target volume is a fundamental need for radiation therapy (RT). Without such information to guide radiation, normal tissue can be overirradiated, introducing experimental uncertainties. This led us to develop high-contrast quantitative bioluminescence tomography (QBLT) for guidance. The use of a 3-dimensional bioluminescence signal, related to cell viability, for preclinical radiation research is one step toward biology-guided RT.Methods and Materials:Our QBLT system enables multiprojection and multispectral bioluminescence imaging to maximize input data for the tomographic reconstruction. Accurate quantification of spectrum and dynamic change of in vivo signal were also accounted for the QBLT. A spectral-derivative method was implemented to eliminate the modeling of the light propagation from animal surface to detector. We demonstrated the QBLT capability of guiding conformal RT using a bioluminescent glioblastoma (GBM) model in vivo. A threshold was determined to delineate QBLT reconstructed gross target volume (GTVQBLT), which provides the best overlap between the GTVQBLT and CBCT contrast labeled GBM (GTV), used as the ground truth for GBM volume. To account for the uncertainty of GTVQBLT in target positioning and volume delineation, a margin was determined and added to the GTVQBLT to form a QBLT planning target volume (PTVQBLT) for guidance.Results:The QBLT can reconstruct in vivo GBM with localization accuracy within 1 mm. A 0.5-mm margin was determined and added to GTVQBLT to form PTVQBLT, largely improving tumor coverage from 75.0% (0 mm margin) to 97.9% in average, while minimizing normal tissue toxicity. With the goal of prescribed dose 5 Gy covering 95% of PTVQBLT, QBLT-guided 7-field conformal RT can effectively irradiate 99.4 ± 1.0% of GTV.Conclusions:The QBLT provides a unique opportunity for investigators to use biologic information for target delineation, guiding conformal irradiation, and reducing normal tissue involvement, which is expected to increase reproducibility of scientific discovery.

Irradiation at Ultra-High (FLASH) Dose Rates Reduces Acute Normal Tissue Toxicity in the Mouse Gastrointestinal System

Preclinical studies using ultra-high dose rate (FLASH) irradiation have demonstrated reduced normal tissue toxicity compared with conventional dose rate (CONV) irradiation, although this finding is not universal. We investigated the effect of temporal pulse structure and average dose rate of FLASH compared with CONV irradiation on acute intestinal toxicity. Whole abdomens of C3H mice were irradiated with a single fraction to various doses, using a 6 MeV electron linear accelerator with single pulse FLASH (dose rate=2-6×106 Gy/s) or conventional (CONV; 0.25 Gy/s) irradiation. At 3.75 days postirradiation, fresh feces were collected for 16S rRNA sequencing to assess changes in the gut microbiota. A Swiss roll-based crypt assay was used to quantify acute damage to the intestinal crypts to determine how tissue toxicity was affected by the different temporal pulse structures of FLASH delivery. We found statistically significant improvements in crypt survival for mice irradiated with FLASH at doses between 7.5 and 12.5 Gy, with a dose modifying factor of 1.1 for FLASH (7.5 Gy, P < .01; 10 Gy, P < .05; 12.5 Gy, P < .01). This sparing effect was lost when the delivery time was increased, either by increasing the number of irradiation pulses or by prolonging the time between 2 successive pulses. Sparing was observed for average dose rates of ≥280 Gy/s. Fecal microbiome analysis showed that FLASH irradiation caused fewer changes to the microbiota than CONV irradiation. This study demonstrates that FLASH irradiation can spare mouse small intestinal crypts and reduce changes in gut microbiome composition compared with CONV irradiation. The higher the average dose rate, the larger the FLASH effect, which is also influenced by temporal pulse structure of the delivery.

Analysis of lncRNA-miRNA-mRNA expression pattern in heart tissue after total body radiation in a mouse model

BackgroundRadiation therapy is integral to effective thoracic cancer treatments, but its application is limited by sensitivity of critical organs such as the heart. The impacts of acute radiation-induced damage and its chronic effects on normal heart cells are highly relevant in radiotherapy with increasing lifespans of patients. Biomarkers for normal tissue damage after radiation exposure, whether accidental or therapeutic, are being studied as indicators of both acute and delayed effects. Recent research has highlighted the potential importance of RNAs, including messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as biomarkers to assess radiation damage. Understanding changes in mRNA and non-coding RNA expression will elucidate biological pathway changes after radiation.MethodsTo identify significant expression changes in mRNAs, lncRNAs, and miRNAs, we performed whole transcriptome microarray analysis of mouse heart tissue at 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray (Gy). We also validated changes in specific lncRNAs through RT-qPCR. Ingenuity Pathway Analysis (IPA) was used to identify pathways associated with gene expression changes.ResultsWe observed sustained increases in lncRNAs and mRNAs, across all doses of radiation. Alas2, Aplnr, and Cxc3r1 were the most significantly downregulated mRNAs across all doses. Among the significantly upregulated mRNAs were cell-cycle arrest biomarkers Gdf15, Cdkn1a, and Ckap2. Additionally, IPA identified significant changes in gene expression relevant to senescence, apoptosis, hemoglobin synthesis, inflammation, and metabolism. LncRNAs Abhd11os, Pvt1, Trp53cor1, and Dino showed increased expression with increasing doses of radiation. We did not observe any miRNAs with sustained up- or downregulation across all doses, but miR-149-3p, miR-6538, miR-8101, miR-7118-5p, miR-211-3p, and miR-3960 were significantly upregulated after 12 Gy.ConclusionsRadiation-induced RNA expression changes may be predictive of normal tissue toxicities and may indicate targetable pathways for radiation countermeasure development and improved radiotherapy treatment plans.

Practice Patterns of Pediatric Total Body Irradiation Techniques: A Children's Oncology Group Survey

The aim of this study was to examine current practice patterns in pediatric total body irradiation (TBI) techniques among COG member institutions. Between November 2019 and February 2020, a questionnaire containing 52 questions related to the technical aspects of TBI was sent to medical physicists at 152 COG institutions. The questions were designed to obtain technical information on commonly used TBI treatment techniques. Another set of 9 questions related to the clinical management of patients undergoing TBI was sent to 152 COG member radiation oncologists at the same institutions. Twelve institutions were excluded because TBI was not performed in their institutions. A total of 88 physicists from 88 institutions (63% response rate) and 96 radiation oncologists from 96 institutions (69% response rate) responded. The anterior-posterior/posterior-anterior (AP/PA) technique was the most common technique reported (49 institutions [56%]); 44 institutions (50%) used the lateral technique, and 14 (16%) used volumetric modulated arc therapy or tomotherapy. Midplane dose rates of 6 to 15 cGy/min were most commonly used. The most common specification for lung dose was the midlung dose for both AP/PA techniques (71%) and lateral techniques (63%). Almost all physician responders agreed with the need to refine current TBI techniques, and 79% supported the investigation of new TBI techniques to further lower the lung dose. There was no consistency in the practice patterns, methods for dose measurement, and reporting of TBI doses among COG institutions. The lack of standardization precludes meaningful correlation between TBI doses and clinical outcomes including disease control and normal tissue toxicity. The COG radiation oncology discipline is currently undertaking several steps to standardize the practice and dose reporting of pediatric TBI using detailed questionnaires and phantom-based credentialing for all COG centers.

Low-Dose Radiation Therapy to Treat COVID-19: Results of the First Phase of Clinical Trials

Using low-dose radiation therapy (LDRT) to treat inflammation, pneumonia, and coronavirus disease 2019 (COVID-19) has been investigated. Results have revealed that LDRT can improve inflammation in different line cells, animals, and humans. It was demonstrated that LDRT with a single dose (0.3-1 Gy) to the lungs could treat pneumonia resulting from COVID-19 by avoiding normal tissue toxicities. These suggested values of doses are obtained from the historical use of ionizing radiation for pneumonia [1]. A clinical study recently treated five patients with COVID-19 in the age range of 64-96 years; the lungs of these patients were exposed to 1.5 Gy of radiation in one fraction. Results showed that their respiratory conditions were quickly improved in four patients in the first 24 hours of exposure. The results of blood tests and imaging also confirmed the positive effect of LDRT on COVID-19 treatment [2]. Short course results of another study carried out on five patients with COVID-19 aged over 60 years, who underwent national COVID-19 therapy protocols, showed that using 0.5 Gy of radiation in one fraction led to the improvement of four patients in the first few days after exposure. Apart from that, they were discharged from the hospital with an average of 6 days, and no radiation toxicity was observed in them [3]. Another clinical investigation has used LDRT on nine patients to treat COVID-19. In this study, patients received 1 Gy to total lungs, and the SatO2/FiO2 index of these patients was evaluated. Results showed that this index significantly improved 72 hours and one week after LDRT, and inflammation of the lungs decreased one week after radiation therapy. Compared to patients who did not receive LDRT, the median days of hospitalization of patients who received LDRT was reduced by approximately one-fifth. Among these patients, seven were discharged, and two patients died [4]. The incidence of cancers such as lung, esophagus, and breast is one of the controversial subjects surrounding the use of LDRT in COVID-19 treatment. According to the Biological Effects of Ionization Radiation VII (BEIR VII) model, the risk of lung cancer was estimated for patients with COVID-19 whose lungs were irradiated to 0.5 Gy. The incidence of lung cancer can increase by 0.84% and 2.3% for males and females aged above 60 years, respectively. On the other hand, for young patients aged 25 years, the incidence of lung cancer was estimated at 1.1% and 3% for males and females, respectively [5]. According to this model, with an increase in the dose received by the lungs, the risk of lung cancer increases linearly; therefore, the incidence of lung cancer for patients whose whole lung receives a dose of 1.5 Gy will be three times for those who have received a dose of 0.5 Gy [6]. Based on these results, exposure of the lungs to the dose in the range 0.5-1.5 Gy can increase the risk of lung cancer up to 9% and 7% for female patients and 3.3% and 2.5% for male patients aged 25 and 65, respectively. Of course, it should be noted that smoking should be considered in estimating the risk of lung cancer in addition to the radiation factor. Besides the lungs, the heart and esophagus may also be exposed to radiation, increasing the risk of esophageal cancer and heart disease. Nevertheless, blood factors, smoking, and a history of heart disease can be influential in the incidence of heart disease in addition to radiation [7,8]. Results of these clinical trials have shown that the recommended dose (0.5-1.5 Gy) can increase lung cancer up to 9%. As one of the possible effects of ionizing radiation is carcinogenicity, no threshold has been defined for its occurrence, but another issue in radiobiology is the risk-benefit of ionizing radiation. As no radiation toxicities were reported in the said clinical studies, it seems that LDRT is safe; however, more clinical studies are needed to prove this claim. We should not hastily recommend the use of LDRT as an adjuvant treatment for COVID-19. To make a definite comment and evaluate the feasibility and efficacy of LDRT to treat COVID-19, we need more clinical studies with many patients.

Normal tissue tolerance amongst paediatric brain tumour patients- current evidence in proton radiotherapy.

Proton radiotherapy (PT) is used increasingly for paediatric brain cancer patients. However, as demonstrated here, the knowledge on normal tissue dose constraints, to minimize side-effects, for this cohort is limited. A search strategy was systematically conducted on MEDLINE® database. 65 papers were evaluated ranging from 2013 to 2021. Large variations in normal tissue tolerance and toxicity reporting across PT studies makes estimation of normal tissue dose constraints difficult, with the potential for significant late effects to go unmeasured. Mean dose delivered to the pituitary gland varies from 20 to 30 Gy across literature. Similarly, the hypothalamic dose delivery ranges from 20 to 54.6 Gy for paediatric patients. There is a significant lack of radiobiological data for paediatric brain cancer patients undergoing proton therapy, often using data from x-ray radiotherapy and adult populations. The way forward is through standardisation of reporting in order to validate relevant dose constraints.

PO-0948 Impact of HPV status on normal tissue toxicities experienced by head & neck cancer patients

PO-0948 Impact of HPV status on normal tissue toxicities experienced by head & neck cancer patients

A COMPARATIVE STUDY ASSESSING THE DIFFERENT PATTERNS OF RADIATION REACTIONS IN HEAD AND NECKCANCER PATIENTS UNDERGOING RADIATION THERAPY AT DIFFERENT TIMES OF THE DAY-IN THE MORNING VERSUS EVENING

Background: Human oral mucosa, is a prime target for radiation induced toxicity in patients undergoing radiotherapy for head and neck cancer. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation. In our study we investigated the role of chronotherapy with respect to radiation induced mucositis occurring in the normal oral mucosa and treatment response in tumor tissue in cancer patients undergoing radiation therapy to head and neck region. Materials and Methods: This non-randomized clinical study was done to compare the two different timing schedules in the management of head and neck cancer by external beam radiation therapy by cobalt-60 (Theratron780C). In morning arm (arm A), Patients received external beam radiotherapy (EBRT) by cobalt-60 with SSD of 80cm with daily fractions, five days a week, between 8AM–10 AM whereas in evening arm (arm B), patients received EBRT by cobalt-60 with daily fractions, five days a week, between 3PM–5 PM. Both the arms received same radiation regimen. Results: The study concluded that in the morning arm the onset of oral mucositis was observed to be significantly delayed and the duration of mucositis was also significantly shorter as compared to the evening arm. Statistically significant difference in severity of mucositis was found between the two arms. Conclusion: Since there is no active measure to minimize normal tissue toxicity, chronomodulated radiotherapy would be a feasible and cost effective treatment strategy that can be put into clinical practice.

In vivo assessment of the safety of standard fractionation Temporally Feathered Radiation Therapy (TFRT) for head and neck squamous cell carcinoma: An R-IDEAL Stage 1/2a first-in-humans/feasibility demonstration of new technology implementation

IntroductionPrior in silico simulations of studies of Temporally Feathered Radiation Therapy (TFRT) have demonstrated potential reduction in normal tissue toxicity. This R-IDEAL Stage 1/2A study seeks to demonstrate the first-in-human implementation of TFRT in treating patients with head and neck squamous cell carcinoma (HNSCC). Materials and methodsPatients with HNSCC treated with definitive radiation therapy were eligible (70 Gy in 35 fractions) were eligible. The primary endpoint was feasibility of TFRT planning as defined by radiation start within 15 business days of CT simulation. Secondary endpoints included estimates of acute grade 3–5 toxicity. ResultsThe study met its accrual goal of 5 patients. TFRT plans were generated in four of the five patients within 15 business days of CT simulation, therefore meeting the primary endpoint. One patient was not treated with TFRT at the physician’s discretion, though the TFRT plan had been generated within sufficient time from the CT simulation. For patients who received TFRT, the median time from CT simulation to radiation start was 10 business days (range 8–15). The average time required for radiation planning was 6 business days. In all patients receiving TFRT, each subplan and every daily fraction was delivered in the correct sequence without error. The OARs feathered included: oral cavity, each submandibular gland, each parotid gland, supraglottis, and posterior pharyngeal wall (OAR pharynx). Prescription dose PTV coverage (>95%) was ensured in each TFRT subplan and the composite TFRT plan. One of five patients developed an acute grade 3 toxicity. ConclusionsThis study demonstrates the first-in-human implementation of TFRT (R-IDEAL Stage 1), proving its feasibility in the modern clinical workflow. Additionally, assessments of acute toxicities and dosimetric comparisons to a standard radiotherapy plan were described (R-IDEAL Stage 2a).

Nitroxyl Radical as a Theranostic Contrast Agent in Magnetic Resonance Redox Imaging.

Significance: In vivo assessment of paramagnetic and diamagnetic conversions of nitroxyl radicals based on cyclic redox mechanism can be an index of tissue redox status. The redox mechanism of nitroxyl radicals, which enables their use as a normal tissue-selective radioprotector, is seen as being attractive on planning radiation therapy.Recent Advances: In vivo redox imaging using nitroxyl radicals as redox-sensitive contrast agents has been developed to assess tissue redox status. Chemical and biological behaviors depending on chemical structures of nitroxyl radical compounds have been understood in detail. Polymer types of nitroxyl radical contrast agents and/or nitroxyl radical-labeled drugs were designed for approaching theranostics.Critical Issues: Nitroxyl radicals as magnetic resonance imaging (MRI) contrast agents have several advantages compared with those used in electron paramagnetic resonance (EPR) imaging, while support by EPR spectroscopy is important to understand information from MRI. Redox-sensitive paramagnetic contrast agents having a medicinal benefit, that is, nitroxyl-labeled drug, have been developed and proposed.Future Directions: A development of suitable nitroxyl contrast agent for translational theranostic applications with high reaction specificity and low normal tissue toxicity is under progress. Nitroxyl radicals as redox-sensitive magnetic resonance contrast agents can be a useful tool to detect an abnormal tissue redox status such as disordered oxidative stress. Antioxid. Redox Signal. 36, 95–121.

Microbeam Radiotherapy-A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma.

Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an ‘MRT-induced immune effect’. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.