Normal Tissue Damage Research Articles

All-in-one inorganic nanoagents for near-infrared-II photothermal-based cancer theranostics

Theranostic nanoplatforms combining various diagnostic and therapeutic units together have attracted increasing attention over the past few decades. Owing to the merits of non-invasiveness, spatiotemporal controllability, high treatment efficacy and low normal-tissue damage, photothermal therapy (PTT) especially near-infrared-II (NIR-II, 1000–1700 nm) light-triggered PTT becomes one of the most popular therapeutic modalities. Interestingly, photothermal agents (PTAs) used for PTT often have an intrinsic photoacoustic (PA) imaging function, which means that PTAs alone can serve as all-in-one theranostic nanoplatforms. With the rapid development of nanomedicine, a single photothermal agent can be endowed with desirable photothermal conversion efficiency (PCE) in the NIR-II biowindow as well as possessing diverse treatment capabilities. This review summarizes the most recent advances of inorganic PTAs for imaging-guided NIR-II PTT, PTT/photodynamic therapy (PDT), PTT/chemodynamic therapy (CDT), PTT/radiotherapy (RT), PTT/sonodynamic therapy (SDT), PTT/PDT/CDT and PTT/SDT/immunotherapy. Potential obstacles and perspectives for future research and clinical translation of such novel nanotheranostics are also discussed.

Forging Forward in Photodynamic Therapy.

In 1978, a Cancer Research article by Dougherty and colleagues reported the first large-scale clinical trial of photodynamic therapy (PDT) for treatment of 113 cutaneous or subcutaneous lesions associated with ten different kinds of malignancies. In classic applications, PDT depends on excitation of a tissue-localized photosensitizer with wavelengths of visible light to damage malignant or otherwise diseased tissues. Thus, in this landmark article, photosensitizer (hematoporphyrin derivative) dose, drug-light interval, and fractionation scheme were evaluated for their therapeutic efficacy and normal tissue damage. From their observations came early evidence of the mechanisms of PDT's antitumor action, and in the decades since this work, our knowledge of these mechanisms has grown to build an understanding of the multifaceted nature of PDT. These facets are comprised of multiple cell death pathways, together with antivascular and immune stimulatory actions that constitute a PDT reaction. Mechanism-informed PDT protocols support the contribution of PDT to multimodality treatment approaches. Moreover, guided by an understanding of its mechanisms, PDT can be applied to clinical needs in fields beyond oncology. Undoubtedly, there still remains more to learn; new modes of cell death continue to be elucidated with relevance to PDT, and factors that drive PDT innate and adaptive immune responses are not yet fully understood. As research continues to forge a path forward for PDT in the clinic, direction is provided by anchoring new applications in mechanistically grounded protocol design, as was first exemplified in the landmark work conducted by Dougherty and colleagues. See related article by Dougherty and colleagues, Cancer Res 1978;38:2628-35.

Development of a magnetic MoS2 system camouflaged by lipid for chemo/phototherapy of cancer

Untargeted release of traditional chemotherapeutic drugs can damage normal tissues in the body and cause serious side effects for patients. Therefore, the research of targeted drug delivery system based on nanomaterials has become a hot topic in the field of cancer therapy. Magnetic molybdenum disulfide (mMoS2) was modified by liposomes with a cell membrane-like structure to prepare nanocarrier complex (mMoS2-Lipid) with high biocompatibility and stability. Then, combined photo-chemotherapeutic therapy was realized both in vitro and in vivo by its ultra-high photothermal conversion efficiency and excellent drug loading profile of mMoS2-Lipid. The characterization showed that the lamellar magnetic molybdenum disulfide modified by liposomes was not easy to aggregate in physiological solution, and had a lower non-specific protein adsorption rate, which was beneficial for biomedical application. In vitro cell experiments exhibited a successful cellular uptake profile of MCF-7 cells with no significant cytotoxicity, while a concentration dependent cytotoxicity for both chemotherapy alone and photo-chemotherapy combined therapy. Compared with the unmodified mMoS2, mMoS2-Lipid injected into mice through tail vein can accumulate more in the tumor site, and in vivo anti-tumor studies have shown that the synergistic treatment of the mMoS2-Lipid has an obvious inhibitory effect on the tumor with less toxic and side effects on mice. In conclusion, mMoS2-Lipid treatment system provides a safe, rapid and effective choice for the treatment of breast cancer in the future.

Pseudocapsule-Based Resection for Pituitary Adenomas via the Endoscopic Endonasal Approach.

IntroductionThe endoscopic endonasal approach (EEA) is a safe and effective treatment for pituitary adenomas (PAs). Since extracapsular resection (ER) of PAs improves tumor resection and endocrine remission rates, the interface between the pseudocapsule and gland draws increasing attention. However, it is difficult to precisely dissect the tumor along the exact boundary, and complete removal of the tumor increases the risks of normal tissue damage and cerebrospinal fluid (CSF) leakage. In this study, we investigated the extracapsular resection as well as the pseudocapsule histology to evaluate the effectiveness and safety of pseudocapsule-related surgical interventions.MethodsFrom December 2017 to December 2019, 189 patients of PAs via EEA in our single center were analyzed retrospectively. The images, operative details, and clinical follow-up of patients were collected. Sixty-four patients underwent pseudocapsule-based ER, and 125 patients also underwent traditional intracapsular resection (IR) with or without intensive excision for FPAs. The clinical characteristics, tumor resection, endocrinological outcomes, and postoperative morbidities of the two groups were compared. Informed consent for publication of our article was obtained from each patient. Histological examination of pseudocapsule was performed using hematoxylin and eosin and reticulin staining.ResultsThe gross total recession was 62 (96.9%) in the ER group and 107 (85.6%) cases in the IR group, whereas the endocrine remission rate was 29/31 (93.5%) and 40/53 (75.5%) cases, respectively. Anterior pituitary functions were not aggravated postoperatively in any patient, but transient diabetes insipidus (DI) occurred more in the IR group (64.0%) than in ER (48.4%). Pseudocapsule specimens were obtained in 93 patients, and clusters of small cell aggregation were detected in 11 pseudocapsule specimens (11.8%) whereas other patients showed no remarkable developed pseudocapsule. Intraoperative CSF leak occurred more in the ER group (28.1%) than in the IR group (13.6%), but no difference was seen between two groups postoperatively. No case of intracranial hematoma or pituitary crisis occurred in both groups. After a mean follow-up of 22.8 months, tumor recurrence was observed in 4 (2.1%) cases.ConclusionPseudocapsule-based extracapsular resection of PAs via EEA is an effective and safe procedure to achieve complete resection with high and sustained endocrine remission and without deteriorating pituitary function.

THE OCCURRENCE OF ACUTE PANCREATITIS AFTER IODINE 131 TREATMENT OF HYPERTHYROIDISM.

Acute pancreatitis is a common and potentially fatal gastrointestinal disease. We report a case of acute pancreatitis induced by iodine-131 therapy for hyperthyroidism. Iodine 131 is distributed through the blood, so it can accumulate and damage normal tissues in other parts of the body that are involved in thyroid hormone metabolis.

Therapeutic implications of exosomes in the treatment of radiation injury.

Radiotherapy is one of the main cancer treatments, but it may damage normal tissue and cause various side effects. At present, radioprotective agents used in clinics have side effects such as nausea, vomiting, diarrhea and hypotension, which limit their clinical application. It has been found that exosomes play an indispensable role in radiation injury. Exosomes are lipid bilayer vesicles that carry various bioactive substances, such as proteins, lipids and microRNA (miRNA), that play a key role in cell-to-cell communication and affect tissue injury and repair. In addition, studies have shown that radiation can increase the uptake of exosomes in cells and affect the composition and secretion of exosomes. Here, we review the existing studies and discuss the effects of radiation on exosomes and the role of exosomes in radiation injury, aiming to provide new insights for the treatment of radiation injury.

Intracellular Amplifiers of Reactive Oxygen Species Affecting Mitochondria as Radiosensitizers.

Simple SummaryProdrugs that increase the level of reactive oxygen species (ROS) specifically in cancer cells while not affecting normal cells can potentially act as radiosensitizers for side effect free radiotherapy (RT). However, previously known ROS-amplifying prodrugs were found to not beuseful for this purpose. Since functional mitochondria are necessary for RT-resistance, we assumed that the problem could be solved by using dual prodrugs as radiosensitizers, both targeting mitochondria and simultaneously inducing ROS. In this paper, we explored this possibility. In particular, we developed an N-alkylaminoferrocene-based prodrug (2c) effective at low μMolar concentrations. Upon conversion to its active form 2c_BA in aqueous solution, it is efficiently taken up by cancer cells. This leads to the decrease of their mitochondrial membrane potential and the amplification of both, intracellular mitochondrial and total ROS generation. We found that 2c_BA acts as an efficient radiosensitizer in human head and neck squamous carcinoma cells in vitro.Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5–7.1 µM in human ovarian carcinoma, Burkitt’s lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers.

DNA strand break induction of aqueous plasmid DNA exposed to 30 MeV protons at ultra-high dose rate.

Radiation cancer therapy with ultra-high dose rate exposure, so called FLASH radiotherapy, appears to reduce normal tissue damage without compromising tumor response. The aim of this study was to clarify whether FLASH exposure of proton beam would be effective in reducing the DNA strand break induction. We applied a simple model system, pBR322 plasmid DNA in aqueous 1 × TE solution, where DNA single strand breaks (SSBs) and double strand breaks (DSBs) can be precisely quantified by gel electrophoresis. Plasmid DNA were exposed to 27.5 MeV protons in the conventional dose rate of 0.05 Gy/s (CONV) and ultra-high dose rate of 40 Gy/s (FLASH). With both dose rate, the kinetics of the SSB and DSB induction were proportional to absorbed dose. The SSB induction of FLASH was significantly less than CONV, which were 8.79 ± 0.14 (10−3 SSB per Gy per molecule) and 10.8 ± 0.68 (10−3 SSB per Gy per molecule), respectively. The DSB induction of FLASH was also slightly less than CONV, but difference was not significant. Altogether, 27.5 MeV proton beam at 40 Gy/s reduced SSB and not DSB, thus its effect may not be significant in reducing lethal DNA damage that become apparent in acute radiation effect.

Peptides of the innate immunity as potential anticancer agents: pros and cons

Surgical resection was the main approach to cancer therapy, often supplemented by radiation and chemotherapy. The effectiveness of such complex treatment in many cases remains low. In this regard, there is an urgent need to search for new compounds that have selective cytotoxic activity against tumor cells and do not damage normal tissues of the organism. The review discusses mechanisms of antitumor action of cationic antimicrobial peptides (AMPs) of the cathelicidin family - human α-helical cathelicidin (LL-37), and a peptide with β-hairpin conformation – protegrin-1 (PG-1) on lung, breast, pancreas, prostate, squamous skin cancer cells, oral cancer, stomach, ovarian, colorectal cancer, melanoma, leukemia, lymphoma, glioma and neuroblastoma cells. An opportunity of antitumor and pro-oncogenic actions of the peptides and an interplay of these effects with mmunomodulatory action of AMPs on tumor-associated macrophages, natural killer cells and T-lymphocytes is discussed. Possible mechanisms of LL-37 and PG-1 selective action upon tumor cells are presented, including the interaction of LL-37 with G-protein-coupled receptors: the N formylpeptide-2 receptor (FPR2), CXC chemokine-2 (CXCR2), Mas-related gene X2 (MrgX2), purinergic (P2Y11), epidermal (EGFR/ErbB1, ERBb2), insulin-like (IGF1R) growth factors, ligand-gated ion channels (LGIC) and Tolllike (TLR) receptors, with expression varying significantly in different types of tumors, as compared to normal tissues. An increase in the level of LL-37 secretion and expression of its CAMP gene are associated with progression of lung adenocarcinoma, breast, pancreas, and prostate cancer, ovarian cancer, melanoma, and squamous cell carcinoma of the skin. In contrast, CAMP expression and LL-37 secretion are significantly reduced in gastric cancer cells, oral squamous cell cancer, colorectal cancer, leukemia, lymphomas, gliomas, and SH-SY5Y neuroblastoma. Therefore, therapeutic effects of LL-37 can only be used for specific types of tumors. The mechanisms of action of PG-1 on tumor cells are still poorly understood, although the available data indicate that protegrin exhibits a more unidirectional effect, i.e., it damages cell membranes. Protegrin-1 and LL-37 can synergistically enhance the antitumor effects of chemotherapy drugs and have a more pronounced effect on tumor cells, than upon normal cells. Natural AMPs appear to be promising candidates for the role of new antitumor agents, which are also active against malignant metastatic, recurrent multidrug-resistant tumors. On the other hand, peptides such as LL-37, in some cases, exhibit properties that can be considered pro-oncogenic, which indicates a need for further detailed studies on the molecular mechanisms of their action on tumor cells.

Optimization and decision-making of novel laser-induced thermal therapy for deep-lying tumor based on multi-objective genetic algorithm and three-way decisions method

In this paper, we develop novel laser-induced thermal therapy (LITT) schemes, multiple and single rotating laser irradiation, for deep-lying breast tumor to maximize tumor killing while minimizing normal tissue damage and preventing the surface overheating without the aid of external media such as nanoparticles and photosensitizers. Combined with numerical simulation and multi-objective genetic algorithm (MOGA), the incident angle, radius, intensity and exposure time of the multiple laser irradiation, as well as the rotational period and exposure time of the single rotating laser irradiation are optimized based on the surface response model, and a series of Pareto-optimal solutions are obtained. The three-way decisions method is utilized to effectively manage the Pareto-optimal solutions and select the ideal solution with a comprehensive consideration of the risk preferences (aversion, proneness and neutralness) of the surgeon. Compared with the traditional LITT, the ideal solution selected by the operator with risk neutralness attitude makes the surface temperature maintain at an acceptable level, and the killing volume of normal tissue is reduced by 80.4% for the multiple laser irradiation and 99.74% for the single rotating laser irradiation in the case of complete tumor killing. Results obtained can be employed as a guideline for the selection of LITT regimens for deep-lying breast tumor under consideration of the surgeon’s risk preferences.

Therapeutic Efficacy of Variable Biological Effectiveness of Proton Therapy in U-CH2 and MUG-Chor1 Human Chordoma Cell Death.

Simple SummaryChordoma is a rare, slow-growing cancer of the spinal cord. Photon radiation therapy and surgery are the standard of care for chordoma. Proton radiation therapy has become an increasingly common treatment in comparison to photon radiation therapy due to the ability to reduce off-target radiation dose. However, there is still an increased risk of toxicity to the surrounding critical structures that lead to poor treatment outcomes. Moreover, the biologic effectiveness of protons to sterilize chordoma cells remains uncertain and likely varies according to the proton energy spectrum throughout the proton field. We aim to investigate the tumoricidal properties of proton radiation therapy at the middle and end of the proton radiation field and elucidate variations in the relative biological effectiveness for chordoma cells. Our study helps quantify the therapeutic value of treating chordoma near the end of the proton field, where linear energy transfer is relatively high.Background: Chordoma is a cancer of spinal cord, skull base, and sacral area. Currently, the standard of care to treat chordoma is resection followed by radiation therapy. Since, chordoma is present in the spinal cord and these are very sensitive structures and often complete removal by surgery is not possible. As a result, chordoma has a high chance of recurrence and developing resistance to radiation therapy. In addition, treatment of chordoma by conventional radiation therapy can also damage normal tissues surrounding chordoma. Thus, current therapeutic options to treat chordoma are insufficient and novel therapies are desperately needed to treat locally advanced and metastatic chordoma. (2) Methods: In the present investigation, human chordoma cell lines of sacral origin MUG-Chor1 and U-CH2 were cultured and irradiated with Proton Beam Radiation using the clinical superconducting cyclotron and pencil-beam (active) scanning at Middle and End of the Spread-Out Bragg Peak (SOBP). Proton radiation was given at the following doses: Mug-Chor1 at 0, 1, 2, 4, and 8 Gy and U-CH2 at 0, 4, 8, 12, and 16 Gy. These doses were selected based on a pilot study in our lab and attempted to produce approximate survival fractions in the range of 1, 0.9, 0.5, 0.1, and 0.01, respectively, chosen for linear quadratic model fitting of the dose response. (3) Results: In this study, we investigated relative biological effectiveness (RBE) of proton radiation at the end of Spread Out Bragg Peak assuming that the reference radiation is a proton radiation in the middle of the SOBP. We observed differences in the survival of both Human chordoma cell lines, U-CH2 and MUG-Chor1. The data showed that there was a significantly higher cell death at the end of the Bragg peak as compared to middle of the Bragg peak. Based on the linear quadratic (LQ) fit for cell survival we calculated the RBE between M-SOBP and E-SOBP at 95% CI level and it was observed that RBE was higher than 1 at E-SOBP and caused significantly higher cell killing. Proton field at E-SOBP caused complex DNA damage in comparison to M-EOBP and the genes such as DNA topoisomerase 1, GTSE1, RAD51B were downregulated in E-SOBP treated cells. Thus, we conclude that there seems to be substantial variation in RBE (1.3–1.7) at the E-SOBP compared with the M-SOBP.

Rationale and Advantages of Endoscopic Spine Surgery.

The goal of a spine surgery is to achieve adequate neural tissue decompression, maintenance of spinal stability, and successful stabilization of an unstable spine. To achieve these surgical goals, damage to normal tissues, including the spinal column and surrounding soft tissues, is inevitable after the beginning of a spine surgery. Extensive damage to normal spinal column and paraspinal collateral tissues during operation can lead to unsuccessful outcomes due to persistent axial pain and additional surgeries due to occurrence of spinal instability. Numerous efforts, such as the usage of microscopy, tubular retractor systems, percutaneous instruments, and trials of new operative approaches have been attempted to reduce normal tissue damage and improve surgical outcomes. Endoscopic spine surgery (ESS) was introduced about 3 decades ago as a minimally invasive spine surgery and has been widely spread with the development of endoscopic surgical instruments and adoption of new endoscopic surgical approaches during the past 2 decades. Theoretically, ESS may be the gold standard method of spine surgery because of its minimal tissue damage and good visualization of the surgical field. However, surgeons hesitate to initiate an ESS due to its steep learning curve and the lack of high-level evidence of surgical outcomes. In this article, the rationale and advantages of performing ESS are discussed by reviewing published articles.

Current Progress and Future Perspectives of Immune Checkpoint in Cancer and Infectious Diseases.

The inhibitory regulators, known as immune checkpoints, prevent overreaction of the immune system, avoid normal tissue damage, and maintain immune homeostasis during the antimicrobial or antiviral immune response. Unfortunately, cancer cells can mimic the ligands of immune checkpoints to evade immune surveillance. Application of immune checkpoint blockade can help dampen the ligands expressed on cancer cells, reverse the exhaustion status of effector T cells, and reinvigorate the antitumor function. Here, we briefly introduce the structure, expression, signaling pathway, and targeted drugs of several inhibitory immune checkpoints (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, VISTA, and IDO1). And we summarize the application of immune checkpoint inhibitors in tumors, such as single agent and combination therapy and adverse reactions. At the same time, we further discussed the correlation between immune checkpoints and microorganisms and the role of immune checkpoints in microbial-infection diseases. This review focused on the current knowledge about the role of the immune checkpoints will help in applying immune checkpoints for clinical therapy of cancer and other diseases.

Amelioration of Radiation-Induced DNA Damage and Immunosuppression by Tanacetum parthenium leaf extract and synthetic parthenolide in Swiss Albino Mice

Radiotherapy potentially offers protection from recurrence of tumor that also causes normal tissue damage and creates major concern. Another important factor is long-term immune suppression in patients treated with radiotherapy. Therefore, crucial need for the survival of surrounding normal cells of tumor by radiation‑protecting agents is the prime focus of this study. Aqueous extract (AE) and ethanolic extract (EE), Tanacetum parthenium extracts100 mg/kg each and parthenolide (PAR) 4mg/kg body weight were orally administered prior to sub-lethal radiation dose exposure. Mice were used for the evaluation of radiation-mediated chromosomal aberrations in bone marrow cells and DNA break by comet assay in the blood lymphocytes of mice. The pro-inflammatory levels were determined by cytokine estimations namely interleukin‑2, interferongamma and tumor necrosis factor-alpha performed in the liver homogenate using ELISA kits. Thus the results demonstrated ameliorating, radio-mitigating and immune-stimulatory efficacy of AE, EE and PAR against radiation ‑induced DNA damage and immunosuppression by regulating cytokine.

Non-coplanar volumetric modulated arc therapy for locoregional radiotherapy of left-sided breast cancer including internal mammary nodes.

BackgroundNon-coplanar volumetric modulated arc therapy (ncVMAT) is proposed to reduce toxicity in heart and lungs for locoregional radiotherapy of left-sided breast cancer, including internal mammary nodes (IMN).Patients and methodsThis retrospective study included 10 patients with left-sided breast cancer who underwent locoregional radiotherapy after breast-conserving surgery. For each patient, the ncVMAT plan was designed with four partial arcs comprising two coplanar arcs and two non-coplanar arcs, with a couch rotating to 90°. The prescribed dose was normalized to cover 95% of planning target volume (PTV), with 50 Gy delivered in 25 fractions. For each ncVMAT plan, dosimetric parameters were compared with the coplanar volumetric modulated arc therapy (coV-MAT) plan.ResultsT here were improvements in conformity index, homogeneity index and V55 of total target volume (PTVall) comparing ncVMAT to coVMAT (p < 0.001). Among the organs at risk, the average V30, V20, V10, V5, and mean dose (Dmean) of the heart decreased significantly (p < 0.001). Furthermore, ncVMAT significantly reduced the mean V20, V10, V5, and Dmean of left lung and the mean V10 and V5 and Dmean of contralateral lung (p < 0.001). An improved sparing of the left anterior descending coronary artery and right breast were also observed with ncVMAT (p < 0.001).ConclusionsCompared to coVMAT, ncVMAT provides improved conformity and homogeneity of whole P TV, better dose sparing of the heart, bilateral lungs, left anterior descending coronary artery (LAD), and right breast for locoregional radiotherapy of left-sided breast cancer with IMN, potentially reducing the risk of normal tissue damage.

First demonstration of the FLASH effect with ultrahigh dose rate high-energy X-rays

PurposeThis study aimed to evaluate whether high-energy X-rays (HEXs) of the PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can produce ultrahigh dose rate (FLASH) X-rays and trigger the FLASH effect. Materials and methodsEBT3 radiochromic film and fast current transformer (FCT) devices were used to measure absolute dose and pulsed beam current of HEXs. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional dose rate radiotherapy (CONV), respectively to observe the tumor control efficiency and normal tissue damage. ResultsThe maximum dose rate of HEXs of PARTER was up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (p < 0.0001) and significant difference in survival curves (p < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a significant difference (p = 0.038) in survival among the three groups, with the risk of death decreased by 81% in the FLASH group compared to that in the CONV group. The survival time of healthy mice irradiated in the abdomen in the FLASH group was undoubtedly higher (62.5% of mice were still alive when we stopped observation) than that in the CONV group (7 days). ConclusionThis study confirmed that HEXs of the PARTER system can produce ultrahigh dose rate X-rays and trigger a FLASH effect, which provides a basis for future scientific research and clinical application of HEX in FLASH radiotherapy.

Tolerance of Normal Rabbit Facial Bones and Teeth to Synchrotron X-Ray Microbeam Irradiation.

Microbeam radiation therapy, an alternative radiosurgical treatment under preclinical investigation, aims to safely treat muzzle tumors in pet animals. This will require data on the largely unknown radiation toxicity of microbeam arrays for bones and teeth. To this end, the muzzle of six young adult New Zealand rabbits was irradiated by a lateral array of microplanar beamlets with peak entrance doses of 200, 330 or 500 Gy. The muzzles were examined 431 days postirradiation by computed microtomographic imaging (micro-CT) ex vivo, and extensive histopathology. The boundaries of the radiation field were identified histologically by microbeam tracks in cartilage and other tissues. There was no radionecrosis of facial bones in any rabbit. Conversely, normal incisor teeth exposed to peak entrance doses of 330 Gy or 500 Gy developed marked caries-like damage, whereas the incisors of the two rabbits exposed to 200 Gy remained unscathed. A single, unidirectional array of microbeams with a peak entrance dose ≤200 Gy (valley dose14 Gy) did not damage normal bone, teeth and soft tissues of the muzzle of normal rabbits longer than one year after irradiation. Because of that, Microbeam radiation therapy of muzzle tumors in pet animals is unlikely to cause sizeable damage to normal teeth, bone and soft tissues, if a single array as used here delivers a limited entrance dose of 200 Gy and a valley dose of ≤14 Gy.

Non-conventional Ultra-High Dose Rate (FLASH) Microbeam Radiotherapy Provides Superior Normal Tissue Sparing in Rat Lung Compared to Non-conventional Ultra-High Dose Rate (FLASH) Radiotherapy.

Conventional radiotherapy is a widely used non-invasive form of treatment for many types of cancer. However, due to a low threshold in the lung for radiation-induced normal tissue damage, it is of less utility in treating lung cancer. For this reason, surgery is the preferred treatment for lung cancer, which has the detriment of being highly invasive. Non-conventional ultra-high dose rate (FLASH) radiotherapy is currently of great interest in the radiotherapy community due to demonstrations of reduced normal tissue toxicity in lung and other anatomy. This study investigates the effects of FLASH microbeam radiotherapy, which in addition to ultra-high dose rate incorporates a spatial segmentation of the radiation field, on the normal lung tissue of rats. With a focus on fibrotic damage, this work demonstrates that FLASH microbeam radiotherapy provides an order of magnitude increase in normal tissue radio-resistance compared to FLASH radiotherapy. This result suggests FLASH microbeam radiotherapy holds promise for much improved non-invasive control of lung cancer.

Response of Normal Tissues to Boron Neutron Capture Therapy (BNCT) with 10B-Borocaptate Sodium (BSH) and 10B-Paraboronophenylalanine (BPA).

Boron neutron capture therapy (BNCT) is a cancer-selective radiotherapy that utilizes the cancer targeting 10B-compound. Cancer cells that take up the compound are substantially damaged by the high liner energy transfer (LET) particles emitted mainly from the 10B(n, α7Li reaction. BNCT can minimize the dose to normal tissues, but it must be performed within the tolerable range of normal tissues. Therefore, it is important to evaluate the response of normal tissues to BNCT. Since BNCT yields a mixture of high and low LET radiations that make it difficult to understand the radiobiological basis of BNCT, it is important to evaluate the relative biological effectiveness (RBE) and compound biological effectiveness (CBE) factors for assessing the responses of normal tissues to BNCT. BSH and BPA are the only 10B-compounds that can be used for clinical BNCT. Their biological behavior and cancer targeting mechanisms are different; therefore, they affect the CBE values differently. In this review, we present the RBE and CBE values of BPA or BSH for normal tissue damage by BNCT irradiation. The skin, brain (spinal cord), mucosa, lung, and liver are included as normal tissues. The CBE values of BPA and BSH for tumor control are also discussed.

First Demonstration of the FLASH Effect With Ultrahigh Dose-Rate High-Energy X-Rays

Purpose/Objective(s)Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. We did this experiment to find out whether PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can trigger FLASH effect.Materials/MethodsSubcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional (CONV) radiotherapy respectively to observe the tumor control and normal tissue damage under different radiation conditions. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH (HEX with FLASH). Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments.ResultsHEX-FLASH was implemented using the superconducting LINAC with the maximum mean dose rate up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (F = 25.14, P < 0.0001) and significantly different in survival curves (P < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a statistically significant difference (P = 0.038) in survival among the three groups. The hazard ratio (HR) was 0.19, 95% confidence intervals (CIs) was 0.035–1.010, and P was 0.0486 between the FLASH and CONV groups; therefore, the risk of death decreased by 81% in the FLASH group compared with that in the CONV group. Although the survival time of healthy mice irradiated on abdomen in the FLASH group was undoubtedly higher (62.5 % of mice were still alive when we stopped observation) than that in the CONV group (7 days), the difference in survival between the two groups was not statistically significant (HR 0.369; 95% CI 0.113–1.202; P = 0.0735). Despite this, the survival trend of mice treated with HEX-FLASH radiotherapy was better. We demonstrated theoretical cellular response analysis of the FLASH effect based on the ROD hypothesis and it showed consistent radioprotective effects in normal cells under FLASH irradiation.ConclusionThis study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications. Ultrahigh dose-rate (FLASH) radiotherapy has attracted immense attention because of its tumor control efficiency and healthy tissue protection during preclinical experiments with electrons, kilo-voltage X-rays, and protons. Using high-energy X-rays (HEXs) in FLASH is advantageous owing to its deep penetration, small divergence, and cost-effectiveness. We did this experiment to find out whether PARTER (platform for advanced radiotherapy research) platform built on CTFEL (Chengdu THz Free Electron Laser facility) can trigger FLASH effect. Subcutaneous tumor-bearing mice and healthy mice were treated with sham, FLASH, and conventional (CONV) radiotherapy respectively to observe the tumor control and normal tissue damage under different radiation conditions. With a high-current and high-energy superconducting linear accelerator, FLASH with a good dose rate and high penetration was achieved. Breast cancers artificially induced in BAL b/c mice were efficiently controlled, and normal tissues surrounding the thorax/abdomen in C57BL/6 mice were protected from radiation with HEX-FLASH (HEX with FLASH). Theoretical analyses of cellular responses following HEX-FLASH irradiation were performed to interpret the experimental results and design further experiments. HEX-FLASH was implemented using the superconducting LINAC with the maximum mean dose rate up to over 1000 Gy/s. Tumor-bearing mice experiment showed a good result on tumor control (F = 25.14, P < 0.0001) and significantly different in survival curves (P < 0.005) among the three groups. In the thorax-irradiated healthy mice experiment, there was a statistically significant difference (P = 0.038) in survival among the three groups. The hazard ratio (HR) was 0.19, 95% confidence intervals (CIs) was 0.035–1.010, and P was 0.0486 between the FLASH and CONV groups; therefore, the risk of death decreased by 81% in the FLASH group compared with that in the CONV group. Although the survival time of healthy mice irradiated on abdomen in the FLASH group was undoubtedly higher (62.5 % of mice were still alive when we stopped observation) than that in the CONV group (7 days), the difference in survival between the two groups was not statistically significant (HR 0.369; 95% CI 0.113–1.202; P = 0.0735). Despite this, the survival trend of mice treated with HEX-FLASH radiotherapy was better. We demonstrated theoretical cellular response analysis of the FLASH effect based on the ROD hypothesis and it showed consistent radioprotective effects in normal cells under FLASH irradiation. This study highlights the generation of HEX-FLASH for the first time and its potential in future clinical applications.