Irradiated Tissue Research Articles

Near-infrared Nrf2 activator IR-61 dye alleviates radiation-induced lung injury

Oxidative stress injury and subsequent inflammatory response are considered to play critical roles in radiation-induced lung injury (RILI). Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates oxidative stress response and represses inflammation, but its therapeutic value in RILI remains elusive. Our previous studies have shown that the near-infrared (NIR) IR-61 dye evokes intracellular antioxidant defense by enhancing Nrf2 signaling and promoting anti-inflammatory effects. We established a model of RILI in mice exposed to whole-thoracic irradiation. The results showed that IR-61 treatment notably improved pulmonary functions by decreasing lung density and diminishing airway resistance. In addition, IR-61 significantly ameliorated radiation-induced inflammatory cell infiltration and proinflammatory cytokine (IL-1β, IL-6, and TNF-α) release, thereby mitigating inflammatory response. Furthermore, IR-61 mitigated radiation-induced lung fibrosis by decreasing the collagen deposition and the levels of fibrogenesis-related factors (collagen I, collagen III, α-SMA, and fibronectin). More importantly, IR-61 was found to accumulate in the mitochondria of macrophages in irradiated lung tissues. Therefore, the functions of IR-61 in macrophages were further studied in irradiated macrophage cell lines, MH-s and RAW 264.7 in vitro. The results indicated that IR-61 upregulated the expression of Nrf2 and heme oxygenase-1 (HO-1) and decreased the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines (IL-1β and IL-6) in macrophages after radiation. In summary, our study suggests that IR-61 effectively mitigates RILI by activating Nrf2 signaling in irradiated lung tissues. In particular, Nrf2-mediated anti-inflammatory and antioxidant effects in irradiated lung tissue macrophages play critical roles in protecting against RILI.

Low-Energy Electron Induced Reactions in Metronidazole at Different Solvation Conditions.

Metronidazole belongs to the class of nitroimidazole molecules and has been considered as a potential radiosensitizer for radiation therapy. During the irradiation of biological tissue, secondary electrons are released that may interact with molecules of the surrounding environment. Here, we present a study of electron attachment to metronidazole that aims to investigate possible reactions in the molecule upon anion formation. Another purpose is to elucidate the effect of microhydration on electron-induced reactions in metronidazole. We use two crossed electron/molecular beam devices with the mass-spectrometric analysis of formed anions. The experiments are supported by quantum chemical calculations on thermodynamic properties such as electron affinities and thresholds of anion formation. For the single molecule, as well as the microhydrated condition, we observe the parent radical anion as the most abundant product anion upon electron attachment. A variety of fragment anions are observed for the isolated molecule, with NO2− as the most abundant fragment species. NO2− and all other fragment anions except weakly abundant OH− are quenched upon microhydration. The relative abundances suggest the parent radical anion of metronidazole as a biologically relevant species after the physicochemical stage of radiation damage. We also conclude from the present results that metronidazole is highly susceptible to low-energy electrons.

Diagnostic Value of 18F-NOTA-FAPI PET/CT in a Rat Model of Radiation-Induced Lung Damage.

In this study, we explore the diagnostic value of a novel PET/CT imaging tracer that specifically targets fibroblast activation protein (FAP), 18F-NOTA-FAPI, in a radiation induced lung damage (RILD) rat model. High focal radiation (40, 60, or 90 Gy) was administered to a 5-mm diameter area of the right lung in Wistar rats for evaluation of RILD induction. Lung tissues exposed to 90 Gy radiation were scanned with 18F-NOTA-FAPI PET/CT and with 18F-FDG. Dynamic 18F-NOTA-FAPI PET/CT scanning was performed on day 42 post-irradiation. After in vivo scanning, lung cryosections were prepared for autoradiography, hematoxylin and eosin (HE) and immunohistochemical (IHC) staining. An animal model of RILD was established and validated by histopathological analysis. On 18F-NOTA-FAPI PET/CT, RILD was first observed on days 42, 35 and 7 in the 40, 60 and 90 Gy groups, respectively. After treatment with 90 Gy, 18F-NOTA-FAPI uptake in an area of RILD emerged on day 7 (0.65 ± 0.05%ID/ml) and reappeared on day 28 (0.81 ± 0.09%ID/ml), remaining stable for 4–6 weeks. Autoradiography and HE staining IHC staining revealed that 18F-NOTA-FAPI accumulated mainly in the center of the irradiated area. IHC staining confirmed the presence of FAP+ macrophages in the RILD area, while FAP+ fibroblasts were observed in the peripheral area of irradiated lung tissue. 18F-NOTA-FAPI represents a promising radiotracer for in vivo imaging of RILD in a dose- and time-dependent manner. Noninvasive imaging of FAP may potentially aiding in the clinical management of radiotherapy patients.

Analytical 3D modeling of accumulative heating under multipulse laser irradiation of inorganic materials and biological tissues

• Analysis of accumulative 3D heating by laser pulses using Green's function method. • Accumulative heating under the pulse-periodic action of three types of heat sources. • Dynamics of residual temperature of titanium, monocrystalline silicon, dry bone. • Results useful for optimization of technological regimes of irradiation. In this paper, using analytical methods of the theory of thermal conductivity, the issue of accumulative 3D heating under multipulse laser irradiation of inorganic materials and biological tissues is studied. For a number of practically important cases, comparatively simple analytical dependences of the residual temperature on the number of laser pulses and their repetition rate have been obtained. The limits of their applicability are discussed. Examples of the application of the developed theory for specific cases of pulse-periodic laser irradiation of various materials, in particular, titanium, monocrystalline silicon, and bone tissue, are demonstrated.

The Effect of Fat Grafting on Expansion Pressures in Expander-Based Postmastectomy Breast Reconstruction: Outcomes in Normal and Irradiated Tissues.

The impact of fat grafting on the viscoelasticity of irradiated tissues is poorly defined. We investigate the effect of subcutaneous fat grafting on postmastectomy tissue expansion in patients undergoing delayed breast reconstruction. We quantify observed viscoelastic and trophic changes of the skin envelope. We hypothesize that fat grafting changes the trophic and viscoelastic properties of the breast soft tissue envelope. Postmastectomy defects delayed more than 2 years and reconstructed with subpectoral tissue expanders were prospectively studied. Control (no irradiation, no fat grafting, n = 7), fat grafted (no irradiation, fat grafting n = 8), and irradiated plus fat grafting (irradiation, fat grafting, n = 9) groups were included. Hydrostatic pressures of the tissue expanders were measured before and immediately after expansion, and again postexpansion day 1. Pressure changes calculated as "postexpansion-relaxation interval": difference between maximal pressure at each expansion and the minimal pressure before the next expansion session. Differences were analyzed between groups. Hydrostatic pressure plots reflect the soft tissue ability to accommodate sequential expansion. Fat grafted breasts demonstrated a statistically significant increased postexpansion-relaxation interval versus the nongrafted control group (P < 0.0001). Irradiated plus fat grafting breasts achieve similar postexpansion relaxation interval to the control group (P = 0.597). These changes are observed at postoperative week 6. Viscoelastic changes impact the overall expansion time: the fat grafted group achieved total expansion 2 weeks earlier than the nongrafted control group (P = 0.019). The fat grafted, radiated group completed expansion in similar time interval as nongrafted control group. Observed viscoelastic changes impact the overall expansion time. Fat grafting in nonradiated mastectomy defects allows for shorter expansion period. Fat grating in radiated postmastectomy defects allows expansion durations equivalent to nonradiated, nonfat grafted control defects. There is a delayed effect of fat grafting observed at postoperative week 6.

Beneficial role of customized intraoral stents in radiotherapy for nasopharyngeal carcinoma.

e18642 Background: The intraoral stent is a mouth-opening device which may be used in nasopharyngeal carcinoma (NPC) patients during radiotherapy with the intention of preventing unnecessary irradiation in normal adjacent tissue. The purpose of this study was to investigate the effects of individualized intraoral stent on the intensity modulated radiation therapy(IMRT) by evaluation dose distribution and consequent radiobiological derived outcomes for NPC patients. Methods: Sixteen patients with NPC who used intraoral stent and 17 patients without intraoral stent were enrolled in this study. All patients underwent Helical Tomotherapy (HT) in our center. For the planning target volume (PTV), the conformity index (CI) and homogeneity index (HI) were used to compare two groups of HT plans (with or without intraoral stent). The mean dose of normal tissues were recorded for the two groups. Oral mucositis, gustatory sense, mouth opening and salivary function of each patients were weekly assessed at the beginning, during and after radiotherapy by clinical examination. Results: The mean dose metrics of oral cavity, mandible, left and right parotid gland in patients with intraoral stent was significantly decreased by 11.6%, 12.2%, 15.4%, and 8.7% on average, respectively (P &lt; 0.05), while the conformity index (CI, P = 0.056) and homogeneity index (HI, P = 0.676) of the tumor target showed no statistically different. The rates of grade I，II, III of oral mucositis of patients with intraoral stent were 43.15%, 43.75%, 12.50% when radiotherapy was just over. While the rates of patients with intraoral stent were 23.53%, 17.65%, 58.82%. There were significantly different in two groups (p = 0.022). There was no significant difference in the decline of taste function among each groups. But the symptoms of xerostomia and mouth opening restriction in the group with intraoral stent had been relieved significantly compared the group without intraoral stent at 1 month and 6 months after radiation. Conclusions: The custom-made intraoral stents showed promising value at sparing normal tissue during radiotherapy for NPC without affecting target dose coverage or tumor control. Clinical trial information: No. NJSH-2021NL-041.

SPAR: A randomized placebo-controlled phase 2 trial of simvastatin in addition to standard chemotherapy and radiation in preoperative treatment for rectal cancer: An AGITG clinical trial.

TPS3646 Background: In retrospective studies statin use during preoperative chemo-radiation (pCRT) for rectal cancer is associated with improved overall survival, pathological tumor response and treatment toxicity. In vivo preclinical studies show that statins radiosensitize cancer cells, with improved tumor control and reduced radiation-induced gastrointestinal (GI) and skin toxicities. A prospective randomized trial is justified to confirm these clinically important benefits. Tumor regression following pCRT has strong prognostic significance, as assessed radiologically (MRI-based tumor regression grading [mrTRG]) prior to, or pathologically (pathTRG) following, surgery. Using mrTRG after each treatment phase in total neoadjuvant therapy (TNT) programs could assess incremental tumor regression and optimize patient management including surgery. Methods: Design: This double-blind phase 2 trial is recruiting 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 17 sites in New Zealand and Australia. Patients are randomized to simvastatin 40mg or placebo daily for 90 days, starting 1 week prior to pCRT, with minimization for major prognostic variables. Pelvic MRI at baseline and 6-8 weeks after pCRT will assess mrTRG. A protocol amendment allows TNT using consolidation chemotherapy after pCRT; MRI timing is unchanged. Primary objective: comparison of rates of grades 1-2 mrTRG following pCRT with simvastatin or placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4-5). Secondary objectives: comparison of rates of grades 1-2 pathTRG in resected tumors; incidence of &gt; grade 2 acute GI and non-GI adverse events (AE); incidence of late GI AE; compliance with intended pCRT and trial medication; proportion of patients undergoing surgical resection post-pCRT; 3-year local recurrence rate, disease-free and cancer-specific survival; and pathological scores for radiation colitis. Tertiary and correlative objectives: association between mrTRG and pathTRG grouping; inter-observer scoring agreement on mrTRG and pathTRG; comparison of the association between tumor CD3+ and/or CD8+ T-cell infiltrates in diagnostic biopsies and pathTRG; intensity and distribution of subsets of infiltrating T-cells in irradiated resected normal and malignant tissue; and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Eligibility criteria exclude statin use within 6 weeks prior to trial entry, patients intolerant of statins, and planned use of oxaliplatin or biological agents during pCRT. Trial recruitment commenced April 2018 and 95 of 222 patients have been recruited as at 21 January 2022. Clinical trial information: ACTRN12617001087347.

The risk of cancer following high, and very high, doses of ionising radiation

It is established that moderate-to-high doses of ionising radiation increase the risk of subsequent cancer in the exposed individual, but the question arises as to the risk of cancer from higher doses, such as those delivered during radiotherapy, accidents, or deliberate acts of malice. In general, the cumulative dose received during a course of radiation treatment is sufficiently high that it would kill a person if delivered as a single dose to the whole body, but therapeutic doses are carefully fractionated and high/very high doses are generally limited to a small tissue volume under controlled conditions. The very high cumulative doses delivered as fractions during radiation treatment are designed to inactivate diseased cells, but inevitably some healthy cells will also receive high/very high doses. How the doses (ranging from <1 Gy to tens of Gy) received by healthy tissues during radiotherapy affect the risk of second primary cancer is an increasingly important issue to address as more cancer patients survive the disease. Studies show that, except for a turndown for thyroid cancer, a linear dose–response for second primary solid cancers seems to exist over a cumulative gamma radiation dose range of tens of gray, but with a gradient of excess relative risk per Gy that varies with the type of second cancer, and which is notably shallower than that found in the Japanese atomic bomb survivors receiving a single moderate-to-high acute dose. The risk of second primary cancer consequent to high/very high doses of radiation is likely to be due to repopulation of heavily irradiated tissues by surviving stem cells, some of which will have been malignantly transformed by radiation exposure, although the exact mechanism is not known, and various models have been proposed. It is important to understand the mechanisms that lead to the raised risk of second primary cancers consequent to the receipt of high/very high doses, in particular so that the risks associated with novel radiation treatment regimens—for example, intensity modulated radiotherapy and volumetric modulated arc therapy that deliver high doses to the target volume while exposing relatively large volumes of healthy tissue to low/moderate doses, and treatments using protons or heavy ions rather than photons—may be properly assessed.

Numerical analysis of thermal damage and oxygen distribution in laser irradiated tissue

Journal of Applied Mathematics and Computational Mechanics, Prace Naukowe Instytutu Matematyki i Informatyki, Politechnika Częstochowska, Scientific Research of the Institute of Mathematics and Computer Science, Czestochowa University of Technology

Histopathological Analysis of the Effect of Photodynamic Action on Post-Chemotherapy Excised Breast Cancer Tissue.

Background and objectives: Breast cancer is the most commonly diagnosed cancer in women and its mortality is increasing. Therefore, research to improve treatment is of paramount importance. One method of treatment is photodynamic therapy. Photodynamic therapy selectively stimulates apoptosis in photosensitizer-treated neoplastic breast cells as a result of cytotoxic singlet oxygen generation via collisions between triplet excited state photosensitizer and triplet ground state oxygen upon tissue irradiation. The aim of this study was to evaluate the effects of photodynamic action on cancerous breast tissue samples as a model of photodynamic therapy. Materials and Methods: Breast cancer tissue samples were obtained from post-operative material and the patterns of histopathological changes in breast cancer tissue before and after photodynamic action on post-chemotherapy tissue were evaluated. Excised tissue samples were obtained from 48 female breast cancer patients who had previously undergone chemotherapy. Breast cancer tissues for this study were taken from macroscopically visible tumors larger than 10 mm. Histopathological analysis was performed to evaluate any morphological changes prior to and after photodynamic action on the post-chemotherapy tissue samples. Eighteen breast cancer tissue samples were analyzed before chemotherapy, fifteen after chemotherapy, and fifteen samples were analyzed after chemotherapy and application of photodynamic action. The photosensitizer Rose Bengal was applied to the samples subjected to photodynamic action. Results: Photodynamic action on post-chemotherapy neoplastic tissue showed histological changes under a light microscope. The results showed that morphological changes in breast cancer tissues after chemotherapy and photodynamic action were dependent on the concentration of Rose Bengal. In all cases, follow-up imaging showed tumor shrinkage of an average of 35% from baseline size. Conclusions: Histopathological examination revealed photosensitizer-concentration-dependent changes after photodynamic action in excised post-chemotherapy tissue. The effects of photodynamic action observed in this study suggest that the application of photodynamic therapy after chemotherapy can aid in breast cancer cell eradication.

Differential effects of cancer modifying agents during radiation therapy on Ehrlich solid tumor-bearing mice: A comparative investigation of metformin and ascorbic acid

BackgroundThis work was carried out to compare the modifying roles of ascorbic and metformin during Ehrlich (ESC) tumor-bearing mice irradiation. MethodsFifty Swiss albino male mice were segmented into seven groups, including one control group and six Ehrlich induced tumors treated with ascorbic, ascorbic plus radiation, metformin, metformin plus radiation, and radiation only. Many tests, including behavioral, biochemical, immunohistochemistry, gene expression, DNA fragmentation, oxidative stress markers, and EPR, were performed to interrogate the modifying effects on tumor and liver tissues. ResultsRemarkable apoptosis was found in metformin irradiated animals compared to irradiated ascorbic counterparts. The irradiated metformin mice showed the greatest reduction in PCNA. There was a significant reduction of DNA fragmentation in the liver tissues of the irradiated metformin group. Irradiated metformin and irradiated ascorbic acid animals showed a reduced signal of ERK as well as c-Fos genes. There was a tendency of metformin and metformin irradiated animals to reduce MDA levels in liver tissues. ESC-bearing mice treated with ascorbic or metformin showed an improvement in the spontaneous alternation percentage (SAP%) and improved short-term memory. There was also an improvement in long memory tests. ConclusionsThe study added more preclinical evidence on the utility of metformin in cancer treatment during radiotherapy. Metformin was shown to reduce lipid peroxidation in irradiated healthy tissues, increase tumor cytotoxicity, downregulate critical pathways involved in tumor progression and proliferation, and enhance tumor apoptosis. Controlled clinical trials using metformin are highly warranted.

In Vivo Characterization of a Red Light-Activated Vasodilation: A Photobiomodulation Study.

Nitric oxide dependent vasodilation is an effective mechanism for restoring blood flow to ischemic tissues. Previously, we established an ex vivo murine model whereby red light (670 nm) facilitates vasodilation via an endothelium derived vasoactive species which contains a functional group that can be reduced to nitric oxide. In the present study we investigated this vasodilator in vivo by measuring blood flow with Laser Doppler Perfusion imaging in mice. The vasodilatory nitric oxide precursor was analyzed in plasma and muscle with triiodide-dependent chemiluminescence. First, a 5–10 min irradiation of a 3 cm2 area in the hind limb at 670 nm (50 mW/cm2) produced optimal vasodilation. The nitric oxide precursor in the irradiated quadriceps tissue decreased significantly from 123 ± 18 pmol/g tissue by both intensity and duration of light treatment to an average of 90 ± 17 pmol/g tissue, while stayed steady (137 ± 21 pmol/g tissue) in unexposed control hindlimb. Second, the blood flow remained elevated 30 min after termination of the light exposure. The nitric oxide precursor content significantly increased by 50% by irradiation then depleted in plasma, while remained stable in the hindlimb muscle. Third, to mimic human peripheral artery disease, an ameroid constrictor was inserted on the proximal femoral artery of mice and caused a significant reduction of flow. Repeated light treatment for 14 days achieved steady and significant increase of perfusion in the constricted limb. Our results strongly support 670 nm light can regulate dilation of conduit vessel by releasing a vasoactive nitric oxide precursor species and may offer a simple home-based therapy in the future to individuals with impaired blood flow in the leg.

Technological advancements in brachytherapy of cancer

Emerging technological advancements in brachytherapy, when used alone or combined with conventional therapies have improved the therapeutic efficacy, leading to enhanced patient survival. Advancements in the use of various isotopes, delivery methods, incorporation of 3D imaging, and 3D printing, have significantly optimized the treatment planning and increased dose delivery accuracy, achieving high target volume irradiation and low normal tissue exposure. Real-time guidance during the implanting of radiation source into the tumor tissue has shown the promising outcome of brachytherapy. Integration of precise in vivo dosimetry methods have reduced the deviations in the measured dose, and associated operational errors, ensuring brachytherapy is accurate, and delivering more targeted doses over the course of the treatment. The use of new forms of radiation sources such as needles, pellets, tubes, overcomes the risk of source clumping and migration. Personalized applicators, biodegradable brachytherapy systems, injectable radiolabeled thermoresponsive polymers offer yet another promising brachytherapy approaches. Here we describe the recent technological innovations in brachytherapy and discuss various strategies adopted to overcome the associated challenges in preclinical and clinical settings.

Laser treatment of chondromalacia lesions in the articular cartilage

Objective: to select optimal parameters of two-wave near-infrared laser irradiation for the arthroscopic treatment of chondromalacia foci in the articular cartilage. Material and methods. Bull articular cartilages were treated with laser light delivered by a fifi ber and having various parameters. Human articular cartilages with chondromalacia foci taken during the total knee replacement were also treated with laser light delivered by a fifi ber and having various parameters. The processed cartilage samples were examined macroscopically and then histologically. Changes in the structure of ar[1] ticular cartilage after laser irradiation were assessed. Results. A two-second irradiation with two-wave laser light (λ = 0.97 μm / 30 W and λ = 1.55 μm / 15 W) causes a rapid “melting” of lesion margins without macroscopically visible carbonization with a wide thermally affected zone in the irradiated area. Histologically, cartilage preparations irradiated with two-wave laser light (wavelengths λ = 1.55 μm / 5 W and λ = 0.97 μm / 3 W) for 2 sec demonstrated slight changes in the cartilage structure without thermal destruction of chondrocytes.Conclusion. The optimal combination for laser irradiation of the cartilage tissue in the saline solution environment which restores articular cartilage shape is two-wave laser light λ = 0.97 μm at power of 3 W and λ = 1.55 μm at power of 5 W from the distance of 1–2 mm under 2 sec exposure.

P144 a Transforming Growth Factor Beta Inhibitor Peptide, Generates Antifibrogenic Effects in a Radiotherapy Induced Fibrosis Model.

Radiation-induced fibrosis (RIF) is a severe side effect related with soft tissues sarcomas (STS) radiotherapy. RIF is a multicellular process initiated primarily by TGF-β1 that is increased in irradiated tissue, whose signaling leads to intracellular Smad2/3 phosphorylation and further induction of profibrotic target genes. P144 (Disetertide©) is a peptide inhibitor of TGF-β1 and is proposed as a candidate compound for reducing RIF associated wound healing problems and muscle fibrosis in STS. Methods: A treatment and control group of WNZ rabbits were employed to implement a brachytherapy animal model, through catheter implantation at the lower limb. Two days after implantation, animals received 20 Gy isodosis, intended to induce a high RIF grade. The treatment group received intravenous P144 administration following a brachytherapy session, repeated at 24–72 h post-radiation, while the control group received placebo. Four weeks later, affected muscular tissues underwent histological processing for collagen quantification and P-Smad2/3 immunohistochemistry through image analysis. Results: High isodosis Brachytherapy produced remarkable fibrosis in this experimental model. Results showed retained macro and microscopical morphology of muscle in the P144 treated group, with reduced extracellular matrix fibrosis, with a lower area of collagen deposition measured through Masson’s trichrome staining. Intravenous P144 also induced a significant reduction in Smad2/3 phosphorylation levels compared with the placebo group. Conclusions: P144 administration clearly reduces RIF and opens a new potential co-treatment approach to reduce complications in soft tissue sarcoma (STS) radiotherapy. Further studies are required to establish whether the dosage and timing optimization of P144 administration, in different RIF phases, might entirely avoid fibrosis associated with STS brachytherapy.

Estimation of absorbed doses in patients’ organs from the released radionuclide-label during radionuclide therapy with &lt;sup&gt;225&lt;/sup&gt;Ac

Today, the treatment of cancer with the use of radiopharmaceuticals is a developing method all over the world. The preparation of the radiopharmaceuticals and its quality control prior to its administration to the patient is one of the important elements of nuclear medicine procedures. The instability of the compound can lead to a change in the distribution of the radionuclide in the patient’s body, a decrease in the effectiveness of treatment, as well as to unjustified irradiation of healthy organs and tissues. The aim of this work was to estimate the absorbed doses in human organs and tissues during radionuclide therapy using 225Ac for the case of the 225Ac release. The absorbed doses were calculated for the model presented in ICRP Publication 141 for healthy people. This model consists of 18 cameras (blood, cortical volume, cortical surface, cortical red bone marrow, trabecular volume, trabecular surface, trabecular red bone marrow, kidneys (two chambers), bladder, liver (two chambers), gonads, contents of the small intestine, contents of the upper large intestine, soft tissues. Time-integrated activities were calculated using the specialized software SAAM II v2.3. The calculation of absorbed doses was performed using the IDAC-Dose 2.1 software. The highest absorbed doses were obtained for liver, testes, ovaries and red bone marrow, which leads to an increase in doses in these organs in comparison with doses from 225Ac-PSMA up to a factor of two. A change in the biodistribution of 225Ac in a patient’s body, associated with the release of a radionuclide from the radiopharmaceuticals, can lead to an increase in doses in healthy radiosensitive organs and tissues, as well as to a decrease in the effectiveness of treatment.

Satellite Cells are Activated in a Rat Model of Radiation-Induced Muscle Fibrosis.

Radiation-induced muscle fibrosis is a long-term side effect of radiotherapy that significantly affects the quality of life and even reduces the survival of cancer patients. We have demonstrated that radiation induces satellite cell (SC) activation at the molecular level; however, cellular evidence in a rat model of radiation-induced muscle fibrosis was lacking. In this study, we evaluated SC activation in vivo and investigated whether radiation affects the proliferation and differentiation potential of SCs in vitro. For in vivo studies, Sprague-Dawley rats were randomly divided into six groups (n = 6 per group): non-irradiated controls, 90 Gy/1 week-, 90 Gy/2 weeks-, 90 Gy/4 weeks-, 90 Gy/12 weeks- and 90 Gy/24 weeks-postirradiation groups. Rats received a single dose of radiation in the left groin area and rectus femoris tissues were collected in the indicated weeks. Fibrosis, apoptosis, and autophagy were evaluated by Masson's trichrome staining, TUNEL staining, and electron microscopy, respectively. SC activation and central nuclear muscle fibers were evaluated by immunofluorescence staining and hematoxylin and eosin staining. IL-1β concentrations in serum and irradiated muscle tissue samples were determined by ELISA. For in vitro studies, SCs were isolated from rats with radiation-induced muscle fibrosis and their proliferation and differentiation were evaluated by immunofluorescence staining. In vivo, fibrosis increased over time postirradiation. Apoptosis and autophagy levels, IL-1β concentrations in serum and irradiated skin tissues, and the numbers of SCs and central nuclear muscle fibers were increased in the irradiated groups when compared with the control group. In vitro, cultured SCs from irradiated muscle were positive for the proliferation marker Pax7, and differentiated SCs were positive for the myogenic differentiation marker MyHC. This study provided cellular evidence of SC activation and proliferation in rats with radiation-induced muscle fibrosis.

Please Place Your Seat in the Full Upright Position: A Technical Framework for Landing Upright Radiation Therapy in the 21st Century.

Delivering radiotherapy to patients in an upright position can allow for increased patient comfort, reduction in normal tissue irradiation, or reduction of machine size and complexity. This paper gives an overview of the requirements for the delivery of contemporary arc and modulated radiation therapy to upright patients. We explore i) patient positioning and immobilization, ii) simulation imaging, iii) treatment planning and iv) online setup and image guidance. Treatment chairs have been designed to reproducibly position seated patients for treatment and can be augmented by several existing immobilisation systems or promising emerging technologies such as soft robotics. There are few solutions for acquiring CT images for upright patients, however, cone beam computed tomography (CBCT) scans of upright patients can be produced using the imaging capabilities of standard Linacs combined with an additional patient rotation device. While these images will require corrections to make them appropriate for treatment planning, several methods indicate the viability of this approach. Treatment planning is largely unchanged apart from translating gantry rotation to patient rotation, allowing for a fixed beam with a patient rotating relative to it. Rotation can be provided by a turntable during treatment delivery. Imaging the patient with the same machinery as used in treatment could be advantageous for online plan adaption. While the current focus is using clinical linacs in existing facilities, developments in this area could also extend to lower-cost and mobile linacs and heavy ion therapy.

Impact of residual air trap in balloon on laser treatment of tubular tissue.

Tubular tissue, such as the bile duct and esophagus, often suffers from stenosis due to chronic inflammation or excessive contraction of smooth muscle. Laser treatment using a balloon catheter has been used to treat tubular tissue stenosis by mechanically expanding the tissue and irradiating laser light circumferentially on the tissue lumen. As the balloon is inflated with saline, the residual air in a delivery channel is often accumulated in the inflated balloon. Thus, the air trap may cause physical discontinuities at air-saline interface, leading to unpredictable and nonuniform photothermal interactions. The aim of the current study was to evaluate the optical-thermal effects of the air trap in the balloon on laser treatment of the tubular tissue by means of numerical simulations and experimental validations. A balloon-assisted diffusing applicator (BDA) was developed to inflate a balloon and deliver uniform and circumferential laser light. Before the balloon inflation, various numbers of deflations (0, 1, 2, 3, and 4) were applied to estimate the average amount of the air removed from the balloon. Ex vivo experiments using porcine liver duct were conducted with two deflation conditions (D0: no deflation for air trap and D3: three deflations for no air trap). The balloon was horizontally situated during laser irradiation to maintain the air trap at the same position in the balloon by minimizing gravity effect. Upon balloon inflation, 532 nm laser light was delivered through the BDA to the tissue (irradiance = 4 W/cm2 ) at 10 W for 45 seconds to assess the optical-thermal effects of the air trap on the ductal tissue. The size of the air trap was noticeably reduced with the number of deflations. The air trap volume in the balloon decreased to 0.5% of the total balloon volume after D3. Ex vivo results demonstrated that thicker coagulative necrosis (CN) for D0 near the air trap region in the tissue than bottom region that contact with saline, representing an asymmetric profile of CN in the tissue. D0 generated 17% thicker and nonuniform CN (overall CN thickness = 1.4 ± 0.7 mm), compared with D3 with no air trap (overall CN thickness = 1.2 ± 0.2 mm; p < 0.05). A threefold larger eccentricity (E) was found in D0 (49 ± 31%) than D3 (15 ± 13%; p < 0.001). Both numerical simulations and experiments validated the effect of the air trap in a balloon on the distribution of CN in a tubular tissue during BDA-assisted laser treatment. Further in vivo studies will assess the current findings on the air trap for clinical translations of BDA-assisted laser treatment of tubular tissue stenosis.

Senescence-associated tumor growth is promoted by 12-Lipoxygenase.

Radiation therapy is a commonly used treatment modality for cancer. Although effective in providing local tumor control, radiation causes oxidative stress, inflammation, immunomodulatory and mitogenic cytokine production, extracellular matrix production, and premature senescence in lung parenchyma. The senescence associated secretory phenotype (SASP) can promote inflammation and stimulate alterations in the surrounding tissue. Therefore, we hypothesized that radiation-induced senescent parenchymal cells in irradiated lung would enhance tumor growth. Using a murine syngeneic tumor model of melanoma and non-small cell lung cancer lung metastasis, we demonstrate that radiation causes a significant increase in markers of premature senescence in lung parenchyma within 4 to 8 weeks. Further, injection of B16F0 (melanoma) or Lewis Lung carcinoma (epidermoid lung cancer) cells at these time points after radiation results in an increase in the number and size of pulmonary tumor nodules relative to unirradiated mice. Treatment of irradiated mice with a senolytic agent (ABT-737) or agents that prevent senescence (rapamycin, INK-128) was sufficient to reduce radiation-induced lung parenchymal senescence and to mitigate radiation-enhanced tumor growth. These agents abrogated radiation-induced expression of 12-Lipoxygenase (12-LOX), a molecule implicated in several deleterious effects of senescence. Deficiency of 12-LOX prevented radiation-enhanced tumor growth. Together, these data demonstrate the pro-tumorigenic role of radiation-induced senescence, introduces the dual TORC inhibitor INK-128 as an effective agent for prevention of radiation-induced normal tissue senescence, and identifies senescence-associated 12-LOX activity as an important component of the pro-tumorigenic irradiated tissue microenvironment. These studies suggest that combining senotherapeutic agents with radiotherapy may decrease post-therapy tumor growth.