Irradiated Tissue Research Articles

A data mining approach to identify key radioresponsive genes in mouse model of radiation induced intestinal injury

Radiation-mediated GI injury (RIGI) in humans either due to accidental or intentional exposures, can only be managed with supporting care with no approved countermeasures available till now. Early detection and monitoring of RIGI is important for effective medical management and improve survival chances in exposed individual. The present study aims to identify new signatures of RIGI using data mining approach followed by validation of selected hub genes in mouse model. Using microarray datasets from Gene Expression Omnibus database, differentially expressed genes were identified. Pathway analysis suggested lipid metabolism as one of the predominant pathways altered in irradiated GI tissue. A protein-protein interaction network revealed top 08 hub genes related to lipid metabolism, namely Fabp1, Fabp2, Fabp6, Npc1l1, Ppar-α, Abcg8, Hnf-4α, and Insig1. qRT-PCR analysis revealed significant up-regulation of Fabp6 and Hnf-4α and down-regulation of Fabp1, Fabp2 and Insig1 transcripts in irradiated intestine. Radiation dose and time kinetics study revealed that the selected 05 genes were altered differentially in the irradiated intestine. Extensive alteration in lipid profiles and modification was observed in irradiated intestine. Finding suggests that lipid metabolism is one of the key targets of radiation and its mediators may act as biomarkers in detection and progression of RIGI.

Non-homogenous intratumor ionizing radiation doses synergize with PD1 and CXCR2 blockade

The efficacy and side effects of radiotherapy (RT) depend on parameters like dose and the volume of irradiated tissue. RT induces modulations of the tumor immune microenvironment (TIME) that are dependent on the dose. Low dose RT (LDRT, i.e., single doses of 0.5–2 Gy) has been shown to promote immune infiltration into the tumor. Here we hypothesize that partial tumor irradiation combining the immunostimulatory/non-lethal properties of LDRT with cell killing/shrinkage properties of high dose RT (HDRT) within the same tumor mass could enhance anti-tumor responses when combined with immunomodulators. In models of colorectal and breast cancer in immunocompetent female mice, partial irradiation (PI) with millimetric precision to deliver LDRT (2 Gy) and HDRT (16 Gy) within the same tumor induces substantial tumor control when combined with anti-PD1. Using flow cytometry, cytokine profiling and single-cell RNA sequencing, we identify a crosstalk between the TIME of the differentially irradiated tumor volumes. PI reshapes tumor-infiltrating CD8+ T cells into more cytotoxic and interferon-activated phenotypes but also increases the infiltration of pro-tumor neutrophils driven by CXCR2. The combination of the CXCR2 antagonist SB225002 with PD1 blockade and PI improves tumor control and mouse survival. Our results suggest a strategy to reduce RT toxicity and improve the therapeutic index of RT and immune checkpoint combinations.

Anti-Radiofibrosis Effect of Dicliptera chinensis Polysaccharide on Rat Dermal Fibroblasts Via The TGF-β1/Smads/CTGF Signaling Pathway

Radiotherapy is an effective treatment for head and neck cancer; however, irradiated normal tissues are inevitably damaged, resulting in skin radioactive fibrosis. Dicliptera chinensis polysaccharide (DCP), the primary active compound extracted from the natural medicinal Dicliptera chinensis, exhibits antioxidant, anti-inflammatory, and anti-radiation properties. In this study, we investigated the protective effects of DCP against radioactive fibrosis in rat dermal fibroblasts (RDF) and explored the underlying mechanisms involved. RDFs were treated with DCP, and the CCK8 assay was used to determine cellular activity. The rates of apoptosis and cell cycle progression were detected using flow cytometry. mRNA expression levels were quantified using real-time polymerase chain reaction. Protein levels were analysed through Western blotting and immunofluorescence staining RESULTS: DCP reduced radiation-induced apoptosis, and the cell cycle G2/M arrest was alleviated. Furthermore, DCP decreased the expression of key fibrosis-related markers, including α-SMA, TGF-β1, Smad3, and CTGF. DCP exhibits a protective effect against radiation-induced fibrosis.

Tailoring Plasmonic Nanoheaters Size for Enhanced Theranostic Agent Performance.

The introduction of optimized nanoheaters, which function as theranostic agents integrating both diagnostic and therapeutic processes, holds significant promise in the medical field. Therefore, developing strategies for selecting and utilizing optimized plasmonic nanoheaters is crucial for the effective use of nanostructured biomedical agents. This work elucidates the use of the Joule number (Jo) as a figure of merit to identify high-performance plasmonic theranostic agents. A framework for optimizing metallic nanoparticles for heat generation was established, uncovering the size dependence of plasmonic nanoparticles optical heating. Gold nanospheres (AuNSs) with a diameter of 50 nm and gold nanorods (AuNRs) with dimensions of 41×10 nm were identified as effective nanoheaters for visible (530 nm) and infrared (808 nm) excitation. Notably, AuNRs achieve higher Jo values than AuNSs, even when accounting for the possible orientations of the nanorods. Theoretical results estimate that 41×10 nm gold nanorods have an average Joule number of 80, which is significantly higher compared to larger rods. The photothermal performance of optimal and suboptimal nanostructures was evaluated using photoacoustic imaging and photothermal therapy procedures. The photoacoustic images indicate that, despite having larger absorption cross-sections, the large nanoparticle volume of bigger particles leads to less efficient conversion of light into heat, which suggests that the use of optimized nanoparticles promotes higher contrast, benefiting photoacoustic-based procedures in diagnostic applications. The photothermal therapy procedure was performed on S180-bearing mice inoculated with 41×10 nm and 90×25 nm PEGylated AuNRs. Five minutes of laser irradiation of tumor tissue with 41×10 nm produced an approximately 9.5% greater temperature rise than using 90×25 AuNRs in the therapy trials. Optimizing metallic nanoparticles for heat generation may reduce the concentration of the nanoheaters used or decrease the light fluence for bioscience applications, paving the way for the development of more economical theranostic agents.

Numerical simulation of heat transfer properties of skin tissue acted on repetitive laser irradiation

Pulsed laser has been widely used in the clinical treatment of various diseases and injuries due to its unique advantages in the process of interaction with skin tissue. In order to ensure the therapeutic effect and patient safety, it is necessary to accurately monitor the time-space response of the whole-field temperature of the target tissue irradiated by pulsed laser. A research strategy to explore the thermal response and incidental thermal damage of skin tissue induced by repeated pulses laser has been proposed in present work. A theoretical model involved variable physical properties was first proposed, in which the dual-phase lag (DPL) equation and Henrique burn equation were employed to evaluate the tissue temperature and thermal damage induced by repeated pulse laser irradiation. With the help of finite difference method, the governing equation with variable physical properties was then numerical solved to obtain the time-space distribution of tissue temperature, and the evolution process of the thermal damage was further calculated. The effects of laser input parameters and variable physical parameters on the laser penetration depth, temperature distribution and burn degree of the irradiated tissue were analyzed.

Pyrroloquinoline Quinone Alleviates Mitochondria Damage in Radiation-Induced Lung Injury in a MOTS-c-Dependent Manner.

Radiation-induced lung injury (RILI) is a prevalent complication of thoracic tumor radiotherapy and accidental radiation exposure. Pyrroloquinoline quinone (PQQ), a novel vitamin B, plays a crucial role in delaying aging, antioxidation, anti-inflammation, and antiapoptosis. This study aims to investigate the protective effect and mechanisms of PQQ against RILI. C57BL/6 mice were exposed to a 20 Gy dose of X-ray radiation on the entire thorax with or without daily oral administration of PQQ for 2 weeks. PQQ effectively mitigated radiation-induced lung tissue damage, inflammation, oxidative stress, and epithelial cell apoptosis. Additionally, PQQ significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells. Mechanistically, PQQ upregulated the mRNA and protein levels of MOTS-c in irradiated lung tissue and MLE-12 cells. Knockdown of MOTS-c by siRNA substantially attenuated the protective effects of PQQ on oxidative stress, inflammation, and apoptosis. In conclusion, PQQ alleviates RILI by preserving mitochondrial function through a MOTS-c-dependent mechanism, suggesting that PQQ may serve as a promising nutraceutical intervention against RILI.

A 24-kilogram retroperitoneal liposarcoma surgical management: A case report

Sarcomas are diverse malignant tumors originating from soft tissues (STS) or bones, with STS being more prevalent. Liposarcoma is the most common type of STS, typically arising in the extremities and retroperitoneum. This case report discusses the management of a rare, giant retroperitoneal liposarcoma (RL) in a 47-year-old man presented with significant abdominal enlargement, post-pharyngeal discharge, and urinary dribbling. Medical history included an inguinal hernia and smoking. Diagnosis through imaging (sonography, CT, MRI) and biopsy confirmed a well-differentiated liposarcoma encasing the left kidney and compressing abdominal organs. The tumor measured 53 × 47 x 20 cm and weighed 24 kg. Surgical management included complete tumor excision, left nephrectomy, iliac artery repair, colectomy, and lymph node dissection. The management of RL is challenging due to its size and proximity to vital organs. Complete surgical resection is crucial for recurrence-free survival. Preoperative radiotherapy can aid in achieving negative margins by defining target volumes and reducing irradiation of adjacent tissues. Chemotherapy is reserved for high-grade tumors with metastatic potential. This report highlights the complexities of managing giant RL, underscoring the importance of thorough surgical planning, multidisciplinary collaboration, and assessing potential adjunct therapies to improve patient prognosis.

Evidence of Alveolar Macrophage Metabolic Shift Following Stereotactic Body Radiation Therapy -Induced Lung Fibrosis in Mice

Radiation-induced pneumopathy is the main dose-limiting factor in cases of chest radiation therapy. Macrophage infiltration is frequently observed in irradiated lung tissues and may participate in lung damage development. Radiation-induced lung fibrosis can be reproduced in rodent models using whole thorax irradiation but suffers from limits concerning the role played by unexposed lung volumes in damage development. Here, we used an accurate stereotactic body radiation therapy preclinical model irradiating 4% of the mouse lung. Tissue damage development and macrophage populations were followed by histology, flow cytometry, and single-cell RNA sequencing. Wild-type and CCR2 KO mice, in which monocyte recruitment is abrogated, were exposed to single doses of radiation, inducing progressive (60 Gy) or rapid (80 Gy) lung fibrosis. Numerous clusters of macrophages were observed around the injured area, during progressive as well as rapid fibrosis. The results indicate that probably CCR2-independent recruitment and/or in situ proliferation may be responsible for macrophage invasion. Alveolar macrophages experience a metabolic shift from fatty acid metabolism to cholesterol biosynthesis, directing them through a possible profibrotic phenotype. Depicted data revealed that the origin and phenotype of macrophages present in the injured area may differ from what has been previously described in preclinical models exposing large lung volumes, representing a potentially interesting trail in the deciphering of radiation-induced lung damage processes. Our study brings new possible clues to the understanding of macrophage implications in radiation-induced lung damage, representing an interesting area for exploration in future studies.

Millimeter wave radiation to measure blood flow in healthy human subjects

Objective.Peripheral Artery Disease (PAD) is a progressive cardiovascular condition affecting 8-10 million adults in the United States. PAD elevates the risk of cardiovascular events, but up to 50% of people with PAD are asymptomatic and undiagnosed. In this study, we tested the ability of a device, REFLO (Rapid Electromagnetic FLOw), to identify low blood flow using electromagnetic radiation and dynamic thermography toward a non-invasive PAD diagnostic.Approach.During REFLO radio frequency (RF) irradiation, the rate of temperature increase is a function of the rate of energy absorption and blood flow to the irradiated tissue. For a given rate of RF energy absorption, a slow rate of temperature increase implies a large blood flow rate to the tissue. This is due to the cooling effect of the blood. Post-irradiation, a slow rate of temperature decrease is associated with a low rate of blood flow to the tissue. Here, we performed two cohorts of controlled flow experiments on human calves during baseline, occluded, and post-occluded conditions. Nonlinear regression was used to fit temperature data and obtain the rate constant, which was used as a metric for blood flow.Main results.In the pilot study, (N= 7) REFLO distinguished between baseline and post-occlusion during the irradiation phase, and between baseline and occlusion in the post-irradiation phase. In the reliability study, (N= 5 with 3 visits each), two-way ANOVA revealed that flow and subject significantly affected skin heating and cooling rates, while visit did not.Significance.Results suggest that MMW irradiation can be used to distinguish between blood flow rates in humans. Utilizing the rate of skin cooling rather than heating is more consistent for distinguishing flow. Future modifications and clinical testing will aim to improve REFLO's ability to distinguish between flow rates and evaluate its ability to accurately identify PAD.

Evaluating an analytical prediction algorithm of positron emitter distributions in patient data for PET monitoring of carbon ion therapy: A simulation study

In vivo treatment monitoring in ion therapy is one of the key issues for improving the treatment quality assurance procedures. Range verification is one of the most relevant and yet complex task used for in vivo treatment monitoring. In carbon ion therapy, positron emission tomography is the most widely used method. This technique exploits the β+-activity of positron emitters created by nuclear interactions between the incoming beam and the irradiated tissue. Currently, high computational efforts and time-consuming Monte Carlo simulation platforms are typically used to predict positron emitter distributions. In order to avoid time-consuming simulations, an extended filtering approach was suggested to analytically predict positron emitter profiles from depth dose distributions in carbon ion therapy. The purpose of this work is to investigate such an analytical prediction model in patient anatomies of varying complexity, highlighting its potential and the need of further improvements, especially in highly heterogeneous anatomies where many air cavities are present in the beam path. The accuracy of range verification showed a mean relative error of ∼3% and a deviation between the simulation and the prediction below 2mm for the three patient cases analysed: a brain case and two head and neck cases. Additional investigations demonstrated the region of applicability of the method for cases of patient data. The analytical method enables range verification in carbon ion therapy by replacing computing-intensive Monte Carlo simulations and thus minimize the PET monitoring burden on the clinical workflow.

Antioxidants Hydroxytyrosol and Thioredoxin-Mimetic Peptide CB3 Protect Irradiated Normal Tissue Cells.

Reducing side effects in non-cancerous tissue is a key aim of modern radiotherapy. Here, we assessed whether the use of the antioxidants hydroxytyrosol (HT) and thioredoxin-mimetic peptide CB3 (TMP) attenuated radiation-induced normal tissue toxicity in vitro. We used primary human umbilical vein endothelial cells (HUVECs) and human epidermal keratinocytes (HaCaT) as normal tissue models. Cells were treated with HT and TMP 24 h or immediately prior to irradiation. Reactive oxygen species (ROS) were assessed via luminescent- and fluorescence-based assays, migration was investigated using digital holographic microscopy, and clonogenic survival was quantified by colony formation assays. Angiogenesis and wound healing were evaluated via time-dependent microscopy. Secreted cytokines were validated in quantitative polymerase chain reaction (qPCR) studies. Treatment with HT or TMP was well tolerated by cells. The application of either antioxidant before irradiation resulted in reduced ROS formation and a distinct decrease in cytokines compared to similarly irradiated, but otherwise untreated, controls. Antioxidant treatment also increased post-radiogenic migration and angiogenesis while accelerating wound healing. HT or TMP treatment immediately before radiotherapy increased clonogenic survival after radiotherapy, while treatment 24 h before radiotherapy enhanced baseline proliferation. Both antioxidants may decrease radiation-induced normal tissue toxicity and deserve further pre-clinical investigation.

A Four-dimensional Computed Tomography Generated Internal Target Volume Approach to Paediatric High Risk Neuroblastoma to Reduce Organ at Risk and Normal Tissue Irradiation

AimsThe magnitude of upper abdominal organ motion in children may be overestimated by current planning target volumes (PTV). A four-dimensional computed tomography (4DCT) – derived internal target volume (ITV) is frequently used in adult radiotherapy to take respiratory-related organ motion into account. In this study, the dosimetric consequences for target coverage and organs at risk from the use of an ITV approach compared to standard PTV margins in children with high-risk neuroblastoma were investigated. Materials and methods14 patients, median age 4.1 years, range 1.5 – 18.9 years, (9 midline targets, 5 lateralised) each had two dual arc volumetric modulated arc therapy (VMAT) plans (14 ×1.5 Gy) generated. One used an ITV-approach; motion information derived from 4DCT (PTV_itv) with a 5mm ITV to PTV expansion, and the other a PTV margin of 10mm from CTV to PTV (PTV_standard). Differences in absolute PTV volume and organ at risk doses are described. ResultsThe ITV approach resulted in a highly significant reduction in PTV size of 38% (p<0.0001). For midline targets, an ITV approach resulted in a small but statistically significant reduction in combined mean kidney dose of 0.8Gy, p 0.01. Mean heart and lung dose were reduced by an average of 1 Gy with an ITV approach. Non-PTV integral dose from 30.4 Gy L to 27.8 Gy L using an ITV approach. ConclusionAn ITV-approach to respiratory related organ motion management in children can significantly reduce absolute PTV volumes, maintain target coverage and reduce dose delivered to normal tissue in proximity to the target. This is an essential step to maximising the benefits of highly conformal radiotherapy techniques including VMAT for this patient group, and in the future with Proton Therapy.

Adaptive radiotherapy for muscle invasive bladder cancer: a retrospective audit of two bladder filling protocols

BackgroundRadical radiotherapy for muscle-invasive bladder cancer (MIBC) is challenging due to large variations in bladder shape, size and volume during treatment, with drinking protocols often employed to mitigate geometric uncertainties. Utilising adaptive radiotherapy together with CBCT imaging to select a treatment plan that best fits the bladder target and reduce normal tissue irradiation is an attractive option to compensate for anatomical changes. The aim of this retrospective study was to compare a bladder empty (BE) protocol to a bladder filling (BF) protocol with regards to variations in target volumes, plan of the day (PoD) selection and plan dosimetry throughout treatment.MethodsForty patients were included in the study; twenty were treated with a BE protocol and twenty with a BF protocol to a total prescribed dose of 55 Gy in 20 fractions. Small, medium and large bladder plans were generated using three different CTV to PTV margins. Bladder (CTV) volumes were delineated on planning CTs and online pre-treatment CBCTs. Differences in CTV volumes throughout treatment, plan selection, PTV volumes and resulting dose metrics were compared for both protocols.ResultsMean bladder volume differed significantly on both the planning CTs and online pre-treatment CBCTs between the protocols (p < 0.05). Significant differences in bladder volumes were observed between the planning CT and pre-treatment CBCTs for BF (p < 0.05) but not for BE (p = 0.11). Both protocols saw a significant decrease in bladder volume between first and final treatment fractions (p < 0.05). Medium plans were preferentially selected for BE whilst when using the BF protocol the small plan was chosen most frequently. With no significant change to PTV coverage between the protocols, the volume of body receiving 25.0–45.8 Gy was found to be significantly smaller for BE patients (p < 0.05).ConclusionsThis work provides evidence in favour of a BE protocol compared to a BF protocol for radical radiotherapy for MIBC. The smaller treatment volumes observed in the BE protocol led to reduced OAR and total body doses and were also observed to be more consistent throughout the treatment course. These results highlight improvements in dosimetry for patients who undergo a BE protocol for MIBC.

Modeling the Effects of Protracted Cosmic Radiation in a Human Organ-on-Chip Platform.

Galactic cosmic radiation (GCR) is one of the most serious risks posed to astronauts during missions to the Moon and Mars. Experimental models capable of recapitulating human physiology are critical to understanding the effects of radiation on human organs and developing radioprotective measures against space travel exposures. The effects of systemic radiation are studied using a multi-organ-on-a-chip (multi-OoC) platform containing engineered tissue models of human bone marrow (site of hematopoiesis and acute radiation damage), cardiac muscle (site of chronic radiation damage) and liver (site of metabolism), linked by vascular circulation with an endothelial barrier separating individual tissue chambers from the vascular perfusate. Following protracted neutron radiation, the most damaging radiation component in deep space, a greater deviation of tissue function is observed as compared to the same cumulative dose delivered acutely. Further, by characterizing engineered bone marrow (eBM)-derived immune cells in circulation, 58 unique genes specific to the effects of protracted neutron dosing are identified, as compared to acutely irradiated and healthy tissues. It propose that this bioengineered platform allows studies of human responses to extended radiation exposure in an "astronaut-on-a-chip" model that can inform measures for mitigating cosmic radiation injury.

On Approach for Analysis of Distribution of Temperature During Effects of Radiation on Biological Tissues

Different types of irradiation take essential role in biological processes directly related to human health. Currently they are widely using in clinical practice. In this situation one can find several works to determine therapeutic effects, which were obtained by actions of the irradiation on living organisms. One type of irradiation of tissues of the considered organisms is electromagnetic radiation. A consequence of the radiation tissues of organisms is their heating. In this paper we introduce a model and an analytical approach to analyze distribution of temperature at effect of radiation on biological tissues. We consider a possibility to control of heat transport in biological tissues by choosing of conditions of heating. Also we present an analytical approach for analysis of the obtained model. The approach takes into account changing of parameters of the considered processes on coordinate and time as well as their nonlinearity.

Full operating parameter recording as an essential component of the reproducibility of laser-tissue interaction and treatments.

The number and diversity of published peer-reviewed studies in the discipline of laser dentistry have grown considerably during the past 10 years. Within primary research, the development of protocols to guide and formulate clinical practice demands precision and ease of reproducibility. Errors in data acquisition and management may become amplified as the applied randomized clinical trials (RCTs) forge new levels of clinical diversity and predictability in the use of laser photonic energy in both ablative (surgical) and sub-ablative (photobiomodulation (PBM) or photodynamic therapy (PDT)) applications. A comprehensive range of empirical and computational operating parameters must be included in published studies to facilitate the uniformity of powerand time-related values of laser irradiation. Choosing the correct "tissue irradiation parameters" is difficult and depends on the pathology and symptoms, the surface area to be treated, laser wavelength, the thermal relaxation time of each targeted tissue, and controlling penetration depth of the light into tissues. Therefore, to allow the reproducibility of the results, it is recommended that authors mention with the greatest care and clarity the irradiation parameters used in their study. This paper outlines the concerns felt regarding the general shortfalls and proposes a minimum range of laser operating parameters that should be represented in future peer-reviewed publications.

A systematic review of normal tissue neurovascular unit damage following brain irradiation-Factors affecting damage severity and timing of effects.

Radiotherapy is key in the treatment of primary and secondary brain tumors. However, normal tissue is inevitably irradiated, causing toxicity and contributing to cognitive dysfunction. The relative importance of vascular damage to cognitive decline is poorly understood. Here, we systematically review the evidence for radiation-induced damage to the entire neurovascular unit (NVU), particularly focusing on establishing the factors that influence damage severity, and timing and duration of vascular effects relative to effects on neural tissue. Using PubMed and Web of Science, we searched preclinical and clinical literature published between January 1, 1970 and December 1, 2022 and evaluated factors influencing NVU damage severity and timing of NVU effects resulting from ionizing radiation. Seventy-two rodents, 4 canines, 1 rabbit, and 5 human studies met inclusion criteria. Radiation increased blood-brain barrier (BBB) permeability, reduced endothelial cell number and extracellular matrix proteoglycans, reduced tight junction proteins, upregulated cellular adhesion molecule expression, reduced activity of glucose and BBB efflux transporters and activated glial cells. In the brain parenchyma, increased metalloproteinases 2 and 9 levels, demyelination, cell death, and inhibited differentiation were observed. Effects on the vasculature and neural compartment were observed across acute, delayed, and late timepoints, and damage extent was higher with low linear energy transfer radiation, higher doses, lower dose rates, broader beams, and in the presence of a tumor. Irradiation of normal brain tissue leads to widespread and varied impacts on the NVU. Data indicate that vascular damage is in most cases an early effect that does not quickly resolve. More studies are needed to confirm sequence of damages, and mechanisms that lead to cognitive dysfunction.

Niraparib efficacy in patients with newly-diagnosed glioblastoma: Clinical readout of a phase 0/2 "trigger" trial.

2002 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met. Methods: Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 (cohort 1) or 8-10 hours (cohort2) following the last dose. Tumor tissue (Gadolinium enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the Phase 2 component of the study and was defined as unbound [niraparib] &gt; 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors in excess of the PK threshold were eligible for Phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib monotherapy. Results: All Phase 0 patients (n=46) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 335.1 nM (n=43) for cohort 1 and 331.9 nM (n=3) for cohort 2. PAR suppression after ex vivo radiation was observed in 73% of the patients (24/33). Nineteen of 27 (70.3%) patients with unmethylated tumors were enrolled into Phase 2. Five patients in Phase 2 experienced Grade 4 thrombocytopenia related to niraparib. All adverse events resolved without sequelae. At time of data cutoff, median progression-free survival was 11.7 months. Mature overall survival (OS) data will be reported for the first time. Conclusions: Niraparib achieves pharmacologically relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Accompanying PD effects were observed in patient tumor tissue. For the first time, we report on the clinical efficacy of the study. A global Phase 3, open-label, randomized 2-arm study comparing niraparib versus temozolomide in adult patients with newly diagnosed, MGMT unmethylated glioblastoma is being planned. Clinical trial information: NCT05076513 .

Stereotactic Body Radiotherapy as a Curative Treatment for De Novo Mucosal Carcinoma of the Head and Neck: A Feasible Alternative Option for Fragile Patients with Small Lesion: A Systematic Review.

Stereotactic body radiotherapy (SBRT) is characterized by a high dose per fraction, well-defined small targets, superior dose conformity, and a steep off-target dose gradient. A literature search was conducted to examine the experience with SBRT as a curative treatment for newly diagnosed mucosal carcinoma of the head and neck (MCHN). Four retrospective case series and one prospective phase I clinical trial published between 2012 and 2020 described 124 patients. SBRT was mainly performed in older patients with different tumor sites. The median size of the planning target volumes ranged from 5.3 to 41 cm3. Different approaches were used to create margins. In two studies, limited elective nodal irradiation was performed. The equivalent doses used were 60-83.33 Gy delivered in five fractions. Considerable heterogeneity was observed in the radiation dose specification. The incidence of grade ≥3 late toxicity was 0-8.3%, with local and regional control ranging from 73% to 100%. Improved or stable quality of life after SBRT was reported in two studies. Curative-intent SBRT for de novo MCHN appears to be an effective and relatively safe treatment for small tumor targets, preferably without concomitant elective tissue irradiation. Standardization of SBRT practice and well-designed prospective clinical trials are needed to better define the role of SBRT in this setting.

Photochemical Crosslinking of Tarsal Collagen as a Treatment for Eyelid Laxity: Evaluation in Ex Vivo Human Tissue

Purpose: Experimental investigation in human eyelids to confirm that exposing excised tarsal plates to ultraviolet-A radiation can induce a stiffening effect through the riboflavin-photosensitized crosslinking of tarsal collagen. Methods: Thirteen tarsal plates excised from nonfrozen human cadavers were irradiated with ultraviolet-A rays (365 nm wavelength) at an irradiance of 75 mW/cm2 for 3 minutes, equivalent to a radiation fluence of 13.5 J/cm2, in the presence of a riboflavin derivative as a photosensitizer. The tensile stress (strength) and Young’s modulus (stiffness) of both nonirradiated and irradiated specimens were measured with the BioTester 5000 in the uniaxial mode at a strain of 10% and analyzed statistically. Individual specimens excised from 2 cadavers were also examined by routine histopathologic protocols to assess the effect of radiation on the Meibomian glands and collagen organization. Results: The irradiation enhanced both stiffness and strength of the human tarsal specimens, the difference between the test samples and controls being statistically significant (p &lt; 0.0002 for n = 13). Histology indicated no damage to tarsal connective tissue or to Meibomian glands, and revealed a more compact packing of the collagen network located around the glands, which may be beneficial. The existence of collagen compaction was also supported by the reduction of samples’ thickness after irradiation (p = 0.0645). Conclusions: The irradiation of tarsal tissue with ultraviolet-A light of tarsus appears to be a safe and effective method for reducing eyelid laxity in human patients.