Normal Tissue Radiation Research Articles

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.

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.

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.

The Value and Safety of Adjuvant Radiation Therapy After Radical Cystectomy in Locally Advanced Urothelial Bladder Cancer: A Controlled Randomized Study

BackgroundAdjuvant radiotherapy after radical cystectomy in locally advanced bladder cancer was revived after the advancement in precise radiotherapy that decreased the normal pelvic tissue radiation hazards. However, there are still scarce controlled randomized studies addressing this issue. Patients and methodsOne hundred thirty-one cystectomized urothelial bladder cancer patients were enrolled; a hundred and twenty-two were randomized to receive adjuvant radiotherapy (ART) 50 Gy/25 fractions, 4 weeks’ post-cystectomy or cystectomy alone (CY). Sixty-two were included in the ART arm and sixty in the CY arm. Twenty-four ART and 30 CY patients received Neoadjuvant chemotherapy. Eleven patients (9%) had cotenant neo-bladder diversion, 6 in ART, and 5 in CY arms. All ART patients were treated with intensity-modulated radiotherapy (IMRT) with daily verification cone-beam CT (CBCT). The median follow-up was 42.7 months. ResultsThe 3-year adjusted Locoregional relapse-free survival (LRFS) rate was higher in the ART arm, measuring 81% (95%CI: 69-94) compared to 71% (95% CI: 60-80) (p=0.0457). ART significantly improved the locoregional relapse-free rate in the cystectomy bed and the pelvic side wall (p= 0.016 and 0.001, respectively). The overall survival, event-free, and distant metastasis-free survival did not rank to the level of statistical significance in the 2 arms. Even though the acute side effects were slightly higher in ART, the late toxicities were almost equal in the two groups. ConclusionsAdjuvant radiotherapy is safe and quite tolerable after radical cystectomy when using precise radiation techniques. These techniques significantly improved the LRFS but had insignificant improvement on the overall survival. ART did not affect the distant metastasis-free survival. Similar studies are performed in different centers around the world to confirm the value of ART in urothelial bladder cancer.

2220: Robust optimization of the GTV is able to reduce normal tissue irradiation in lung SBRT

2220: Robust optimization of the GTV is able to reduce normal tissue irradiation in lung SBRT

Approaches to Reducing Normal Tissue Radiation from Radiolabeled Antibodies.

Radiolabeled antibodies are powerful tools for both imaging and therapy in the field of nuclear medicine. Radiolabeling methods that do not release radionuclides from parent antibodies are essential for radiolabeling antibodies, and practical radiolabeling protocols that provide high in vivo stability have been established for many radionuclides, with a few exceptions. However, several limitations remain, including undesirable side effects on the biodistribution profiles of antibodies. This review summarizes the numerous efforts made to tackle this problem and the recent advances, mainly in preclinical studies. These include pretargeting approaches, engineered antibody fragments and constructs, the secondary injection of clearing agents, and the insertion of metabolizable linkages. Finally, we discuss the potential of these approaches and their prospects for further clinical application.

High-Dose-Rate Yttrium-90 (90Y) Episcleral Plaque Brachytherapy for Iris and Iridociliary Melanoma

PurposeTo describe a pilot study on the use of single-session, high-dose-rate, FDA-cleared, yttrium-90 (90Y) plaque brachytherapy for iris and iridociliary melanoma. DesignA single-center, clinical case series. ParticipantsSix consecutive patients were included in this study. Each was diagnosed with an iris or iridociliary melanoma based on clinical examination with or without biopsy. MethodsEach tumor was staged according to AJCC criteria and received 90Y eye plaque brachytherapy. The main variables were tumor size, patient age, sex, and method of diagnosis (clinical or biopsy). Surgical techniques, treatment durations, and ocular side effects were recorded. Local control was defined as a lack of tumor growth or regression determined by clinical examinations, including slit-lamp and gonio photography, as well as high-frequency ultrasound measurements. Toxicity parameters included acute and short-term corneal/scleral change, anterior segment inflammation, and cataract progression. ResultsHigh-dose-rate 90Y plaque brachytherapy was used to treat small (AJCC cT1) category melanomas. Single-surgery high-dose-rate irradiations were performed under anesthesia. Due to short treatment durations, high-dose-rate 90Y did not require the additional procedures used for low-dose-rate plaque (e.g., sutures, amniotic membrane epicorneal buffering, Gunderson flaps, and second surgeries for plaque removal). Only conjunctival recession was used to avoid normal tissue irradiation. high-dose-rate 90Y treatment durations averaged 8.8 minutes (median 7.9, range 5.8-12.9). High-dose-rate 90Y brachytherapy was associated with no periorbital, corneal (Descemet’s folds), and/or conjunctival edema. There was no acute or short-term anterior uveitis, secondary cataract, scleropathy, radiation retinopathy, maculopathy, or optic neuropathy. Follow-up was a mean of 16.0 (range 12 to 24) months. Evidence of local control included a lack of expansion of tumor borders (n=6, 100%), darkening and/or atrophy of the tumor surface (n=5/6, 83%), and a mean 24.5% reduction in ultrasonographically measured tumor thickness. There were no cases of metastatic disease. ConclusionHigh-dose-rate 90Y brachytherapy allowed for single-surgery, minimally invasive, outpatient irradiation of iris and iridociliary melanomas.

The MIRD Schema for Radiopharmaceutical Dosimetry: A Review.

Internal dosimetry evaluates the amount and spatial and temporal distributions of radiation energy deposited in tissue from radionuclides within the body. Historically, nuclear medicine had been largely a diagnostic specialty, and the implicitly performed risk-benefit analyses have been straightforward, with relatively low administered activities yielding important diagnostic information whose benefit far outweighs any potential risk associated with the attendant normal-tissue radiation doses. Although dose estimates based on anatomic models and population-average kinetics in this setting may deviate rather significantly from the actual normal-organ doses for individual patients, the large benefit-to-risk ratios are very forgiving of any such inaccuracies. It is in this context that the MIRD schema was originally developed and has been largely applied. The MIRD schema, created and maintained by the MIRD committee of the Society of Nuclear Medicine and Molecular Imaging, comprises the notation, terminology, mathematic formulas, and reference data for calculating tissue radiation doses from radiopharmaceuticals administered to patients. However, with the ongoing development of new radiopharmaceuticals and the increasing therapeutic application of such agents, internal dosimetry in nuclear medicine and the MIRD schema continue to evolve-from population-average and organ-level to patient-specific and suborgan to voxel-level to cell-level dose estimation. This article will review the basic MIRD schema, relevant quantities and units, reference anatomic models, and its adaptation to small-scale and patient-specific dosimetry.

Abstract B065: Enhancing the therapeutic gain of proton radiotherapy in Locally Advanced Rectal Cancer (LARC) through manipulation of WSB1, ATM, and β-Catenin/c-Myc pathway Ubiquitination

Abstract Just 20% of patients with LARC attain a complete response to preoperative chemoradiotherapy which portends an excellent prognosis and opportunity to preserve the rectum through nonoperative surveillance. Moreover, normal tissue radiation toxicity can lead to significant morbidity, and becomes an even more important consideration in non-operative approaches where irradiated tissue is not resected. The geometry of conventional proton beams is already being used clinically to spare patient’s normal tissue, but the biology of entrance (ENT) vs. Bragg Peak (BP) protons has yet to be fully exploited to enhance tumor efficacy. Protons, unlike conventional x-ray radiation, spare normal tissue by lacking an exit dose - but they also exhibit a Bragg Peak (BP), which causes more complex DNA damage and is more biologically effective. ATM is critical in the repair of double strand DNA breaks (DSBs) and our lab has demonstrated that inhibitors of ATM (iATM) preferentially radiosensitize BP protons in CRC (Fig. 1A). Overactivation of the Wnt/β-catenin pathway via loss of function of APC is the most common genetic mutation in colorectal cancer (75-80%) and β-catenin over-expression negatively correlates with prognosis. WSB1 has been discovered by our lab to regulate ATM ubiquitination and degradation, it decreases metastates-free survival in CRC, and also forms a positive feedback loop with β-catenin and c-Myc that drives oncogenic progression. It is unknown if this upregulation of WSB1 promotes ATM degredation in LARC specifically, and a deubiquitinase (DUB) for ATM (which would counter WSB1) has yet to be identified. We preformed a comprehensive database search (UbiBrowser 2.0) for the most likely predicted DUBs for ATM (Fig. 1B), several of which have been identified as regulators of β-catenin/c-Myc, DSB repair pathways, and correlated with poor prognosis in CRC. We have also performed a screen of DUBs predicted to interact with ATM, and have preliminary evidence suggesting USP14 as the worlds first identified DUB of ATM (Fig 1C). USP14 expression is upregulated in CRC compared to surrounding normal tissue, promotes radioresistance, and promotes Wnt/β-catenin signalling. Higher USP14 expression in CRC is associated with liver and lymph node metastases and worse overall survival. USP14 regulates β-catenin by deubiquitinating K63-linked polyubiquitin chains of Dvl, and several small molecule inhibitors of USP14 have been identified. Our lab has preliminary data demonstrating USP14 is preferentially activated after BP proton irradiation (Fig. 1D), suggesting ATM may be necessary for repair of complex DSBs. While more work will be necessary to confirm these findings, many of the other predicted DUBs of ATM have overlapping functions regulating DSB repair and/or β-catenin/c-Myc signalling. We hypothesize that targeting ATM ubiquitination will open a therapeutic window in LARC by disrupting β-catenin/c-Myc signalling and selectively radiosensitizing BP protons. Citation Format: Sonja Dragojevic, Cameron M. Callaghan. Enhancing the therapeutic gain of proton radiotherapy in Locally Advanced Rectal Cancer (LARC) through manipulation of WSB1, ATM, and β-Catenin/c-Myc pathway Ubiquitination [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B065.

Dosimetric characterization of a new surface-conforming electron MLC prototype.

The purpose is toreduce normal tissue radiation toxicity for electron therapy through the creation of a surface-conforming electron multileaf collimator (SCEM). The SCEM combines the benefits of skin collimation, electron conformal radiotherapy, and modulated electron radiotherapy. An early concept for the SCEM was constructed. It consists of leaves that protrude towards the patient, allowing the leaves to conform closely to irregular patient surfaces. The leaves are made of acrylic to decrease bremsstrahlung, thereby decreasing the out-of-field dose. Water tank scans were performed with the SCEM in place for various field sizes for all available electron energies (6, 9, 12, and 15 MeV) with a 0.5cm air gap to the water surface at 100cm source-to-surface distance (SSD). These measurements were compared with Cerrobend cutouts with the field size-matched at 100 and 110cm SSD. Output factor measurements were taken in solid water for each energy at dmax for both the cerrobend cutouts and SCEM at 100cm SSD. Percent depth dose (PDD) curves for the SCEM shifted shallower for all energies and field sizes. The SCEM also produced a higher surface dose relative to Cerrobend cutouts, with the maximum being a 9.8% increase for the 3cm × 9cm field at 9 MeV. When compared to the Cerrobend cutouts at 110cm SSD, the SCEM showed a significant decrease in the penumbra, particularly for lower energies (i.e., 6 and 9 MeV). The SCEM also showed reduced out-of-field dose and lower bremsstrahlung production than the Cerrobend cutouts. The SCEM provides significant improvement in the penumbra and out-of-field dose by allowing collimation close to the skin surface compared to Cerrobend cutouts. However, the added scatter from the SCEM increases shallow PDD values. Future work will focus on reducing this scatter while maintaining the penumbra and out-of-field benefits the SCEM has over conventional collimation.

Progression-Free Survival in Patients with WHO-2 Meningioma Undergoing Active Surveillance Based on DOTATATE PET Evidence of Gross Total Resection: Prospective Observational Study

MRI is the standard of care for meningioma radiotherapy planning, but lacks sensitivity for postoperative small volume disease and osseous or parenchymal invasion. NRG-BN003 (NCT03180268) randomizes patients with WHO-2 meningiomas and MRI-determined gross total resection (GTR) to observation or 60 Gy IMRT to the resection bed. More sensitive and specific imaging biomarkers than MRI may improve clinical outcomes in meningioma by limiting unnecessary irradiation of normal tissues and improving radiotherapy targeting. [68Ga]-DOTATATE, a PET radiotracer targeting somatostatin receptor 2 (SSTR2) is a highly sensitive and specific meningioma biomarker. Our dedicated DOTATATE brain PET/MRI and PET/CT protocol allows meningioma differentiation from post-treatment change, using SUV analysis and Patlak modeling. Our prospective IRB-approved observational trial (NCT04081701) has imaged >100 patients with meningioma. In the sub-analysis presented here, we prospectively evaluated PFS in patients with WHO-2 tumors and postoperative GTR as determined by [68Ga]-DOTATATE brain PET/MRI or PET/CT who were managed solely with active surveillance. We hypothesized that the PFS of patients with GTR by PET managed with active surveillance would be higher than reported PFS data for patients with MRI-determined GTR, using NRG-BN003's observation arm (randomized trial comparing observation to fractionated RT) as a reference standard. From the cohort of >100 patients with SSTR2-positive brain neoplasms enrolled between 9/2019 and 10/2022 and imaged according to our previously published protocol, a sub-cohort of patients were selected with WHO-2 meningioma, postoperative findings of GTR, and postoperative active surveillance with periodic MRI every 3-6 months. Kaplan-Meier survival analysis was performed. A total of 12 patients met inclusion criteria. Mean patient age was 64 years and 5 (42%) were female. Mean follow up period was 23.4 months (range: 7-38). 83% (10/12) patients underwent postoperative PET/MRI and 17% (2/12) underwent PET/CT. 2 patients (17%) progressed, at 22 and 34 months, respectively; the remainder remain progression-free. Both patients who had progression were successfully salvaged with focal fractionated radiosurgery. Kaplan-Meier analysis demonstrated PFS at almost 3 years to be 75%, which is substantially higher than the reported 3-year PFS of 60% in the literature. Overall survival was 100%. [68Ga]-DOTATATE PET can improve the specificity of imaging-based assessment of the extent of resection of WHO-2 meningiomas, thereby improving clinical outcomes. In this cohort of patients with completely resected WHO-2 meningiomas (as assessed by postoperative gadolinium-enhanced MRI and DOTATATE PET) who are conservatively managed, recurrences have been rare and amenable to radiosurgical salvage.

Deep Learning-Based Pipeline for Automatic Identification of Intestinal Regenerating Crypts in Mouse Histological Images

A classical approach for evaluating normal tissue radiation response is to count the number of intestinal regenerating crypts in mouse histological images acquired after abdominal radiation. However, manual counting is time-consuming and subject to inter-observer variations. The goal of this study is to build a deep learning-based pipeline for automatically identifying intestinal regenerating crypts to facilitate high-throughput studies. Sixty-six healthy C57BL/6 female mice underwent 16 MeV whole abdominal electron irradiation. The small bowel was collected from each mouse 4 days post-irradiation, and 9 jejunal cross-sections from each were processed together in a single slide. The slides were stained with hematoxylin and eosin (H&E) and subsequently scanned (x20), providing one electronic histological image per mouse. Regenerating crypts, consisting of more than 10 basophilic crypt epithelial cells, were manually identified using point annotations in histological images. The pipeline was built to take the input of the image containing 9 cross sections and automatically identify the regenerating crypts on each cross section. It mainly consists of two components, cross section segmentation using intensity thresholding and morphological operations and crypt identification using a UNet. The dataset was randomly split into 46, 10, and 10 slide images for UNet training, validation, and testing. Each slide image was split into grid tiles with a voxel size of 200 × 200, and 40 × 40 square masks were placed with centers at manual point annotations on tiles with regenerating crypts. 5203/5198 tiles (w/wo crypt mask) were extracted to train UNet by minimizing dice loss. The mask probability map generated by the UNet was post-processed to identify the crypt position. Postprocessing hyperparameters were tuned using the validation dataset. The model accuracy was evaluated using the testing dataset by computing the mean absolute error (MAE) of the crypt number averaged across all cross sections. The number of regenerating crypts on testing cross sections ranges from 1 to 63. The testing cross-section-wise MAE achieved by the platform is 3.5±4.8 crypts. 81.25% of testing cross sections have absolute number differences less than or equal to 5 crypts. Our established deep learning-based pipeline can accurately count the number of regenerating crypts in mouse intestinal histological images. We have integrated it into an online platform that enables automatic crypt identification and allows users to interactively modify auto-identified crypt annotations. The acquired annotations from the platform will be used to finetune the deep learning model to achieve better identification performance.

Proposal of a New Conformal Factor and Normal Tissue Penalty Factor for Radiosurgery Treatments.

The quality of a treatment plan is evaluated by the conformality of the prescribed isodose around the target and the homogeneity of dose distribution inside the target. Presently, to check the target volume conformality, a number of published conformity indices are in use. Most of these indices are based on the target volume coverage by prescribed isodose, with respect to the total volume of the target. Some take into account the normal tissue covered by the prescribed isodose and suitably weigh the target coverage to evaluate conformity. In this study, for the irradiation of normal tissue by the prescription isodose, a normal tissue penalty factor is proposed and for the target conformality, a new conformal factor is proposed by applying this normal tissue penalty factor to the target coverage. The proposed conformal factor is evaluated for a few sample analytical cases and the results are compared with those obtained using the published conformity indices.

Matching between Clinical and Dosimetric Results in Comparing Intensity Modulated Radiotherapy with Three-Dimensional Conformal Radiotherapy in Locally Advanced Lung Cancer

Background Radiation therapy plays an essential role in the treatment of locally advanced lung cancer, but it inevitably leads to incidental and unnecessary dose to critical organs, including the lung, heart, and esophagus. Objective A dosimetric study to compare 3D CRT to IMRT in locally advanced lung cancer as regards normal tissue irradiation and target coverage using COSI &amp; modified COSI indices, DVH, homogeneity index, conformity index, target coverage index. Also to evaluate acute and late toxicity of esophagus, heart and lung in three-dimensional conformal radiotherapy and intensity modulated radiotherapy, in patients with locally advanced lung cancer who received definitive concurrent chemo-radiation or sequential chemo-radiation according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Patients and Methods 20 patients were selected to participate in our retrospective study from 2014 till 2019. They were recruited from bronchogenic cancer clinic, clinical oncology department in Ain Shams University Hospitals using a convenient sampling method. Diagnosis of NSCLC or SCLC was confirmed histologically and further radiological assessment for TNM staging was performed. All patients where 18 years old or older and were prescribed for either combined or sequential chemoradiotherapy for treatment of locally invasive lung cancer with ECOG PS equal or less than 2. They received 3D CRT of total 60 Gy. On the same CT contour defined for 3D CRT another plan was done for IMRT by computer based inverse planning with specific dose constrains to surrounding organs. Results In our study IMRT technique helped in sparing doses delivered to heart, lung &amp; esophagus in comparison with 3D CRT, but it was statistically significant for the lung only with p-value = 0.003. As regard the dosimetric indices IMRT showed better target coverage, dose homogenity &amp; dose conformity in comaparison with 3D CRT, but it was statistically significant for CI with p-value= 0.028. Using the COSI &amp; mCOSI also was in favor of IMRT but it was stastistically significant in mCOSI with pvalue=0.023 Conclusion IMRT showed superior outcomes as regards delivered doses (both to target and at-risk organs) compared to the conventional 3D CRT achieving the main purpose for patients with locally advanced lung cancer receiving chemoradiothrapy which is better target volume coverage and less unnecessary dose to at-risk nearby vital organs. As IMRT spares OAR it’s expected that clinical toxicity noticed with 3DCRT will be less thus, more tolerability to CCRT.

Nordic anal cancer (NOAC) group consensus guidelines for risk-adapted delineation of the elective clinical target volume in anal cancer

Background: To date, anal cancer patients are treated with radiotherapy to similar volumes despite a marked difference in risk profile based on tumor location and stage. A more individualized approach to delineation of the elective clinical target volume (CTVe) could potentially provide better oncological outcomes as well as improved quality of life. The aim of the present work was to establish Nordic Anal Cancer (NOAC) group guidelines for delineation of the CTVe in anal cancer. Methods: First, 12 radiation oncologists reviewed the literature in one of the following four areas: (1) previous delineation guidelines; (2) patterns of recurrence; (3) anatomical studies; (4) common iliac and para-aortic recurrences and delineation guidelines. Second, areas of controversy were identified and discussed with the aim of reaching consensus. Results: We present consensus-based recommendations for CTVe delineation in anal cancer regarding (a) which regions to include, and (b) how the regions should be delineated. Some of our recommendations deviate from current international guidelines. For instance, the posterolateral part of the inguinal region is excluded, decreasing the volume of irradiated normal tissue. For the external iliac region and the cranial border of the CTVe, we agreed on specifying two different recommendations, both considered acceptable. One of these recommendations is novel and risk-adapted; the external iliac region is omitted for low-risk patients, and several different cranial borders are used depending on the individual level of risk. Conclusion: We present NOAC consensus guidelines for delineation of the CTVe in anal cancer, including a risk-adapted strategy.

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects.

Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug pharmacokinetics to prolong circulation and normal tissue irradiation. Here we report the first covalent protein TRT, which, through reacting with the target irreversibly, increases radioactive dose to the tumor without altering the drug's pharmacokinetic profile or normal tissue biodistribution. Through genetic code expansion, we engineered a latent bioreactive amino acid into a nanobody, which binds to its target protein and forms a covalent linkage via the proximity-enabled reactivity, cross-linking the target irreversibly in vitro, on cancer cells, and on tumors in vivo. The radiolabeled covalent nanobody markedly increases radioisotope levels in tumors and extends tumor residence time while maintaining rapid systemic clearance. Furthermore, the covalent nanobody conjugated to the α-emitter actinium-225 inhibits tumor growth more effectively than the noncovalent nanobody without causing tissue toxicity. Shifting the protein-based TRT from noncovalent to covalent mode, this chemical strategy improves tumor responses to TRTs and can be readily scaled to diverse protein radiopharmaceuticals engaging broad tumor targets.

Phase 1 trial of GD2-SADA:177Lu-DOTA drug complex in patients with recurrent or refractory metastatic solid tumors known to express GD2 including small cell lung cancer (SCLC), sarcoma, and malignant melanoma.

TPS3162 Background: GD2 is a disialoganglioside with high expression in small cell lung cancers (SCLC), sarcomas and melanomas and limited expression in normal tissues. The SADA platform represents a 2-step pretargeted radioimmunotherapy approach developed to optimize tumor targeting and reduce normal tissue irradiation. The GD2-SADA molecule is composed of a non-radioactive, bispecific antibody (anti-GD2 x anti-DOTA) linked to a tetramerization sequence from the p53 protein. In the first step, the GD2-SADA molecule is administered in a tetrameric form with a high affinity to the GD2 tumor target. In preclinical research, any unbound GD2-SADA molecule will disassemble to monomers and has shown to clear via the kidneys. In the second step, the radioactive payload 177Lu-DOTA is administered, which binds to the anti-DOTA part of the GD2-SADA and leads to radiation-induced damage at the target and has shown limited exposure to non-target tissues in preclinical research. This pre-targeting approach supports the concept of highly focused irradiation of the tumor target with the potential of administering higher radioactivity doses. Methods: Trial 1001 (NCT05130255) is a first-in-human, dose-escalation, single-arm, open-label, non-randomized, multicenter phase 1 trial with the purpose of evaluating safety and tolerability of GD2-SADA:177Lu-DOTA. The trial is composed of 3 parts: Part A is dose escalation of the GD2-SADA dose and testing of different intervals between GD2-SADA and 177Lu-DOTA. Part B is dose escalation of the 177Lu-DOTA radioactivity dose to establish its maximum tolerated dose (MTD). Part C involves repeated dosing to assess the safety profile and determine the Recommended Phase 2 Dose (RP2D). Parts B and C may only begin upon completion of dose-limiting toxicity (DLT) observation period of Parts A and B, respectively. Escalation is based on classical 3+3 design. Parts A, B, and C will include 18, 12, and 32 patients, respectively. Patients can only be assigned to one part of the trial. The trial will include adult/adolescent patients with either SCLC, sarcoma, or melanoma with radiographical relapse/progression on standard therapies. The patients must be in ECOG performance status 0-1 and have adequate hematological, renal, and liver function. The patients must have measurable disease according to RECIST 1.1. Patients with active CNS metastases are ineligible. Safety endpoints (DLTs and adverse events) will be summarized by trial part and cohort. Objective response according to RECIST 1.1 and disease control rates at 6, 12 and 24 months will be presented with exact 95% CI. PFS, OS, and duration of response will be estimated using Kaplan-Meier methods. Additional objectives include dosimetry, PK, and immunogenicity data. The study is actively enrolling at US sites. Clinical trial information: NCT05130255 .

Polydatin radiosensitizes lung cancer while preventing radiation injuries by modulating tumor-infiltrating B cells

BackgroundAcquired radio-resistance and the undesired normal tissue radiation injuries seriously discount the therapeutic effect of lung cancer radiotherapy. In this study, we aimed to explore the role and potential mechanism of polydatin in simultaneously decreasing radioresistance and radiation injuries.MethodsThe tumor-bearing model of nude mice was used to investigate the tumor inhibition of polydatin on lung cancer and its effect on radiosensitivity, and the effect of polydatin on B cell infiltration in cancerous tissue was investigated. In addition, we performed systemic radiotherapy on BABL/C mice and evaluated the protective effect of polydatin on radiation injury by the Kaplan–Meier survival curve. Moreover, the regulation of polydatin on proliferation and apoptosis of A549 cells was also investigated in vitro.ResultsIn this study, it is first found that polydatin inhibits the growth and promotes the radiosensitivity of lung cancer while reducing the radiation damage of the healthy tissue. Further, it is evidenced that the major mechanism relies on its regulation on body’s immune function, and in particular, the inhibition of radiation-induced B cell infiltration in tumor tissue.ConclusionThese findings show that in addition to tumor inhibition, polydatin also promotes the sensitivity and reduces the adverse reactions of radiotherapy, making itself a promising candidate for boosting lung cancer radiotherapy efficacy.