Additional Toxicity Research Articles

Potential risk to aquatic biota from aerial application of firefighting water additives

The frequency and severity of forest fires is increasing due to climate change. Consequently, there will be an increased use of forest firefighting additives, which increase the ability of water to extinguish fires and prevent reignition. Increased use will potentially result in increased exposure to aquatic ecosystems within forests. This study examined the toxicity of nine firefighting water additives that are currently on the market to three species of freshwater invertebrates that occupy different niches within freshwater ecosystems. The toxicity of the water additives varied up to three orders of magnitude. Pelagic and epibenthic invertebrates are affected at lower rates of application than endobenthic invertebrates. A field relevant application rate of three of the nine water additives tested represent a hazard to freshwater ecosystems under varies exposure scenarios represented by the depth of a theoretical water body (15–200 cm). This study highlights the importance of application buffers around water bodies and the selection of water additives that pose the lowest hazard to freshwater ecosystem, assuming that the efficacy of the additives in extinguishing fires is similar.

Behavioral Alterations Following Exposure to a Mixture of Lead and Atrazine During Early Development in the Zebrafish Model System

Lead (Pb) and atrazine (ATZ) are hazardous environmental toxicants that can exist as a mixture in potable water. Numerous single chemical studies on Pb and ATZ support adverse health outcomes, including neurotoxicity, but mixture studies are limited. Th e aim of this study is to test the hypothesis that Pb and ATZ mixtures result in a greater than additive toxicity, causing increased adverse health outcomes than single chemical exposures. Th e zebrafish model system was exposed to 3 or 30 ppb (µg/L) ATZ, 10 ppb (equivalent to 0.1 µg/dL) or 100 ppb Pb, along with mixtures of each beginning at 1 hour postfertilization (hpf) and continuing through 120 hpf. A visual motor response behavioral assay was then conducted using the Noldus DanioVision. The visual motor response assay tracks locomotor movement over five alternating periods of dark and light. Th e behavior data was analyzed by phase with a repeated measures ANOVA. Th e 10 ppb Pb mixture behavior data showed significant hypoactivity in the 10 ppb Pb, 30 ppb ATZ, 3 ppb ATZ/10 ppb Pb, and 30 ppb ATZ/10 ppb Pb treatments for all parameters in multiple phases (p < 0.05). Th e 100 ppb Pb mixture behavior data also showed significant hypoactivity in the 100 ppb Pb and 30 ppb ATZ treatment groups, along with hypoactivity in both mixture treatment groups (p < 0.05). Additionally, the 3 ppb ATZ treatment group had hyperactivity in the third dark phase (p < 0.05). Th ese data align with past single chemical behavior studies and indicate a greater than additive mixture toxicity.

LBSUN178 Teniposide Improves Adeno-associated Virus-mediated Insulin Gene Therapy In Diabetic Mice.

Abstract Type 1 Diabetes Mellitus (T1DM) results from the autoimmune destruction of insulin-producing pancreatic β cells. Despite advances in our understanding of the pathogenesis and management of diabetes, as well as treatment options, which primarily include injectable insulin and whole pancreas transplant, these advancements remain unsatisfactory, with only a small percentage of patients achieving their glycemic goals. Insulin gene therapy refers to the development of β cell substitutes by introducing an insulin producing gene into endogenous cell populations that do not normally produce insulin. This strategy has the promise to overcome the limitations of current treatments. Adeno-associated viral (AAV) vector-based gene therapy holds great promise for the treatment of inherited and many complex acquired disorders. The success of AAV vectors is determined by two major factors: 1) cell transduction efficiency, and 2) persistence of the introduced gene with minimal or no host immune response following vector administration. Previous research has suggested that certain small molecules can improve AAV vector transduction efficiency and lower the vector dose below the immunological response threshold. We explore the use of teniposide, a chemotherapeutic agent, in improving the efficacy of gene therapy using AAV. We co-administered teniposide at a final dosage of 20 mg/kg with an AAV vector encoding an insulin gene controlled by a liver-specific promotor into streptozotocin (STZ) induced diabetic Hsd: ICR mice. Teniposide co-treatment produced up to a 3-fold decrease in AAV dose compared to vector alone while reducing diabetic hyperglycemia to comparable degrees as AAV delivery alone. There was no additional systemic toxicity. While the mechanism of action of teniposide-enhanced viral delivery of gene therapy is unknown, our data suggest that teniposide co-administration could significantly enhance AAV transduction in vivo and provide a novel, useful strategy to improve the clinical efficacy of gene therapy. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Atmospheric deposition of particulate matter from beef cattle feedlots is a likely contributor of pyrethroid occurrence in isolated wetland sediment: Source apportionment and ecological risk assessment

Industrial cattle feeding operations (feedlots) have been subject to public scrutiny in recent decades regarding environmental impacts of site runoff and aerial dispersion of agrochemical-laden particulate matter (PM). However, source apportionment of multi-use pesticides is challenging in mixed agricultural settings. Beef cattle on feed and row crop production are heavily concentrated in the Southern Great Plains of North America, where playa wetlands are vulnerable to agrochemical inputs and sedimentation from surrounding land use. In the current study, playa basin sediment (n = 33) was analyzed via UHPLC-MS for 21 agrochemicals spanning eight classes (macrocyclic lactones, neonicotinoids, organophosphates, pyrethroids, triazoles, β-methoxyacrylates, a carboximide, and phenylpyrazole). Pyrethroids were detected most frequently (75.8% of basins). Sediment pyrethroid concentrations were also significantly correlated (R2 = 0.178, p = 0.007) with feedlot proximity (<1–50 km). Principal component analysis (PCA) of land use metrics extracted three principal components (74.3% of total variance), with principal component regression (PCR) showing the greatest agrochemical occurrence in basins heavily weighted by cropland buffer acreage (≤1 km) and feedlot proximity. Sediment toxicity benchmarks protective of two benthic invertebrates (Hyallela azteca and Chironomus spp.) identified λ-cyhalothrin, fenvalerate, and esfenvalerate as individual compounds exceeding levels of acute (RQ > 0.5) and chronic (RQ > 1) concern in >5% and >50% of cases, respectively. However, additive toxicity of co-occurring pyrethroids represents an acute high risk (RI > 1; median RI; acute = 2.4, chronic = 38.6) to benthic invertebrates in >75% of cases, which may threaten higher-order wetland taxa via bioaccumulation and trophic transfer.

TOXICOLOGICAL ASSESSMENT OF FOOD ADDITIVES BY BIOASSAY

The paper is devoted to the study of the toxicity levels of food additives by bioassay using Daphnia magna as model organisms. The directions and methods of research have been described. The toxicity of most food additives has been determined for the maximum permissible concentrations. The following widely used food additives have been tested: tartrazine (E102), sunset yellow (E110), azorubine (E122), Ponceau 4R (E124), indigo carmine (E132), brilliant blue (E133), sorbic acid (E200), potassium sorbate (E202), benzoic acid (E210), sodium benzoate (E211), formaldehyde (E240), sodium nitrite (E250), boric acid (E284), sodium isoscorbate (E316), citric acid (E330), phosphate Biophos 90 (E339), guar gum (E412), glycerol (E422), copper sulphate (E519), aspartame (E951), saccharin (E954). It has been proposed that the concentrations present in food products be used for bioassay of the additives Sodium Isoascorbate E316, Citric acid E330, Guar gum E412, Glycerol E422, the maximum concentrations of which are not prescribed in the Sanitary Rules and Regulations. The paper determines the acute and chronic toxic effects that each food additive under study produces on Daphnia magna. For tartrazine E102, sunset yellow E110, Ponceau 4R E124, and copper sulphate E519, no acute toxic impact was recorded, since the mortality of the model organisms did not exceed 25%. A synergistic effect of the use of popular combinations of food additives in various products has been revealed, namely that of: benzoic acid E210 and sorbic acid E200, sodium benzoate E211 and potassium sorbate E202, sodium nitrite E250 and sodium phosphate E339. The combination that caused the greatest lethality (more than 75%) during the bioassay was that of the additives E211 and E202. It has been established that all combinations of these food additives produce the greatest toxic effect, as compared with the toxic effect of individual additives. Further research in this direction has been proposed. The research results determine the need to reduce the maximum permissible levels of food additives that are currently in effect.

Liberal use of local anaesthetic and the risk of toxicity in elective arthroplasties at a tertiary teaching hospital

Background Local anaesthetic systemic toxicity (LAST) is a life-threatening potential complication that may follow the administration of local anaesthetic (LA) drugs, and is cumulative across the drug class. Local anaesthetics are commonly administered via different routes for elective orthopaedic procedures – both by anaesthetists and surgeons. We hypothesized that total doses of LA may be routinely encroaching upon toxicity. Methods All total hip or knee arthroplasties (THAs and TKAs) performed within a 3 month period at the John Hunter Hospital (tertiary referral centre and teaching hospital) were audited to assess total administration of LA. Demographics, surgical characteristics, use of general anaesthesia or sedation, and use of local anaesthetic via any route of administration was recorded. For each patient, a weight-based theoretical maximum safe dose was calculated and compared against the dose they received. Data is presented as mean ± SD, percentages. Statistical significance was determined at p &lt; 0.05. Results 130 THAs and TKAs were identified within the audit period. 52 patients exceeded their drug-class theoretical maximum safe dose. 49 patients exceeded their weight-based maximum dose for a single LA agent, in all cases ropivacaine. Non-obese individuals receive significantly higher mean dose than obese individuals (119.4% [98.6–140.3] vs 78.82% [65.95–91.69], p = 0.001). No LAST events were identified. Conclusions Patients who received elective total hip or knee arthroplasties were exposed to concerningly high total doses of local anaesthetic, suggesting that greater awareness of the additive toxicity of drugs within this class is required.

Clinical Outcomes Following Stereotactic Body Radiation Therapy (SBRT) for Non-Spinal Bone Metastases: A Systematic Review and Meta-Analysis

<h3>Purpose/Objective(s)</h3> There is limited data available on clinical outcomes following stereotactic body radiation therapy (SBRT) for non-spinal bone metastases. As such, we aimed to perform a systematic review and meta-analysis to characterize local control (LC), overall survival (OS), pain control, and toxicity following SBRT. <h3>Materials/Methods</h3> A PICOS/PRISMA/MOOSE selection criterion was utilized to identify studies. Primary outcomes were 1-year LC and incidences of acute and late Grade 3-5 toxicities. The secondary outcomes were 1-year OS and pain control at 3 months. Weighted random effects meta-analyses were conducted to estimate effect sizes. Mixed effects weighted regression models were utilized to assess for correlations between median biologically effective dose (BED₁₀), LC, and toxicity incidence. <h3>Results</h3> We identified 460 patients with 580 non-spinal bone lesions across 9 studies treated with SBRT. The median age was 64 years (range: 36-91). The most common primaries were prostate (28.7%), lung (23.0%), renal cell carcinoma (16.5%), and breast (14.3%). For those on information with weight-bearing status, 424/571 lesions (74.3%) were weight-bearing. The median dose and fractionation were 35 Gy/5 fractions with a median BED₁₀ of 59.5 Gy (range: 26.4-81.6 Gy). The estimated 1-year OS rate was 71.0% (95% CI: 51.7-87.0%). The estimated 1-year LC rate was 94.6% (95% CI: 87.0-99.0%). The estimated combined acute and late Grade 3-5 toxicity rate was 0.5% (95% CI: 0-5.0%). The estimated 3-month combined partial and total pain response rate following SBRT was 87.7% (95% CI: 55.1-100.0%). We did not note a correlation between BED₁₀ and LC, toxicity indigence, or pain-response rates. <h3>Conclusion</h3> SBRT resulted in excellent LC as well and palliative outcomes with minimal related toxicity. Additional dose escalation was not found to be associated with either improved outcomes or additional toxicity. Prospective investigations are warranted to further examine the role of SBRT for patients with non-spinal bone metastases in order to inform the ideal dose/fractionation schema and approaches to planning.

ReIGNITE RT Boost: An International Study Testing the Feasibility, Accuracy and Reliability of Using Restriction Spectrum Imaging (RSI) MRI to Guide Radiotherapy Target Volume Delineation for Prostate Cancer Tumor Boost

<h3>Purpose/Objective(s)</h3> Recently the FLAME clinical trial showed adding a radiation boost to the visible tumor improves prostate cancer control without additional toxicity. In FLAME, a radiologist assisted in each tumor delineation. Even for radiologists, there is substantial dependence on reader experience for prostate MRI. Radiation oncologists' ability to reliably identify prostate tumors is critical to wide adoption and patients benefitting from tumor radiotherapy boost. We have developed a quantitative diffusion MRI metric for prostate cancer based on the restriction spectrum imaging (RSI) framework, called the RSI restriction score (RSI_rs). RSI_rs has been shown to improve accuracy over guideline-recommended standard ADC maps. RSI_rs maps can be overlaid on conventional T2-weighted MRI sequences and used to identify prostate cancer. We hypothesize that contouring on RSI_rs maps will improve the accuracy and reliability of prostate tumor delineation. <h3>Materials/Methods</h3> Radiation oncologists (participants) from multiple institutions contoured prostate tumors on 20 patient cases. An expert radiologist contoured each tumor to establish ground truth. Participants were either board certified or a resident who had completed a clinical genitourinary cancer rotation. Participants were provided the patient's age, PSA level, biopsy result and radiologist's report (e.g., "PI-RADS 5 lesion in right lateral peripheral zone at the base"). Participants delineated volumes on either standard MRI alone (50% of cases; included T2-weighted, DWI, ADC) or standard MRI with RSI_rs map. Accuracy was quantified by comparing to the expert volume by distance to agreement, Dice coefficient, and Jaccard coefficient. Reliability was measured as variation across participants by the Volume Ratio (VR) method. <h3>Results</h3> In this interim analysis of an ongoing study, 126 target volumes have been analyzed from 6 participants. Comparing participant and expert volumes, use of RSI_rs maps significantly improved the mean distance to agreement (3.87mm vs. 1.68mm, p<0.01), Dice coefficient (0.45 vs. 0.65, p<0.001), and Jaccard coefficient (0.32 vs. 0.50, p<0.001). Target volume variability was also significantly improved; VR was reduced from 19.23 to 5.90 (p<0.05). Notably, there were 9 complete misses when participants contoured on standard MRI alone but no misses when RSI_rs maps were provided. 63 global participants have been enrolled in this study and additional data collection and analysis are in process. <h3>Conclusion</h3> The addition of RSI_rs maps to standard MRI improves the reliability and accuracy of target delineation for prostate tumor boost. RSI_rs maps have the potential to increase the feasibility of widely implementing the benefits of focal tumor boost for patients undergoing prostate radiotherapy.

Hypofractionated Regional Nodal Irradiation in Breast Cancer: Initial Results of a Prospective Clinical Trial

<h3>Purpose/Objective(s)</h3> Randomized clinical trials have validated the efficacy and safety of hypofractionated whole breast irradiation (HWBI) in patients with early-stage breast cancer. Toxicities associated with hypofractionated treatment in patients requiring regional nodal irradiation are less well described, and the utilization of hypofractionation in these patients is uncommon in the United States. We report an interim analysis of acute toxicity of a prospective trial of hypofractionated regional nodal irritation (H-RNI). <h3>Materials/Methods</h3> This is a prospective, single-arm trial at a single institution. Eligible patients comprised those with locally advanced, non-metastatic breast cancer and required adjuvant radiation therapy to the regional lymphatics in addition to the breast or chest wall. Patients were stratified into two groups based on extent of axillary surgery: ≤ 5 lymph nodes (Group 1) and > 5 lymph nodes removed (Group 2). We enrolled 31 patients (23 in Group 1, 8 in Group 2) from 11/2018 to 12/2021. Patients received a dose of 42.56 Gy in 16 fractions to the breast/chest wall and regional lymphatics with a sequential boost of 10-12.5 Gy in 4-5 fractions to the surgical cavity or mastectomy scar. Circumferential arm measurements at 10 cm intervals were taken at baseline and predefined intervals following treatment. The primary endpoint is clinically significant lymphedema, defined as a ≥ 10% difference in ipsilateral arm, forearm, or both, compared to the contralateral side. Additional toxicities were assessed using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. <h3>Results</h3> The median follow up was 19 months and the median age was 59 years. Acute lymphedema and CTCAE toxicities were analyzed in 27 and 31 patients, respectively. One patient (3.2%) in Group 2 met the predetermined criteria for clinically significant lymphedema. One patient experienced symptomatic lymphedema, requiring a compression sleeve. However, her measurements did not meet the threshold for clinically significant lymphedema. The most prevalent Grade 1 toxicities were hyperpigmentation (66.7%), fatigue (66.7%), breast pain (63.3%), and radiation dermatitis (63.3%). The most prevalent Grade 2 toxicities were radiation dermatitis (26.7%) and hyperpigmentation (20%). The incidence of any ≥ Grade 3 toxicity was 6.5% (n=2) related to hyperpigmentation. One patient (3.2%) developed grade 2 pneumonitis. All cosmetic outcomes were rated as good or excellent at 3 months. There were no grade 4 or 5 toxicities. <h3>Conclusion</h3> Our preliminary data suggest that H-RNI is well tolerated. The rates of acute lymphedema and acute toxicity were very low. A matched comparison with patients treated with conventionally fractionated RNI at our institution is ongoing.

High-Dose Spatially Fractionated Radiotherapy, Lattice Radiotherapy in Bulky Tumors: Results after One Year Follow-Up

<h3>Purpose/Objective(s)</h3> Spatially Fractionated Radiotherapy (SFRT) or Lattice Radiotherapy (LRT) is a radiotherapy technique that allows to deliver a very high radiation doses spheres inside the tumor in a single fraction, maintaining low dose in OAR, generating an inhomogeneous dose distribution inside the GTV and maintains the PTV marginal dose within planned dose within a multifraction treatment. This can be an option for bulky unresectable tumors with poor local control with standard radiotherapy. The main objective of this study is to assess LTR toxicity in patients with tumors greater than 45 cc and poor candidates for other treatment modalities. <h3>Materials/Methods</h3> From 1 January 2020 to 31 December 2020, 21 patients were treated in our institution. We prescribe 1 cm spheres with a maximum dose over 15 Gy in a single fraction and at least 4 vertices distributed inside of GTV. PTV dose continues as standard dose fractionation of 2.5-3Gy in the LRT session as prescribed in conventional or hypofractionated treatment. Simulation and treatment delivery is as SBRT. LTV (Lattice Tumor Volume) is the structure inside GTV where the VTV spheres (Vertex Tumor Volume), overdose volumes, are located, separated by 2.5-3.0 cm. VV (Valley Volume) is the subtraction of GTV-VTV that must be under 5 Gy. <h3>Results</h3> 21 patients (66,6% of tumors were in the thorax, 28,6% abdomen/pelvis and 4,8% head and neck) were treated. The median follow-up was 12 months (3-25). The median age of the patients was 64 years old (42-84). The median GTV volume was 236cc (80-896cc) and 73 mm (47– 123mm) in greatest axial diameter. The analysis of the results showed 4 patients with complete response (20%), 12 with partial response (57%) and 5 with stable disease (23%). Tumor reduction bigger than 50% has been observed in 75% of cases 2 weeks after LTR session. Local control was 75% at 6 months. Cumulative probability of survival was 76% (95% CI 51-89%) and 59% (95% CI 33-77%) at 6 and 12 months respectively. No additional toxicity has been related. No major grade 3 toxicities were reported according to CTCAE v5.0 grading. <h3>Conclusion</h3> Our experience with LTR protocol is feasible as a technique to be included in radiotherapy treatments for poor prognosis bulky tumors, with reproducibility and adaptability. Our early results confirm good local response and no added toxicity. Further large prospective studies are required to validate these results.

Surface Dose and Skin Toxicity in Low-Magnetic Field MR-Linac

<h3>Purpose/Objective(s)</h3> Radiation induced skin toxicity is a common side effect that results in poor patient satisfaction and unplanned treatment breaks thus prolonging the overall treatment time with poor outcome. It is hypothesized that treatments on low-field MR-Linac will not produce higher surface dose which is investigated in this study. <h3>Materials/Methods</h3> Skin dose has always been an area of active clinical interest that is dependent on many parameters including beam energy, field size, material thickness and atomic number in the beam, material distance from surface, source to surface distance, beam angle (obliquity factor), concomitant chemotherapy etc. Along with these parameters, magnetic field is also a critical parameter that affect surface dose. With the development of the MRL system focus has shifted towards Lawrence force giving rise to electron return effect along with other treatment parameters affecting the skin dose. A Linac equipped with 6MV FFF photons with 90 cm source to axis distance is used. A Markus parallel plate ionization chamber is used in a solid water phantom with proper correction factor to investigate surface and buildup dose with six different gantry angles 15⁰ apart gantry (equivalent of standard Linac 0⁰, 15⁰, 30⁰, 45⁰, 60⁰, and 75⁰) for field sizes of 1.66 × 1.66 cm² (small), 9.96 × 9.9 cm² (reference) and 24.1 × 24.1 cm² (maximum). Measurements were made with increasing buildup thickness in steps of 1 mm to 20 mm of solid water in 0.35 T magnetic field. <h3>Results</h3> In traditional linear accelerators surface dose is 30-40% for a 6MV photon beam, without any modifier. This value increases significantly with beam angle. In MR-Linac, surface dose is relatively low, 12.6%, 14.9% and 16.7% for small, reference and maximum fields at zero-degree gantry angle, respectively. These values are 12% to 2% higher (at 0⁰ and 75⁰ respectively) for maximum field size compared to the reference field size. For lower field sizes minimum variation of 10% was observed at 75° for reference field size. The surface dose increases with increasing radiation field size but magnitude is still lower as the case with traditional lilacs. Table 1 shows the surface dose with field size and gantry angles. <h3>Conclusion</h3> Surface dose in low-field magnetic environment is relatively lower than traditional accelerators. It is concluded that low-field MR-Linac system may not add any additional skin toxicity compared to conventional Linac. However, the effect may be different for high-field MR-Linac system, and appropriate skin evaluation needs to be performed to differentiate between radiation induced toxicity specially for the oblique beams versus RF-thermal effect.

A Multi-Centric Evaluation of AI-Driven Synthetic CT Generation Form Low Field Magnetic Resonance Imaging

<h3>Purpose/Objective(s)</h3> Magnetic Resonance is an essential modality in the context of radiotherapy primarily for providing additional information with respect to tumor functional information leading to better target delineation (brain, prostate, etc.) and secondary in the context of emergence of magnetic resonance guided radiotherapy. However, in both cases computed tomography acquisition remains necessary for dosimetric purposes hampering the workflow, introducing additional cost and dose simulation/optimization discrepancies (due to the registration issues between MR & CT) while being associated with additional patient toxicity. This study aims to investigate in a retrospective manner the relevance deep learning synthetic CT generation as an alternative for simulation and planning for pelvic tumors treated with low field (0.35T) MRgRT. <h3>Materials/Methods</h3> In the context of this study, a cycle generative adversarial neural network (GAN) deep learning architecture was trained to determine a bijective transformation between a low field (0.35T) MR and the associated computed tomography scan acquisition. The training set involved 350 pairs of weakly aligned data of pelvis cases. A retrospective cohort involving 20 test cases coming from eight different institutions (US: 2, EU: 5, AS: 1) involving different CT vendors was considered for testing. <h3>Results</h3> Reconstruction performance was assessed using the OARs used for treatment. The observed average scaled (between maximum and minimum HU values of the CT) difference between the reconstructed and the CT used for planning was 35.08 with significant discrepancies across organs. Femoral heads were the most reliably reconstructed (4.51 & 4.77) while rectum and sigmoid were the less precise ones (53.13 & 51.48). In terms of qualitative evaluation, the presence of fiducial markers heavily penalizes the reconstruction due to the implicit propagation of errors associated with the "convolution" nature of deep learning. The presence of air bubbles visible on the CT (sigmoid and rectum) is also an issue since these elements are marginally perceptible in the MR and therefore can hardly be predicted from generator. Detailed reconstruction results per organ are appended. <h3>Conclusion</h3> This retrospective multi-centric study is a first step toward assessing the potential of a fully low field MR-based treatment planning workflow that eliminates the need of CT acquisition. Integration of the synthetic CT in the simulation/optimization and assessment of the induced dosimetric errors are necessary steps to determine the clinical relevance of our preliminary findings.

3-Dimensional Volumetric Distribution and Dispersion Analysis of the Radioenhancer NBTXR3 in Various Solid Malignancies

<h3>Purpose/Objective(s)</h3> NBTXR3, a first-in-class radioenhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral (IT) injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of RT without additional toxicity to surrounding healthy tissue. In addition, NBTXR3 has been shown to prime the adaptive immune response in cancer models, with clinical indication of systemic response. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas (STS) and is under investigation in multiple tumor types. Here we report on the feasibility and intra-tumor dispersion of IT NBTXR3 injection in patients with various solid malignancies, including STS, head and neck squamous cell carcinoma (HNSCC), hepatocellular carcinoma (HCC), liver metastases, lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma. <h3>Materials/Methods</h3> In the phase II/III randomized Act.in.Sarc [NCT02379845] trial patients with locally advanced STS received either NBTXR3+RT or RT alone followed by tumor resection. Elderly patients with HNSCC of the oropharynx or oral cavity, ineligible to cisplatin or cetuximab, received a single IT injection of NBTXR3 and IMRT [NCT01946867]. In a Phase I trial patients with HCC or liver metastases received an IT injection of NBTXR3 followed by SBRT [NCT02721056]. Safety and efficacy of NBTXR3 + SBRT in combination with anti-PD-1 is being evaluated in three cohorts of patients with advanced cancers in the Phase I 1100 [NCT03589339] trial. In a phase I study evaluating NBTXR3 intra prostate injection patients with newly diagnosed Unfavorable Intermediate Risk (UIR) or High Risk (HR) prostate adenocarcinoma were treated with EBRT or brachytherapy boost and EBRT. <h3>Results</h3> IT injection in patients with STS, HNSCC, HCC, liver or lung metastases, and intra-prostate injection in patients with prostate adenocarcinoma is feasible. There was no leakage of NBTXR3 observed in surrounding healthy tissues as assessed by CT scan. IT dispersion of NBTXR3 ranged from 4.9%-28.2% of tumor volume in patients, depending on tumor size, with treatment doses of NBTXR3 ranging from 5-22% in HNSCC, HCC, lung metastasis, STS, and prostate. Favorable signs of efficacy were observed among these patients indicating the potential for NBTXR3 to improve patient outcomes at the doses tested and with dispersion within the tumor of up to 28.3%. <h3>Conclusion</h3> IT injection of NBTXR3 is feasible and safe in multiple tumor types. NBTXR3 injection has shown favorable safety and is continuing to be assessed in several Phase I studies. NBTXR3 demonstrated efficacy in a Phase II/III study in patients with STS. and promising signs of efficacy have been observed in other tumor types. Future consideration of dispersion analysis may include association with response and possibly dose-painting with simultaneous integrated boost secondary to preferential NBTXR3 loading.

International Guidelines for Intratumoral and Intranodal Injection of NTBXR3 Nanoparticles in Head and Neck Cancers

<h3>Purpose/Objective(s)</h3> NBTXR3, a first-in-class radio enhancer, composed of functionalized hafnium oxide nanoparticles, is administered by one-time intratumoral injection and activated by radiotherapy (RT). NBTXR3 is designed to locally amplify the tumor-killing effect of radiotherapy without additional toxicity to surrounding healthy tissue. NBTXR3 has been shown to prime the adaptive immune response in cancer models. NBTXR3 obtained EU marketing approval in preoperative treatment of locally advanced soft tissue sarcomas and is under investigation in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), with a phase 3 trial recruiting. However, there is currently no guidance on how to treat oropharyngeal and oral cavity SCC and cervical lymph nodes with NBTXR3. We therefore sought to develop expert consensus guidelines that facilitate injection of NBTXR3 in oropharyngeal and oral cavity SCC and cervical lymph nodes. <h3>Materials/Methods</h3> A multidisciplinary team of experts aimed to provide consensus guidelines using the Delphi method with two rounds of voting to support the injection of NBTXR3 in head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, and cervical lymph nodes and to address safety, feasibility, and procedure of administration. A steering committee composed of 4 experts and a monitoring committee composed of 10 experts wrote and revised the guidelines on intratumoral and intranodal injection. An independent multidisciplinary reading committee composed of 3 members reviewed the entirety of the recommendations. <h3>Results</h3> After 2 rounds of voting a strong consensus was obtained on all of the recommendations. The reading committee recommended simplifying and clarifying the elements not commented on by the monitoring committee. Intratumoral and intranodal injection is feasible. The NBTXR3 volume calculation, choice of patients, preparation and injection procedure, potential side effects, post injection and post treatment follow-up are described in detail in these guidelines. Here we present the most important recommendations. <h3>Conclusion</h3> The recommendations on injection of NBTXR3 hafnium oxide nanoparticles have been defined by a multidisciplinary international panel of experts, thus allowing an international standardization of injection practice.

Preliminary Outcome and Quality of Life among Geriatric Head and Neck Cancer (GHNC) Patients Treated with Institutional Nimorad (Nimotuzumab-Modulated Radiotherapy) Protocol

<h3>Purpose/Objective(s)</h3> Treatment for geriatric head and neck squamous carcinomas (GHNC) remain challenging due to multiple patient and treatment related factors. We analyzed radical intent treatment for GHNC with modulated arc therapy (VMAT) and concurrent Nimotuzumab (Nim) as part of prospectively maintained database NIMORAD (Nimotuzumab-modulated radiotherapy) for early clinical outcome and toxicity. <h3>Materials/Methods</h3> 30 (M:25, F:5) patients of biopsy proven locally advanced squamous cell carcinomas staged by whole body PETCT scan (stage III-IVB) were analyzed. All were above 70 years (Range: 70-88 years) and received uniform treatment with VMAT (66-70 Gy/33 fractions) and Inj Nim 200mg weekly for 6 cycles. Cisplatin ineligibility was in terms of age>70, multiple comorbidities, deranged kidney or hearing functions. Patients more than 80 years were selected for NIMORAD only if baseline G8 screening score was 14 or more. All the cases were discussed in Institutional GHNCC (Geriatric head neck cancer clinic). Institutional comprehensive geriatric assessment was followed with G8 scoring, activities of daily living (ADL) by Katz index, nutritional scoring by subjective global assessment (SGA) and co-morbidity scoring with Charlsons comorbidity index (CCI). Primary analysis was related to survival (disease free survival, local control and overall survival) and toxicity. First surveillance PETCT was between 10-14 weeks post treatment. The toxicities were graded as per CTCAE version 3.0. Follow up was every 3 months with 2^nd surveillance PETCT 6-8 months depending on 1^st response. Statistical analyses were carried out using statistical software. <h3>Results</h3> Median follow-up, age and G8 screening score were 18 months, 77 years and 13 respectively. 83.3% patients were male and 60% had oropharyngeal primaries with 10% HPV positive. At 1^st follow up complete response (CR) at primary site was 85% on both FOL and PETCT. Till last follow up 60% had complete response, 16% had loco-regional failure and 2% distant metastases. Nine patients died till last follow up and 5 were lost to follow up. All P16 positive patients (3) had loco-regional and distant control till last follow up. The acute grade 2 mucositis and dysphagia were 70% and 90% respectively with 30% grade 3 dysphagia. Long term tube dependency rates were 10% mostly beyond 80 years. 20% had hematological grade 2 plus toxicity and 10% had skin rash due to Nim. The other notable adverse events were grade 3 trismus, osteoradionecrosis and aspiration pneumonia between 2-5%. Median Katz index was 5, SGA and CCI were higher for hospitalized patients. <h3>Conclusion</h3> This single Institution NIMORAD protocol for GHNC shows promising clinical results with no additional toxicity profile. This can be an option for improved disease control in locally advanced GHNC. Future large cohort prospective documentation with longer follow up is warranted.

Human clinical trial using diagnostic ultrasound and microbubbles to enhance neoadjuvant chemotherapy in HER2- negative breast cancer.

In vivo and in vitro experiments have demonstrated that diagnostic ultrasound combined with microbubbles (USMB) can enhance tumor chemotherapy, but few clinical studies have explored the effect of USMB in human HER2-negative breast cancer. We aimed to compare USMB combined with neoadjuvant chemotherapy (NAC) with NAC alone in the treatment of human HER2-negative breast cancer. Patients (n=10) enrolled in the study were treated with TAC (taxane - (docetaxel), anthracycline - (epirubicin or doxorubicin liposomes), and cyclophosphamide) and ultrasound using a commercial clinical ultrasound scanner for 20min after each chemotherapy session, followed by intermittent injections of SonoVue® to induce sonoporation and enhance therapeutic efficacy. Contrast-enhanced ultrasound (CEUS) was used to record tumor perfusion before and after ultrasound treatment. After completion of chemotherapy, the maximum tumor diameter of patients in the combined treatment group (n=10) was significantly smaller than that in the control group (n=16) (p=0.017). Although the combined treatment group had higher overall response and clinical benefit rates than those in the control group, there was no statistically significant difference in RECIST between the combined treatment group and the control groups (p=0.590). More patients in the combination therapy group achieved pathologic complete response than in the control group (p=0.014). For combined treatment, CEUS revealed that the peak intensity, mean transit time, and area under the curve were higher after treatment than before treatment (p<0.001, p<0.001, p=0.003, respectively). Combined therapy did not cause additional toxicity or increase side effects. USMB and chemotherapy can be combined in a clinical setting using commercially available equipment, without additional toxicity, and may improve the efficacy of NAC in HER2-negative breast cancer.

Safety and Efficacy of Intraventricular Immunovirotherapy with Oncolytic HSV-1 for CNS Cancers.

Oncolytic virotherapy with herpes simplex virus-1 (HSV) has shown promise for the treatment of pediatric and adult brain tumors; however, completed and ongoing clinical trials have utilized intratumoral/peritumoral oncolytic HSV (oHSV) inoculation due to intraventricular/intrathecal toxicity concerns. Intratumoral delivery requires an invasive neurosurgical procedure, limits repeat injections, and precludes direct targeting of metastatic and leptomeningeal disease. To address these limitations, we determined causes of toxicity from intraventricular oHSV and established methods for mitigating toxicity to treat disseminated brain tumors in mice. HSV-sensitive CBA/J mice received intraventricular vehicle, inactivated oHSV, or treatment doses (1×107 plaque-forming units) of oHSV, and toxicity was assessed by weight loss and IHC. Protective strategies to reduce oHSV toxicity, including intraventricular low-dose oHSV or interferon inducer polyinosinic-polycytidylic acid (poly I:C) prior to oHSV treatment dose, were evaluated and then utilized to assess intraventricular oHSV treatment of multiple models of disseminated CNS disease. A standard treatment dose of intraventricular oHSV damaged ependymal cells via virus replication and induction of CD8+ T cells, whereas vehicle or inactivated virus resulted in no toxicity. Subsequent doses of intraventricular oHSV caused little additional toxicity. Interferon induction with phosphorylation of eukaryotic initiation factor-2α (eIF2α) via intraventricular pretreatment with low-dose oHSV or poly I:C mitigated ependyma toxicity. This approach enabled the safe delivery of multiple treatment doses of clinically relevant oHSV G207 and prolonged survival in disseminated brain tumor models. Toxicity from intraventricular oHSV can be mitigated, resulting in therapeutic benefit. These data support the clinical translation of intraventricular G207.

Epigenetic potentiation of somatostatin-2 by guadecitabine in neuroendocrine neoplasias as a novel method to allow delivery of peptide receptor radiotherapy

BackgroundSomatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. MethodsThe effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. ResultsPyrosequencing of cell lines illustrated differential methylation indices – BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p < 0.05) was observed. In vivo, guadecitabine treatment resulted in a 70% increase in [18F]-FETO uptake in BON-1 tumour models compared models with low baseline percentage methylation (p < 0.05). No additive toxicity was observed with the combination treatment of PRRT and guadecitabine in vivo. Methylation index in clinical samples was 10.5% compared to 5.2% in controls (p = 0.03) and correlated with SSTR2 expression (Wilcoxon rank sign −3.75,p < 0.01). ConclusionGuadecitabine increases SSTR2 expression both in vitro and in vivo. The combination of demethylation agents with PRRT warrants further investigation.

Prise en charge des formes oligométastatiques : l’avis de l’oncologue thoracique

The concept of oligometastatic disease applies to a subpopulation of patients with a low tumor burden clinically characterized by a limited number of metastases. These oligometastatic stages could benefit of intensive therapeutic options combining systemic treatment and radical local treatment of secondary and primary lesions, as surgery, conventional or stereotaxic radiotherapy and interventional radiology. Evaluation of immunotherapy combined with radiotherapy is ongoing in this particular clinical setting. Patients’ identification who could be suitable candidates for such therapeutic strategies remains difficult in order to achieve significant clinical benefit without additional toxicities. Besides clinical prognostic factors (PS, stage N, chronology of occurrence and/or site of metastases…), determination of predictive biomarkers (micro-RNA, genomic signatures…) would be useful to optimize management of oligometastatic patients.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

S957 Identification and Characterization of a Single-Center Cohort of Patients With Refractory or Relapsing Immune Checkpoint Inhibitor-Induced Colitis

S957 Identification and Characterization of a Single-Center Cohort of Patients With Refractory or Relapsing Immune Checkpoint Inhibitor-Induced Colitis