Isotoxic Dose Research Articles

3127: MR-guided SABR re-irradiation: patterns of care and identifying potential isotoxic dose escalation

3127: MR-guided SABR re-irradiation: patterns of care and identifying potential isotoxic dose escalation

High dose proton and photon-based radiation therapy for 213 liver lesions: a multi-institutional dosimetric comparison with a clinical perspective

BackgroundStereotactic radiotherapy (SRT) and Proton therapy (PT) are both options in the management of liver lesions. Limited clinical-dosimetric comparison are available. Moreover, dose-constraint routinely used in liver PT and SRT considers only the liver spared, while optimization strategies to limit the liver damaged are poorly reported.MethodsPrimary endpoint was to assess and compare liver sparing of four contemporary RT techniques. Secondary endpoints were freedom from local recurrence (FFLR), overall survival (OS), acute and late toxicity. We hypothesize that Focal Liver Reaction (FLR) is determined by a similar biologic dose. FLR was delineated on follow-up MRI. Mean C.I. was computed for all the schedules used. A so-called Fall-off Volume (FOV) was defined as the area of healthy liver (liver-PTV) receiving more than the isotoxic dose. Fall-off Volume Ratio (FOVR) was defined as ratio between FOV and PTV.Results213 lesions were identified. Mean best fitting isodose (isotoxic doses) for FLR were 18Gy, 21.5 Gy and 28.5 Gy for 3, 5 and 15 fractions. Among photons, an advantage in terms of healthy liver sparing was found for Vmat FFF with 5mm jaws (p = 0.013) and Cyberknife (p = 0.03). FOV and FOVR resulted lower for PT (p < 0.001). Three years FFLR resulted 83%. Classic Radiation induced liver disease (RILD, any grade) affected 2 patients.ConclusionsCyberknife and V-MAT FFF with 5mm jaws spare more liver than V-MAT FF with 10 mm jaws. PT spare more liver compared to photons. FOV and FOVR allows a quantitative analysis of healthy tissue sparing performance showing also the quality of plan in terms of dose fall-off.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12)

Background and purposeThe PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methodsA total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. ResultsMedian NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11–0.29) and 0.42 (range 0.18–0.54), respectively. NTCPex was a median of 1.77 (range 1.60–1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66–2.35). The defined constraints for the organs at risk were feasible. ConclusionWhen considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

Abnormal Global Longitudinal Strain During Anthracycline Treatment Predicts Future Cardiotoxicity in Children.

Global longitudinal strain (GLS) is a sensitive predictor of cardiotoxicity in adults with cancer. However, the significance of abnormal GLS during childhood cancer treatment is less well-understood. The objective was to evaluate the use of GLS for predicting later cardiac dysfunction in pediatric cancer survivors exposed to high-dose anthracyclines. This was a retrospective study of pediatric patients exposed to a doxorubicin isotoxic equivalent dose of ≥ 225mg/m2. Transthoracic echocardiograms (TTE) were obtained prior to chemotherapy (T1), during anthracycline therapy (T2), and following completion of therapy (T3). Cardiotoxicity was defined as meeting at least one of the following criteria after anthracycline therapy: a decrease in left ventricle ejection fraction (LVEF) by 10% from baseline to a value < 55%, fractional shortening < 28%, or a decrease in GLS by ≥ 15% from baseline. Nineteen of 57 (33%) patients met criteria for cardiotoxicity at T3. Cardiotoxicity was associated with a lower LVEF at T2 (p = 0.0003) and a decrease in GLS by ≥ 15% at T2 compared to baseline (p = < 0.0001). ROC analysis revealed that the best predictor of cardiotoxicity at T3 was the percent change in GLS at T2 compared to baseline (AUC 0.87). A subgroup analysis revealed that a decrease in GLS by ≥ 15% from baseline at 0-6months from completion of anthracycline therapy was associated with cardiotoxicity > 1-year post-treatment (p = 0.017). A decline in GLS during chemotherapy was the best predictor of cardiotoxicity post-treatment. GLS serves as an important marker of cardiac function in pediatric patients undergoing treatment with anthracyclines.

Subsequent primary neoplasms after childhood cancer therapy – design and description of the German nested case–control study STATT-SCAR

BackgroundSubsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case–control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN.MethodsBased on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion.Results1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy.ConclusionsBased on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments.Trial registrationThe study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].

Pulmonary magnetic resonance-guided online adaptive radiotherapy of locally advanced non-small-cell lung cancer: the PUMA trial

BackgroundPatients with locally-advanced non-small-cell lung cancer (LA-NSCLC) are often ineligible for surgery, so that definitive chemoradiotherapy (CRT) represents the treatment of choice. Nevertheless, long-term tumor control is often not achieved. Intensification of radiotherapy (RT) to improve locoregional tumor control is limited by the detrimental effect of higher radiation exposure of thoracic organs-at-risk (OAR). This narrow therapeutic ratio may be expanded by exploiting the advantages of magnetic resonance (MR) linear accelerators, mainly the online adaptation of the treatment plan to the current anatomy based on daily acquired MR images. However, MR-guidance is both labor-intensive and increases treatment times, which raises the question of its clinical feasibility to treat LA-NSCLC. Therefore, the PUMA trial was designed as a prospective, multicenter phase I trial to demonstrate the clinical feasibility of MR-guided online adaptive RT in LA-NSCLC.MethodsThirty patients with LA-NSCLC in stage III A-C will be accrued at three German university hospitals to receive MR-guided online adaptive RT at two different MR-linac systems (MRIdian Linac®, View Ray Inc. and Elekta Unity®, Elekta AB) with concurrent chemotherapy. Conventionally fractioned RT with isotoxic dose escalation up to 70 Gy is applied. Online plan adaptation is performed once weekly or in case of major anatomical changes. Patients are followed-up by thoracic CT- and MR-imaging for 24 months after treatment. The primary endpoint is twofold: (1) successfully completed online adapted fractions, (2) on-table time. Main secondary endpoints include adaptation frequency, toxicity, local tumor control, progression-free and overall survival.DiscussionPUMA aims to demonstrate the clinical feasibility of MR-guided online adaptive RT of LA-NSCLC. If successful, PUMA will be followed by a clinical phase II trial that further investigates the clinical benefits of this approach. Moreover, PUMA is part of a large multidisciplinary project to develop MR-guidance techniques.Trial registrationClinicalTrials.gov: NCT05237453.

PO-1966 Isotoxic dose escalation with proton beam therapy for distal oesophageal cancer

PO-1966 Isotoxic dose escalation with proton beam therapy for distal oesophageal cancer

Isotoxic dose escalated radiotherapy for glioblastoma based on diffusion-weighted MRI and tumor control probability-an in-silico study.

Glioblastoma (GBM) is the most common malignant primary brain tumor with local recurrence after radiotherapy (RT), the most common mode of failure. Standard RT practice applies the prescription dose uniformly across tumor volume disregarding radiological tumor heterogeneity. We present a novel strategy using diffusion-weighted (DW-) MRI to calculate the cellular density within the gross tumor volume (GTV) in order to facilitate dose escalation to a biological target volume (BTV) to improve tumor control probability (TCP). The pre-treatment apparent diffusion coefficient (ADC) maps derived from DW-MRI of ten GBM patients treated with radical chemoradiotherapy were used to calculate the local cellular density based on published data. Then, a TCP model was used to calculate TCP maps from the derived cell density values. The dose was escalated using a simultaneous integrated boost (SIB) to the BTV, defined as the voxels for which the expected pre-boost TCP was in the lowest quartile of the TCP range for each patient. The SIB dose was chosen so that the TCP in the BTV increased to match the average TCP of the whole tumor. By applying a SIB of between 3.60 Gy and 16.80 Gy isotoxically to the BTV, the cohort's calculated TCP increased by a mean of 8.44% (ranging from 7.19 to 16.84%). The radiation dose to organ at risk is still under their tolerance. Our findings indicate that TCPs of GBM patients could be increased by escalating radiation doses to intratumoral locations guided by the patient's biology (i.e., cellularity), moreover offering the possibility for personalized RT GBM treatments. A personalized and voxel level SIB radiotherapy method for GBM is proposed using DW-MRI, which can increase the tumor control probability and maintain organ at risk dose constraints.

Investigation of Isotoxic Dose Escalation and Plan Quality with TDABC Analysis on a 0.35 T MR-Linac (MRL) System in Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided Radiation Therapy (MRgRT) for Primary Pancreatic Cancer.

This study investigates plan quality generated by an MR-Linac (MRL) treatment planning system (TPS) for 5-fraction stereotactic body radiation therapy (SBRT) of primary pancreatic cancer (PCa). In addition, an isotoxic dose escalation was investigated with the MRL TPS based on stereotactic MR-guided adaptive radiation therapy (SMART) trial constraints. A clinical workflow was developed for adaptive and non-adaptive treatments with the MRL, on which a time-driven activity-based costing (TDABC) analysis was performed to quantify clinical efficacy. Fifteen PCa patients previously treated with a conventional Linac were retrospectively re-planned for this study. Three plans were generated for each patient using the original prescription dose (PD) and organ at risk (OAR) constraints (Plan 1), following SMART trial’s OAR constraints but with the original PD (Plan 2), starting with Plan 2, following an isotoxic dose escalation strategy where the dose was escalated until any one of the SMART trial’s OAR constraints reached its limit (Plan 3). Conformity index (CI) and the ratio of the 50% isodose volume to PTV (R50%) conformity metrics were calculated for all 45 MRL plans, in addition to standard dose-volume indices. Forty-five MRL plans were created which met their respective dosimetric criteria described above. For Plan 1, the MRL TPS successfully achieved equivalent or lower OAR doses while maintaining the prescribed PTV coverage for the 15 plans. A maximum dose to the small bowel was reduced on average by 4.97 Gy (range: 1.11–10.58 Gy). For Plan 2, the MRL TPS successfully met all SMART trial OAR constraints while maintaining equivalent PTV coverage. For Plan 3, the MRL TPS was able to escalate the prescription dose from the original 25–33 Gy by, on average, 36 Gy (range: 15–70 Gy), and dose to the PTV was successfully escalated to at least 50 Gy for all 15 plans. These achievements were made possible, in part, due to the omission of the ITV afforded by the MRL’s real-time target tracking technology and sharper dose penumbra due to its unique dual-focus MLC design. The 0.35T MRL TPS can generate plans that are equivalent to conventional Linac-based plans for SBRT of PCa. Through analyzing Plan 2 and 3 strategies, and due to the real-time target localization capabilities of the MRL system, increased OAR sparing and/or target dose escalation are possible.

Potential for Isotoxic Re-irradiation Stereotactic Ablative Body Radiotherapy in Locally Recurrent Rectal Cancer

AimsThe non-surgical management of locally recurrent rectal cancer (LRRC) is an area of unmet need, with no defined standard treatment and extremely poor outcomes. Patients typically receive radiotherapy during initial multimodality treatment and historically re-irradiation has been limited to conservative doses with subsequent short-term symptom control. Recently, stereotactic ablative body radiotherapy (SABR) has shown promise in re-irradiation of LRRC in England, but is limited to a relatively modest dose prescription of 30Gy in five fractions. We propose that SABR can be achieved in LRRC to higher doses using an isotoxic dose prescription with fixed 15% per annum tissue recovery for acceptable organ at risk (OAR) constraints. Materials and methodsPatients with LRRC at a local centre treated with SABR re-irradiation were audited. Patients were identified, the dose and time since previous radiotherapy determined, re-irradiation OAR constraints calculated and retrospective re-planning carried out. ResultsIn patients currently receiving SABR (17 patients, 21 targets), dose escalation above 30 Gy in five fractions was achievable, with a biological effective dose of 80 Gy (alpha/beta = 10) deliverable to 80% or more of the planning target volume in eight of the 21 targets. ConclusionsIsotoxic SABR re-irradiation should be considered a potential treatment option for LRRC to maximise patient outcomes while limiting excess toxicity. Although probably conservative, clinical outcome data are needed to determine the suitability of OAR constraints using 15% per annum tissue recovery and the impact on local control rates, patient quality of life and overall survival of isotoxic SABR.

Морфо-функціональні зміни клітин інфузорій Tetrahymena pyriformis W за впливу регуляторів росту рослин — похідних n-оксид піридину

The aim of the Research. To identify morphological changes in Tetrahymena pyriformis W infusoria under the acute exposure to plant growth regulators (PGR) — derivatives of pyridine-N-oxide and compare them to functional disorders of cells. Materials and Methods. In the research we used the 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids (succinic, maleic) or metal salts (ZnCl2, ZnI 2, CoCl2, MnCl2) (a total of 15 substances), synthesized at the Institute of Bioorganic chemistry and Petrochemistry, NAS, Ukraine. Studies were performed on Tetrahymena pyriformis W infusoria in isotoxic doses — at the level of toxic concentrations — LC50, LC16 and inactive concentrations (LC0). Morphological changes in cells of infusoria were assessed visually with the use of a light microscope. Structural changes in infusoria were compared to functional changes in cells (motor activity and energy state) obtained under the same experiment. Results and Conclusions. It is demonstrated that 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids (succinic, maleic) or metal salts (ZnCl2, ZnI2, CoCl 2, MnCl2) cause functional and morphostructural changes in infusoria, the extent of which depends on the current concentration. Morphostructural changes in infusoria under the influence of the studied PGRs are characterized by a change of shape, growth of the contractile vacuole, vesiculation, damage to the integrity of the cytoplasmic membrane, emission of cytoplasm and structural elements of cells into the nutrient medium. Complexes of methyl derivatives of pyridine-N-oxide with metal salts in the studied concentrations reduce speed and increase energy expenditure on movement, cause changes in behavioural reactions and structure of cells to a greater extent than 2-methylpyridine-N-oxide, 2,6-dimethylpyridine-N-oxide and their complexes with organic acids. Both functional and morphological changes in infusoria are more evident under the influence of studied PGR occurring at concentrations corresponding to LC50. At lower concentrations the changes in the functional activity of infusoria were observed. Comparison of the obtained functional and morphostructural indicators of the state of infusoria shows that complexes of methyl derivatives of Pyridine-N-oxide with metal salts have more toxic effects on infusoria than complexes of methyl derivatives of pyridine-N-oxide with organic acids. Reduced motor activity and an increase in energy consumption per a unit of a path of motion, together with the morphological changes of cell structure, are the indicators of toxicity of xenobiotics for infusoria and criteria for assessing their viability. Key Words: methyl derivatives of Pyridine-N-oxide, Tetrahymena pyriformis W, morphofunctional changes.

High dose radiation therapy based on normal tissue constraints with concurrent chemotherapy achieves promising survival of patients with unresectable stage III non-small cell lung cancer

Background and purposeWe aimed to investigate the potential of individual isotoxic dose escalation based on normal tissue constraints (NTC), hypothesizing that high dose radiation therapy would be superior to standard-dose in concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC). Materials and methodsIndividually prescribed radiation doses were calculated based on NTC. Patients with total tumour radiation doses ≥66 Gy were assigned to the high dose (HD, ≥66 Gy) group, and all other patients were assigned to the standard-dose (SD, <66 Gy) group. Each patient was retrospectively assigned an Eighth edition of American Joint Committee on Cancer disease stage based on the imaging data of initial diagnosis to avoid over- and under-staging. Intensity modulated radiation therapy plans were optimized to minimize the volumes of organs at risk exposed to radiation. The primary endpoint was overall survival. ResultsFrom March 2006 to September 2012, 140 patients were enrolled and assigned to two groups: 71 patients into the HD group and 69 patients into the SD group. The median survival time (MST) was significantly higher in the HD group (33.5 months) than in the SD group (21 months), (p < 0.0001). Overall 5-year survival rates were significantly higher in the HD group than in the SD group (37.8% vs 16.7%). Median progression-free survival was 19 months in the HD group and 11 months in the SD group (p < 0.0001). No difference in severe (grade 3–5) toxic effects was noted between the two groups. ConclusionsThe significant positive association observed between prescribed dose and survival suggests that individualized isotoxic dose-escalated radiation based on NTC might improve survival in this cohort of stage III NSCLC Chinese patients.

OC-0307 Feasibility of cardiac sparing in isotoxic dose escalated radiotherapy for NSCLC

OC-0307 Feasibility of cardiac sparing in isotoxic dose escalated radiotherapy for NSCLC

Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study

BackgroundStage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy. Patients and methodsPatients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity. ResultsFrom May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ± 12.8 Gy (36–73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3–22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%. ConclusionsINDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients.

Біомаркери експозиції та ефекту фосфорорганічних сполук (огляд даних літератури та результати власних досліджень)

Objective: analysis and summary of the literature data and own studies on the possibility of using biomarkers of exposure and effect of organophosphorus compounds (OPCs), determination of immunological biomarkers of the effect under exposure to OPCs that cause delayed neurotoxicity (DN). Materials and Methods. Analytical methods were used in the work: collection of scientific information on the topic, analysis of data and scientific summary of the results. Re-assessment of the effect of OPCs causing DN was performed from the perspective of determination of the most informative immunological biomarkers of the effect of known neurotoxicants. Analysis of the study results of the effect of neurotoxic OPCs, triorthocresyl phosphate (TOCP), Afos on the immune system was performed using the most sensitive model — chicken breed Leghorn in isotoxic doses (500 mg/kg and 200 mg/kg, respectively) using common immunotoxicology methods. Results and Conclusions. The article analyses and concludes current literary data on the justified use of biomarkers of exposure and effect of OPCs that are widespread in the environmental objects and are one of the reasons of acute and chronic poisoning in the population. We’ve reviewed aspects of the necessity for implementation of scientifically justified approach to the development and assessment of biomarkers and creation of the unified diagnostic complex that includes biomarkers of exposure, specific and non-specific action, with wider diagnostic abilities compared with determination of isolated parameters that is the basis for diagnostics, efficient treatment and prediction of consequences of poisoning with OPCs. Based on the results of own studies, we proposed the use of some parameters as the immunological biomarkers of the effect of OPCs with DN: the level of finely dispersed circulating immune complexes in the blood serum and the level of anti-brain antibodies, the number and functional activity of blood neutrophils; the number of T-and B-lymphocytes and their functional activity; the number of NK-cells, T-helper cells, and T-suppressors.

Isotoxic Dose Escalation with Real-Time Imaging on an MR-Linac in Lung Radiation Therapy

Lung cancer survival is poor with only 5% survival at 10 years. Recent studies suggest that dose escalation in chemoradiotherapy is required to increase survival. However, dose escalation can be limited by dose constraints placed on surrounding organs as risk to limit potentially fatal side effects. MR-Linac offer real-time imaging during radiotherapy. It is hypothesized that MR-Linac tracking techniques may allow PTV margin reduction, leading to a meaningful dose escalation with no expected increase in toxicity. To calculate a range of CTV-PTV margins required for real-time tracking on an MR-Linac, MR systematic tracking errors were taken from literature, combined with contouring errors (1 mm) and random per-fraction localization errors (1 mm) as per van Herk et al. An ideal case of 0 PTV margin and the standard clinical margin were also used for comparison. 4DCT scans from 10 locally advanced NSCLC patients were used to create a range of isotoxic plans based on the mid-ventilation phase and varying PTV margins. Planning aims and constraints were taken from standard clinical practice and the UK IDEAL-CRT trial, and the PTV dose per fraction was increased until one or more OAR constraint-level was reached. The planned doses were used to estimate the expected two-year disease free survival (DFS) using a radiobiological model in lung cancer by Partridge et al. An increase of ≥ 5% DFS was considered clinically useful. MR systematic tracking errors of 0.2 mm and 1.35 mm were used for PTVMRtrack_hi_acc and PTVMRtrack_lo_acc. Median isotoxically-prescribed doses of 72.8, 74.8 and 76.5 Gy could be delivered to PTVMRtrack_lo_acc, PTVMRtrack_hi_acc and PTVMRtrack_ideal leading to modelled gains in DFS of 4.2, 9.0 and 14.0% respectively when compared to PTVstandard median dose of 71.0 Gy. Depending on tumor location and proximity of nearby OARs, prescribed doses were limited by constraints on the heart, pulmonary artery, esophagus, aorta and trachea in 11, 9, 9, 7 and 4 cases respectively.Abstract 1102; Table 1Prescribed doses achieved during isotoxic dose escalationStructureStructure compositionMedian (range) dose to 95% PTV (Gy)Median (range) BED10 (Gy-1)Median 2-year DFS ratioPTVstandardITV + 5 mm (CTV) + 5 mm (PTV)71.0 (64.1 – 90.0)76.4 (66.4 - 105.6)0.36PTVMRtrack_lo_accGTVmidV + 5 mm (CTV) + 5 mm (PTV)72.8 (66.7 – 92.6)79.1 (70.1 - 109.8)0.41PTVMRtrack_hi_accGTVmidV + 5 mm (CTV) + 2 mm (PTV)74.8 (69.7 – 109.9)82.0 (74.4 - 138.8)0.45PTVMRtrack_idealGTVmidV + 5 mm (CTV) + 0 mm (PTV)76.5 (70.0 – 131.5)84.6 (74.9 - 177.7)0.50 Open table in a new tab MR-Linacs with the capability of real-time tracking potentially allow the PTV margin to be reduced, leading to notable increases in isotoxically-prescribed doses, and useful gains in modelled two-year disease free survival.

Locally Advanced Non-Small Cell Lung Cancer: Excellent Results of Isotoxic Dose Escalation after FDG-PET-Guided Target Volume Reduction – Results of a Prospective Randomized Multicenter Trial

Locally Advanced Non-Small Cell Lung Cancer: Excellent Results of Isotoxic Dose Escalation after FDG-PET-Guided Target Volume Reduction – Results of a Prospective Randomized Multicenter Trial

Вплив нових регуляторів росту рослин — похідних n-оксид піридину на рухову активність і енергетичний стан інфузорій tetrahymena pyriformis w

The study objective was to determine the functional state of infusoria Tetrahymena pyriformis W by parameters of motor activity and energy consumption for movements under acute effects of plant growth regulators — N-oxide pyridine derivatives, their complexes with organic acids and metal salts. Materials and methods. 2,6-dimethylpyridine-N-oxide, 2-methylpyridine-N-oxide and their complexes with organic acids (succinic, maleic) or metal salts (ZnCl2, ZnI2, CoCl2, MnCl2) — in total, 13 substances, synthesized at the Institute of Bioorganic Chemistry and Petrochemistry of the National Academy of Sciences of Ukraine have been used in the work. Studies have been carried out on the infusoria Tetrahymena pyriformis W in isotoxic doses — at the level of toxic concentrations — LC50, LC16 and inactive concentrations (LC0). Motor activity and energy state of infusoria using an automated laser Doppler spectrometer were evaluated. Results and conclusion. It was shown that the studied N-oxide pyridine derivatives and their complexes with organic acids or metal salts inhibit the motor activity of the infusoria and increase energy consumption for movements with the greatest effect in the concentrations of the corresponding LC50. 2,6-dimethylpyridine-N-oxide, 2-methylpyridine-N-oxide, and their complexes with succinic acid and metal salts of CoCl2 and ZnCl2 were the most toxic for the viability of infusoria. Therefore in order to assess the toxicity ofxenobiotics and viability of infusoria Tetrahymena pyriformis W, it is reasonable to recommend parameters of motor activity and energy consumption per unit of the rout that have the highest criterial significance. Key words: toxicity, plant growth regulators, N-oxide pyridine derivatives, Tetrahymena pyriformis W.

P257] Feasibility planning study to improve local control for muscle-invasive bladder cancer using theragnostic imaging and isotoxic dose escalation

Purpose Outcomes for muscle-invasive bladder cancer (MIBC) have changed little over recent decades, with long-term survival remaining around 50% in the UK [1] . Standard radiotherapy treatment involves trans-urethral resection and uniform radiotherapy to the whole bladder. Visualisation of bladder tumour on computed tomography (CT) is poor, but diffusion-weighted magnetic resonance imaging (DW-MRI) provides good visibility of volumes of high tumour burden. Theragnostic imaging using DW-MRI could therefore enable dose escalation to such volumes, however, geometric distortion inherent in DW-MRI requires consideration. In this study geometric distortion was quantified and accounted for, and dose was escalated isotoxically to simulated tumours within the bladder, with calculation of corresponding increases in local control. The aim was to facilitate individualised patient treatments with biologically-adapted radiotherapy (BART) to isotoxically increase tumour control probability (TCP). Methods An in-house bladder phantom was imaged using CT and DW-MRI and distortion in DW-MRI quantified. Tumours were simulated on a patient planning CT in various locations within the bladder and a margin added to accommodate distortion effects, emulating DW-MRI-registered images. Dose distributions were calculated with tumours receiving the maximum possible dose escalation beyond the standard 64 Gy in 32 fractions whilst maintaining normal tissue constraints, and bladder wall receiving 48 Gy, 52 Gy or 56 Gy. Poisson-based TCP models fitted to clinical trials data were used with clonogenic cell density assumed to be 10 7 cm - 3 in tumours and ranging between 0 and 10 7 cm - 3 within the bladder wall. Feasibility of delivery and effect on TCP was assessed via dose accumulation using cone beam CT. Results Maximum dose escalation to 78 Gy was possible for all inferior tumours. Superior, anterior, posterior and lateral tumours could be isotoxically escalated to 70 Gy, 71 Gy, 72 Gy and 72 Gy respectively regardless of tumour volume. Corresponding improvements in TCP ranged from 6 – 8% for superior tumours to 10 – 15% for inferior tumours. Conclusions Theragnostic imaging using DW-MRI was investigated for BART aiming to isotoxically increase TCP. This study indicates that such an approach could enable personalised radiotherapy treatment for MIBC and isotoxically improve outcomes.