Initial Radiation Research Articles

The care cascade following a supportive management intervention for patients presenting to a radiation oncology clinic

Patients with cancer have many psychosocial needs, some of which may be addressed by implementation of a screening tool. However, it is unknown what ultimately happens (i.e., the “care cascade”) to patients following these interventions. The objective of this study was to evaluate the care cascade for patients following the implementation of a psychosocial needs screening tool. This was a prospective cohort study conducted at a university hospital radiation oncology clinic. Participants who were 18 years or older and presenting for their initial radiation oncology appointment were asked to complete a screening survey. From December 2019 to January 2021, 242 patients completed the survey. 70% of patients were seen for consideration of definitive therapy. 62% of patients checked “yes” to at least one item, most commonly supportive/palliative care (33%), exercise/PT (26%) and advance care planning (26%). Among definitive patients, the most common were supportive/palliative care (33%) and exercise/PT (26%). Among palliative patients, the most common were supportive/palliative care (42%) and advance care planning (32%). Participants were followed for 6 months after taking the survey. 74% of patients with a positive screening survey were contacted by a social worker and/or had a new referral placed with 47% of those patients ultimately attending a new appointment. Screening tools are commonly implemented to quickly identify needs in oncology patients. This study tracked patients following this type of intervention to determine what proportion of patients ultimately received care related to the identified need. Despite the majority of patients being referred to a relevant provider, fewer than half ultimately attended appointments. The combination of a screening tool with social work triage may be an effective way to distribute resources and properly route patients to supportive care providers.

Monte Carlo simulations demonstrating physics of equivalency of gamma, electron-beam, and X-ray for radiation sterilization

The sterilization of medical devices using the gamma rays from the decay of cobalt-60 has accumulated decades of experience of the performance of the materials and devices that are irradiated. The use of radiation using electron beams and x-rays has much less experience and this leads to questions of equivalency between these three technologies. Computer simulations were conducted to model the relevant physical processes of the interactions of each of the three forms of radiation in order to compare the spectra of electron energies at energies below 500 keV. It is predominantly the electrons below this threshold that produce the sterilization dose. No difference in energy spectra was seen between the three types of initial radiation. It is concluded that there is no energy dependent difference between gamma, electron, and x-ray for radiation sterilization.

RT-7 DIFFERENTIATION AND TREATMENT OF RECURRENCE AND RADIATION NECROSIS IN THE TREATMENT OF MALIGNANT GLIOMAS

Abstract Background In the course of treatment of malignant gliomas, the appearance of contrast-enhanced lesions and surrounding T2/FLAIR high-signal after treatment is often experienced. There is no modality that can reliably diagnose whether the lesion is a recurrence or a response to treatment, including radiation necrosis. Furthermore, the choice of treatment modality is often difficult, such as reexcision, stereotactic irradiation, Avastin. Very few reports have examined the relationship between the irradiation field and histology. Methods Thirty-seven lesions in 30 patients who underwent repeat resection of malignant gliomas at our institution from October 2019 to December 2021 were analyzed retrospectively. Based on postoperative pathology, the patients were classified into two groups: recurrence group and radiation necrosis group.In each group, age, gender, histology at initial surgery, IDH status, radiation and chemotherapy, TNR of Methionine-PET, and the number of days after the end of treatment until the appearance of contrast lesions were considered. Results The recurrence group consisted of 20 patients with 26 lesions, mean age 48 years, male/female = 13/7, pathology was GBM 13, DA 1, AA 3, AO 2, AE 1, TNR 3.33 (1.41-6.32), and time to contrast appearance 547 (14-2427) days. PDT in combination with initial surgery was seen in 9 patients.The necrosis group consisted of 10 patients with 11 lesions, mean age 47 years, male/female = 4/6, pathology GBM 5, AA 2, AO 1, PXA 2. TNR 2.51 (1.20-3.75), 318 (24-678) days to contrast appearance, 2 patients had PDT. Conclusions Radiation necrosis tended to have lower TNR and shorter time to lesion appearance than recurrence, but no significant difference was observed. Improvement of diagnostic accuracy with modalities is desirable, and unnecessary irradiation is highly likely to contribute to ADL deterioration such as leukoencephalopathy and higher functional impairment.

ISSUES OF DEVELOPMENT AND OPTIMIZATION OF CUVETTE TURBIDIMETERS FOR WATER TURBIDITY CONTROL

The issues of development and optimization of cuvette turbidimeters for water turbidity control are considered. The principle of constructing a universal turbidimeter with a variable course of the liquid beam inside the cuvette is described. The problem of optimization of cuvette laser turbidimeters in the mode of the presence of a rigid coupling function between the varying value of the initial laser radiation intensity and the length of the beam path in the liquid in the cuvette is investigated. It is shown that a turbidimeter with a changing beam path in a cuvette and a changing radiation intensity can have the highest average integral sensitivity if a decrease in the beam path is accompanied by a proportional logarithmic increase in the radiation intensity.

Effect of phototherapy on psychoemotional state in psoriasis: assessment of depression, anxiety and quality of life

BACKGROUND: Psoriasis is a widespread chronic genetically determined inflammatory dermatosis that affects approximately 125 million people worldwide. In the vast majority of cases, the first rashes appear in people younger than 35 years old who are just starting to build a career and start a family. Localization of psoriatic rashes on visible areas of the skin and stigmatization in society, regular exacerbations and multiple courses of expensive and insufficiently effective treatment negatively affect the quality of life and emotional state of patients up to the development of depressive and anxiety disorders, and even suicide attempts. An imbalance of mental status leads to the progression of psoriasis, which further aggravates the course of the skin process. This necessitates a personalized approach to the choice of a therapy method, taking into account high efficiency and maximum comfort for patients, which will improve their psychoemotional state.
 AIM: to study the effect of phototherapy (PUVA and UVB-311 nm) on the mental status of psoriasis patients
 MATERIALS AND METHODS: A prospective study was conducted on the basis of FGKU Central Polyclinic and V.A. Rakhmanovs clinic of skin and venereal diseases of Sechenov University with the participation of 228 patients with moderate-to-severe psoriasis who received UVB-311 nm (n=116) and PUVA therapy (n=112), including psoriasis vulgaris (n=193), guttate psoriasis (n=14), exudative psoriasis (n=21). Before and after treatment, patients were assessed for the severity of psoriasis (PASI), quality of life (DQLI), as well as the presence of depression and anxiety disorders (panic disorder, social phobia) using PHQ-9 and GAD-7 questionnaire tests. The initial radiation dose was 1 J/cm2 at PUVA and 0.10.2 J/cm2 at UVB-311 nm with a gradual increase in the dose every 12 sessions by 0.5 J/cm2 and 0.1 J/cm2, respectively. As photosensitizers ammifurin and oxoralen were used. The treatment was carried out according to the method of four-time irradiation per week using the UV-7001K cabin (Waldmann, Germany).
 RESULTS: Among 228 patients there were 108 women and 120 men aged 438.2 years. The UVB-311 nm group included 102 patients with moderate psoriasis vulgaris and 14 guttate psoriasis, the second group (PUVA) included patients with severe recalcitrant psoriasis vulgaris (n=91) and exudative psoriasis (n=21). In the first group, the course of therapy consisted of 282 procedures of UVB-311 nm. Before treatment, minimal depression was observed in 19 (16%) patients, mild depression in 87 (75%), moderate depression in 10 (9%). A high level of anxiety was observed in 94 (81%), the average level in 22 (19%) patients. At the end of the course of UVB, PASI 90 was achieved in 94% (n=109) of patients, PASI 100 in 88% (n=102); at the same time, on average, anxiety decreased by 80%, depressive symptoms decreased by 73%, quality of life increased by 92%. In the second group, the PUVA course consisted of 253 irradiation sessions. Before starting therapy, minimal depression was observed in 12 (11%) cases, mild depression in 73 (65%), moderate depression in 27 (24%). A high level of anxiety was characteristic of 100% of patients. As a result of therapy, PASI 90 was achieved in 95.5% (n=107) of cases, PASI 100 in 90% (n=101). The average severity of anxiety, depression, and quality of life improved by 88%, 83%, and 96% respectively.
 CONCLUSION: PUVA and UVB-311 nm have demonstrated high efficacy and safety in moderate-to -severe psoriasis, contributing to the rapid cleansing of the skin from rashes and improving the psycho-emotional state, which not only significantly improves the quality, but also increases the life expectancy of patients.
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Single production of vectorlike B quarks decaying into bh at the CLIC

New vectorlike quarks have been predicted in many scenarios of new physics beyond the Standard Model, which may be potentially discovered at the current and future high-energy colliders. Based on a model-independent framework, we study the single production process of the doublet vectorlike B-quark (VLQ-B) at the future Compact Linear Collider (CLIC) and explore the possible signals through the decay channel B→bh with subsequent decay mode of the Higgs boson: h→WW⁎→ℓνjj. By performing a rapid detector simulation of the signal and background events as well as considering the initial state radiation and beamstrahlung effects, the exclusion limit at the 95% confidence level and the 5σ discovery reach in the parameter spaces (the coupling strength κB and the VLQ-B mass) are obtained at the future 3 TeV CLIC with an integrated luminosity of 5 ab−1.

Post-irradiation sarcoma after definitive radiation therapy for nasopharyngeal carcinoma

Background and purposePostirradiation sarcoma (PIS) is a rare radiation-induced malignancy after nasopharyngeal carcinoma (NPC) treatment. Materials and methodsWe retrospectively screened 9,185 NPC patients between 2000 and 2020 and identified 41 patients with PIS according to the modified Cahan’s criteria: (1) the PIS must have arisen within a previous radiation field; (2) a latent period must have existed; (3) histologically proved sarcoma; (4) the tissue in which the PIS arose must have been healthy prior to the radiation. The initial radiation therapy techniques used were 2D (25; 61.0%), 3D (7; 17.1%), and IMRT (9; 22%). ResultsThe time (year) from radiotherapy (RT) to PIS was longer when using 2D or 3D irradiation techniques (median, 14.2; range, 3.4–28.1; Q1-Q3, 8.6–19.7) than when using IMRT (median, 6.6; range, 3.8–15.7; Q1-Q3, 4.5–11.7; P =.026). The time (year) from RT to PIS diagnosis was significantly longer when using lower radiation energy from cobalt-60 (median, 15.8; range, 10.4–28.4; Q1-Q3, 12.5–23.8) than when using a higher radiation energy of 6 or 10 MV (median, 10.2; range, 3.4–23.3; Q1-Q3, 6.5–16.1; P =.006). The 2-year overall survival rates for patients who underwent surgery, radical radiotherapy, systemic therapy alone and no treatment were 60.7 %, 42.9 %, 0 % and 0 %, respectively (P =.000). Of the 3 retrievable initial RT dosimetry plans for NPC, the D95 values (dose that covers 95 % of the PIS volume) for PIS were 6267, 6344 and 5820 cGy, respectively. ConclusionHigh radiation energy and modern techniques may shorten NPC PIS latency. Surgery may be associated with improved survival if feasible.

SECOND-HARMONIC GENERATION IN A THIN SPHERICAL LAYER OF A SMALL RADIUS BY COHERENT SOURCES OF ELLIPTICALLY POLARIZED RADIATION

Explicit forms of the power density and the total radiation power of the second-harmonic generation in a thin spherical layer of a small radius are determined. The conditions for a maximal total power of the second harmonic and the direction of observation of the maximum intensity of the second harmonic are found analytically for special cases of the second-order dielectric susceptibility tensor. A numerical maximization of the energy characteristics of the second-harmonic generated radiation is carried out using one and two coherent sources with the same ellipticity of radiation. The advantage of using several coherent sources compared to a single source of initial radiation is shown.

CTNI-61. CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA

Abstract Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson’s r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPK-pathway alterations, and patients with relatively high CBF.

The role of initial state radiation in quenched jets

Jet quenching in heavy ion collisions and in particular the sub-structure of quenched jets are promising tools for investigating the microscopic processes underlying jet quenching and the background medium's response to energy and momentum depositions. A quantitative understanding of the data can, however, be complicated by the presence of initial state radiation in reconstructed jets. Using an extended version of Jewel the effect of initial state radiation on different jet observables is studied in proton-proton and heavy ion collisions. It is shown that, depending on the observable and the jet radius, the initial state contributions can be sizable. Some general insights into when sizable effects can be expected also emerges.

CTIM-18. PHASE 2 STUDY OF PD-1 BLOCKADE WITH PEMBROLIZUMAB PLUS RE-IRRADIATION FOR RECURRENT GLIOBLASTOMA (RGBM) (NCT03661723)

Abstract Re-irradiation is therapeutically considered for select rGBM patients and may induce immunogenic cell death to stimulate anti-tumor immune responses. Our phase 2 study of re-irradiation with pembrolizumab among rGBM patients evaluated the efficacy and safety of this regimen. METHODS Adult rGBM patients with KPS ≥ 70, a maximum supratentorial tumor diameter of 6 cm who were on ≤ 2mg dexamethasone/day and were ≥ 6 months from initial conventional radiation therapy were eligible. Cohort A (bevacizumab [BEV]-naïve) had ≤ 2 prior progressions while cohort B (BEV-refractory) allowed unlimited progressions but only one on prior BEV. Re-irradiation included 35 Gy over 10 fractions to residual enhancing (cohort A) as well as enhancing + non-enhancing (cohort B) disease. Pembrolizumab was administered at 200 mg every three weeks beginning within one week of re-irradiation start. BEV was administered at 15 mg/kg every three weeks for cohort B only. RESULTS Sixty patients enrolled (n = 30 per cohort) with a median age of 61 years (range 20-76), 47% were female and 53% enrolled after 2 or more progressions. Grade 3 events deemed at least possibly related to study therapy in > one patient for cohort A included headache (n = 2) and for cohort B included elevated ALT (n = 2) and hypertension (n = 5). No grade 4 events occurred in more than single patients per cohort and no grade 5 events occurred. Median PFS and PFS-6 were 4.9 months (95% CI: 3.5, 5.6) and 26.0% (95% CI: 12.3%, 43.0%) for cohort A and 4.14 months (95% CI: 3.45, 5.42) and 16.9% (95% CI: 5.4, 33.7) for cohort B. Median survival for cohorts A and B were 11.5 months (95% CI: 9.6, 14.1) and 7.6 months (95% CI 5.5, 9.3), respectively. CONCLUSIONS Re-irradiation with pembrolizumab was overall well tolerated and achieved comparable efficacy to historical salvage therapy established with lomustine.

Initial State Radiation and Beamstrahlung in the production of a resonance of mass mZ0 in 3-3-1 model

In this work we study the effects of Initial State Radiation (ISR) and Beamstrahlung (BS), in the production of Z 0 in the 3-3-1 model with heavy leptons. The impact of the ISR and BS on precision measurements strongly afects the behaviour of the production cross section around the resonance points: mZ0 = 5976.43(6830.21; 8539.47) GeV for vχ = 3.5(4.0; 5.0) TeV, at the Compact Linear Collider (CLIC).

Extreme Multistability in a Hopfield Neural Network Based on Two Biological Neuronal Systems

Based on different biological neuronal systems, various memristive neuron and neuron network models are generated. In this brief, a three-neurons-based Hopfield neural network with two biological neural mechanisms is investigated, with one of three neurons exposed to electromagnetic radiation and one of the synaptic weights replaced by a memristor. The effects of electromagnetic radiation and memristive synaptic weight on neural networks are investigated. It is found that coexisting behaviors exist in the neural network by adjusting the memristive synaptic weight. Moreover, infinitely many coexisting behaviors are observed by changing the initial electromagnetic radiation. That is, both of them are critical to the system and have the potential to complicate it. Furthermore, circuits of the neural network are implemented in Pspice and DSP board, and the experimental results are in agreement with numerical ones.

Long-term follow-up results of endorectal balloon-assisted helical tomotherapy for localized prostate cancer patients in the high-risk group of gastrointestinal adverse events.

Endorectal balloon (ERB) has been shown to reduce rectal radiation dose and late gastrointestinal toxicities in patients with prostate cancer. However, the usefulness of ERBs for patients with prostate cancer whose rectal shape or size is suboptimal has not been investigated. The purpose of this study was to present the long-term follow-up results of ERB-assisted helical tomotherapy for localized prostate cancer patients whose initial radiation treatment planning (RTP) was unacceptable due to suboptimal rectal shape or size. Of 541 consecutive patients with localized prostate cancer, 10 were included in this study whose RTPs without ERBs did not meet dose constraints due to: 1) Intestinal intrusion, 2) Small rectum; or 3) Unstable rectal shape. We re-planned using ERBs and delivered 76 Gy in 38 fractions, and evaluated the long-term usefulness and safety of ERB-assisted helical tomotherapy. At a median follow-up of 109 months, there were no local recurrences of prostate cancer. The overall, cause-specific, and progression-free survivals at 10 years were 90.0%, 100%, and 83%, respectively. Adverse events of grade 3 or higher were not observed during or after ERB-assisted helical tomotherapy. When intestinal intrusion, a small rectum, or an unstable rectal shape is an obstacle for administering helical tomotherapy, ERBs might be the solution.

Probabilistic fire risk analysis of process pipelines

Pool fires are considered catastrophic events in hydrocarbon liquid process pipelines. There is much research performed on fire risk analysis of liquid pipelines; however, probabilistic-quantitative methods that are based on the leak size are yet to be further developed. This paper develops a framework for quantitative fire risk analysis in liquid process pipelines based on probabilistic analysis and computational fluid dynamics. The significance of leaked volume and its dependency on the leak size, here the pipeline failure frequency is distributed into the frequencies of different leak sizes using historical data and the Bayesian network. The frequency of fire occurrence is then determined by combining the ignition probability of each leakage rate, the flammability specification of released materials, and the frequency of each leak size. In the vulnerability assessment, the thermal dose received by individuals is modified to account for the possibility of escape. The developed framework is next employed in a gasoline pipeline with a 1 km length. Results show that the pool fire scenario resulting from the rupture of the pipeline, with a frequency of 1.18 × 10−7 (km−1. y−1) and an area of exposure of 5498.4 m2, is the maximum-credible scenario. Two separate escape routes with different distances to the fire center are defined. As well, two escape speeds of 4 and 6 m/s are considered. The results show that the initial radiation and the escape speed can significantly affect the sustained damage to individuals. This study is a step forward in dynamic-quantitative individual risk analysis in pool fires of hydrocarbon liquid pipelines.

Outcomes of Brain Metastases Managed with Resection and Aggressive Reirradiation after Initial Radiosurgery Failure

<h3>Purpose/Objective(s)</h3> To evaluate local control, overall survival, and toxicity profiles in patients with brain metastases aggressively treated with initial radiation followed by resection and aggressive re-irradiation upon pathological confirmation of failure of prior radiosurgery treatment. <h3>Materials/Methods</h3> A retrospective chart review identified 55 lesions in 51 patients that were initially treated with stereotactic radiosurgery (SRS), then demonstrated evidence of recurrence with pathologic confirmation and underwent high dose re-irradiation either with radiosurgery (n=43, 78.2%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 21.8%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of re-treatment. Overall survival (OS) and local control were evaluated using the Kaplan-Meier method. <h3>Results</h3> Median follow-up from re-irradiation was 32.5 months (IQR 18-45 months). The majority of cohort patients were female (66.7 %), with median age at first SRS of 56.3 years old. Primary histology was non-small cell lung cancer (NSCLC) in 19 cases (37.2%) and breast cancer in 12 cases (23.53%). Ten individuals had previous WBRT (19.5%) prior to initial stereotactic therapy. The most common dose fractionation for initial SRS was 18 Gy x 1 fraction (18 lesions, 32.7%), and the most common dose fractionation for repeat SRS was 8 Gy in 3 fractions (15 lesions, 27.3%). Twenty-five lesions (45.4%) required use of steroids after re-irradiation. Among all patients, 21.8% experienced evidence of grade 3 or 4 neurotoxicity. There was no statistically significant difference in the rate of steroid use or grade 3-4 neurotoxicity between lesions re-irradiated with SRS vs. brachytherapy (25.6% vs. 8.33% grade 3-4 neurotoxicity; p=0.201 and 51.2% vs 25% steroid use; p=0.108). Forty percent had imaging changes of possible pseudoprogression, radiation necrosis, or true progression. Of patients with imaging changes, 27% (10.9% of all treated patients) were confirmed necrosis by pathology. Median OS was 14.1 months (95% CI 7.63 – 24.3). The 2-year OS was 52% (95% CI 39, 69.3%) and 2-year local control rate was 79.5% (95% CI 61.7, 68.3%). <h3>Conclusion</h3> Aggressive re-irradiation with radiosurgery or brachytherapy after resection for pathologically confirmed progression after prior radiosurgery is appropriately effective and demonstrate similar toxicity profiles.

Recursive Partitioning Analysis to Define Prognostic Groups Using a Large Single Institution Experience of Multimodality Radiation Therapy for Bladder Cancer

<h3>Purpose/Objective(s)</h3> We analyzed a cohort of patients who received definitive trimodality therapy (TMT) for bladder cancer at a single high-volume institution. We hypothesized that a recursive partitioning analysis (RPA) including patient and tumor characteristics would allow stratification of patients into clinically meaningful prognostic groups for local recurrence. <h3>Materials/Methods</h3> A retrospective cohort analysis was performed for bladder cancer patients treated with definitive radiation or chemoradiation therapy from 2006 to 2021 at our institution. We assessed overall and disease-free survival for the cohort and as a function of clinical and pathologic features. We performed an RPA for multivariate decision tree analysis to associate outcomes with individual clinical and pathologic variables. <h3>Results</h3> 175 patients were identified who were treated with definitive radiation (28%) or chemoradiation (72%) and had adequate follow-up data for analysis. Median follow up time was 23 months (Median age=78 [IQR 71-84], 77% male). While Grade 1-2 toxicities were common, Grade ≥3 toxicities were rare and there were no treatment related deaths. Cumulative 2yr and 5yr CSS were 79% and 61%, respectively. Radical cystectomy (RCx) eligible patients (35%) had a significantly longer OS after bladder sparing therapy compared to RCx ineligible patients (5y OS 54% vs 29%, Log-Rank p=0.003), however no difference in cancer specific survival was seen between groups (5y CSS 61% vs 58%, Log-Rank p = 0.851). Tumor size greater than 5cm did not correlate with risk of recurrence (Log-Rank p=0.194). The most common site of recurrence in the cohort was distant (35%), followed by locoregional (19%) and bladder only (6%). Nine patients (5%) underwent salvage cystectomy (7 for invasive local recurrence) after initial definitive radiation therapy. Using RPA and decision tree analysis, the presence of CIS and older age at treatment were the strongest predictors of local recurrence. The RPA results confirmed no significant association between tumor size and risk of local recurrence. <h3>Conclusion</h3> Multimodality bladder preservation had CSS comparable to modern surgical series and high rates of functional organ preservation. Cystectomy candidacy was a strong predictor of overall survival but not cancer specific survival, suggesting group level mismatches in competing risks of death. Extensive CIS was associated with increased risk of local failure, but tumor size may not be a reliable predictor of treatment response. RPA prognostic groups were generated which may be used to guide clinical decision making and improve patient selection for bladder preservation.

Pain Response Rates after Conventional Radiation Therapy for Bone Metastases Assessed Using International Consensus Pain Response Endpoints: A Systematic Review and Meta-Analysis of Initial Radiation Therapy and Re-Irradiation

<h3>Purpose/Objective(s)</h3> Previous systematic reviews of conventional radiation therapy (RT) for painful bone metastases showed response rates of 72%<b>–</b>75% for initial RT and 68% for re-irradiation. However, the definition of pain response differed among studies included in these reviews. The International Consensus Pain Response Endpoints (ICPRE) was published in 2002 and revised in 2012 to unify evaluation methods for pain response internationally and has been used in many studies. We conducted a systematic review and meta-analysis to determine the pain response rates assessed by ICPRE for both initial RT and re-irradiation. <h3>Materials/Methods</h3> A literature search was conducted in PubMed and Scopus for articles published between 2002 and 2021. The inclusion criteria were as follows: (i) the study designs of randomized controlled trials (RCTs), prospective studies, or studies based on prospectively collected data; and (ii) studies in which pain response was assessed using ICPRE. Our primary outcomes of interest were overall response (OR) rates (sum of complete response rate and partial response rate) for both initial RT and re-irradiation. The following subgroup analyses were performed for OR rates of initial RT: RCT vs. non-randomized studies, with vs. without exclusion criteria for complicated bone metastases, with vs. without eligibility criteria for no change in analgesic use at enrollment, and timing of response assessment (≤1 month vs. >1 month). Random effects logistic models were used to estimate pooled response rates. <h3>Results</h3> Of the 6470 articles identified in our database search, 32 and 3 met the inclusion criteria for analysis of initial RT and re-irradiation, respectively. The OR rates of initial RT in evaluable patients (n = 4775) and intent-to-treat patients (n = 6775) were 60.4% (95% confidence interval [CI], 55.2–65.4) and 45.4% (95% CI, 38.7–52.4), respectively. The OR rates of re-irradiation in evaluable patients (n = 733) and intent-to-treat patients (n = 1085) were 70.8% (95% CI, 15.7–96.9) and 62.2% (95% CI, 5.3–98.0), respectively. Subgroup analyses of initial RT showed no significant differences in any of the comparisons, indicating similar response rates across different study designs. <h3>Conclusion</h3> We determined the pain response rates of initial RT for painful bone metastases assessed by ICPRE. The OR rate assessed by ICPRE was lower than previously reported. The present review may provide benchmarks for future RCTs and non-randomized studies. Regarding the response rate for re-irradiation, the wide range of the 95% CI warrants that the OR rate based on ICPRE requires further investigation.

Imaging of Primary and Metastatic Tumors Treated with Radiotherapy-Directed Antigen-Capturing Nanoparticles, Reducing Metastasis-Seeding and Colonization, under PDL-1 Blockade

<h3>Purpose/Objective(s)</h3> We tested a treatment combining radiotherapy with antigen-capturing nanoparticles (AC-NPs; 112 ± 73 nm) containing digitoxin and anti-STAT-3 inhibitor (HJC0152) encapsulated in nanocapsules (545 ± 24 nm), which release their contents upon radiation exposure. We conducted two radiotherapy sessions: 1) treatment of primary tumor and metastases by immuno-radiotherapy and abscopal effect with PDL-1 blockade, respectively, and 2) reduction of new metastasis seeding and colonization by dissociation of circulating tumor cell (CTC)-clusters using digitoxin, and by impairing premetastatic niche (PMN) formation using a STAT-3 inhibitor (HJC0152), respectively. <h3>Materials/Methods</h3> In session one, nanocapsules were generated by mixing iopamiron, 400 mg of an anti-PD-L1 antibody (Ab), and 10 µg/mL HJC0152 with a 1.0 mL solution containing 4.0% alginate, 3.0% hyaluronate, and 1 µg/mL P-selectin. This mixture was sprayed into 0.5 mmol/l FeCl₂ supplemented with 1 µg/mL anti-VEGFR-1/2 Ab. In session two, 400 nM digitoxin was encapsulated in poly lactic-co-glycolic acid (PLGA) AC-NPs using the nanoprecipitation method. The particles were mixed with the above cocktail and sprayed into 0.5 mmol/L FeCl₂ with 1 µg/mL anti-P-selectin Ab. This yielded encapsulated PLGA AC-NPs containing digitoxin. In session one, 1 × 10¹⁰ nanocapsules were intravenously injected into BALB/c mice exhibiting a primary 4TI mammary carcinoma in the left hind leg and lung metastases. Tumor accumulation was monitored by computed tomography (CT). Subsequently, 10 or 20 Gy ⁶⁰Co γ-radiation was locally administered to primary tumors and lung metastasis. In session two, 1 × 10¹⁰ nanocapsules were injected i.v. and allowed to interact with P-selectin for 9 h; additionally, 10 or 20 Gy ⁶⁰Co γ-radiation was administered solely to the primary tumor. <h3>Results</h3> In session one, CT imaging of the accumulation of anti-VEGFR-1/2 nanocapsules around the primary and metastatic tumors improved their diagnosis. The nanocapsules released P-selectin, anti-PD-L1 Ab, and HJC0152 in response to the initial radiation dose. After session two, the nanocapsules accumulated around the primary tumor via a P-selectin Ag-Ab reaction. PLGA AC-NPs captured tumor-derived protein antigens released by the second radiation dose and intensified DC-mediated CD8⁺ T-cell priming. The primed CD8⁺ T-cells attacked PD-L1-suppressed primary and metastatic tumors. PLGA AC-NPs also released digitoxin, which dissociated CTC-clusters and reduced new metastasis seeding; the colonization of seeded tumor cells was subsequently inhibited through impaired PMN formation by HJC0152. Additionally, HJC0152 intensified DC-mediated CD8⁺ T-cell priming. These treatments significantly increased the antitumor effect (EF 1.7) and reduced metastasis by 88.8%. <h3>Conclusion</h3> Our CT-detectable nanocapsules will lead to better diagnosis and tumor treatment.

Multi-photon Monte Carlo event generator KKMCee for lepton and quark pair production in lepton colliders

We present the KKMCee 5.00.2 Monte Carlo event generator for lepton and quark pair production for the high energy electron-positron annihilation process. It is still the most sophisticated event generator for such processes. Its entire source code is re-written in the modern C++ language. It reproduces all features of the older KKMC code in Fortran 77. However, a number of improvements in the Monte Carlo algorithm are also implemented. Most importantly, it is intended to be a starting point for the future improvements, which will be mandatory for the future high precision lepton collider projects. As in the older version, in addition to higher order QED corrections, it includes so-called O(α1.5) genuine weak corrections using a version of the classic DIZET library and polarized τ decays using TAUOLA program. Both DIZET and TAUOLA external libraries are still in Fortran 77. In addition, a HEPMC3 interface to other MC programs, like parton showers and detector simulation, replaces the older HepEvt interface. The HEPMC3 interface is also exploited in the implementation of the additional photon final state emissions in τ decays using an external PHOTOS library rewritten in C. Program summaryProgram title:KKMCee 5.00.2CPC Library link to program files:https://doi.org/10.17632/7drvvhbw92.1Licensing provisions: GPL-3.0Programming languages:C++, FORTRAN77External routines:CERN ROOT library, PHOTOS, HepMC v.3.0, TAUOLA, PHOTOS, FOAM, HEPMC3Nature of the problem: Fermion pair production is and will be used as an important data source for precise tests of the standard electroweak theory at a high luminosity future circular collider near the Z resonance and above and/or at the future linear lepton colliders of higher energies than those at LEP. The QED corrections to fermion pair production (especially τ leptons) have to be known to at least second order, including spin polarization effects, with 4-5 digit precision. The Standard Model predictions at the sub-permille precision level, taking into account multiple emission of photons for realistic experimental acceptances, can only be obtained using a Monte Carlo event generator. The realistic and precise simulation of τ lepton decays taking into account spin effects is an indispensable ingredient in the Monte Carlo event generator for the fermion pair production process.Solution method: Monte Carlo methods are used to simulate most of the two-fermion final-state processes in e+e− collisions in the presence of multiphoton initial and final state radiation. The multiphoton effects are described in the framework of coherent exclusive exponentiation (CEEX) extending/upgrading the older Yennie–Frautschi–Suura exclusive exponentiation (EEX) scheme. CEEX treats correctly to infinite order not only infrared cancellations but also QED interferences, including suppression of initial-final state interferences for narrow resonances. The matrix element according to the older YFS exponentiation is also implemented for the testing purpose. For τ leptons, the appropriate simulation of a very rich spectrum of the decays is included. Beam polarization and spin effects, both longitudinal and transverse, in tau decays are properly taken into account. Gaussian beam spread and an arbitrary spectrum of the beamstrahlung are also optionally simulated. The present version of the program is rewritten to C++ but in many respects corresponds to its FORTRAN predecessor KKMC v.4.13 [1] with later minor modifications in v. 4.32 [2].Additional comments including restrictions and unusual features: In the present version, electron (Bhabha) and t-quark final states are not included. (It is planned for a future version.) Third-order QED corrections in the leading-logarithmic approximation are included only in the auxiliary older YFS/EEX matrix element. The electroweak corrections should not be trusted above the t-quark threshold. The total cross section for light quarks for s<10 GeV (including narrow resonances) requires an improvement using experimental data. The program does not provide any handles for the beyond the Standard Model (BSM) physics, for instance in the Born Z boson couplings or in the electroweak (EW) formfactors.Running time depends on the CMS energy, final fermion type, upper phase space limit of the photon energy, and whether variable weight events or WT=1 events are generated. On a PC/Linux with a 2.2 GHz processor, producing 100k variable weight events at s=MZ takes 25 sec. of CPU time for μ-pairs and 30 sec. for τ-pairs including decays. At s=189 GeV 100k events with WT=1 costs 1200 sec. for μ-pairs and 830 sec. for τ-pairs (less hard photons).