Conventional Radiation Treatment Research Articles

Neoadjuvant immunotherapy for head and neck squamous cell carcinoma.

The neoadjuvant immunotherapy approach marks a significant shift in the treatment paradigm of potentially curable HNSCC. Here, current therapies, despite being highly individualized and advanced, often fall short in achieving satisfactory long-term survival rates and are frequently associated with substantial morbidity.The primary advantage of this approach lies in its potential to intensify and enhance treatment regimens, offering a distinct modality that complements the existing triad of surgery, radiotherapy, and chemotherapy. Checkpoint inhibitors have been at the forefront of this evolution. Demonstrating moderate yet significant survival benefits in the recurrent-metastatic setting with a relatively better safety profile compared to conventional treatments, these agents hold promise when considered for earlier stages of HNSCC.On the other hand, a significant potential benefit of introducing immunotherapy in the neoadjuvant phase is the possibility of treatment de-escalation. By reducing the tumor burden before surgery, this strategy could lead to less invasive surgical interventions. The prospect of organ-sparing protocols becomes a realistic and highly valued goal in this context. Further, the early application of immunotherapy might catalyze a more effective and durable immune response. The induction of an immune memory may potentially lead to a more effective surveillance of residual disease, decreasing the rates of local, regional, and distant recurrences, thereby enhancing overall and recurrence-free survival.However, neoadjuvant immunotherapy is not without its challenges. One of the primary concerns is the safety and adverse events profile. While data suggest that adverse events are relatively rare and manageable, the long-term safety profile in the neoadjuvant setting, especially in the context of curative intent, remains a subject for ongoing research. Another unsolved issue lies in the accurate assessment of treatment response. The discrepancy between radiographic assessment using RECIST criteria and histological findings has been noted, indicating a gap in current imaging techniques' ability to accurately reflect the true efficacy of immunotherapy. This gap underscores the necessity for improved imaging methodologies and the development of new radiologic and pathologic criteria tailored to evaluate the response to immunotherapy accurately.Treatment combinations and timing represent another layer of complexity. There is a vast array of possibilities in combining immunotherapy agents with conventional chemotherapy, targeted therapy, radiation, and other experimental treatments. Determining the optimal treatment regimen for individual patients becomes an intricate task, especially when comparing small, single-arm, non-randomized trials with varying regimens and outcome measures.Moreover, one needs to consider the importance of pre- and intraoperative decision-making in the context of neoadjuvant immunotherapy. As experience with this treatment paradigm grows, there is potential for more tailored surgical approaches based on the patient's remaining disease post-neoadjuvant treatment. This consideration is particularly relevant in extensive surgeries, where organ-sparing protocols could be evaluated.In practical terms, the multi-modal nature of this treatment strategy introduces complexities, especially outside clinical trial settings. Patients face challenges in navigating the treatment landscape, which involves coordination across multiple medical disciplines, highlighting the necessity for streamlined care pathways at specialized centers to facilitate effective treatment management if the neoadjuvant approach is introduced to the real-world.These potential harms and open questions underscore the critical need for meticulously designed clinical trials and correlational studies to ensure patient safety and efficacy. Only these can ensure that this new treatment approach is introduced in a safe way and fulfils the promise it theoretically holds.

Low-dose ionizing γ-radiation elicits the extrusion of neutrophil extracellular traps.

Cancer patients frequently undergo radiotherapy in their clinical management with unintended irradiation of blood vessels and copiously irrigated organs in which polymorphonuclear leukocytes circulate. Following the observation that such low doses of ionizing radiation are able to induce neutrophils to extrude neutrophil extracellular traps (NETs), we have investigated the mechanisms, consequences and the occurrence of such phenomena in patients undergoing radiotherapy. NETosis was analyzed in cultures of neutrophils isolated from healthy donors, cancer patients and cancer-bearing mice under confocal microscopy. Cocultures of radiation-induced NETs, immune effector lymphocytes and tumor cells were used to study the effects of irradiation-induced NETs on immune cytotoxicity. Radiation-induced NETs were intravenously injected to mice assessing their effects on metastasis. Circulating NETs in irradiated cancer patients were measured by ELISA methods detecting MPO-DNA complexes and citrullinated H3. Very low γ-radiation doses (0.5-1 Gy) given to neutrophils elicit NET formation in a manner dependent on oxidative stress, NADPH oxidase activity and autocrine interleukin-8. Radiation-induced NETs interfere with NK- and T-cell cytotoxicity. As a consequence, pre-injection of irradiation-induced NETs increases the number of successful metastases in mouse tumor models. Increases in circulating NETs were readily detected in two prospective series of patients following the first fraction of their radiotherapy courses. NETosis is induced by low-dose ionizing irradiation in a neutrophil-intrinsic fashion and radiation-induced NETs are able to interfere with immune-mediated cytotoxicity. Radiation-induced NETs foster metastasis in mouse models and can be detected in the circulation of patients undergoing conventional radiotherapy treatments.

Investigation of Hydrogen Peroxide for 45MV 5-Aminolevulinic Acid-Mediated Radiodynamic Therapy

Cytotoxicity caused by the reactive oxygen species (ROS), such as singlet oxygen species (1O2), superoxide radical (O2-), and hydroxyl radical (HO), is a mechanism for treating cancer cells in radiation therapy. 5-aminolevulinic acid (5-ALA)-mediated radiodynamic therapy (RDT) is more effective in killing tumor cells than conventional radiation therapy. ROS is produced not only by ionizing radiation but also by Cherenkov light-activated protoporphyrin IX (PpIX), which is metabolized endogenously from 5-ALA. Moreover, PpIX also catalyzes hydrogen peroxide to generate 1O2, and an enhanced catalytic yield of 1O2 was observed in X-ray irradiation in vitro. Therefore, using an in-vivo mouse model, this study aimed to investigate the effect of hydrogen peroxide as a coenzyme catalyst on a novel 45MV 5-ALA-mediated RDT. A subcutaneous C57BL/6 mouse model of KP1 cell line was used. The tumors (n = 240) were randomized into six groups, consisting of untreated, conventional radiation treatment (RT), and RDT with or without hydrogen peroxide: 1. control (untreated), 2. hydrogen peroxide, 3. 45MV RT, 4. 45MV RT + hydrogen peroxide, 5. 45MV RDT, 6. 45MV RDT + hydrogen peroxide. For 45MV photon irradiation, a single fraction of 4 Gy was delivered to the tumors. 5-ALA was systemically injected at 100 mg/kg by tail-vein 4 hours before the treatment for endogenous PpIX accumulation in the tumor. Carbamide peroxide was used to deliver hydrogen peroxide to tissue and was administered at 60 mg/kg intratumorally into tumors ∼3-5 min before the treatment. The treatment effect of a single fraction of treatment was measured by calculating tumor growth, measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment), 3 and 7 days post-treatment. Two-way repeated ANOVA with Bonferroni correction was used to compare each treatment group to determine the statistically significant difference in tumor growth. A total of 45MV RDT with hydrogen peroxide was shown to significantly delay the tumor growth for the mouse model and cell line investigated in this work. 45MV RDT with hydrogen peroxide group resulted in a decrease in tumor growth by 51.3 ± 4.1 % and 56.1 ± 5.1 % compared to the control group on 3 and 7 days post-treatment, respectively (P<0.001), and 43.4 ± 0.8 % and 50.9 ± 0.8 % compared to 45MV RT alone on 3 and 7 days post-treatment, respectively. Moreover, the enhancement effect of hydrogen peroxide on 45MV RDT was 2.2-4.7 times greater on 45MV RT alone (P<0.05). Hydrogen peroxide did not contribute to tumor growth when administered alone. A total of 45MV 5-ALA-mediated RDT with hydrogen peroxide resulted in the most significant tumor growth delay compared to the other groups. The catalytic effect of PpIX and hydrogen peroxide was observed in-vivo. These preliminary results demonstrate an effective cancer treatment modality.

Tumor Regression with 5-Aminolevulinic Acid (5-ALA)-Mediated Radiodynamic Therapy (RDT) Using Different Megavoltage Energies

5-aminolevulinic acid (5-ALA) accumulates in target tumor cells, where it is metabolized to a photosensitizer - protoporphyrin IX (PpIX). Cherenkov light induced by high-energy photon beams effectively activates the PpIX due to the Soret band. The activated photosensitizers lead to cellular toxicities to kill malignant tumor cells by converting surrounding tissue oxygens into singlet oxygens. Radiodynamic therapy (RDT) utilizes cellular damage caused by both radiation dose and activated photosensitizer. The emission of Cherenkov light was observed higher with higher energy irradiation in phantom and ex-vivo tissues. Therefore, using an in-vivo mouse model, this study aimed to investigate the efficacy and energy dependency of RDT combined with 5-ALA and different ranges of megavoltage photon irradiation. In order to investigate individual and synergistic effects of 5-ALA administration and radiation treatment, the tumors (n = 344) were randomized into eight groups: control (untreated), 5-ALA only, 6-, 15-, and 45-MV conventional radiation treatment (RT) only, 6-, 15-, and 45-MV RDT. 4 Gy in a single fraction was delivered to the tumors using three different energy photons for RT only and RDT groups. 5-ALA was systemically injected into 5-ALA only and RDT groups at 100 mg/kg by tail-vein 4 hours before irradiation for endogenous PpIX accumulation in the tumor. Tumor growth was measured using a 1.5 T MR scanner on the day of treatment (prior to the treatment), 3, 7, and 14 days post-treatment. Two-way repeated ANOVA with Bonferroni correction was used to compare each treatment group to determine the statistically significant difference in tumor growth. A total of 45 MV RDT resulted in the most significant decrease in tumor growth by 58.8 ± 3.4 %, 58.0 ± 3.0 %, and 55.0 ± 3.0 % compared to 5-ALA, 45 MV RT, and control group on 7 days post-treatment (P<0.001), respectively. Moreover, a synergistic effect of 45 MV RDT causes a 47.1-54.1 % additional decrease in tumor growth toward the effective treatment outcome. Compared to the different energies, 45 MV RDT resulted in a 52.2 ± 3.1 % and 19.7 ± 7.2 % decrease in tumor growth compared to 6 MV RDT and 15 MV RDT on 7 days post-treatment, respectively (P<0.001), whereas the conventional RT was not. Radiodynamic therapy using 5-ALA administration and 45MV photon beam irradiation resulted in the most significant tumor growth control. A photon energy dependency was observed in radiodynamic therapy. 45MV photon beams showed greater in activating PpIX, improving the synergistic effects of radiation dose and activated photosensitizer than the other energies. The preliminary results provide a foundation for new innovative treatment strategies that have the potential to improve cancer treatment.

A Molecular Approach to Characterize the Effects of Fluence, Fluence Rate and LET on Radiation Damage

Effects of fluence, fluence rate and LET on radiation damage are not resolved using traditional methods of measuring energy deposited by ionization events. The deficiency led to the use of empirical RBE factors in the clinical applications of particle therapy. The use of ionization dosimetry is similarly challenged when applied to development of radiation treatment at ultrahigh (FLASH) dose rate. This study reports a molecular method using plasmid DNA as a more comprehensive model for radiation dosimetry than ionization measurements. Aqueous solutions of purified supercoiled plasmid DNA, pUC19 (2686 bp), were prepared at different scavenging conditions and injected into 5x5x1 mm3 wells as detector elements. Irradiated samples were analyzed using base excision repair enzymes (Nth and Fpg) and gel electrophoresis to measure yields for DNA single and double strand breaks (SSB and DSB), and clustered lesions. The low LET characteristics of conventional radiation treatment was modeled using orthovoltage 150 kVp x-rays to deliver 2-110 Gy at 90 and 0.5 Gy/s. Higher LET irradiations in the range of 2 - 14 keV/μm were facilitated by measurements in the pristine Bragg peak region using synchrotron-produced 142.2 MeV protons to deliver dose at 2 - 160 Gy at 600 and 1 Gy/s. The DNA wells were inserted into a solid water equivalent phantom for proton irradiation. Only 4 wells could be positioned in the short Bragg peak region in water (∼ 2 cm). To alleviate the uncertainties due to rapidly varying dose and LET distributions, we innovated the use of a 3% water density (i.e., Styrofoam) medium to extend the Bragg peak region from 2 cm to 20 cm, enabling the placement of 20 well containers. Quantity and quality of molecular damage in the plasmid DNA model varies with fluence, fluence rate and LET of radiation. At high fluence (> 30 Gy) of low-LET radiations, the yields of DNA SSB and non-DSB clustered lesions depend on the fluence rate. These yields decrease by two times between ultrahigh and conventional dose rate irradiation. At a given fluence and fluence rate, the yields for the formation of DNA DSB and non-DSB clustered lesions increase linearly with LET. The low-density phantom allows significant (∼ 10 folds) increase in the number of sampling points and more accurate sample positioning at specific LET compared to water-equivalent phantom. Monte-Carlo track structure simulation of yields for different DNA lesions is being developed to model the molecular damage. In parallel, approaches to improve the sensitivity of the measurements to dose are being investigated. Our results suggest that a molecular-based approach can be used to differentiate the effects of fluence, fluence rate, and LET on radiation damage. The approach demonstrates the potential to improve on the modeling of radiation effects in biological systems than using measured ionization energy. Correlation of the molecular changes to biological outcome for in vitro and in vivo systems are under investigation.

Dosimetric and radiobiological comparison between conventional and hypofractionated breast treatment plans using the Halcyon system.

The objective of this research is to compare the efficacy of conventional and hypofractionated radiotherapy treatment plans for breast cancer patients, with a specific focus on the unique features of the Halcyon system. The study collected and analyzed dose volume histogram (DVH) data for two groups of treatment plans implemented using the Halcyon system. The first group consisted of 19 patients who received conventional fractionated (CF) treatment with a total dose of 50 Gy in 25 fractions, while the second group comprised 9 patients who received hypofractionated (HF) treatment with a total dose of 42.56 Gy in 16 fractions. The DVH data was used to calculate various parameters, including tumor control probability (TCP), normal tissue complication probability (NTCP), and equivalent uniform dose (EUD), using radiobiological models. The results indicated that the CF plan resulted in higher TCP but lower NTCP for the lungs compared to the HF plan. The EUD for the HF plan was approximately 49 Gy (114% of its total dose) while that for the CF plan was around 53 Gy (107% of its total dose). The analysis suggests that while the CF plan is better at controlling tumors, it is not as effective as the HF plan in minimizing side effects. Additionally, it is suggested that there may be an optimal configuration for the HF plan that can provide the same or higher EUD than the CF plan.

Comparison of Tumor Control and Skin Damage in a Mouse Model after Ultra-High Dose Rate Irradiation and Conventional Irradiation.

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose.

Suppression of NANOG Expression Reduces Drug Resistance of Cancer Stem Cells in Glioblastoma.

Glioblastoma (GBM) is an aggressive and incurable primary brain tumor that harbors therapy-resistant cancer stem cells (CSCs). Due to the limited effectiveness of conventional chemotherapies and radiation treatments against CSCs, there is a critical need for the development of innovative therapeutic approaches. Our previous research revealed the significant expression of embryonic stemness genes, NANOG and OCT4, in CSCs, suggesting their role in enhancing cancer-specific stemness and drug resistance. In our current study, we employed RNA interference (RNAi) to suppress the expression of these genes and observed an increased susceptibility of CSCs to the anticancer drug, temozolomide (TMZ). Suppression of NANOG expression induced cell cycle arrest in CSCs, specifically in the G0 phase, and it concomitantly decreased the expression of PDK1. Since PDK1 activates the PI3K/AKT pathway to promote cell proliferation and survival, our findings suggest that NANOG contributes to chemotherapy resistance in CSCs through PI3K/AKT pathway activation. Therefore, the combination of TMZ treatment with RNAi targeting NANOG holds promise as a therapeutic strategy for GBM.

Cancer Stem Cells in Tumours of the Central Nervous System in Children: A Comprehensive Review.

Cancer stem cells (CSCs) are a subgroup of cells found in various kinds of tumours with stem cell characteristics, such as self-renewal, induced differentiation, and tumourigenicity. The existence of CSCs is regarded as a major source of tumour recurrence, metastasis, and resistance to conventional chemotherapy and radiation treatment. Tumours of the central nervous system (CNS) are the most common solid tumours in children, which have many different types including highly malignant embryonal tumours and midline gliomas, and low-grade gliomas with favourable prognoses. Stem cells from the CNS tumours have been largely found and reported by researchers in the last decade and their roles in tumour biology have been deeply studied. However, the cross-talk of CSCs among different CNS tumour types and their clinical impacts have been rarely discussed. This article comprehensively reviews the achievements in research on CSCs in paediatric CNS tumours. Biological functions, diagnostic values, and therapeutic perspectives are reviewed in detail. Further investigations into CSCs are warranted to improve the clinical practice in treating children with CNS tumours.

Examining the Effect of Ionizing Radiations in Ion-Exchange Membranes of Interest in Biomedical Applications.

The possible effects of ionizing radiation on four commercial membranes, which are typically used as electrolytes in fuel cells supplying energy to a huge variety of medical implantable devices, were studied. These devices could obtain energy from the biological environment through a glucose fuel cell, which could be a good candidate to replace conventional batteries as a power source. In these applications, materials with high radiation stability for the fuel cell elements would be disabled. The polymeric membrane is one of the key elements in fuel cells. Membrane swelling properties are very important because they affect the fuel cell's performance. For this reason, the swelling behaviors of various samples of each membrane irradiated with different doses were analyzed. Each sample was irradiated with a typical dose of a conventional radiotherapy treatment, and the regular conditions of the biological working environment were simulated. The target was to examine the possible effect of the received radiation on the membranes. The results show that the ionizing radiation influenced their swelling properties, as well as that dimensional changes were dependent on the existence of reinforcement, be it internal or external, in the membrane structure.

Enhanced electron beam and X-ray beam therapy by applying nanoparticle heterojunctions: A Monte Carlo simulation

Cancer has become one of the major diseases that seriously threaten human health. In order to improve the therapeutic gain ratio (TGF) of conventional X-ray and electron beams, we studied the dose enhancement effect and secondary electrons emission of Au–Fe nanoparticle heterostructures by Monte Carlo method. Under the irradiation of 6 MeV photon and 6 MeV electron beams, the Au–Fe mixture has a dose enhancement effect. For this reason, we explored the secondary electrons production that leads to dose enhancement. For 6 MeV electron beam irradiation, Au–Fe nanoparticle heterojunctions have an higher electrons emission than Au and Fe nanoparticles. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au–Fe nanoparticles is the highest, with a maximum value of 0.00024. For 6 MV X-ray beam irradiation, Au nanoparticle and Au–Fe nanoparticle heterojunction have similar electrons emission, while Fe nanoparticle has the lowest one. When cubic, spherical and cylindrical heterogeneous structures are considered, the electron emission of the columnar Au–Fe nanoparticles is the highest, with a maximum value of 0.000118. This study contributes to improve the tumor-killing effect of conventional X-ray radiotherapy treatment and has guiding significance for the research of new nanoparticles.

Mitochondria-Targeted Nanosystem Enhances Radio-Radiodynamic-Chemodynamic Therapy on Triple Negative Breast Cancer.

Radiodynamic therapy (RDT), which produces 1O2 and other reactive oxygen species (ROS) in response to X-rays, can be used in conjunction with radiation therapy (RT) to drastically lower X-ray dosage and reduce radio resistance associated with conventional radiation treatment. However, radiation-radiodynamic therapy (RT-RDT) is still impotent in a hypoxic environment in solid tumors due to its oxygen-dependent nature. Chemodynamic therapy (CDT) can generate reactive oxygen species and O2 by decomposing H2O2 in hypoxic cells and thus potentiate RT-RDT to achieve synergy. Herein, we developed a multifunctional nanosystem, AuCu-Ce6-TPP (ACCT), for RT-RDT-CDT. Ce6 photosensitizers were conjugated to AuCu nanoparticles via Au-S bonds to realize radiodynamic sensitization. Cu can be oxidized by H2O2 and catalyze the degradation of H2O2 to generate •OH through the Fenton-like reaction to realize CDT. Meanwhile, the degradation byproduct oxygen can alleviate hypoxia while Au can consume glutathione to increase the oxidative stress. We then attached mercaptoethyl-triphenylphosphonium (TPP-SH) to the nanosystem, targeting ACCT to mitochondria (colocalization Pearson coefficient 0.98) to directly disrupt mitochondrial membranes and more efficiently induce apoptosis. We confirmed that ACCT efficiently generates 1O2 and •OH upon X-ray irradiation, resulting in strong anticancer efficacy in both normoxic and hypoxic 4T1 cells. The down-regulation of hypoxia-inducible factor 1α expression and reduction of intracellular H2O2 concentrations suggested that ACCT could significantly alleviate hypoxia in 4T1 cells. ACCT-enhanced RT-RDT-CDT can successfully shrink or remove tumors in radioresistant 4T1 tumor-bearing mice upon 4 Gy of X-ray irradiation. Our work thus presents a new strategy to treat radioresistant hypoxic tumors.

In vitro and in vivo Evaluation of Folic Acid Modified DOX-Loaded 32P-nHA Nanoparticles in Prostate Cancer Therapy.

Prostate cancer (PCa) ranks second in the incidence of all malignancies in male worldwide. The presence of multi-organ metastases and tumor heterogeneity often leads to unsatisfactory outcomes of conventional radiotherapy treatments. This study aimed to develop a novel folate-targeted nanohydroxyapatite (nHA) coupling to deliver adriamycin (Doxorubicin, DOX), 32P, and 99mTc simultaneously for the diagnosis and treatment of prostate-specific membrane antigen (PSMA) positive prostate cancer. The spherical nHA was prepared by the biomimetic method and characterized. Folic acid (FA) was coupled to nHA with polyethylene glycol (PEG), and the grafting ratio of PEG-nHA and FA-PEG-nHA was determined by the thermogravimetric analysis (TGA) method. In addition, 32P, 99mTc, and DOX were loaded on nHA by physisorption. And the labeling rate and stability of radionuclides were measured by a γ-counter. The loading and release of DOX at different pH were determined by the dialysis method. Targeting of FA-PEG-nHA loaded with 99mTc was verified by in vivo SPECT imaging. In vitro anti-tumor effect of 32P/DOX-FA-PEG-nHA was assessed with apoptosis assay. The safety of the nano-drugs was verified by histopathological analysis. The SEM images showed that the synthesized nHA was spherical with uniform particle size (average diameter of about 100nm). The grafting ratio is about 10% for PEG and about 20% for FA. The drug loading and the delayed release of DOX at different pH confirmed its long-term therapeutic ability. The labeling of 32P and 99mTc was stable and the labeling rate was great. SPECT showed that FA-PEG-nHA showed well in vivo tumor targeting and less damage to normal tissues. FA-targeted nHA loaded with 32P, 99mTc, and DOX may be a new diagnostic and therapeutic strategy for targeting PSMA-positive prostate cancer tumors, which may achieve better therapeutic results while circumventing the severe toxic side effects of conventional chemotherapeutic agents.

Does shortening the duration of radiotherapy treatment in breast cancer increase the risk of radiation pneumonia: A retrospective study.

Randomized studies evaluating hypofractionation and conventional fractionation radiotherapy treatments (RT) in patients with breast cancer have shown that hypofractionation achieves similar results to conventional fractionation in terms of survival and local control rates. It has also been shown that their long-term toxicities are similar. This study aimed to evaluate the effects of hypofractionated radiotherapy (H-RT) and conventional radiotherapy (C-RT) on lung toxicity and identify factors affecting this toxicity in patients with breast cancer. The study included 118 patients who underwent adjuvant RT following breast-conserving surgery (BCS). Out of these, 63 patients were assigned to receive C-RT, while the remaining 55 were assigned to receive H-RT. To clarify, we treated 63 patients with C-RT and 55 patients with H-RT. 60 patients were treated using 3-dimensional conformal radiotherapy (3DCRT) and 58 patients were treated using intensity modulated radiotherapy (IMRT). The patients were evaluated weekly for toxicity during radiotherapy (RT) treatment and were called every 3 months for routine controls after the treatment. The first control was performed 1 month after the treatment. Statistical analysis was performed using the SPSS20 program, and a P value of <.005 was considered statistically significant. The study found that the median age of the participants was 54.9 years and tomographic findings were observed in 70 patients. Radiological findings were detected at a median of 5 months after RT. The mean lung dose (MLD) on the treated breast side (referred to as ipsilateral lung or OAR) was 10.4 Gy for the entire group. Among patients who received 18 MV energy in RT, those with an area volume (V20) of the lung on the treated breast side >18.5%, those with a mean dose of the treated breast side lung (ipsilateral lung) >10.5 Gy, and those who received concurrent hormone therapy had significantly more tomographic findings. However, patients treated with YART had fewer tomographic findings. No symptomatic patients were observed during the follow-up period. Our findings show that the risk of lung toxicity is similar with H-RT and C-RT, and H-RT can be considered an effective and safe treatment option for breast cancer. The key factors affecting the development of lung toxicity were found to be the type of RT energy used, RT to the side breast, volume receiving 20 Gy in the side lung, side lung mean dose, and simultaneous hormonal therapy.

ALKBH1 contributes to renal cell carcinoma progression by reducing N6-methyladenine of GPR137.

Renal cell carcinoma (RCC) accounts for approximately 4% of all adult malignancies with high mortality worldwide. Although conventional chemotherapy and radiotherapy treatment has been applied for RCC in clinic, the mortality rate of patients is increasing each year, and patients with metastatic RCC are still suffering from poor prognosis. Thus, further investigation of the molecular mechanisms responsible for the development and progression of RCC is of particular importance. Total of 10 pairs of RCC tissues and adjacent nontumor tissues were collected for examination of ALKBH1 and GPR137 expression. The correlations between ALKBH1 and GPR137 expression in RCC patient were assessed by GEPIA online tool and were analyzed using auto best cutoff. The human RCC cell lines Caki-1, 786-O, ACHN, Osrc2, A498, and 769-P, were used for mechanistic investigation. Here, we report that the expression of AlkB homologue 1 (ALKBH1) is upregulated in RCC tissues, which is correlated with G-protein-coupled receptor 137 (GPR137) expression. The elevated expression of ALKBH1 is associated with RCC cell malignant characteristics, including cell proliferation and movement (migration and invasion). Mechanistic investigation further reveals that ALKBH1 reduces m6 A levels of GPR137 mRNA in RCC cells, which upregulates GPR137 mRNA levels, resulting in the increased GPR137 protein expression subsequently and the enhanced RCC cell biological actions consequently. In contrast, the suppression of GPR137 effectively alleviates the ALKBH1-induced malignancies of RCC cells. Our results indicate that ALKBH1-GPR137 axis might be used as a potential therapeutic target in RCC, contributing to finding new prognostic biomarkers for RCC at an early stage.

Abstract P6-05-55: Financial Toxicity Outcomes on a Phase I 5-fraction Partial Breast Irradiation Protocol for Early Stage Breast Cancer

Abstract Purpose/Objectives: Accelerated partial breast irradiation (APBI) has been shown to have both acceptable oncologic and cosmetic outcomes for early stage breast cancer following breast-conserving surgery (BCS). Given the demonstrated financial toxicity (FT) of conventional radiation treatments on breast cancer patients, we wanted to quantitatively assess the FT on patients treated with APBI in our phase I five fraction stereotactic APBI (S-PBI) trial, which could be generalized across APBI treatment regimens. Methods: A phase I dose escalation trial of S-PBI for early stage breast cancer following BCS was conducted. Women age &amp;gt; 18 years with in-situ or stage I-II (AJCC 7) invasive breast cancer &amp;lt; 3 cm following BCS with &amp;gt; 2 mm margins were treated with S-PBI in 5 fractions to a total dose of 30 to 40 Gy over 2.5 Gy increments (Clinical trials.gov ID NCT01162200). One month following completion of treatment, patients were asked to complete our novel “Patient Perspective Cost and Convenience of Care Questionnaire” developed at our institution. Results: Of 75 patients enrolled and treated, questionnaire data was available for 66 patients. Our trial encompassed a wide spectrum of annual household incomes, with 25.5% of patients (n=14/55) reporting income of less than $30k and 45.5% (n=25/55) reporting incomes of more than $80k. Educational status was also well represented with 53.1% completing at least some college (n= 34/64), 25% holding post graduate or professional degrees (n=16/64), and 21.9% patients reporting a high school equivalent or less (n=14/64). Overall 48.4% of patients (n=30/62) said that oncologic treatment did not present a financial burden; however, 29.0% (n=20/62) patients reported a somewhat to significant financial burden. Neither household income nor patient education status predicted perceived FT. Of the 6 patients (9.7%) who reported significant FT, 5 reported travelling at least 25 miles one way for treatment with 2 of these patient travelling over 175 miles. Half of the patients reported having private insurance for medication (49.2%, n=32/65), 33.8% had governmental coverage (n=22/65), 6.1% had both private and government coverage, 7.7% had no coverage (n=5/65), and 3.0% were unsure of their coverage (n=2/65). Only 1 of the 6 patients with significant FT had no coverage. Over half of the patients (54.2%, n=34/62) reported a co-pay during their treatment with a median out of pocket cost of $300 for treatment (range $10-10000, n=16). Over half of the patients were working full or part time during treatment (54.2%, n=32/59). All 26 patients that were working full time had to take time off work for treatment (median of 5 days, range 0.25 days – 10 days). Over a third of these patients (34.6%, n=9) had to use vacation time or unpaid time off. There was an additional patient who reported months off without pay. Additionally, 24.2% of patients (n=15/62) reported they had family or friends take time off work due to the patient’s treatment. Finally, patients were surveyed on the treatment related disruption to their daily activities and enjoyment of life rated on a scale 0-10, with 0 being no disruption, median values were 3 and 1, respectively. Patients also reported a median score of 10 (scale 0-10, 10 being most satisfied) on satisfaction with treatment time. Conclusions: In this cohort of patients, interestingly FT was significant primarily in the 10% of patients who traveled a significant distance for these treatments. However, despite this, and the fact that patients were undergoing cytotoxic cancer therapy, impressively, all patients were uniformly satisfied with treatment time (median score of 10), and most did not express significant disruption to their life. We plan to explore the impact of further reducing treatment fractions (with our single fraction S-PBI studies) on FT and quality of life in future studies. Citation Format: Ambrosia Simmons, David Sher, Dong W. Nathan Kim, Marilyn Leitch, Rachel Wooldridge, Sally Goudreau, Stephen Seiler, Sarah Neufeld, Maggie Stein, Kevin Albuquerque, Ann Spangler, John Heinzerling, Dan Gardwoood, Stella Stevenson, Chul Ahn, Chuxiong Ding, Robert Timmerman, Asal Rahimi. Financial Toxicity Outcomes on a Phase I 5-fraction Partial Breast Irradiation Protocol for Early Stage Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-55.

MRI-LINAC: A transformative technology in radiation oncology.

Advances in radiotherapy technologies have enabled more precise target guidance, improved treatment verification, and greater control and versatility in radiation delivery. Amongst the recent novel technologies, Magnetic Resonance Imaging (MRI) guided radiotherapy (MRgRT) may hold the greatest potential to improve the therapeutic gains of image-guided delivery of radiation dose. The ability of the MRI linear accelerator (LINAC) to image tumors and organs with on-table MRI, to manage organ motion and dose delivery in real-time, and to adapt the radiotherapy plan on the day of treatment while the patient is on the table are major advances relative to current conventional radiation treatments. These advanced techniques demand efficient coordination and communication between members of the treatment team. MRgRT could fundamentally transform the radiotherapy delivery process within radiation oncology centers through the reorganization of the patient and treatment team workflow process. However, the MRgRT technology currently is limited by accessibility due to the cost of capital investment and the time and personnel allocation needed for each fractional treatment and the unclear clinical benefit compared to conventional radiotherapy platforms. As the technology evolves and becomes more widely available, we present the case that MRgRT has the potential to become a widely utilized treatment platform and transform the radiation oncology treatment process just as earlier disruptive radiation therapy technologies have done.

A plan comparison study between rapid arc and conventional intensity-modulated radiation treatment plans in nasopharyngeal carcinoma patients.

Head and neck cancers are one of the common malignancies in Indian population. It's entity, nasopharyngeal carcinoma is among the aggressive malignancies with its location and spread near very critical structures. Thus requires a highly conformal radiotherapy delivery techniques. The aim of the study is to dosimetrically evaluate and to compare Intensity modulated radiation therapy (IMRT) plans and RAPID ARC plans for irradiation of nasopharyngeal carcinoma. A retrospective study is done on 10 nasopharyngeal carcinoma patients, who were treated with Radiotherapy at ATRCTRI Bikaner. Radiotherapy was delivered by IMRT technique (Total of 70 Gy in 33 fractions). Same patients are now planned on Rapid arc technique. Dosimetric comparison is done in terms of PTV coverage, OAR dose, conformity index, homogeneity index. PTV coverage is similar with both the plans. Homogeneity index is higher for IMRT plans 0.119+/- 0.020 compared to 0.104 +/- 0.018 for Rapid arc plans (statistically significant).The Rapid arc plans achieved slightly better conformity 1.018+/-0.09, whereas 1.105+/-0.12 for IMRT plans. Rapid arc achieved better results for OAR, statistically significant for Brainstem (54.4 +/-10.4 Gy for IMRT and 49.7+/-4.2 Gy for Rapid Arc, Lens (Left lens and Right lens received 10.55+/-5.8 Gy and 9.44+/-9.08 by IMRT and 6.12+/-6.1 Gy and 5.45+/-6.05 Gy for Rapid Arc), optic nerves (Right and Left optic nerve received 34.36 and 35.01 Gy for IMRT plans and 30.06 and 30.05 Gy for Rapid Arc plans. However the gains are statistically insignificant for spinal cord and vestibulocochlear nerve. No major difference found for Right and left parotid between both the arms. Rapid Arc is better technique compared to IMRT for Nasopharyngeal carcinoma treatment, that provides better dose conformity, more homogeneous coverage and OAR sparing. However study is retrospective and has lesser patients, thus requires prospective study with more number of patients along with comparison of clinical outcome.

Interdisciplinary Review of the Qualities of Glioblastoma Multiforme

Brain cancer, despite being one of the rarest forms of cancer, is one of the most substantially impactful cancers known to humankind. In this review, a comprehensive analysis of the multifaceted nature of brain cancer is conducted, with a particular focus placed on Glioblastoma Multiforme (GBM). Epidemiology, prevention measures, treatment techniques, and determinants of susceptibility are investigated to gain a deeper understanding of GBM. Additionally, the biophysical concepts used in Computed Tomography (CT) scanning for tumour detection are explored. Radiation therapy as a treatment modality for GBM is examined using Intensity Modulated Radiation Therapy (IMRT). Furthermore, the mechanism of action of Temozolomide, the prevailing chemotherapeutic drug used to hinder GBM growth by methylating target DNA sites, was also analyzed. Additionally, a cell survival curve outlining a traditional fractionation schedule of 2.21 Gy installments was created to effectively model a conventional radiation treatment plan. As a result, we are able to gauge the efficacy of such radiation treatments. In summation, we present a broad synopsis of the current strategies, insight, and approaches used to detect, image, and treat the malignant growth of GBM.

Does PARP Inhibition Sensitize Chondrosarcoma Cell Lines to Chemotherapy or Radiotherapy? Results From a Three-dimensional Spheroid Cell Model.

Chondrosarcomas are well known for their resistance to conventional chemotherapy and radiotherapy treatment regimens, which is particularly detrimental in patients who have unresectable tumors. Recently, inhibition of poly(ADP-ribose) polymerase (PARP) by talazoparib was shown to sensitize chondrosarcoma cell lines to chemotherapy (temozolomide) or radiotherapy, irrespective of isocitrate dehydrogenase (IDH) mutation status. Because two-dimensionally grown cell lines have limitations and may not accurately represent the clinical response to drug treatment, we aimed to use a more representative three-dimensional alginate spheroid chondrosarcoma model. It is important to test therapeutic agents in vitro before testing them in animals or humans; therefore, we aimed to determine the effectiveness of a PARP inhibitor in reducing the viability of chondrosarcoma spheroids. Using a more stringent, complex in vitro model refines future therapeutic options for further investigation in animal models, increasing efficiency, reducing unnecessary animal use, and saving time and cost. (1) Does talazoparib treatment slow or inhibit the growth of chondrosarcoma spheroids, and does an increased treatment duration change the drug's effect? (2) Does talazoparib work in synergy with temozolomide treatment to reduce the viability of chondrosarcoma spheroids? (3) Does talazoparib work in synergy with radiotherapy treatment to reduce the viability of chondrosarcoma spheroids? Three representative conventional chondrosarcoma cell lines (CH2879 [IDH wildtype], JJ012 [IDH1 mutant], and SW1353 [IDH2 mutant]) were cultured as alginate spheroids and treated with talazoparib (0.001 to 10 µM), temozolomide (0.01 to 100 µM), or combinations of these drugs for 3, 7, and 14 days, representing different stages of spheroid growth. The cell lines were selected to represent a variety of IDH mutation statuses and were previously validated in spheroid culturing. Temozolomide was chosen because of its previous success when combined with PARP inhibitors, dissimilar to other commonly used chemotherapies. The effect on spheroid viability was assessed using three cell viability assays. Additionally, spheroid count, morphology, proliferation, and apoptosis were assessed. The effect of talazoparib (5 to 10 nM) combined with ƴ-radiation applied using a 137 C source (0 to 6 Gy) was assessed as surviving fractions by counting the number of spheroids (three). The therapeutic synergy of low-concentration talazoparib (5 to 10 nM) with temozolomide or radiotherapy was determined by calculating Excess over Bliss scores. Talazoparib treatment reduced the spheroid viability of all three cell lines after 14 days (IC 50 ± SD of CH2879: 0.1 ± 0.03 µM, fold change: 220; JJ012: 12 ± 1.4 µM, fold change: 4.8; and SW1353: 1.0 ± 0.2 µM, fold change: 154), compared with 3-day treatments of mature spheroids. After 14 days of treatment, the Excess over Bliss scores for 100 µM temozolomide and talazoparib indicated synergistic efficacy (Excess over Bliss scores: CH2879 59% [lower 95% CI 52%], JJ012 18% [lower 95% CI 8%], and SW1353 55% [lower 95% CI 25%]) of this combination treatment. A stable synergistic effect of talazoparib and radiotherapy was present only in JJ012 spheroids at a 4Gƴ radiation dose (Excess over Bliss score: 22% [lower 95% CI 6%]). In our study, long-term PARP inhibition was more effective than short-term treatment, and only one of the three chondrosarcoma spheroid lines was sensitive to combined PARP inhibition and radiotherapy. These findings suggest subsequent animal studies should focus on long-term PARP inhibition, and temozolomide combined with talazoparib has a higher chance of success than combination with radiotherapy. Combination treatment of talazoparib and temozolomide was effective in reducing the viability of chondrosarcoma spheroids and spheroid growth, regardless of IDH mutation status, providing rationale to replicate this treatment combination in an animal chondrosarcoma model.