Low-dose Radiotherapy Research Articles

Low-Dose Radiation Therapy Impacts Microglial Inflammatory Response without Modulating Amyloid Load in Female TgF344-AD Rats.

Low-dose radiation therapy (LD-RT) has demonstrated in preclinical and clinical studies interesting properties in the perspective of targeting Alzheimer's disease (AD), including anti-amyloid and anti-inflammatory effects. Nevertheless, studies were highly heterogenous with respect to total doses, fractionation protocols, sex, age at the time of treatment and delay post treatment. Recently, we demonstrated that LD-RT reduced amyloid peptides and inflammatory markers in 9-month-old TgF344-AD (TgAD) males. As multiple studies demonstrated a sex effect in AD, we wanted to validate that LD-RT benefits are also observed in TgAD females analyzed at the same age. Females were bilaterally treated with 2 Gy×5 daily fractions, 2 Gy×5 weekly fractions, or 10 fractions of 1 Gy delivered twice a week. The effect of each treatment on amyloid load and inflammation was evaluated using immunohistology and biochemistry. A daily treatment did not affect amyloid and reduced only microglial-mediated inflammation markers, the opposite of the results obtained in our previous male study. Moreover, altered fractionations (2 Gy×5 weekly fractions or 10 fractions of 1 Gy delivered twice a week) did not influence the amyloid load or neuroinflammatory response in females. A daily treatment consequently appears to be the most efficient for AD. This study also shows that the anti-amyloid and anti-inflammatory response to LD-RT are, at least partly, two distinct mechanisms. It also emphasizes the necessity to assess the sex impact when evaluating responses in ongoing pilot clinical trials testing LD-RT against AD.

166 Radiation Therapy and IRreversible Electroporation (RTIRE) for Intermediate Risk Prostate Cancer

OBJECTIVES/GOALS: Prostate cancer treatment is associated with significant genitourinary side effects. There is a critical need for treatment with decreased morbidity. We report the development of a novel treatment paradigm combining irreversible electroporation and lower dose radiation to provide prostate cancer patients with a less morbid treatment. METHODS/STUDY POPULATION: Intermediate risk prostate cancer patients will undergo focal irreversible electroporation followed by low dose, whole gland radiation therapy. The primary endpoint is freedom from clinically significant cancer on biopsy at 12-month follow up. Secondary endpoints include safety profile, oncologic efficacy, effectiveness of RT and need for secondary treatment. This trial (NCT05345444) and currently actively recruiting patients after initial feasibility trial. Sample size is calculated to detect an increase in the proportion of patients who are cancer free at 1-year, from 0.80 to 0.95. An exact binomial test with a 10% one-sided significance level will have 94.3% power to detect the difference between the null and alternative hypothesis when the sample size is 42. RESULTS/ANTICIPATED RESULTS: This is a clinical trial in progress. DISCUSSION/SIGNIFICANCE: Combined irreversible electroporation (IRE) and a lower dose radiotherapy (RTIRE) may provide prostate cancer patients a treatment with minimal side effects.

Treatment Plan Optimization Following Laser Interstitial Thermal Therapy (LITT) for Recurrent Metastasis Using Cleveland Clinic Scaling System (CCSS)

INTRODUCTION: Laser interstitial thermal therapy (LITT) is an effective treatment option for recurrent metastasis (RM). However, determining the best treatment approach for each patient following LITT remains challenging due to mixed pathology and lack of consensus. The Cleveland Clinic Scaling System (CCSS) has been proposed to facilitate decision-making in patients with radiation necrosis (RN) and/or RM following LITT. METHODS: We conducted a retrospective analysis of data from 20 patients who underwent LITT for RN and/or RM between 2019 and 2022 at Cleveland Clinic. Based on the symptomatic RN and/or RM which was confirmed by MRI, LITT, and biopsy were carried out. Three samples were acquired from the superficial, middle, and deep parts of each patient’s lesion. The samples were then classified into three main categories: RN, RM, or a mixture of the two, based on pathological results. Patient management was guided by our novel CCSS. According to CCSS, patients with 100% RN underwent continued observation with a 3-month MRI, individuals with >20% tumor component received a low-dose or standard-dose radiation therapy ± CNS-penetrating targeted therapy, while those with <20% tumor underwent short-term observation with 6-week MRIs ± CNS-penetrating targeted therapy. RESULTS: Among the patients, 57% were females, lung cancer was the most prevalent malignancy (61.4%), and the median age was 52 years (ranging from 25 to 83 years). Our analysis demonstrated that the application of the CCSS protocol significantly improved treatment outcomes after LITT, resulting in 93% lesion control at the 10-month follow-up. CONCLUSIONS: The use of the CCSS protocol can refine the treatment plan for patients with RN and/or RM following LITT. This approach has the potential to enhance patient safety by improving tumor control and minimizing unnecessary radiation.

Significance of HIV status in cervical cancer patients receiving curative chemoradiation therapy, definitive radiation alone, or palliative radiation in Botswana.

Cervical cancer associated with human papillomavirus has the highest cancer incidence and mortality for women in Botswana because of a high HIV prevalence and limited screening. This study investigates the significance of HIV on the overall survival (OS) of patients with locally advanced cervical cancer by various treatment categories (curative chemoradiation, definitive radiation [RT] alone, or palliative RT alone). This study included patients diagnosed with cervical cancer between 2013 and 2020, prospectively enrolled in the Botswana Prospective Cancer Cohort. OS based on HIV status and completion of planned treatment regimen was estimated by the Kaplan-Meier method. Comparisons of 2-year OS by HIV status was performed by the log-rank test, univariate and multivariable Cox analyses adjusting for cancer stage, RT dose, number of chemotherapy cycles, and baseline hemoglobin levels. Of 1131 patients diagnosed with stage IB-IVB cervical cancer, 69.8% were women living with HIV (n=789). For patients receiving curative chemoradiation, HIV status was not significantly associated with OS in unadjusted (p=.987) and adjusted (p=.578) analyses. For RT only treatment and definitive (high-dose) RT alone, HIV status was significantly associated with OS in unadjusted analysis (HR=1.77, p=.002; HR=1.95, p=.014), but not in adjusted analysis (p=.227, p=.73). For patients receiving palliative (low-dose) RT, HIV status was not associated with OS in unadjusted (p=.835) or adjusted analysis (p=.359). In Botswana, a resource-limited setting, HIV status had no significant effect on 2-year OS in patients with cervical cancer with well-managed HIV receiving chemoradiation, RT alone, or palliative RT. This demonstrates that patients living with HIV receiving antiretroviral treatment can receive clinically appropriate treatment with no evidence that HIV may lead to poorer outcomes.

Abstract 697: Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell therapy

Abstract Background: Solid tumors remain a significant challenge in cancer therapy due to their resistance to conventional treatments. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising approach for treating solid tumors, but its effectiveness is often limited by the poor infiltration of CAR-T cells into the tumor microenvironment. Thus, enhancing a robust infiltration of chimeric antigen receptor T cells into solid tumors is essential for an effective antitumor response and therapeutic success. Methods: In this study, we investigated the combined effects of multiple doses of low-dose radiotherapy (LD-RT) and CAR T-cell therapy on tumor growth and survival using two models of NSG mice implanted with gastric carcinoma (GSU) or pancreatic adenocarcinoma (CAPAN-2) cells. The engineered CAR-T cells were designed to target guanyl cyclase-C (GCC) or mesothelin, respectively. Furthermore, our study employed atomic force microscopy (AFM) in a small cohort to investigate the impact of LD-RT and CAR-T cell therapy on tumor stiffness and plasticity. Results: The synergistic effect of combining low-dose radiotherapy (LD-RT) with T-cell therapy resulted in enhanced tumor control and prolonged survival in mice with tumors, surpassing the outcomes observed with either monotherapy alone. This combined treatment holds promise for improving responses in patients with solid tumors by leveraging LD-RT to enhance the intratumoral infiltration of effector T cells. Our findings suggest that the nanomechanical signature may be a potential biomarker for LD-RT combined CAR T cell therapy in solid tumors. Conclusions: Our findings substantially contribute to treating solid tumors using cell therapies, highlighting the potential for improved infiltration of adoptively transferred T cells following radiotherapy (RT), which can transform existing therapeutic strategies for solid tumors while minimizing toxicity. Citation Format: Nahum Puebla, Gitika Srivastava, Sara Nizzero, Natalie Wall Fowlkes, Hampartsoum Barsoumian, Yun Hu, Carola Leuschner, Thomas Riad, Marko Loparic, Marija Plodinec, James Welsh. Enhanced tumor control and survival in solid tumor models following combined low dose radiotherapy and T cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 697.

Melatonin administration in testicular damage caused by low and high-dose rate radiotherapy: An experimental study

ObjectiveThis study aimed to explore the radioprotective effect of melatonin against acute testicular injury caused by low- and high-dose-rate radiotherapy in rats. Materials and methodsA total of 40 12-week-old adult male rats were divided into 5 groups (n = 8). Group 1 comprised control rats who were not subjected to any procedures. A single dose of 8 Gy (Gy) radiotherapy was administered to the abdominopelvic regions of Group 2 (low-dose rate radiotherapy (LDRR) group) and Group 4 (high-dose rate radiotherapy (HDRR) group) rats at dose rates of 400 MU/min and 1400 MU/min, respectively. A single dose of 8 Gy radiotherapy was administered to Group 3 (low-dose rate radiotherapy + melatonin (LDRR + MEL) group) and Group 5 (high-dose rate radiotherapy + melatonin (HDRR + MEL) group) rats at dose rates of 400 MU/min and 1400 MU/min, respectively. Following this, 50 mg/kg/intraperitoneal melatonin was given to the rats 15 min before radiotherapy. The subjects were sacrificed 48 h after radiotherapy. Histological, immunohistochemical, immunofluorescence, and biochemical analyses of testicular tissue samples were performed. ResultsAs a result of comparing the FF and FFF radiotherapy groups with the control group, a statistically significant difference was observed in histopathological, biochemical, immunohistochemical and immunofluorescent parameters (p < 0.001). An improvement in these parameters was observed in the groups where melatonin was applied along with radiotherapy (p < 0.001). Additionally, no statistically significant difference was found between FF and FFF dose rates (p > 0.05). ConclusionNo significant difference was observed between these low- and high-dose rates of radiotherapy in terms of testicular damage and the effect of melatonin. Further, melatonin may be useful in preventing testicular damage caused by low- and high-dose rate radiotherapy.

Phosphate Coordination to Metal-Organic Layer Secondary Building Units Prolongs Drug Retention for Synergistic Chemoradiotherapy.

Chemoradiotherapy combines radiotherapy with concurrent chemotherapy to potentiate antitumor activity but exacerbates toxicities and causes debilitating side effects in cancer patients. Herein, we report the use of a nanoscale metal-organic layer (MOL) as a 2D nanoradiosensitizer and a reservoir for the slow release of chemotherapeutics to amplify the antitumor effects of radiotherapy. Coordination of phosphate-containing drugs to MOL secondary building units prolongs their intratumoral retention, allowing for continuous release of gemcitabine monophosphate (GMP) for effective localized chemotherapy. In the meantime, the MOL sensitizes cancer cells to X-ray irradiation and provides potent radiotherapeutic effects. GMP-loaded MOL (GMP/MOL) enhances cytotoxicity by 2-fold and improves radiotherapeutic effects over free GMP in vitro. In a colon cancer model, GMP/MOL retains GMP in tumors for more than four days and, when combined with low-dose radiotherapy, inhibits tumor growth by 98 %. The synergistic chemoradiotherapy enabled by GMP/MOL shows a cure rate of 50 %, improves survival, and ameliorates cancer-proliferation histological biomarkers.

Low-dose radiotherapy synergizes with iRGD-antiCD3-modified T cells by facilitating T cell infiltration

Background and purposePoor penetration of transferred T cells represents a critical factor impeding the development of adoptive cell therapy in solid tumors. We demonstrated that iRGD-antiCD3 modification promoted both T cell infiltration and activation in our previous work. Interest in low-dose radiotherapy has recently been renewed due to its immuno-stimulatory effects including T cell recruitment. This study aims to explore the synergistic effects between low-dose radiotherapy and iRGD-antiCD3-modified T cells. Materials and methodsFlow cytometry was performed to assess the expression of iRGD receptors and chemokines. T cell infiltration was evaluated by immunohistofluorescence and in vivo real-time fluorescence imaging and antitumor effects were investigated by in vivo bioluminescence imaging in the gastric cancer peritoneal metastasis mouse model. ResultsWe found that 2 Gy irradiation upregulated the expression of all three iRGD receptors and T-cell chemokines. The addition of 2 Gy low-dose irradiation boosted the accumulation and penetration of iRGD-antiCD3-modified T cells in peritoneal tumor nodules. Combining 2 Gy low-dose irradiation with iRGD-antiCD3-modified T cells significantly inhibited tumor growth and prolonged survival in the peritoneal metastasis mouse model with a favorable safety profile. ConclusionAltogether, we demonstrated that low-dose radiotherapy could improve the antitumor potency of iRGD-antiCD3-modified T cells by promoting T cell infiltration, providing a rationale for exploring low-dose radiotherapy in combination of other adoptive T cell therapies in solid tumors.

Fine-Tuning Low Dose Total Skin Electron Therapy for Optimal Management of Cutaneous T-Cell Lymphoma: A Comparative Analysis of Regimens

BackgroundLow-dose total skin electron beam therapy (TSEBT) is a proven treatment for managing cutaneous T-cell lymphoma (CTCL) and Sezary syndrome with skin burden. We performed a retrospective comparison of response rates and time to progression for patients receiving low-dose TSEBT based on dose per fractionation, total dose, and stage. MethodsOne hundred and ten patients with CTCL and Sezary syndrome were treated with 135 courses of low-dose (400-1500 cGy) TSEBT or STSEBT (subtotal skin electron therapy) at multiple centers of a single institution between 8/2003 and 6/2023. Patients were stratified according to total dose, dose per fraction, and stage. ResultsThe median follow-up was 301 days [IQR 141, 767]. The median age at treatment was 69.9 years (range 29.7 – 96.5). T-stage distribution was as follows: 3 (2.7%) T1, 74 (67.3%) T2, 16 (14.5%) T3, and 17 (15.5%) T4. AJCC 8th edition Stage distribution was as follows: 3 (2.7%) IA, 53 (48.2%) IB, 3 (2.7%) IIA, 16 (14.5%) IIB, 8 (7.3%) IIIA, 19 (17.3%) IVA, 8 (7.3%) IVB. There was no significant difference in disease distribution between patients treated with different fractionation schemes. The overall response rate was 89.6%. Forty-four courses (32.6%), 34 courses (25.2%), and 43 (31.9%) resulted in a complete, near-complete, and partial response, respectively. Fourteen courses (10.4%) resulted in no clinical response. For all patients, the median time to response was 43.0 days (IQR 23.0 – 70). The median time to skin progression for all patients was 107.5 days [IQR 67.8 – 233.5]. ConclusionsThis analysis demonstrated that CTCL patients treated with low-dose RT delivered over various fractionation schemes had similar overall response rates and median time to progression.

Technical feasibility of novel immunostimulatory low-dose radiation for polymetastatic disease with CBCT-based online adaptive and conventional approaches.

A workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon="conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated. Using retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes. All initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50% ), maximum dose at 2cm from PTV (D2cm ), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 =0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 =0.68, 0.63 and 0.69, respectively). This study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Efficacy of radiotherapy in combined treatment of hepatocellular carcinoma patients with portal vein tumor thrombus: a real-world study

Background and aimsHepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) has an extremely poor prognosis. A previous study proved that low-dose radiotherapy (RT) could prolong the prognosis of HCC patients with PVTT. This study aims to explore the sensitivity of PVTT to RT treatment.MethodsPatients were selected based on imaging diagnosis of HCC accompanied by PVTT and received combined treatment of radiotherapy, antiangiogenic drugs and immune checkpoint inhibitors, followed by hepatectomy or liver transplantation from January 2019 to August 2022. The efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) guidelines and pathological assessment. The sensitivity of tumor cells to the treatment was compared between the primary tumor (PT)and PVTT by analyzing their residual tumor and pathologic complete remission (PCR) incidence.ResultsData from 14 patients were collected in the study. After combined treatment, the size of PVTT decreased more significantly than that of the primary tumor in the imaging study (p < 0.05). The residual cancer was significantly more restrictive than that of primary tumor in paired patients based on pathological measurement (p = 0.008). The PCR incidence of the primary tumor (21.42%) was significantly lower (p = 0.008) than that of PVTT in the pathologic study (78.57%).ConclusionPVTT is more sensitive to radiotherapy treatment than the primary tumor in patients with HCC. This combination therapy might be an effective option as a downstaging therapy for patients with HCC with PVTT.

Low-dose radiation therapy for COVID-19

Background. Radiation therapy is one of the most effective treatments in patients with malignant neoplasms, it also plays an important role in the treatment of non-oncological di­seases. The coronavirus disease 2019 (COVID-19) pandemic has prompted a review of the long-forgotten idea of using low-dose radiation therapy (LDRT) in patients with lobar and interstitial pneumonia. Historically, from 1905 to the mid-1940s, LDRT was used to treat pneumonia, and evidence suggests that it might improve survival and provide rapid relief of respiratory symptoms. The purpose was to summarize current information about ­using low-dose radiation therapy in the treatment of patients with ­COVID-19. Materials and methods. A selection of publications was carried out, which covered information on the possibilities of using low-dose radiation therapy in the treatment of patients with COVID-19. At the first stage, a search was conducted for lite­rary sources using the keywords: COVID-19, low-dose radiation therapy. At the second stage, summaries of articles were studied and publications that did not meet the research criteria were excluded. At the third stage, the full texts of the selected articles were studied for compliance with the criteria for inclusion in the reference list and research relevance. Results. As of August 1, 2023, according to ClinicalTrials.gov, among 9,244 clinical trials associated with COVID-19, sixteen are currently being conduc­ted. They examine the effectiveness of LDRT in the treatment of patients with COVID-19 and already involve 1,038 patients. The largest number of studies is conducted in European countries. It has been shown that LDRT selectively attenuates oxidative stress to an inflammatory stimulus and inhibits the nitric oxide production pathway. This may contribute to its anti-inflammatory and vascular effects. At the same time, heme oxygenase 1 and other antioxidants are induced, they are mediated by Nrf2, which is the main regulator of endogenous antioxidant, anti-stress, analgesic reactions, and is also closely related to nicotinamide adenine dinucleotide phosphate and the metabolic pathway of pentose phosphate. Nrf2 may be critical for pain relief associated with edema formation and possibly plays a major role in the effects of LDRT, whereas direct functional effects of low-dose radiation on the autonomic nervous system and nociception are likely to be smaller. Conclusions. From 1905 to 1946, researchers published the results of more than 15 clinical studies on the effectiveness of radiotherapy for inflammatory lung diseases, which included more than 850 patients and demonstrated the high therapeutic effectiveness of radiation therapy in the indicated pathology. Today, there are 16 ongoing clinical trials in the world devoted to the study of LDRT effectiveness in the treatment of patients with COVID-19, in which 1,038 patients have already been involved. The risk of radiation-induced lung and breast cancer in a 25-year-old woman exposed to 1 Gy whole chest radiation may be as high as 5.9 and 5.5 %, respectively.

Ulcerating skin lesions from blastic plasmacytoid dendritic cell neoplasm responding to low-dose radiotherapy-acase report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is arare hematologic malignancy that can manifest with skin nodules and erythematous plaques. In most cases BPDCN progresses rapidly, causing multiple skin lesions and also affecting internal organs and bone marrow, warranting initiation of systemic therapies or hematopoietic stem cell transplantation (HCT). Although not curative, radiotherapy for isolated lesions might be indicated in case of (imminent) ulceration and large or symptomatic lesions. To this end, doses of 27.0-51.0 Gy have been reported. Here, we present the case of an 80-year-old male with BPDCN with multiple large, nodular, and ulcerating lesions of the thorax, abdomen, and face. Low-dose radiotherapy of 2 × 4.0 Gy was administered to several lesions, which resolved completely within 1week with only light residual hyperpigmentation of the skin in affected areas and reliably prevented further ulceration. Radiotoxicity was not reported. Therefore, low-dose radiotherapy can be an effective and low-key treatment in selected cases of BPDCN, especially in apalliative setting, with afavorable toxicity profile.

A light-controlled single-atom nanozyme hydrogels for glutathione depletion mediated low-dose radiotherapy

Due to the unique ability to mimic natural enzymes, single-atom nanoenzymes (SAE) have garnered significant attention and research in tumor therapy. However, their efficacy often faces challenges in terms of drug delivery methods, and the research regarding their applications in radiotherapy is scarce. Herein, we introduce a light-controlled SAE hydrogel platform (SH) for glutathione-depletion-mediated low-dose radiotherapy. The SH incorporates a Cu single-atom enzyme (CuSA), and upon irradiation with 1064 nm near-infrared light, the CuSA can convert light energy into heat, which in turn degrades the hydrogel, enabling the release of CuSA into tumor cells or tissues. The diffused CuSA not only can facilitate the conversion of H2O2 into hydroxyl radicals (•OH), but also can effectively depletes cellular glutathione. This leads to increased sensitivity of tumor cells to radiotherapy, resulting in enhanced cytotoxicity even at low doses. The animal study results further confirmed the good tumor-killing efficacy of this SH system. To the best of our knowledge, this stands as the pioneering report on leveraging a single-atom enzyme for GSH depletion-mediated low-dose radiotherapy.

Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma.

A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy. Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs. TLS+, TLSHigh, TLS+GC+ and CD8High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs. We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

Assembling Au8 clusters on surfaces of bifunctional nanoimmunomodulators for synergistically enhanced low dose radiotherapy of metastatic tumor

BackgroundRadiotherapy is one of the mainstays of cancer therapy and has been used for treating 65–75% of patients with solid tumors. However, radiotherapy of tumors has two limitations: high-dose X-rays damage adjacent normal tissue and tumor metastases cannot be prevented.ResultsTherefore, to overcome the two limitations of radiotherapy, a multifunctional core–shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer were fabricated by assembling Au8NCs on the surface of a bifunctional nanoimmunomodulator R837/BMS nanocore using nanoprecipitation followed by electrostatic assembly. Formed R837/BMS@Au8 NP composed of R837, BMS-1, and Au8 clusters. Au8NC can enhance X-ray absorption at the tumor site to reduce X-ray dose and releases a large number of tumor-associated antigens under X-ray irradiation. With the help of immune adjuvant R837, dendritic cells can effectively process and present tumor-associated antigens to activate effector T cells, meanwhile, a small-molecule PD-L1 inhibitor BMS-1 can block PD-1/PD-L1 pathway to reactivate cytotoxic T lymphocyte, resulting in a strong systemic antitumor immune response that is beneficial for limiting tumor metastasis. According to in vivo and in vitro experiments, radioimmunotherapy based on R837/BMS@Au8 nanoparticles can increase calreticulin expression on of cancer cells, reactive oxygen species generation, and DNA breakage and decrease colony formation. The results revealed that distant tumors were 78.2% inhibited depending on radioimmunotherapy of primary tumors. Therefore, the use of a novel radiosensitizer R837/BMS@Au8 NPs realizes low-dose radiotherapy combined with immunotherapy against advanced cancer.ConclusionIn conclusion, the multifunctional core–shell R837/BMS@Au8 nanoparticles as a novel radiosensitizer effectively limiting tumor metastasis and decrease X-ray dose to 1 Gy, providing an efective strategy for the construction of nanosystems with radiosensitizing function.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

The Correlation Between Low-Dose Radiotherapy Area of the Mediastinum and CD8+T Cells and the Efficacy of Radiotherapy for Non-Small Cell Lung Cancer.

Radiation therapy (RT) can cause changes in peripheral blood immune cells. The relationship between the efficacy of radiation therapy for non-small cell lung cancer (NSCLC) and immune cell changes and the study of how mediastinal radiation dose parameters affect immune cell changes is still unclear. This study aims to analyze the relationship between immune cell changes induced by radiotherapy and the efficacy of NSCLC radiotherapy, as well as the relationship between radiotherapy dose parameters and immune cell changes. We retrospectively analyzed the data of NSCLC patients receiving mediastinal radiation therapy from 2020 to 2022. Collect lymphocytes and circulating immune cells within one week before and after radiotherapy and collect the dose-volume parameters of the whole mediastinum in the patient's RT planning system. Analyze the changes in lymphocytes and radiotherapy effects after radiotherapy, and explore the relationship between radiotherapy dose parameters and immune cell changes. A total of 72 patients were enrolled. Compared with before radiotherapy, the proportion of CD3+T cells, CD8+T cells, and CD8/Treg in peripheral blood significantly increased after radiotherapy (P<0.05). The increase in CD8+T cells and CD8/Treg after radiotherapy was correlated with Objective response rate (ORR) (P<0.05). Based on binary logistic univariate and multivariate regression analysis, an increase in CD8+T cells after radiotherapy is an independent predictor of objective tumor response after radiotherapy (OR=12.71, 95% CI=3.64-44.64, P=0.01), and Volume of 200 cGy irradiation (V2) is an independent positive predictor of an increase in CD8+T lymphocyte ratio after radiotherapy (high group, OR=3.40, 95% CI=1.13-10.36, P=0.03). The increase in CD8+T cells after radiotherapy can positively predict the short-term efficacy of radiotherapy. Mediastinal low-dose radiation therapy can increase CD8+T cells, thereby improving the short-term efficacy of radiotherapy. These potentially related mechanisms are worth further verification and exploration.

Fine-Needle Aspiration Biopsy as a Diagnostic Modality for Orbital Adnexal Lymphoma

Introduction: The aim of this study was to evaluate fine-needle aspiration biopsy (FNAB) as a diagnostic tool for lymphoproliferative orbital lesions in light of recent improvements in cytomorphological and immunologic analyses. Method: Retrospective case series including all orbital FNABs with a lymphoproliferative outcome at Karolinska University Hospital, Stockholm, Sweden during the period 2005–2015. Results: Of the 38 patients included, 31 (82%) were conclusively diagnosed as having lymphoma according to the first FNAB. Disease in 20 patients (65%) could be subclassified. The diagnosis in 7 patients (18%) was either inconclusive, suggestive of lymphoma, or reactive lymphatic infiltrate. These 7 patients were re-investigated, and the initial suspected diagnosis of malignant lymphoma was confirmed in four. Two of the remaining 3 patients were initially diagnosed as having non-lymphoproliferative disease; however, this was later changed to a lymphoproliferative diagnosis following reinvestigation, while the results of both reFNAB and incisional biopsy were inconclusive in the third. Conclusion: In the majority of the 38 patients, a definitive diagnosis of lymphoma could be made based on FNAB alone, using cytomorphological and immunological workup, and subclassification was possible in 20 patients (65%). Primary low-grade malignant orbital lymphomas are traditionally treated with low-dose radiotherapy regardless of subtype, and incisional biopsy was not needed to initiate treatment. Our findings suggest that FNAB is a valid first option for the diagnosis of suspected orbital lymphomas due to the minimal risk of complications compared to incisional biopsy, and the fact that it can be performed as an outpatient procedure with no anesthesia.

Enhancing efficacy and safety of glioma treatment: optimization and evaluation of a novel dual-cavity capsule structure through orthogonal testing

Existing glioma treatments face challenges in simultaneously combining radiotherapy and chemotherapy while achieving long-term, stable continuous irradiation at low doses. To address this clinical challenge, two types of radiochemotherapy integrated dual-cavity capsules, single-capsule dual-cavity, and dual-capsule dual-cavity, were designed in this research. We employed finite element simulation and the Monte Carlo method to conduct stress-deformation simulation and dose analysis on the structure and manufacturing materials of the capsules. Based on these simulations, the structure of the dual-cavity capsule was optimized through orthogonal tests to obtain optimal results for tumor radiation therapy. Dose analysis experiments revealed that the dual-capsule dual-cavity structure exhibited improved irradiation effects on the lesion while minimizing damage to surrounding tissues and organs compared to the single-capsule dual-cavity structure. Stress-deformation simulation indicated that using polyetheretherketone as the capsule material enabled higher central dose rates and reduced deformation. Furthermore, the material’s ease of processing and low-cost characteristics facilitated the development of personalized and precise treatment approaches. The proposed capsule structure realizes the integrated combination of internal radiotherapy and internal chemotherapy, establishing a new mode of long-term stable local high-dose and peripheral low-dose radiation therapy. This scheme offers a novel treatment plan and advanced technical reserve for the integrated treatment of intracranial glioma radiotherapy and chemotherapy.