Combined Radiation Therapy Research Articles

DNAR-11. INHIBITION OF RAD52 ACTIVITY INDUCES DNA DAMAGE BY ACCUMULATING R-LOOPS IN DIFFUSE MIDLINE GLIOMA

Abstract Diffuse midline glioma (DMG) is one of the most devastating childhood cancers with a median survival of < 1year from diagnosis. There is a critical need for new therapeutics for improving treatment outcomes for DMG patients. We performed genome-wide CRISPR/Cas9 screening and identified RAD52 as a potential therapeutic target in DMG cells. RAD52 inhibition, using shRNA-mediated RAD52 depletion and treatment with RAD52 inhibitor, D-I03, suppressed DMG cell proliferation. Western blotting revealed that RAD52 inhibition increased DNA double-starand breaks (DSBs) marker γH2AX while it decreased repair markers BRCA1 and RAD51. Also, RAD52 inhibition causes a sustained level of phosphorylated RAD50 and γH2AX in irradiated DMG cells over 24 hours. Immunocytochemistry (ICC) of γH2AX and repair marker 53BP1 showed that RAD52 inhibition sustained DNA damage with high levels of γH2AX at 24 hours following radiation while the level of 53BPI was decreased, thereby inhibiting DNA DSB repair. DNA repair assay showed that RAD52 inhibition suppressed DNA DSB repair through a homologous recombination pathway. RNA sequencing showed that RAD52 inhibition downregulated genes associated with the DNA repair pathway. Importantly, RAD52 inhibition increased the radiosensitivity of DMG cells. To understand the mechanism of RAD52 inhibition on DNA damage, we performed dot plot assay and ICC of S9.6 which recognizes DNA-RNA hybrids (also known as R-loops) and found accumulation of R-loop formation in DMG cells treated with RAD52 inhibitor. In addition, RAD52 inhibition decreased the expression of RNA polymerase II. Finally, the combination therapy of RAD52 inhibitor and radiation inhibited tumor growth and increased survival of mice bearing DMG patient-derived xenografts, outperforming either monotherapy. Together, our results highlight that RAD52 inhibition induces DNA damage by accumulating R-loops, results in reducing DMG cell proliferation, while also increase DMG radiosensitivty, and providing a rationale for developing combination therapy with radiation for the treatment of DMG.

EXTH-82. TUMOR ORGANOID PREDICTED THERAPEUTIC RESPONSES TO NOVEL EPIGENETIC DRUGS VIA HIGH-THROUGHPUT SCREENING

Abstract INTRODUCTION The treatment choices for pediatric brain tumors are still very limited. Epigenetic therapy emerges as a promising option recently. The lack of in vitro models that represent tumors in vivo and can be scalable for large scale drug screening is major barrier. We have developed tumor organoids from patient-derived orthotopic xenograft and performed a multi-stage high throughput screening for single or combined epigenetic agents and radiation therapy in tumor organoids. METHOD Primary xenograft tumor cells were cultured in matrix and cancer stem cell culture medium in 384-well plates. Radiation sensitivity was examined at 5 different doses. Epigen40 (40 drugs/compounds) targeting various epigenetic modifications was used alone to identify agents with the most cell killing (4 doses for up to 19 days). The drugs that showed partial activity were combined with radiation (at 5 doses) to evaluate additive or synergistic effects. The anti-tumor efficacy of selected drug was then evaluated in vivo. RESULTS The conditions of organoid growth and screen variability were optimized. 7 tumor organoids including 4 glioblastomas and 3 medulloblastomas were successfully established and characterized. The different radio-sensitivities were observed among these models. 7 compounds (JIB-04, SP2509, AS-8351, GSK J4 HCI, 3-Deazaneplanocin A HCL, Chaetocin, TC-E-5003) were shown to effectively suppress organoid growth. Chaetocin, methyltransferase SUV39H inhibitor, demonstrated broadly active and highly potent inhibition across all 7 tested organoids. In addition, bioinformatic analysis identified a subset of epigenetic inhibitors combined with radiation that produced additive anti-tumor activities in vitro. Unfortunately, in vivo treatment of Chaetocin (0.25mg/kg) didn’t convey consistent anti-tumor effects as shown in vitro whereas a high risk of drug toxicity to the mice. CONCLUSION Tumor organoids were successfully developed from primary tumors. With our optimized assay using primary tumor organoids and a multi-stage high throughput drug screening, a novel panel of epigenetic drugs that effective alone or additively with radiation was identified.

Comparing Black and White Patients in Treatment of Advanced Prostate Cancer and Survival in an Equal Access Health System.

Racial disparities in prostate cancer treatment and survival in the U.S. have been attributed to differences in access to care and medical insurance. We aimed to compare treatment and survival of advanced prostate cancers between White and Black men in the equal access Military Health System (MHS). We accessed the MilCanEpi database to study a cohort of non-Hispanic White and Black men diagnosed with stage III or IV prostate cancer between 1998 and 2014 in the MHS. The racial groups were compared in receiving curative treatment of radical prostatectomy (RP) only, RP with (neo)adjuvant radiation or hormone therapy, radiation only, or combination radiation and hormone therapy; and overall survival using multivariable regression models. The study included 1476 White and 531 Black men. Overall, there was no racial difference in receiving any curative treatment (AOR = 0.85, 95% CI = 0.67, 1.08 for Black vs. White). By treatment type, Black men were statistically as likely to receive RP only (AOR = 0.87, 95% CI = 0.67, 1.14), radiation only (AOR = 0.81, 95% CI = 0.49, 1.34), or combination radiation and hormone therapy (AOR = 1.12, 95% CI = 0.71, 1.78) but statistically less likely to receive RP with (neo)adjuvant treatment (AOR = 0.56, 95% CI = 0.37, 0.86) relative to no curative treatment compared to White men. The difference in RP with (neo)adjuvant treatment was also statistically significant among patients with stage III tumors, but not stage IV. Survival was similar overall (AHR = 1.12, 95% CI = 0.88, 1.42 for Black vs. White) and when evaluated by tumor stage. In the MHS, the overall likelihood to receive any treatment for advanced prostate cancers and survival was similar between races, which might result from universal health care. Racial differences in receipt of RP with (neo)adjuvant treatment, especially for patients with stage III prostate cancer, may be related to factors other than access to care and warrants further research.

Risk score model for predicting mortality among patients with lung cancer.

To develop an accurate mortality risk predictive model among patients with lung cancer. The development cohort included 96,255 patients with lung cancer aged ≥19 years, who underwent a Korean National Health Insurance Service health check-up from 2005 to 2015. The validation cohort consisted of 18,432 patients (≥19 years) with lung cancer from another region. The outcome was all-cause mortality between January 1, 2005, and December 31, 2020. Approximately 60.5% of the development cohort died within a median follow-up period of 2.32 (0.72-5.00) years. Risk score was highest in participants aged ≥65 years, followed by those who underwent treatment, had a history of emergency room visits, and were current smokers. Participants treated by surgery had the lowest risk score, followed by combined surgery and chemotherapy, combined surgery and radiation therapy, women, and regular exercisers. The C statistic in the development and validation cohorts was 0.78 (95% confidence interval, 0.77-0.78) and 0.81 (95% confidence interval, 0.78-0.84), respectively. Advanced age, lung cancer stage, and treatment type were strong risk factors of mortality in lung cancer patients, while being a woman and exercise were preventive factors. These will aid in the prediction of mortality and management of lung cancer patients.

Efficacy of radiotherapy combined with hepatic arterial infusion chemotherapy, TKI and ICI for hepatocellular carcinoma with portal vein tumor thrombus: a retrospective cohort study.

This retrospective study was conducted to evaluate the effectiveness and safety of a new combination therapy of radiotherapy (RT), hepatic arterial infusion chemotherapy (HAIC), tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) for hepatocellular carcinoma (HCC) patients involving portal vein tumor thrombus (PVTT). A total of 71 HCC patients with PVTT were retrospectively analyzed: 45 patients were treated by 'HAIC + TKI + ICI' therapy and 26 patients by the new combination therapy. The primary outcomes were overall survival (OS), progression-free survival (PFS), and cumulative survival rate. The PFS in the 'New combination therapy' group was longer than that in the 'HAIC + TKI + ICI' group (HR 0.459, 95%CI 0.253-0.832; P = 0.008). Meanwhile, the OS in the 'New combination therapy' group was also longer than that in the 'HAIC + TKI + ICI' group (HR 0.420, 95%CI 0.198-0.894; P = 0.024). Compared with 'HAIC + TKI + ICI' group patients, the 'New combination therapy' group patients had higher 1-year PFS rate and 1-year OS rate (P = 0.029; P = 0.015). There was no significant difference in the incidence of adverse events between the two groups. The new combination therapy was an effective and safe non-surgical treatment for HCC patients with PVTT and could be considered a preferred therapy option.

PULSAR Effect: Revealing potential synergies in combined radiation therapy and immunotherapy via differential equations

PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) is a form of radiotherapy method where a patient is given a large dose or “pulse” of radiation a couple of weeks apart rather than daily small doses. The tumor response is then monitored to determine when the subsequent pulse should be given. Pre-clinical trials have shown better tumor response in mice that received immunotherapy along with pulses spaced 10 days apart. However, this was not the case when the pulses were 1 or 4 days apart. Therefore, a synergistic effect between immunotherapy and PULSAR is observed when the pulses are spaced out by a certain number of days. In our study, we aimed to develop a mathematical model that can capture the synergistic effect by considering a time-dependent weight function that takes into account the spacing between pulses. We determined feasible parameters by fitting murine tumor volume data of six treatment groups via simulated annealing algorithm. Applying these parameters to the model we simulated 4000 trials with varying sequencing of pulses. These simulations indicated that if pulses were spaced apart by at least 9 days the tumor volume was about 200 mm3 to 250 mm3 smaller when treated with PULSAR combined with immunotherapy. We successfully demonstrate that our model is simple to implement and can generate tumor volume data that is consistent with the pre-clinical trial data. Our model has the potential to aid in the development of clinical trials of PULSAR therapy.

AI-derived Tumor Volume from Multiparametric MRI and Outcomes in Localized Prostate Cancer.

Background An artificial intelligence (AI)-based method for measuring intraprostatic tumor volume based on data from MRI may provide prognostic information. Purpose To evaluate whether the total volume of intraprostatic tumor from AI-generated segmentations (VAI) provides independent prognostic information in patients with localized prostate cancer treated with radiation therapy (RT) or radical prostatectomy (RP). Materials and Methods For this retrospective, single-center study (January 2021 to August 2023), patients with cT1-3N0M0 prostate cancer who underwent MRI and were treated with RT or RP were identified. Patients who underwent RT were randomly divided into cross-validation and test RT groups. An AI segmentation algorithm was trained to delineate Prostate Imaging Reporting and Data System (PI-RADS) 3-5 lesions in the cross-validation RT group before providing segmentations for the test RT and RP groups. Cox regression models were used to evaluate the association between VAI and time to metastasis and adjusted for clinical and radiologic factors for combined RT (ie, cross-validation RT and test RT) and RP groups. Areas under the receiver operating characteristic curve (AUCs) were calculated for VAI and National Comprehensive Cancer Network (NCCN) risk categorization for prediction of 5-year metastasis (RP group) and 7-year metastasis (combined RT group). Results Overall, 732 patients were included (combined RT group, 438 patients; RP group, 294 patients). Median ages were 68 years (IQR, 62-73 years) and 61 years (IQR, 56-66 years) for the combined RT group and the RP group, respectively. VAI was associated with metastasis in the combined RT group (median follow-up, 6.9 years; adjusted hazard ratio [AHR], 1.09 per milliliter increase; 95% CI: 1.04, 1.15; P = .001) and the RP group (median follow-up, 5.5 years; AHR, 1.22; 95% CI: 1.08, 1.39; P = .001). AUCs for 7-year metastasis for the combined RT group for VAI and NCCN risk category were 0.84 (95% CI: 0.74, 0.94) and 0.74 (95% CI: 0.80, 0.98), respectively (P = .02). Five-year AUCs for the RP group for VAI and NCCN risk category were 0.89 (95% CI: 0.80, 0.98) and 0.79 (95% CI: 0.64, 0.94), respectively (P = .25). Conclusion The volume of AI-segmented lesions was an independent, prognostic factor for localized prostate cancer. © RSNA, 2024 Supplemental material is available for this article.

IL15/IL15Rα complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to induce expansion of progenitor TCF1+ CD8 T cells.

This work seeks to understand whether IL15-incorporating treatments improve response to radiotherapy and uncover mechanistic rationale for overcoming resistance to IL15 agonism using novel therapeutic combinations. Orthotopic tumor models of PDAC were used to determine response to treatment. IL15-/- and Rag1-/- mouse models were employed to determine dependence on IL15 and CTLs, respectively. Flow cytometry was used to assess immune cell frequency and activation state. Phospho-proteomic analyses were used to characterize intracellular signaling pathways. We show that the combination of radiation therapy (RT) and an IL15/IL15Ra fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response is elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- mice, we demonstrate that response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT + PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rβγ binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed significant upregulation of activation and functionality in CD8 T cells treated with RT + PD1-IL2v. Finally, we show the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation in the absence of functional IL15 signaling. Our results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rβ signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.

TLR7 agonist, DSP-0509, with radiation combination therapy enhances anti-tumor activity and modulates T cell dependent immune activation

BackgroundTLR7 is a key player in the antiviral immunity. TLR7 signaling activates antigen-presenting cells including DCs and macrophages. This activation results in the adaptive immunity including T cells and B cells. Therefore, TLR7 is an important molecule of the immune system. Based on these observations, TLR7 agonists considered to become a therapy weaponize the immune system against cancer. Radiation therapy (RT) is one of the standard cancer therapies and is reported to modulate the tumor immune response. In this study, we aimed to investigate the anti-tumor activity in combination of TLR7 agonist, DSP-0509, with RT and underlying mechanism.ResultWe showed that anti-tumor activity is enhanced by combining RT with the TLR7 agonist DSP-0509 in the CT26, LM8, and 4T1 inoculated mice models. We found that once- weekly (q1w) dosing of DSP-0509 rather than biweekly (q2w) dosing is needed to achieve superior anti-tumor activities in CT26 model. Spleen cells from the mice in RT/DSP-0509 combination treatment group showed increased tumor lytic activity, inversely correlated with tumor volume, as measured by the chromium-release cytotoxicity assay. We also found the level of cytotoxic T lymphocytes (CTLs) increased in the spleens of completely cured mice. When the mice completely cured by combination therapy were re-challenged with CT26 cells, all mice rejected CT26 cells but accepted Renca cells. This rejection was not observed with CD8 depletion. Furthermore, levels of splenic effector memory CD8 T cells were increased in the combination therapy group. To explore the factors responsible for complete cure by combination therapy, we analyzed peripheral blood leukocytes (PBLs) mRNA from completely cured mice. We found that Havcr2low, Cd274low, Cd80high, and Il6low were a predictive signature for the complete response to combination therapy. An analysis of tumor-derived mRNA showed that combination of RT and DSP-0509 strongly increased the expression of anti-tumor effector molecules including Gzmb and Il12.ConclusionThese data suggest that TLR7 agonist, DSP-0509, can be a promising concomitant when used in combination with RT by upregulating CTLs activity and gene expression of effector molecules. This combination can be an expecting new radio-immunotherapeutic strategy in clinical trials.

Hypofractionated radiation therapy combined with androgen deprivation therapy for clinically node-positive prostate cancer.

This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer. Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2-3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded. The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4-5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates. This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT.

DIPG-73. FOCUSED ULTRASOUND FOR TREATMENT OF CHILDREN DIAGNOSED WITH DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Diffuse midline glioma (DMG) is a highly aggressive and fatal brain tumor that predominantly impacts children and young adults. The infiltrative pattern and rapid growth characteristics of DMG causes a significant challenge in finding an effective treatment. Additionally, the blood-brain barrier (BBB) poses a significant challenge by restricting the passage of therapeutic drugs to tumor bed. Currently the established standard of care is radiotherapy (RT), which is transitory. Thus there is a need for improved treatment options. OBJECTIVE Focused ultrasound (FUS) is an advancing non-invasive technology that has been used to open BBB and enhance drug delivery. We hypothesize that a combination therapy of FUS with pharmacological agents will be an effective and non-invasive treatment option for children diagnosed with DMG. METHOD Syngeneic DMG murine models were used to study the combination therapy of FUS with ONC201, FUS with anti-PD1 and FUS with RT. FUS mediated BBB opening was monitored with contrast-enhanced T1-weighted MRI. FUS-mediated drug delivery was validated with western blot, assessment of ROS, and optical label imaging. Kaplan Meier analysis was used to assess survival benefits. Single cell RNA-sequencing (scRNA-Seq) analysis is being done to assess the treatment effects of FUS and RT combination therapy. RESULTS/CONCLUSION We found that FUS and ONC201 combination therapy resulted in a decrease in NDUFA12 protein (a biomarker of ONC201 response) and an increase in ROS production compared to ONC201 monotherapy. For FUS and anti-PD1 combination therapy, an increased anti-PD1 delivery to the brainstem was detected. The overall survival of mice treated with FUS and anti-PD1 combination therapy increased when compared to anti-PD1 alone. Our preliminary scRNA-Seq analysis showed that combination therapy of FUS and RT induces innate immune response compared to the untreated group. Combination therapy with focused ultrasound shows a promising outcome by increasing the efficacy of therapeutic drugs and immunotherapy.

DIPG-41. CONVECTION ENHANCED DELIVERY-MEDIATED RADIOSENSITIZATION FOR DIFFUSE MIDLINE GLIOMA

Abstract BACKGROUND Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. The only approved standard of care is radiation therapy (RT). Studies examining the role of other systemic agents have failed to demonstrate a survival benefit, partially due to tumor extension to areas of the brain where the blood-brain barrier (BBB) remains intact. As our laboratory has recently determined active NAD(P)H Quinone Dehydrogenase 1 (NQO1) expression in patient-derived DMG tumor samples, we sought to investigate NQO1 bioactivatable agent Napabucasin to augment reactive oxygen species (ROS) production and overcome radioresistance in DMG. Furthermore, we explore the safety and feasibility of convection-enhanced deliver (CED) to overcome limitations of the BBB. METHODS Using two DMG cell lines, we performed clonogenic survival assays with increasing doses of RT with and without Napabucasin. We then created subcutaneous xenograft mouse models, treating with (1) vehicle control, (2) Napabucasin, (3) 2 Gy of RT daily, or (4) combination treatment with RT and Napabucasin. Using a syngeneic orthotopic DMG mouse model, we implanted 7-day osmotic infusion pumps containing either vehicle control or 80uM Napabucasin. Mice then underwent a second randomization with or without daily RT for 5 days. RESULTS We identified a robust radiosensitizing effect with Napabucasin using in vitro clonogenic survival assays. In subcutaneous flank models, combination treatment led to a statistically significant smaller tumor volume post-treatment completion when compared to any monotherapy. In our syngeneic orthotopic DMG mouse model, RT after CED pump implantation in the brainstem did not lead to significant morbidity or mortality. Combination RT and CED of Napabucasin led to a significant survival benefit when compared to monotherapy. CONCLUSIONS In this study, we show Napabucasin as a promising radiosensitizer in DMG. Furthermore, this is the first preclinical study showing safety/efficacy of CED with concurrent RT in DMG.

TRLS-03. A PHASE 1/2 STUDY ASSESSING SAFETY AND PHARMACOKINETICS OF CEMIPLIMAB IN PEDIATRIC PATIENTS WITH RELAPSED OR REFRACTORY SOLID OR CENTRAL-NERVOUS-SYSTEM TUMORS AND SAFETY AND EFFICACY OF CEMIPLIMAB IN COMBINATION WITH RADIOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA, NEWLY DIAGNOSED HIGH-GRADE GLIOMA, OR RECURRENT HIGH-GRADE GLIOMA

Abstract BACKGROUND We investigated, for the first time, combination PD-1 inhibition (cemiplimab) and radiation therapy (RT) followed by cemiplimab monotherapy in children with solid tumors, diffuse intrinsic pontine glioma (DIPG) and high-grade glioma (HGG). METHODS We conducted a multicenter study through the Pediatric Neuro-Oncology Consortium. Phase 1 established the safety/pharmacokinetics of cemiplimab monotherapy in children (<18 years) with recurrent solid and central-nervous-system (CNS) tumors. Phase 2 evaluated cemiplimab/RT in children and young adults (3-25 years) with newly diagnosed (nd) DIPG, ndHGG or recurrent HGG (rHGG). Patients with ndDIPG and ndHGG were randomized to hypofractionated RT (hfRT) or conventionally fractionated RT (cRT). Primary endpoints included overall survival at 12 months (OS12) for ndDIPG and rHGG and progression-free survival at 12 months (PFS12) for ndHGG. Correlates included quality-of-life, circulating tumor DNA (ctDNA), immunogenicity, and PD-1 pathway components. RESULTS 25 patients (solid tumors, n=8; CNS tumors, n=17) were treated in phase 1; serum drug concentrations were comparable to adults. 32 patients were treated in phase 2. OS12 was 33.3% for ndDIPG treated with cemiplimab/hfRT (n=6), 0.0% for ndDIPG with cemiplimab/cRT (n=5), and 31.3% for rHGG (n=9). PFS12 was not estimable for ndHGG treated with cemiplimab/hfRT (n=5) and 20.0% for ndHGG treated with cemiplimab/cRT (n=7). 20 patients (35.1%) had grade 3/4 treatment-related AEs (TRAEs) and 13 (22.8%) had serious TRAEs. The most frequent grade 3/4 TRAE was decreased lymphocyte count (n=4 [7.0%]). 12 patients (21.1%) demonstrated treatment-emergent pseudo-progression, 2 (3.5%) grade 3/4. The most frequent serious TRAE was pseudo-progression (n=3 [5.3%]). CONCLUSIONS Cemiplimab/RT did not demonstrate an improvement in OS (ndDIPG and rHGG) or PFS (ndHGG), leading to early stopping for futility. However, the combination was tolerable, demonstrated similar outcomes across RT schedules, and showed similar exposure in serum compared to adults. Biologic and clinical correlate analyses are underway.

Outcomes for Patients With Head and Neck Sarcoma Treated Curatively With Radiation Therapy and Surgery

Soft tissue sarcomas (STSs) of the head and neck (H&N) are rare malignancies that are challenging to manage. We sought to describe the outcomes of patients treated with curative intent using combined surgery and radiation therapy (RT) for H&N STS. We performed a single-institution retrospective review of patients with nonmetastatic STS of the H&N who were treated from 1968 to 2020. The Kaplan-Meier method was used to estimate disease-specific survival (DSS) and local control (LC). Multivariable analyses (MVAs) were conducted using Cox proportional hazards model. One hundred ninety-two patients had a median follow-up of 82 months. Tumors arose in the neck (n = 50, 26%), paranasal sinuses (n = 36, 19%), or face (n = 23, 12%). Most patients were treated with postoperative RT (n = 134, 70%). Postoperative RT doses were higher (median, 60 Gy; preoperative dose, 50 Gy; P < .001). Treatment sequence was not associated with LC (preoperative RT, 78% [63%-88%]; postoperative RT, 75% [66%-82%]; P = .48). On MVA, positive/uncertain margin was the only variable associated with LC (hazard ratio [HR], 2.54; 95% CI, 1.34-4.82; P = .004). LC was significant on MVA (HR, 4.48; 95% CI, 2.62-7.67; P < .001) for DSS. Patients who received postoperative RT were less likely to experience a major wound complication (7.5% vs 22.4%; HR, 0.28; 95% CI, 0.11-0.68; P = .005). There was no difference in the rate of late toxicities between patients who received preoperative or postoperative RT. H&N STS continues to have relatively poorer LC than STS of the trunk or extremities. We found LC to be associated with DSS. Timing of RT did not impact oncologic or long-term toxicity outcomes; however, preoperative RT did increase the chance of developing a major wound complication.

Recent Advances in the Surgical Management of Radiation-Induced Fractures following Soft Tissue Sarcomas.

Background: Post-radiation fractures are a significant complication of cancer treatment, often being challenging to manage and impacting patients' quality of life. This study systematically reviews the literature on fractures in irradiated bones, focusing on risk factors, treatment modalities, and prevention strategies. Factors increasing fracture risk include exposure to high doses of radiation of at least 50 Gy, female gender, menopausal age, and periosteal stripping. Additionally further risk factors are the size of the original tumor and osteoporosis. Methods: A search of PubMed yielded 541 articles, with 4 were ultimately included in the review. These retrospective studies focused on patients undergoing Combined Limb-Sparing Surgery and Radiation Therapy for soft tissue sarcoma. Results: Results show post-radiation fractures affect approximately 4% of patients, with the femur being the most frequently affected site. Intramedullary nailing emerges as the gold standard treatment, with prosthetic replacement or megaprostheses used in the metaepiphyseal region and as salvage procedures. Non-union and infection remain formidable complications. Conclusions: This study highlights the importance of prophylactic nailing in fracture prevention and the efficacy of free vascularized fibular flaps to achieve bone union during revision surgeries. Limited case availability and patient follow-up hinder comprehensive studies, impacting treatment outcomes.

Combination of proton- or X-irradiation with anti-PDL1 immunotherapy in two murine oral cancers

Combining radiation therapy with immunotherapy is a strategy to improve both treatments. The purpose of this study was to compare responses for two syngeneic head and neck cancer (HNC) tumor models in mice following X-ray or proton irradiation with or without immune checkpoint inhibition (ICI). MOC1 (immunogenic) and MOC2 (less immunogenic) tumors were inoculated in the right hind leg of each mouse (C57BL/6J, n = 398). Mice were injected with anti-PDL1 (10 mg/kg, twice weekly for 2 weeks), and tumors were treated with single-dose irradiation (5–30 Gy) with X-rays or protons. MOC2 tumors grew faster and were more radioresistant than MOC1 tumors, and all mice with MOC2 tumors developed metastases. Irradiation reduced the tumor volume in a dose-dependent manner. ICI alone reduced the tumor volume for MOC1 with 20% compared to controls, while no reduction was seen for MOC2. For MOC1, there was a clear treatment synergy when combining irradiation with ICI for radiation doses above 5 Gy and there was a tendency for X-rays being slightly more biologically effective compared to protons. For MOC2, there was a tendency of protons being more effective than X-rays, but both radiation types showed a small synergy when combined with ICI. Although the responses and magnitudes of the therapeutic effect varied, the optimal radiation dose for maximal synergy appeared to be in the order of 10–15 Gy, regardless of tumor model.

A review of type III GEJ adenocarcinoma and the importance of early detection of gastric cancer

Gastric adenocarcinoma is the most common type of gastric cancer in the United States. Multiple factors can predispose a patient to develop such a malignancy, including having a history of Helicobacter pylori infection, tobacco use, alcohol use, specific genetic mutations, and being of Asian or Hispanic descent. Surgery is currently the only curative treatment for localized disease. With metastatic disease, the rate of survival decreases significantly, and most often, the only treatment option is palliative chemotherapy with or without combination radiation therapy. In the case of a 58-year-old man diagnosed with a gastroesophageal junction type III gastric adenocarcinoma that extended into the distal esophagus, what was thought to be a resectable tumor had already invaded vital neighboring organs, therefore, we were unable to eradicate the disease from this patient.

Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells

ABSTRACT Background The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. It is necessary to identify natural compounds that can complement combination radiation therapy. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear. Study Design and Methods The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. An NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo. Results Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. Downregulation of claspin was confirmed in arenobufagin-induced apoptosis. Combined treatment with arenobufagin and mitogen-activated protein kinase inhibitors demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo. Conclusion Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may have clinical utility in treating NPC due to its suppression of claspin and inhibition of the JNK pathway.

Longitudinal Assessment of Tumor-Infiltrating Lymphocytes in Primary Breast Cancer Following Neoadjuvant Radiation Therapy

Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials. We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes. Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART. This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials.

Hormonal Therapy and Radiation Therapy in Prostate Cancer: 5-Year Outcomes From a Trial Evaluating Combined Androgen Blockade With 5-Alpha Reductase Inhibitors as an Alternative to Gonadotropin Releasing Hormone Agonists

BackgroundWe previously reported that for men undergoing combined androgen deprivation therapy (ADT) and radiation therapy (RT) for prostate cancer, substitution of LHRH-agonists with 5-α- reductase inhibitors (5-ARIs) led to improved preservation of 6-month hormonal quality of life (hQOL). With longer term follow-up, we evaluated disease control. MethodsIn this non-randomized trial, men with unfavorable intermediate or high-risk prostate cancer, aged ≥70 years or with Charlson Comorbidity Index ≥2, were treated with RT (78-79.2 Gy in 39-44 fractions) and either oral ADT (oADT; 5-ARI with antiandrogen) or standard of care ADT (SOC; leuprolide with antiandrogen) for up to 28 months. The primary endpoint was EPIC hQOL; secondary endpoints included biochemical control and survival as well as changes in cholesterol and hemoglobin levels. ResultsBetween 2011 and 2018, 70 men were enrolled (40 in oADT; 30 in SOC). Median follow-up was 65 months [IQR 36-94]. Five-year freedom from biochemical failure for oADT and SOC was 89% versus 86%, disease free survival was 62% versus 69%, cancer-specific survival was 100% versus 96%, and overall survival was 70% versus 81% (all P>.1). Testosterone (2 mo through 3 yr) and hemoglobin levels (2 mo through 2 yr) were higher, and cholesterol levels (1 yr) were lower in the oADT groups (all P < .05). ConclusionsIn this non-randomized study, men treated with combined RT and oADT had better preservation of hQOL and comparable 5-year disease outcomes to men treated with SOC. Eugonadal testosterone with this approach may yield measurable benefits in cholesterol and hemoglobin levels.