Target For Radiotherapy Research Articles

Variation in Left Anterior Descending Coronary Artery Accumulated Dose Estimates during Breast Cancer Radiotherapy

Left anterior descending (LAD) coronary artery RT dose has been associated with the risk of coronary ischemic events in patients with breast cancer treated with radiotherapy (RT). However, consensus dose constraints commonly utilize mean heart dose, which has been shown to be an inadequate surrogate for LAD dose. Given the LAD is adjacent to the steep dose gradients of the left breast/chest wall, we hypothesize that variations in patient positioning or depth of breath hold may contribute to significant deviations in daily LAD dose exposure compared to predicted. Our objective was to investigate variations in accumulated LAD dose in patients with left-sided breast cancer treated with RT. Retrospective analysis of 10 consecutive patients with left-sided breast cancer treated between 2019-2022 with volumetric modulated arc therapy (VMAT) in the supine position. RT was delivered using daily cone beam computed tomography (CBCT) image guidance with deep-inspiratory breath hold technique and an optical surface monitoring system. Daily CBCT scans were individually registered to each planning CT based on daily positional changes. The LAD was manually segmented and transformed to each CBCT. Daily fractional dose was calculated (mean, volume receiving 15 Gy [V15 Gy], V30 Gy, and max) and summed to produce an accumulated dose which was compared to the predicted dose. Significant deviations in accumulated dose were defined as at least ±15% from predicted. The RT targets included breast/chest wall only (n = 1), supraclavicular nodes (n = 8), and/or internal mammary chain (n = 5). All plans were prescribed to 50 Gy in 25 fractions. The median predicted mean heart dose was 5.1 Gy. Overall, there were no significant differences between the median predicted vs. accumulated LAD doses: mean 10.4 vs. 10.2 Gy, V15 Gy 21% vs. 25%, V30 Gy 0% vs. 1%, max 24.5 vs 25.7 Gy (all p>.05). However, there was a subset of patients (n = 5, 50%) with significant deviations in accumulated vs. predicted dose (at least ±15%). For LAD mean, n = 2 had higher accumulated vs. predicted doses (16.6 vs. 11.6 Gy; 14.6 vs. 12.8 Gy), while n = 3 had lower (21.8 vs. 26.5 Gy; 2.7 vs. 4.2 Gy; 13.9 vs. 16.5 Gy). For LAD V15 Gy, n = 3 had higher accumulated vs. predicted doses (43 vs. 35%; 51% vs. 25%; 14% vs. 9%), while n = 2 had lower (49% vs. 61%; 37% vs. 56%). For LAD V30 Gy, n = 4 had higher accumulated vs. predicted doses (12% vs. 5%; 5% vs. 0%; 4% vs. 0%; 4% vs. 2%), while n = 1 had lower (32% vs. 44%). Daily setup differences, including the extent of inspiratory breath hold, may contribute to deviations in accumulated LAD dose (more than 15% of predicted) in approximately half of patients and were more pronounced in V15 and V30 Gy metrics. The potential for significant LAD dose uncertainty in a clinically meaningful subset of patients should be recognized and warrants further analysis in an expanded cohort.

SENP5 promotes homologous recombination-mediated DNA damage repair in colorectal cancer cells through H2AZ deSUMOylation

BackgroundNeoadjuvant radiotherapy has been used as the standard treatment of colorectal cancer (CRC). However, radiotherapy resistance often results in treatment failure. To identify radioresistant genes will provide novel targets for combined treatments and prognostic markers.MethodsThrough high content screening and tissue array from CRC patients who are resistant or sensitive to radiotherapy, we identified a potent resistant gene SUMO specific peptidase 5 (SENP5). Then, the effect of SENP5 on radiosensitivity was investigated by CCK8, clone formation, comet assay, immunofluorescence and flow cytometric analysis of apoptosis and cell cycle to investigate the effect of SENP5 on radiosensitivity. SUMO-proteomic mass spectrometry combined with co-immunoprecipitation assay were used to identify the targets of SENP5. Patient-derived organoids (PDO) and xenograft (PDX) models were used to explore the possibility of clinical application.ResultsWe identified SENP5 as a potent radioresistant gene through high content screening and CRC patients tissue array analysis. Patients with high SENP5 expression showed increased resistance to radiotherapy. In vitro and in vivo experiments demonstrated that SENP5 knockdown significantly increased radiosensitivity in CRC cells. SENP5 was further demonstrated essential for efficient DNA damage repair in homologous recombination (HR) dependent manner. Through SUMO mass spectrometry analysis, we characterized H2AZ as a deSUMOylation substrate of SENP5, and depicted the SUMOylation balance of H2AZ in HR repair and cancer resistance. By using PDO and PDX models, we found targeting SENP5 significantly increased the therapeutic efficacy of radiotherapy.ConclusionOur findings revealed novel role of SENP5 in HR mediated DNA damage repair and cancer resistance, which could be applied as potent prognostic marker and intervention target for cancer radiotherapy.

CircRNF13, a novel N6-methyladenosine-modified circular RNA, enhances radioresistance in cervical cancer by increasing CXCL1 mRNA stability

BackgroundCircular RNAs (circRNAs) and N6-methyladenosine (m6A) have been shown to play an increasingly critical role in the development of different cancers. However, there is limited evidence on how circRNAs and m6A interact to affect the radiosensitivity of cervical cancer (CC). This study provides a mechanistic understanding of the novel m6A-regulated circRNF13 in enhancing radioresistance in CC.MethodsDifferentially expressed circRNAs were identified from radiosensitive and radioresistant CC tissues. Meanwhile, these circRNAs were subjected to methylated RNA immunoprecipitation (Me-RIP). Finally, the effects of these circRNAs on radiosensitivity were characterized.ResultsCircRNF13 was poorly expressed in CC patients that were sensitive to concurrent radiochemotherapy. Experiments conducted both in vitro and in vivo confirmed that the knockdown of circRNF13 potentiated the radiosensitivity of CC cells. Further mechanistic studies revealed that METTL3/YTHDF2 promoted the degradation of circRNF13 and subsequently affected the stability of CXC motif chemokine ligand 1 (CXCL1), ultimately enhancing the radiosensitivity of CC cells.ConclusionThis study identified circRNF13 as a novel m6A-modified circRNA and validated the METTL3/YTHDF2/circRNF13/CXCL1 axis as a potential target for CC radiotherapy.

Discovery of [1,2,3]Triazolo[4,5-c]quinoline Derivatives as a New Class of Ataxia-Telangiectasia Mutated Kinase Inhibitors.

Ataxia-telangiectasia mutated (ATM) is an atypical serine/threonine protein kinase which is implicated in the repair of DNA double-strand breaks. Numerous reports have shown that ATM inhibition is an attractive target for radiotherapy and chemotherapy sensitization. Herein we report a new series of ATM kinase inhibitors containing the 1H-[1,2,3]triazolo[4,5-c]quinoline scaffold, which was obtained by virtual screening, structural optimization, and structure-activity relationship studies. Among the inhibitors, A011 was one of the most potent, with an IC50 value of 1.0 nM against ATM. In colorectal cancer cells (SW620 and HCT116), A011 was able to inhibit activation of ATM signaling induced by irinotecan (CPT-11) and ionizing radiation and then increased the sensitivity of colorectal cancer cells to irinotecan and ionizing radiation through increasing G2/M arrest and inducing apoptosis. In the SW620 human colorectal adenocarcinoma tumor xenograft model, A011 sensitized SW620 to CPT-11 by inhibiting ATM activity. Collectively, this work has identified a promising lead in the discovery of potent inhibitors against ATM.

Effect of Stereotactic Body Radiation Therapy on Diverse Organ Lesions in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs. The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test. A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively. The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT.

From netrin‐1‐targeted SPECT/CT to internal radiotherapy for management of advanced solid tumors

Targeted radionuclide therapy is a revolutionary tool for the treatment of highly spread metastatic cancers. Most current approaches rely on the use of vectors to deliver radionuclides to tumor cells, targeting membrane‐bound cancer‐specific moieties. Here, we report the embryonic navigation cue netrin‐1 as an unanticipated target for vectorized radiotherapy. While netrin‐1, known to be re‐expressed in tumoral cells to promote cancer progression, is usually characterized as a diffusible ligand, we demonstrate here that netrin‐1 is actually poorly diffusible and bound to the extracellular matrix. A therapeutic anti‐netrin‐1 monoclonal antibody (NP137) has been preclinically developed and was tested in various clinical trials showing an excellent safety profile. In order to provide a companion test detecting netrin‐1 in solid tumors and allowing the selection of therapy‐eligible patients, we used the clinical‐grade NP137 agent and developed an indium‐111‐NODAGA‐NP137 single photon emission computed tomography (SPECT) contrast agent. NP137‐111In provided specific detection of netrin‐1‐positive tumors with an excellent signal‐to‐noise ratio using SPECT/CT imaging in different mouse models. The high specificity and strong affinity of NP137 paved the way for the generation of lutetium‐177‐DOTA‐NP137, a novel vectorized radiotherapy, which specifically accumulated in netrin‐1‐positive tumors. We demonstrate here, using tumor cell‐engrafted mouse models and a genetically engineered mouse model, that a single systemic injection of NP137‐177Lu provides important antitumor effects and prolonged mouse survival. Together, these data support the view that NP137‐111In and NP137‐177Lu may represent original and unexplored imaging and therapeutic tools against advanced solid cancers.

Bridging the Communication Gaps: A Prospective Single-Arm Pilot Study Testing the Feasibility of Interdisciplinary Radiotherapy Planning in Locally Advanced Lung Cancer

The treatment of locally advanced lung cancer (LALC) with radiotherapy (RT) can be challenging. Multidisciplinary collaboration between radiologists and radiation oncologists (ROs) may optimize RT planning, reduce uncertainty in follow-up imaging interpretation, and improve outcomes. In this prospective clinical treatment trial (clinicaltrials.gov XXX), 37 patients receiving definitive RT for LALC, six attending ROs, and three thoracic radiologists were consented and enrolled across four treatment centers. Prior to RT plan finalization, representative computed tomography (CT) slices with overlaid outlines of preliminary irradiation targets were shared with the team of radiologists. The primary endpoint was to assess feasibility of receiving feedback no later than 4 business days of RT simulation on at least 50% of plans. Thirty-seven patients with lung cancer were enrolled, and 35 of 37 RT plans were reviewed. Of the 35 patients reviewed, mean age was 69 years. For 27 of 37 plans (73%), feedback was received within 4 or fewer days (interquartile range 3-4 days). Thirteen of 35 cases (37%) received feedback that the delineated target potentially did not include all sites suspicious for tumor involvement. In total, changes to the RT plan were recommended for over- or undercoverage in 16 of 35 cases (46%) and implemented in all cases. Radiology review resulted in no treatment delays and substantial changes to irradiated volumes: gross tumor volume, -1.9 to +96.1%; planning target volume, -37.5 to +116.5%. Interdisciplinary collaborative RT planning using a simplified workflow was feasible, produced no treatment delays, and prompted substantial changes in RT targets.

Cancer-associated fibroblasts induce growth and radioresistance of breast cancer cells through paracrine IL-6

In breast cancer, the most numerous stromal cells are cancer-associated fibroblasts (CAFs), which are associated with disease progression and chemoresistance. However, few studies have explored the function of CAFs in breast cancer cell radiosensitivity. Here, CAF-derived conditioned media was observed to induce breast cancer cell growth and radioresistance. CAFs secrete interleukin 6 (IL-6) which activates signal transducer and activator of transcription 3 (STAT3) signaling pathway, thus promoting the growth and radioresistance of breast cancer cells. Treatment with an inhibitor of STAT3 or an IL-6 neutralizing antibody blocked the growth and radioresistance induced by CAFs. In in vivo mouse models, tocilizumab (an IL-6 receptor monoclonal antibody) abrogated CAF-induced growth and radioresistance. Moreover, in breast cancer, a poor response to radiotherapy was associated with IL-6 and p-STAT3 expression. These results indicated that IL-6 mediates cross-talk between breast cancer cells and CAFs in the tumor microenvironment. Our results identified the IL-6/STAT3 signaling pathway as an important therapeutic target in breast cancer radiotherapy.

Molecular mechanisms of long noncoding RNAs associated with cervical cancer radiosensitivity.

Despite advances in cervical cancer screening and human papilloma virus (HPV) vaccines, cervical cancer remains a global health burden. The standard treatment of cervical cancer includes surgery, radiation therapy, and chemotherapy. Radiotherapy (RT) is the primary treatment for advanced-stage disease. However, due to radioresistance, most patients in the advanced stage have an adverse outcome. Recent studies have shown that long noncoding RNAs (lncRNAs) participate in the regulation of cancer radiosensitivity by regulating DNA damage repair, apoptosis, cancer stem cells (CSCs), and epithelial-mesenchymal transition (EMT). In this review, we summarize the molecular mechanisms of long noncoding RNAs in cervical cancer and radiosensitivity, hoping to provide a theoretical basis and a new molecular target for the cervical cancer RT in the clinic.

Novel insight into metabolic reprogrammming in cancer radioresistance: A promising therapeutic target in radiotherapy.

Currently, cancer treatment mainly consists of surgery, radiotherapy, chemotherapy, immunotherapy, and molecular targeted therapy, of which radiotherapy is one of the major pillars. However, the occurrence of radioresistance largely limits its therapeutic effect. Metabolic reprogramming is an important hallmark in cancer progression and treatment resistance. In radiotherapy, DNA breakage is the major mechanism of cell damage, and in turn, cancer cells are prone to increase the metabolic flux of glucose, glutamine, serine, arginine, fatty acids etc., thus providing sufficient substrates and energy for DNA damage repair. Therefore, studying the linkage between metabolic reprogramming and cancer radioresistance may provide new ideas for improving the efficacy of tumor therapy. This review mainly focuses on the role of metabolic alterations, including glucose, amino acid, lipid, nucleotide and other ion metabolism, in radioresistance, and proposes possible therapeutic targets to improve the efficacy of cancer radiotherapy.

Changing Role of PET/CT in Cancer Care With a Focus on Radiotherapy.

Positron emission tomography (PET) integrated with computed tomography (CT) has brought revolutionary changes in improving cancer care (CC) for patients. These include improved detection of previously unrecognizable disease, ability to identify oligometastatic status enabling more aggressive treatment strategies when the disease burden is lower, its use in better defining treatment targets in radiotherapy (RT), ability to monitor treatment responses early and thus improve the ability for early interventions of non-responding tumors, and as a prognosticating tool as well as outcome predicting tool. PET/CT has enabled the emergence of new concepts such as radiobiotherapy (RBT), radioimmunotherapy, theranostics, and pharmaco-radiotherapy. This is a rapidly evolving field, and this primer is to help summarize the current status and to give an impetus to developing new ideas, clinical trials, and CC outcome improvements.

Harmonica consensus, controversies, and future directions in radiotherapy for pediatric Wilms tumors.

Radiotherapy (RT) is essential for multimodality treatment of pediatric renal tumors, particularly in higher-risk and metastatic disease. Despite decades of use, particularly for Wilms tumor, there remain controversies regarding RT indications, timing, dose, and targets. To align global management, we address these issues in this international HARMONIsation and CollAboration (HARMONICA) project. There are multiple knowledge gaps and opportunities for future research including: (1) utilization of advanced RT technologies, including intensity-modulated RT, proton beam therapy, combined with image-guided RT to reduce target volumes; (2) impact of molecular biomarkers including loss of heterozygosity at 1p, 16q, and 1q gain on RT indications; (3) mitigation of reproductive toxicity following RT; (4) promotion of RT late effects research; and (5) support to overcome challenges in RT utilization in low- and middle-income countries where 90% of the world's children reside. Here, we outline current status and future directions for RT in pediatric renal tumors.

The Expression of Connexin 26 Regulates the Radiosensitivity of Hepatocellular Carcinoma Cells through a Mitogen-Activated Protein Kinases Signal Pathway.

Connexin 26 (Cx26) is a protein that constitutes a gap junction and is widely expressed in the liver. Abnormal expression of Cx26 is one of the important mechanisms of liver cancer, and is closely related to the transmission of radiation damage signals between cells. In the present study, we investigated the radiosensitivity of hepatocellular carcinoma (HCC) cells HepG2, with low expression of Cx26, and SK-hep-1, with high expression of Cx26 after X-ray irradiation. The cell survival, micronucleus formation and protein expressions of the mitogen-activated protein kinases (MAPK) signaling pathway were detected. The expression level of Cx26 could affect the radiosensitivity of liver cancer cells by affecting the phosphorylation of p38 and ERK proteins and regulating the expression of downstream NF-κB. Cell lines with knock-out and overexpression of Cx26 were also built to confirm the findings. Our results suggested that Cx26 might play an important role in the radiosensitivity of liver cancer and could be a potential target for clinical radiotherapy of liver cancer.

Construction of a predictive model of abdominal lymph node metastasis in thoracic esophageal squamous cell carcinoma and preliminary analysis of its effect on target for postoperative radiotherapy.

To investigate the influencing factors of abdominal lymph node metastasis in thoracic esophageal squamous cell carcinoma (TESCC), and to construct its predictive model, in order to analyze the targets for postoperative radiotherapy. From January 2008 to December 2014, the clinicopathological data of 479 patients who underwent radical resection for esophageal cancer in the Fourth Hospital of Hebei Medical University were collected and retrospectively analyzed. The influencing factors of postoperative abdominal lymph node metastasis were analyzed, and a predictive model was constructed based on their independent influencing factors. Receiver operating characteristic (ROC) curve was utilized to analyze the predictive value of this model; in the meantime, the postoperative locoregional recurrence (LRR) of this group was analyzed. The postoperative pathology of all patients showed that the lymph node metastasis rate (LNR) was 39.7%, of which the abdominal lymph node metastasis rate was 22.0%. Logistic regression analysis revealed that the patient's lesion location, pN stage, vascular invasion, LND and mediastinal lymph node metastasis were independent risk factors for the positive rate of abdominal lymph nodes after surgery (P = 0.000, 0.000, 0.033, 0.000, 0.000). The probability of abdominal lymph node metastasis was Y = ex/(1 + ex), and X = -5.502 + 1.569 × lesion location + 4.269 × pN stage + 1.890 × vascular invasion + 1.950 × LND-4.248 × mediastinal lymph node metastasis. The area under the ROC curve (AUC) of this model in predicting abdominal lymph node metastasis was 0.962 (95% CI, 0.946-0.977). This mathematical model had a high predictive value for the occurrence of abdominal lymph node metastasis (P = 0.000), and the sensitivity and specificity of prediction were 94.6% and 88.3% respectively. The overall survival rate was significantly higher (X2 = 29.178, P = 0.000), while abdominal lymph node recurrence rate was lower in patients with negative abdominal lymph nodes than in those with negative lymph nodes (1.4%&7.7%, X2 = 12.254, P = 0.000). The lesion location, pN stage, vascular invasion, LND and mediastinal lymph node metastasis are independent influencing factors of abdominal lymph node metastasis in patients with TESCC. The mathematical model constructed by these indicators can accurately predict abdominal lymph node metastasis, which can help clinicians to choose the targets for postoperative radiotherapy.

PIG3 downregulation enhances the radiosensitivity of NSCLC cells by promoting G2/M cell cycle arrest and apoptosis

ObjectiveTo investigate the mechanism of p53-induced gene 3 (PIG3)-regulation of radioresistance in human non-small cell lung cancer (NSCLC) cells, in order to explore new biomarkers and therapeutic targets to combat radioresistance and improve the 5-year survival rate. MethodsThe PIG3 gene was knocked down in A549 ​cells using siRNA, and was overexpressed in H1299 ​cells using a PIG3 expression plasmid. After confirming PIG3 knockdown and overexpression through the Western blot analysis, the radiosensitivity, DNA damage, cell cycle distribution, and apoptosis in these cells were analyzed using colony formation assay, immunofluorescence staining for γH2AX, and flow cytometry, respectively. ResultsPIG3 silencing markedly increased the radiosensitivity of NSCLC cells, with radiosensitization ratios of 1.12 and 1.25. Compared with the corresponding negative control, PIG3 knockdown significantly enhanced G2/M phase arrest (siNC: 26.12 ​± ​2.50, siPIG3#1: 34.98 ​± ​4.19, siPIG3#2: 37.79 ​± ​3.53, P ​< ​0.05), promoted radiation-induced apoptosis (siNC: 14.61 ​± ​1.85, siPIG3#1: 17.26 ​± ​1.14, siPIG3#2: 20.70 ​± ​2.04, P ​< ​0.05), and reduced the number of γ-H2AX foci 0.5, 1, and 2 ​h after radiation (P ​< ​0.05). Conversely, PIG3 overexpression markedly decreased the radiosensitivity of NSCLC cells, as evidenced by the reduction of G2/M phase arrest (NC: 33.18 ​± ​2.11 vs. PIG3: 24.21 ​± ​3.09, P ​< ​0.05) and apoptosis (NC: 15.49 ​± ​0.56 vs. PIG3: 12.79 ​± ​0.29, P ​< ​0.05), and increased DNA damage (P ​< ​0.05). ConclusionsPIG3 downregulation increases the radiosensitivity of NSCLC cells, and PIG3-upregulation leads to the progression in radioresistance. Therefore, PIG3 is a potential target for radiotherapy for NSCLC.

RECQL4 Remodels the Tumor Immune Microenvironment via the cGAS-STING Pathway in Hepatocellular Carcinoma

<h3>Purpose/Objective(s)</h3> RECQL4 was considered a susceptible target for cancer therapy by playing diverse roles in the maintenance of genomic stability. Understanding more about the molecular characteristics of RECQL4 enables the better selection of HCC patients who would derive benefit from radiation therapy (RT) combined with immune checkpoint immunotherapies (ICIs). <h3>Materials/Methods</h3> We collected RNA sequencing data of 1175 HCC and 767 adjacent non-tumor tissues from 5 cohorts, followed by comprehensive evaluation of the expression patterns and multi-omics characteristics of RECQL4. Then, the expression of RECQL4 was systematically associated with HCC genomic instability and tumor microenvironment (TME) with multi-omics data and multicolor immunofluorescence staining. cGAS^−/− and STING^−/- mice were used to determine the relation of RECQL4 and cGAS-STING signaling pathway in HCC in vivo. Finally, clinical and pathologic data were collected retrospectively on HCC patients at the Zhongshan Hospital of Fudan University and associations with survival were determined. <h3>Results</h3> We found that RECQL4 was specifically overexpressed in HCC and significantly associated with a poor prognosis. The CNV results showed RECQL4 mutations was mainly caused by 8q24 and the expression was positive correlation with CNV burden. Moreover, RECQL4 expression was significantly and negatively correlated with the infiltrating levels of dendritic cells (DCs) and CD8 + T cells, which means high RECQL4 designed a non-inflamed TME. Low RECQL4 induces DCs maturation and antigen presentation by triggering the cGAS-STING pathway, and further activates CD8 + T cell-mediated the adaptive immunity. The result was further confirmed in RT combined with ICIs of HCC, which suggests that low RECQL4 bridges the DNA damaging capacity of RT with the CD8+ cytotoxic T cell-mediated destruction of cancer through innate immune signaling cGAS–STING to make the combined therapy better efficacy. Retrospective analysis also showed that HCC patients with low RECQL4 expression were more sensitive to RT with ICIs. <h3>Conclusion</h3> RECQL4 mediates a non-inflamed TME by regulating the cGAS-STING pathway on immune cells in HCC. HCC patients with low RECQL4 could derive response and benefit from several treatment options. RECQL4 serves as a new target for HCC radiotherapy combined with immunotherapy.

Immunotherapy with Concurrent Radiotherapy in Patients with Metastatic Cancer: An Analysis from the National Cancer Data Base

<h3>Purpose/Objective(s)</h3> Immuno-radiotherapy (iRT) is the concept of combining immunotherapy with radiation therapy (RT). Retrospective and early prospective studies have shown that iRT is not associated with high levels of toxicity and may improve oncologic outcomes in patients with metastatic cancer. The purpose of this study was to assess patterns of care among patients with metastatic cancers treated with iRT and explore factors associated with differences in overall survival (OS). <h3>Materials/Methods</h3> The National Cancer Database was probed to identify patients with metastatic disease at diagnosis who received iRT, which was defined as the receipt of RT within 21 days of receiving immunotherapy. We hypothesized that shorter courses of radiotherapy would be associated with better clinical outcomes and defined two fractionation schedules: 1-5 and ≥6 fractions of radiotherapy. Median OS was estimated using the Kaplan-Meier method. The sites of primary cancer and RT treatment sites were analyzed for differences in OS between the two fractionation groups. <h3>Results</h3> 3,879 patients were included. The years of treatment spanned from 2005 to 2018. Utilization of radiation has dramatically increased in recent years. For instance, the number of patients treated with radiotherapy were 3, 63, and 2,455 in years 2010, 2014, and 2018, respectively. Median follow up was 17.1 months. Radiotherapy in 1-5 fractions was delivered to 1,538 patients and in ≥6 fractions to 2,341 patients. The most common primary cancers were NSCLC, melanoma, and renal cell carcinoma. The sites most commonly treated with radiotherapy were the brain, skeletal spine, and lung. Median OS in the entire cohort was 20.6 months. In patients treated with 1-5 fractions of RT, the median OS was 25.5 months (95% CI: 21.4 – 30.3) compared to 18.1 months (95% CI: 15.7 – 20.4) for those receiving ≥6 fractions. When evaluating the primary cancer and site of radiotherapy, the improvement in median OS in the 1-5 fraction cohort compared to ≥6 fractions was more pronounced in lung primary (28 months [95% CI: 20.7 – 37.2] vs 11 months [95% CI: 8.3 – 15.6]) and in those with intracranial radiotherapy targets (29 months [95% CI: 23.4 – 38.1] vs 12 months [95% CI: 8.7 – 15.2]. <h3>Conclusion</h3> This NCDB analysis suggests that patients with metastatic cancer who received radiotherapy within 21 days of immunotherapy may have improved overall survival when receiving 1-5 fractions compared to 6 or more fractions of radiotherapy. This difference was greater in patients with lung primary cancer and in those receiving intracranial radiation.

GDF15 Contributes to Radioresistance by Mediating the EMT and Stemness of Breast Cancer Cells.

Radiotherapy is one of the conventional methods for the clinical treatment of breast cancer. However, radioresistance has an adverse effect on the prognosis of breast cancer patients after radiotherapy. In this study, using bioinformatic analysis of GSE59732 and GSE59733 datasets in the Gene Expression Omnibus (GEO) database together with the prognosis database of breast cancer patients after radiotherapy, the GDF15 gene was screened out to be related to the poor prognosis of breast cancer after radiotherapy. Compared with radiosensitive parental breast cancer cells, breast cancer cells with acquired radioresistance exhibited a high level of GDF15 expression and enhanced epithelial-to-mesenchymal transition (EMT) properties of migration and invasion, as well as obvious stem-like traits, including the increases of mammosphere formation ability, the proportion of stem cells (CD44+ CD24− cells), and the expressions of stem cell-related markers (SOX2, NANOG). Moreover, knockdown of GDF15 sensitized the radioresistance cells to irradiation and significantly inhibited their EMT and stem-like traits, indicating that GDF15 promoted the radioresistance of breast cancer by enhancing the properties of EMT and stemness. Conclusively, GDF15 may be applicable as a novel prognosis-related biomarker and a potential therapeutic target for breast cancer radiotherapy.

Physical characteristics in cone beam computed Tomography (CBCT) imaging for small motion target in different directions

Purpose: Fiducial marker has been an effective and intuitive way to localize motion target for lung Stereotactic Body Radiotherapy (SBRT). However, due to the complexity for motion target imaging, the optimal target localization strategy still need to be developed to improve the efficiency and effectiveness of the clinical procedure. In this study, the golden marker moving in different directions was characterized in CBCT images for optimal localization application. Method and Materials: A Visicoil linear fiducial marker was selected for this study. The length and diameter of the marker were 5mm and 1mm. The motion was generated by Real Time Position Management (RPM) phantom from Varian Medical System. The motion was simulated to be 2.3 second breathing period and about 1cm amplitude. The motion was at three directions along the anterior-posterior (AP), left-right (LR), and In-Out (IO) of the couch. Their CBCT images were taken, and targets were done by auto-contouring with HU range from minus 900 to positive 4000. The targets were post-processed with keeping the largest part and converted to high resolution segment. Their characteristics were described by shape, volume, center of the volume and volume pixel information, which were attained by MIM Software. Results: In this CBCT study, the volume of motion visicoil gold maker were 0.283cc, 0.348cc, and 0.271cc as moving along AP, IO and LR direction. They were corresponding to 143%, 163% and 236% of the static volume. The max HUs for each moving target were 3395, 343 and 3097, which were 49 %, 13% and 44% of those of the static visicoil. The center distances comparing to those of the static targets were 0.63cm with standard deviation at 0.02cm. Conclusions: When the gold makers were applied for localization of treatment target in Lung SBRT, the geometric distance can be reflected in accurate level; however, the direction of motions could generate large HU difference, which could be one of factors resulted in local failure due to undefined boundary of tumor. And dosimetric characteristic in region of interest should be further investigated to understand the potential effect of local failure case even when marker tracking or soft tissue technique for localization is used.

The Role of Nutrition in Primary and Secondary Prevention of Cardiovascular Damage in Childhood Cancer Survivors.

Innovative therapeutic strategies in childhood cancer led to a significant reduction in cancer-related mortality. Cancer survivors are a growing fragile population, at risk of long-term side effects of cancer treatments, thus requiring customized clinical attention. Antineoplastic drugs have a wide toxicity profile that can limit their clinical usage and spoil patients’ life, even years after the end of treatment. The cardiovascular system is a well-known target of antineoplastic treatments, including anthracyclines, chest radiotherapy and new molecules, such as tyrosine kinase inhibitors. We investigated nutritional changes in children with cancer from the diagnosis to the end of treatment and dietary habits in cancer survivors. At diagnosis, children with cancer may present variable degrees of malnutrition, potentially affecting drug tolerability and prognosis. During cancer treatment, the usage of corticosteroids can lead to rapid weight gain, exposing children to overweight and obesity. Moreover, dietary habits and lifestyle often dramatically change in cancer survivors, who acquire sedentary behavior and weak adherence to dietary guidelines. Furthermore, we speculated on the role of nutrition in the primary prevention of cardiac damage, investigating the potential cardioprotective role of diet-derived compounds with antioxidative properties. Finally, we summarized practical advice to improve the dietary habits of cancer survivors and their families.