Induction chemotherapy reduces target volume drift in patients with locoregionally advanced nasopharyngeal carcinoma undergoing adaptive intensity-modulated radiotherapy: a retrospective cohort study.

Background: Adaptive radiotherapy (ART) provides real-time correction of the target and dose of radiation based on repeat computed tomography (CT) imaging and replanning during intensity-modulated radiation therapy (IMRT) and is important for locoregionally advanced nasopharyngeal carcinoma (NPC). However, repeat CT imaging and replanning are time-consuming and hinder the broader application of ART. The optimum dose and frequency of replanning time have been published in previous reports. The purpose of this study was to determine whether induction chemotherapy (IC) reduces target volume drift during IMRT, potentially reducing the replanning workload. Methods: From January 2012 to December 2017, 40 patients with locoregionally advanced, nonmetastatic stage III-IVa NPC treated in the Department of Radiation Oncology in the First Affiliated Hospital, College of Medicine, Zhejiang University, were enrolled into this study. Of the 40 patients, 20 received 2-3 cycles of IC before concurrent chemoradiotherapy (IC + CCRT), and the other 20 patients were treated with CCRT plus adjuvant chemotherapy (CCRT + AC). During CCRT, all patients underwent weekly simulated CT for 6 weeks. The gross tumor volume (GTV), clinical target volume (CTV), and body weight were measured weekly and compared between the 2 groups. Results: Compared with the baseline, the mean weight loss after 25 fractions was 7.0 kg (13.6%; range, 3.9-25.5%) in the CCRT + AC group and 5.7 kg (8.3%; range, 3.6-20%) in the IC + CCRT group. The mean GTV and CTV decreased by 16.55 mL (15.7%; range, 6.1-33.7%) and 61.25 mL (9.33%; range, 4.4-17.0%), respectively, in the IC + CCRT group, and by 39.86 mL (38.79%; range, 25.3-50.7%) and 87.72 mL (12.7%; range, 6.7-22.9%), respectively, in the CCRT + AC group. The degree of weekly reduction in the GTV of the IC + CCRT group was not significantly higher than that of the CCRT + AC group, with the following P values of each percentage reduction in comparison with the previous week over 5 weeks, respectively: P<0.001, P=0.015, P=0.01, P=0.01, and P<0.001. The weekly CTV reduction only significantly correlated with weight loss (P=0.005) in the IC + CCRT group. Conclusions: IC significantly decreased the degree of weight loss, GTV shrinkage, and CTV reduction during CCRT, consequently decreasing the anatomical and target dose drift during the adaptive replanning of IMRT. This may lead to a reduction in the recurrence of locoregionally advanced NPC, especially among patients with large metastatic cervical lymph nodes, potentially improving survival. This result provides favorable evidence that IC improves locoregional recurrence-free survival (LRFS) and overall survival (OS) in patients with locoregionally advanced NPC.

Protective Role of Shenmai Injection on Radiation-Induced Heart Injury.

Radiation-induced heart injury (RIHI) limits the dose delivery of radiotherapy for thoracic cancer. Shenmai injection (SMI) is reported to have potential cytoprotective properties and is commonly used in cardiovascular diseases. So, we aimed to investigate the potential protective effects of SMI treatment on RIHI. In this study, we established the RIHI model using Sprague-Dawley rats and H9c2 cell line. In vivo, the biochemical assay was used to measure serum cardiac injury-related biomarkers and echocardiography to evaluate heart function. The pathological analysis was also applied to observe the myocardial structural changes. In vitro, we further measured the cell viability and reactive oxygen species (ROS) levels after irradiation with or without SMI treatment. Our data showed the administration of SMI reduced the level of serum cardiac injury biomarkers and ameliorated cardiac dysfunction after irradiation in rats. Pathological analysis revealed that SMI mitigated cardiac structural damage, fibrosis, and macrophage infiltration. Besides, treatment with SMI increased cell viability and decreased excess ROS production after irradiation in vitro. Taken together, our study demonstrated the protective role of SMI treatment on RIHI by inhibiting oxidative stress and decreasing structural remodeling.

STC2 activates PRMT5 to induce radioresistance through DNA damage repair and ferroptosis pathways in esophageal squamous cell carcinoma.

Radioresistance is the major reason for the failure of radiotherapy in esophageal squamous cell carcinoma (ESCC). Previous evidence indicated that stanniocalcin 2 (STC2) participates in various biological processes of malignant tumors. However, researches on its effect on radioresistance in cancers are limited. In this study, STC2 was screened out by RNA-sequencing and bioinformatics analyses as a potential prognosis predictor of ESCC radiosensitivity and then was determined to facilitate radioresistance. We found that STC2 expression is increased in ESCC tissues compared to adjacent normal tissues, and a higher level of STC2 is associated with poor prognosis. Also, STC2 mRNA and protein expression levels were higher in radioresistant cells than in their parental cells. Further investigation revealed that STC2 could interact with protein methyltransferase 5 (PRMT5) and activate PRMT5, thus leading to the increased expression of symmetric dimethylation of histone H4 on Arg 3 (H4R3me2s). Mechanistically, STC2 can promote DDR through the homologous recombination and non-homologous end joining pathways by activating PRMT5. Meanwhile, STC2 can participate in SLC7A11-mediated ferroptosis in a PRMT5-dependent manner. Finally, these results were validated through in vivo experiments. These findings uncovered that STC2 might be an attractive therapeutic target to overcome ESCC radioresistance.

Prognostic implications of necroptosis-related long noncoding RNA signatures in muscle-invasive bladder cancer.

Background: Bladder cancer (BLCA) is the sixth most common cancer in men, with an increasing incidence of morbidity and mortality. Necroptosis is a type of programmed cell death and plays a critical role in the biological processes of bladder cancer (BLCA). However, current studies focusing on long noncoding RNA (lncRNA) and necroptosis in cancer are limited, and there is no research about necroptosis-related lncRNAs (NRLs) in BLCA. Methods: We obtained the RNA-seq data and corresponding clinical information of BLCA from The Cancer Genome Atlas (TCGA) database. The seven determined prognostic NLRs were analyzed by several methods and verified by RT-qPCR. Then, a risk signature was established based on the aforementioned prognostic NLRs. To identify it, we evaluated its prognostic value by Kaplan-Meier (K-M) survival curve and receiver operating characteristics (ROC) curve analysis. Moreover, the relationships between risk signature and clinical features, functional enrichment, immune landscape, and drug resistance were explored as well. Results: We constructed a signature based on seven defined NLRs (HMGA2-AS1, LINC02489, ETV7-AS1, EMSLR, AC005954.1, STAG3L5P-PVRIG2P-PILRB, and LINC02178). Patients in the low-risk cohort had longer survival times than those in the high-risk cohort, and the area under the ROC curve (AUC) value of risk signature was higher than other clinical variables. Functional analyses, the infiltrating level of immune cells and functions, ESTIMATE score, and immune checkpoint analysis all indicated that the high-risk group was in a relatively immune-activated state. In terms of treatments, patients in the high-risk group were more sensitive to immunotherapy, especially anti-PD1/PD-L1 immunotherapy and conventional chemotherapy. Conclusion: The novel NLR signature acts as an invaluable tool for predicting prognosis, immune microenvironment, and drug resistance in muscle-invasive bladder cancer (MIBC) patients.

The global burden of nasopharyngeal carcinoma from 2009 to 2019: an observational study based on the Global Burden of Disease Study 2019.

PURPOSE: The incidence and mortality rate of nasopharyngeal carcinoma (NPC) has changed in recent years. Our goal is to determine the epidemiological pattern of NPC to help policymakers allocate limited medical resources. METHODS: Detailed information about NPC from 2009 to 2019 was collected from the Global Burden of Disease 2019 database. Age-standardized rates (ASRs) and corresponding estimated annual percentage changes (EAPCs) were calculated to assess NPC's incidence and mortality trends. RESULTS: Globally, there was a consistent increase in the NPC incidence cases from 2009 to 2019 (from 121.65 × 103 cases in 2009 to 176.50 × 103 cases in 2019, increasing by 45.09%). The age-standardized incidence rate (ASIR) of NPC increased from 1.81 in 2009 to 2.12 in 2019 (EAPC = 1.59, 95% CI 1.36-1.81). On the contrary, the mortality of NPC showed a downward trend (ASDR: 0.93 in 2009 and 0.86 in 2019; EAPC = - 0.63, 95% CI - 0.78 to - 0.48), and it was negatively correlated with the social demographic index (SDI) in most regions. Both incidence and mortality rates of high-incidence territories tended to be stable or decline. Males had significantly higher incidence and mortality of NPC than females. The number of patients with onset age greater than 50 years old accounted for the highest proportion. We found that smoking, occupational exposure to formaldehyde, and alcohol use were the main risk factors for NPC-related mortality. CONCLUSION: Globally, the incidence rate of NPC has been slightly increasing, while the mortality and disability-adjusted life years (DALYs) have been decreasing. NPC burden in high-middle and middle SDI areas was the heaviest. The current prevention strategy should be repositioned, and some countries should formulate more targeted approaches to reduce the current burden of NPC.

Immobilization-assisted abdominal deep inspiration breath-hold in post-mastectomy radiotherapy of left-sided breast cancer with internal mammary chain coverage.

BACKGROUND: Whether to prophylactically irradiate the ipsilateral internal mammary chain (IMC) in post-mastectomy radiotherapy (PMRT) remains controversial because of equivocal clinical benefits against the added toxicities. Our previous study revealed that the cardiac dose was decreased during left-sided breast radiotherapy with abdominal deep inspiration breath-hold (aDIBH) as compared with free-breathing (FB) and thoracic deep inspiration breath-hold (tDIBH). Here we present the dosimetric advantage of aDIBH for patients undergoing PMRT with IMC coverage. METHODS: We prospectively analyzed 19 patients with left-sided breast cancer who underwent PMRT. Patients underwent computed tomography (CT) simulation under both free-breathing (FB) and aDIBH. The heart, left anterior descending coronary artery (LAD), lungs, and the contralateral breast was defined as organs at risk (OARs). Three-dimensional conformal radiation therapy (3D-CRT), inverse planning intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) were used to calculate the doses received by both the planning target volume (PTV) and OARs, which were compared using the Wilcoxon signed-rank test. RESULTS: Compared with FB, the Dmean of the heart and LAD were respectively reduced by 3.5 Gy (P<0.003) and 8.9 Gy (P<0.001) in 3D-CRT, 2.6 Gy (P<0.001), and 7.8 Gy (P=0.001) in IMRT, 1.5 Gy (P<0.001) and 4.5 Gy (P=0.001) in VMAT plans under aDIBH. Among all these plans, the Dmean of the heart was lowest in aDIBH IMRT and 1.3 Gy lower than in aDIBH VMAT (P=0.002). aDIBH IMRT also resulted in a significantly reduced dose to the ipsilateral lung than plans under FB (P<0.05). Dmean and V5 to the contralateral lung and breast were higher in VMAT plans (P<0.05). CONCLUSIONS: Using an immobilization-assisted aDIBH technique, radiation doses to the heart can be kept at reasonably low levels even if IMC is included in the clinical target volume (CTV). Among 3D-CRT, IMRT, and VMAT plans, IMRT plus aDIBH results in the best heart-sparing effect. We recommend that the aDIBH technique be routinely applied in suitable patients if the IMC is irradiated.

Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer.

PURPOSE: Esophageal cancer (EC) is an aggressive malignancy and is often resistant to currently available therapies. Inhibition of ribonucleotide reductase small subunit M2 (RRM2) in tumors is speculated to mediate chemosensitization. Previous studies have reported that Osalmid could act as an RRM2 inhibitor. We explored whether RRM2 was involved in radioresistance and the antitumor effects of Osalmid in EC. METHODS AND MATERIALS: RRM2 expression was detected by immunohistochemistry in EC tissues. The effects of Osalmid on cell proliferation, apoptosis, and cell cycle were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphhenyl tetrazolium, colony formation, and flow cytometry assays. DNA damage, cell apoptosis, and senescence induced by Osalmid or ionizing radiation (IR) alone, or both, were detected with immunofluorescence, flow cytometry, Western blot, and ß-galactosidase staining. A xenograft mouse model of EC was used to investigate the potential synergistic effects of Osalmid and IR in vivo. RESULTS: The expression of RRM2 in treatment-resistant EC tissues is much higher than in treatment-sensitive EC, and strong staining of RRM2 was correlated with shorter overall survival. We observed direct cytotoxicity of Osalmid in EC cells. Osalmid also produced inhibition of the ERK1/2 signal transduction pathway and substantially enhanced IR-induced DNA damage, apoptosis, and senescence. Furthermore, treatment with Osalmid and IR significantly suppressed tumor growth in xenograft EC models without additional toxicity to the hematologic system and internal organs. CONCLUSIONS: Our study revealed that RRM2 played a vital role in radioresistance in EC, and Osalmid synergized with IR to exert its antitumor effects both in vitro and in vivo.

The Therapeutic Potential of Adipose Tissue-Derived Mesenchymal Stem Cells to Enhance Radiotherapy Effects on Hepatocellular Carcinoma.

Several studies have investigated strategies to improve the clinical efficacy of radiotherapy (RT) against hepatocellular carcinoma (HCC), yet the prognosis remains poor. Human adipose tissue-derived mesenchymal stem cells (AT-MSCs), easily accessible and abundant in quantity, have represented as an attractive therapeutic tool for the stem cell-based treatment for cancer diseases. Through direct co-culture and indirect separate culture experiments, we showed that AT-MSCs could enhance inhibitory effect of RT on reducing HCC cell growth, migration and invasion in both in vitro and in vivo experiments. RNA-sequencing analysis revealed a noticeable interferon-induced transmembrane 1 (IFITM1)-induced tumor gene signature. Gain and loss of mechanistic studies indicated that mechanism was attributed to downregulated expression of signal transducer and activator of transcription 3 (STAT3) and matrix metallopeptidases (MMPs) and upregulated expression of P53 and caspases. Collectively, our findings suggest that AT-MSCs might enhance the therapeutic effects of RT on HCC, providing a rationale for AT-MSCs and RT combination therapy as a new remedy for HCC.

The role of radioprotective spacers in clinical practice: a review.

The delivery of high dose radiotherapy to tumors is often limited by the proximity of the surrounding radiosensitive normal tissues, even using modern techniques such as intensity modulated radiation therapy (IMRT). Previous studies have reported that placement of a spacer can effectively displace normal tissues. So that they are some distance away from the lesion, thus allowing for the safe delivery of high-dose radiation. The application of radioprotective spacers was first reported 30 years ago regarding radiotherapy of tongue and abdominal cancers; more recently, they are increasingly being used in prostate cancer. This review focuses on the published data concerning the features of different types of spacers and their application in various tumor sites. Placement-related complications and the cost-effectiveness of the spacers are also discussed. With the increasing use of high-precision radiotherapy in clinical practice, especially the paradigm-changing stereotactic body radiotherapy (SBRT), more robust studies are warranted to further establish the role of radioprotective spacers through materials development and novel placement techniques.

Comparison of computed tomography and magnetic resonance imaging in cervical cancer brachytherapy: A systematic review.

PURPOSE: The aim of this overview was to assess the accuracy of computed tomography (CT)-based imaging technology and to compare it with magnetic resonance imaging (MRI) for the treatment planning of high-dose rate brachytherapy in cervical cancer. METHODS AND MATERIALS: A systematic search in PubMed, Embase, and the Cochrane Central was performed to identify clinical studies involving brachytherapy of cervical cancer and published before February 1, 2016. Outcomes of interest were geometric dimensions, dose parameters, and clinical results. RESULTS: After screening 675 articles, 13 clinical studies involving 465 patients were included for critical appraisal; 10 studies compared CT with MRI and three compared hybrid (CT/MRI based) with MRI only-based imaging technologies. The geometric dimensions of the high-risk clinical target volume (HR-CTV), dose parameters, and clinical outcomes were reported in 11, 10, and 1 studies, respectively. CONCLUSIONS: Among those geometric parameters of HR-CTV, width was significantly overestimated on CT compared with MRI. Height might be underestimated, and thickness was comparable. The dose parameters for HR-CTV were lower on CT only-based technique compared with MRI-based one. It is proposed that at least one pre- or at brachytherapy MRI is required to assess the tumor extension. With the help of MRI information, CT contouring will be much more accurate in cervical cancer brachytherapy.