Radiotherapy Response Research Articles

Predicting pathological complete response of neoadjuvant radiotherapy and targeted therapy for soft tissue sarcoma by whole-tumor texture analysis of multisequence MRI imaging

ObjectivesTo construct effective prediction models for neoadjuvant radiotherapy (RT) and targeted therapy based on whole-tumor texture analysis of multisequence MRI for soft tissue sarcoma (STS) patients.MethodsThirty patients with STS of the extremities or trunk from a prospective phase II trial were enrolled for this analysis. All patients underwent pre- and post-neoadjuvant RT MRI examinations from which whole-tumor texture features were extracted, including T1-weighted with fat saturation and contrast enhancement (T1FSGd), T2-weighted with fat saturation (T2FS), and diffusion-weighted imaging (DWI) sequences and their corresponding apparent diffusion coefficient (ADC) maps. According to the postoperative pathological results, the patients were divided into pathological complete response (pCR) and non-pCR (N-pCR) groups. pCR was defined as less than 5% of residual tumor cells by postoperative pathology. Delta features were defined as the percentage change in a texture feature from pre- to post-neoadjuvant RT MRI. After data reduction and feature selection, logistic regression was used to build prediction models. ROC analysis was performed to assess the diagnostic performance.ResultsFive of 30 patients (16.7%) achieved pCR. The Delta_Model (AUC 0.92) had a better predictive ability than the Pre_Model (AUC 0.78) and Post_Model (AUC 0.76) and was better than AJCC staging (AUC 0.52) and RECIST 1.1 criteria (AUC 0.52). The Combined_Model (pre, post, and delta features) had the best predictive performance (AUC 0.95).ConclusionWhole-tumor texture analysis of multisequence MRI can well predict pCR status after neoadjuvant RT and targeted therapy in STS patients, with better performance than RECIST 1.1 and AJCC staging.Key points• MRI multisequence texture analysis could predict the efficacy of neoadjuvant RT and targeted therapy for STS patients.• Texture features showed incremental value beyond routine clinical factors.• The Combined_Model with features at multiple time points showed the best performance.

Oxygen-enhanced MRI and radiotherapy in patients with oropharyngeal squamous cell carcinoma

Background and purposeThis study aimed to assess the role of T1 mapping and oxygen-enhanced MRI in patients undergoing radical dose radiotherapy for HPV positive oropharyngeal cancer, which has not yet been examined in an OE-MRI study. Materials and methodsVariable Flip Angle T1 maps were acquired on a 3T MRI scanner while patients (n = 12) breathed air and/or 100 % oxygen, before and after fraction 10 of the planned 30 fractions of chemoradiotherapy (‘visit 1’ and ‘visit 2’, respectively). The analysis aimed to assess to what extent (1) native R1 relates to patient outcome; (2) OE-MRI response relates to patient outcome; (3) changes in mean R1 before and after radiotherapy related to clinical outcome in patients with oropharyngeal squamous cell carcinoma. ResultsDue to the radiotherapy being largely successful, the sample sizes of non-responder groups were small, and therefore it was not possible to properly assess the predictive nature of OE-MRI. The tumour R1 increased in some patients while decreasing in others, in a pattern that was overall consistent with the underlying OE-MRI theory and previously reported tumour OE-MRI responses. In addition, we discuss some practical challenges faced when integrating this technique into a clinical trial, with the aim that sharing this is helpful to researchers planning to use OE-MRI in future clinical studies. ConclusionAltogether, these results suggest that further clinical OE-MRI studies to assess hypoxia and radiotherapy response are worth pursuing, and that there is important work to be done to improve the robustness of the OE-MRI technique in human applications in order for it to be useful as a widespread clinical technique.

Immune infiltration could predict the efficacy of short-term radiotherapy in patients with cervical cancer.

Radiotherapyis the main treatment forcervical cancer. It is usually applied alone or in combination with surgery and/or chemotherapy. To explore the association between immune microenvironment of cervical cancer and radiotherapy response, we collected 20 paired cervical cancer tumor samples before and after radiotherapy and partial clinical information. With paired-end RNA-seq, we quantified the immune infiltration and tumor purity of these samples, and obtained 6350 differentially expressed genes before and after radiotherapy. With the help of R language, the function enrichment analysis and 22 immune cells infiltration analysis were carried out. Moreover, we built a random forest model based on the immune microenvironment to predict the short-term efficacy of radiotherapy. We found that the effect of radiotherapy on the immune microenvironment of stage III and IV cervical cancer patients was weaker than that of stage I and II cervical cancer patients. Radiotherapy can significantly reduce the tumor purity and increase immune infiltration. The proportions of the immune infiltrating cells are predictive of the radiotherapy efficacy. In addition, the local mucositis caused by radiotherapy can improve the curative effect of radiotherapy.

18F-FET-PET imaging in high-grade gliomas and brain metastases: a systematic review and meta-analysis.

To provide a summary of the diagnostic performance of 18F-FET-PET in the management of patients with high-grade brain gliomas or metastases from extracranial primary malignancies. MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews databases were searched for studies that reported on diagnostic test parameters in radiotherapy planning, response assessment, and tumour recurrence/treatment-related changes differentiation. Radiomic studies were excluded. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool and the GRADE approach. A bivariate, random-effects model was used to produce summary estimates of sensitivity and specificity. Twenty-six studies with a total of 1206 patients/lesions were included in the analysis. For radiotherapy planning of glioma, the pooled proportion of patients from 3 studies with 18F-FET uptake extending beyond the 20mm margin from the gadolinium enhancement on standard MRI was 39% (95% CI, 10-73%). In 3 studies, 18F-FET-PET was also shown to be predictive of early responders to treatment, whereas MRI failed to show any prognostic value. For the differentiation of glioma recurrence from treatment-related changes, the pooled sensitivity and specificity of TBRmax 1.9-2.3 from 6 studies were 91% (95% CI, 74-97%) and 84% (95% CI, 69-93%), respectively. The respective values for brain metastases from 4 studies were 82% (95% CI, 74-88%) and 82% (95% CI, 74-88%) using TBRmax 2.15-3.11. While 18F-FET shows promise as a complementary modality to standard-of-care MRI for the management of primary and metastatic brain malignancies, further validation with standardized image interpretation methods in well-designed prospective studies are warranted.

Targeting Na-H exchanger 1 overcomes nuclear factor kappa B-mediated tumor resistance to radiotherapy

Intrinsic or acquired radioresistance often limits the efficacy of radiation therapy (RT), thereby leading to local control failure. Cancerous cells have abnormal pH dynamics due to high metabolic demands, but it is unclear how pH dynamics contribute to radioresistance. In this study, we investigated the role of Na-H exchange 1 (NHE1), the major intracellular pH (pHi) regulator, in RT response. We observed that RT increased NHE1 expression and modulated pHi in MDA-MB-231 human breast cancer cells. When combined with RT, pharmacological NHE1 inhibition by 5-(N-Ethyl-N-isopropyl)amiloride (EIPA) reduced pHi and clonogenic survival. EIPA attenuated radiation-damaged DNA repair, increasing G2/M cell cycle arrest. The combination of EIPA and RT increased apoptotic cell death while decreasing phosphorylation of NF-κB p65. Similarly, the knockdown of NHE1 increased radiosensitivity with lower pHi and increased apoptosis. Consistent with in vitro data, the EIPA plus RT inhibited the growth of MDA-MB-231 xenograft tumors in mice to a greater extent than either EIPA or RT alone. EIPA abrogated the RT-induced increase in NHE1 and phospho-NF-κB p65 expression in tumor tissues. Such coincidence of increased NHE1 level, pHi, and NF-κB activation was also found in radioresistant MDA-MB-231 cells, which were reversed by EIPA treatment. Bioinformatics analysis of RNA sequencing data revealed that inhibiting NHE1 reversed three core gene networks that were up-regulated in radioresistant cells and correlated with high NHE1 expression in patient samples: NF-κB, senescence, and extracellular matrix. Taken together, our findings suggest that NHE1 contributes to RT resistance via NF-κB-mediated signaling networks, and NHE1 may be a promising target for improving RT outcomes.

Improving the prediction for the response to radiotherapy of clinical tumor samples by using combinatorial model of MicroRNA expression.

Purpose: Radiation therapy (RT) is one of the main treatments for cancer. The response to radiotherapy varies widely between individuals and some patients have poor response to RT treatment due to tumor radioresistance. Stratifying patients according to molecular signatures of individual tumor characteristics can improve clinical treatment. In here, we aimed to use clinical and genomic databases to develop miRNA signatures that can predict response to radiotherapy in various cancer types. Methods: We analyzed the miRNAs profiles using tumor samples treated with RT across eight types of human cancers from TCGA database. These samples were divided into response group (S, n = 224) and progressive disease group (R, n = 134) based on RT response of tumors. To enhance the discrimination for S and R samples, the predictive models based on binary logistic regression were developed to identify the best combinations of multiple miRNAs. Results: The miRNAs differentially expressed between the groups S and R in each caner type were identified. Total 47 miRNAs were identified in eight cancer types (p values <0.05, t-test), including several miRNAs previously reported to be associated with radiotherapy sensitivity. Functional enrichment analysis revealed that epithelial-to-mesenchymal transition (EMT), stem cell, NF-κB signal, immune response, cell death, cell cycle, and DNA damage response and DNA damage repair processes were significantly enriched. The cancer-type-specific miRNA signatures were identified, which consist of 2-13 of miRNAs in each caner type. Receiver operating characteristic (ROC) analyses showed that the most of individual miRNAs were effective in distinguishing responsive and non-responsive patients (the area under the curve (AUC) ranging from 0.606 to 0.889). The patient stratification was further improved by applying the combinatorial model of miRNA expression (AUC ranging from 0.711 to 0.992). Also, five miRNAs that were significantly associated with overall survival were identified as prognostic miRNAs. Conclusion: These mRNA signatures could be used as potential biomarkers selecting patients who will benefit from radiotherapy. Our study identified a series of miRNA that were differentially expressed between RT good responders and poor responders, providing useful clues for further functional assays to demonstrate a possible regulatory role in radioresistance.

OTUD4-mediated GSDME deubiquitination enhances radiosensitivity in nasopharyngeal carcinoma by inducing pyroptosis

BackgroundRadioresistance is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure. Previous studies have focused on the deficits in cellular apoptosis as a mechanism for radioresistance; however, additional potential death modes involved in modulating radiosensitivity of NPC have not been explored.MethodsPyroptosis was assessed by phase-contrast imaging, LDH release assays, live cell imaging, and Western blotting. In vitro and in vivo assays were used to investigate the function of gasdermin E (GSDME) and ovarian tumor family deubiquitinase 4 (OTUD4). NPC tissues were analyzed using Western blotting, immunohistochemistry, and real-time PCR. The molecular mechanism was determined using immunoprecipitation assays and mass spectrometry.ResultsLive cell imaging revealed that 40—75% of irradiation-induced dead NPC cells were pyroptotic cells. Furthermore, irradiation-induced pyroptosis is triggered by GSDME, which are cleaved by activated caspase-3 in the intrinsic mitochondrial pathway. Additionally, GSDME was significantly downregulated in radioresistant NPC specimens. Low GSDME expression was a predictor of worse prognosis and conferred NPC radioresistance both in vitro and in vivo. Mechanistically, OTUD4 deubiquitinated and stabilized GSDME, enhancing radiosensitivity of NPC cells by promoting pyroptosis. Clinically, OTUD4 was significantly correlated with GSDME in NPC biopsies, and patients with low expression of both OTUD4 and GSDME suffered the worst radiotherapy response and survival.ConclusionsGSDME-dependent pyroptosis is a critical determinant of radiosensitivity in NPC, and is modulated by OTUD4 via deubiquitinating and stabilizing GSDME. These findings reveal a promising novel direction to investigate radioresistance and suggest potential therapeutic targets for sensitizing NPC to radiotherapy.

PRDM15 interacts with DNA-PK-Ku complex to promote radioresistance in rectal cancer by facilitating DNA damage repair

Neoadjuvant radiotherapy is a standard treatment for locally advanced rectal cancer, however, resistance to chemoradiotherapy is one of the main obstacles to improving treatment outcomes. The goal of this study was to explore the role of PRDM15 involved in the radioresistance of colorectal cancer and to clarify the underlying mechanism. In present study, we demonstrated that, after DNA damage, PRDM15 was upregulated and localized to DNA damage sites, co-localizing with γ-H2AX. Knockdown of PRDM15 inhibited DNA damage repair and increased radiosensitivity in colorectal cancer cells. Mechanistically, PRDM15 promoted DNA repair by interacting with DNA-PKcs and Ku70/Ku80 complex. In preclinical models of rectal cancer, knockdown of PRDM15 sensitized cell derived xenograft and patient derived xenograft to radiotherapy. In 80 rectal cancer patients treated with neoadjuvant chemoradiotherapy, higher PRDM15 expression was observed associated with weaker tumor regression and poorer prognosis. Our findings revealed that inhibiting PRDM15 was potent to overcome radioresistance through abrogating DNA repair in colorectal cancer cells. Additionally, the expression level of PRDM15 could be applied to predict radiotherapy responsiveness and the outcome of neoadjuvant radiotherapy in rectal cancer patients.

Panaxadiol targeting IL2 inducible T cell kinase promotes T cell immunity in radiotherapy.

Ginseng, as a traditional Chinese medicine, has a good protective effect against radiotherapy, but its mechanism in radiotherapy still needs to be further explored. The active ingredients of Ginseng were analyzed according to pharmacodynamics in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database, and the target genes of active ingredients were screened by UniProt, PubChem and Swiss target prediction database. The differentially expressed genes of GSE6871 and GSE20162 were analyzed from the GEO database. Further, cluster analysis and enrichment analysis were carried out through protein-protein interaction network to determine hub gene. Next, build the drug-disease target network, conduct molecular docking simulation, and determine the key ingredients and targets of Ginseng on radiotherapy. We screened 16 active ingredients of Ginseng and 747 target genes from the TCMSP database. Eighty-two common differentially expressed genes were obtained by the GEO database. After topological analysis, we finally determined CD28, FYN, IL2 inducible T cell kinase (ITK), MYC and CD247 as hub genes. After integrating the drug-disease target network and molecular docking, we found that Panaxadiol, as an active ingredient of Ginseng, can target ITK to participate in T cell signal receptor pathway and act on radiotherapy. Panaxadiol can act on the key target ITK of radiotherapy, participate in T cell signal receptor pathway, and then affect the proliferation, differentiation and immune response of radiotherapy T cells, so as to reduce the side effects of radiotherapy.

H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.

Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation led to the downregulation of DNA repair pathways. This resulted in enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG led to the accumulation of extrachromosomal DNA, which activated the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier-permeable PARP inhibitor pamiparib and the cell-cycle checkpoint CHK1/2 inhibitor AZD7762), and these combinations resulted in long-term survival for approximately 50% of the mice. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induced immune-mediated therapeutic efficacy in G34-mutant pHGG.

BIOM-54. ANALYTICAL VALIDATION OF A TARGETED GENE EXPRESSION BIOMARKER PREDICTING MENINGIOMA OUTCOMES AND RADIOTHERAPY RESPONSES

Abstract BACKGROUND Improvements in meningioma risk stratification are needed to guide postoperative management. We previously developed and externally validated a targeted gene expression biomarker predicting meningioma outcomes and radiotherapy response using fresh frozen meningiomas. Here, we present the analytical validity, test-retest and cross-platform reproducibility, intra-tumor heterogeneity, and formalin fixed paraffin embedded (FFPE) concordance for this biomarker. METHODS Matched FFPE and fresh frozen samples from 50 meningiomas underwent RNA extraction for concordance testing using a custom Nanostring gene expression panel comprised of 34 meningioma genes and 7 housekeeping genes. Matched Nanostring gene expression profiling and RNA-sequencing was available from 173 fresh frozen meningiomas. Nanostring batch, machine, and technician variability was tested on 10 FFPE meningiomas using 2 independent batches of biomarker reagents that were processed at 2 independent laboratories. To study intra-tumor heterogeneity, 68 spatially distinct meningioma biopsies obtained under stereotactic guidance from 13 tumors were analyzed using the Nanostring gene expression biomarker. RESULTS Matched FFPE and fresh frozen meningioma samples (N=50) demonstrated high gene expression concordance (Pearson R=0.89, F-test P&amp;lt; 2.2e-16) and risk score concordance (R=0.78, F-test P&amp;lt; 1.8e-11, residual standard error 0.12). The biomarker achieved high performance on FFPE samples (local freedom from recurrence [LFFR] c-index 0.75±SEM 0.05, 5y LFFR AUC 0.84, 95% interval 0.67-0.96). Test-retest concordance on FFPE samples (N=10) across independent reagent batches, machines, and technicians was high (gene expression concordance: R=0.97; risk score concordance R=0.94). Transcript counts were concordant across Nanostring and RNA sequencing approaches (N=173 frozen samples, R=0.90). Stereotactic intra-operative sampling (N=68 samples from 13 patients) revealed low levels of intra-tumor heterogeneity (median inter-quartile risk score within tumor: 0.10±0.01). CONCLUSIONS We demonstrate analytical reproducibility and robustness of a gene expression biomarker predicting meningioma outcomes and radiotherapy responses in FFPE and frozen samples across multiple conditions and platforms.

EPCO-01. EPIGENETIC REPROGRAMMING SHAPES THE MOLECULAR AND CELLULAR LANDSCAPE OF SCHWANNOMA

Abstract DNA methylation profiling provides robust classification of nervous system tumors, but mechanisms driving epigenetic identity of individual tumor types are incompletely understood. Integrating DNA methylation profiling (n=76), RNA sequencing (n=24), single-cell RNA-sequencing (n=9), and mass cytometry (n=9), we discovered vestibular schwannomas are comprised of two epigenetic groups distinguished by neural crest development pathways or repair and regeneration pathways driving immune infiltration. Analyses of preoperative magnetic resonance imaging studies (n=66) or paired primary and recurrent schwannomas (n=13) suggested radiotherapy was sufficient but not necessary for epigenetic reprogramming of neural crest enriched schwannomas into immune enriched schwannomas. In support of this hypothesis, DNA methylation profiling, RNA sequencing, single-cell RNA sequencing, proteomic mass spectrometry, and lymphocyte migration assays demonstrated radiotherapy epigenetically reprogramed viable schwannoma cells to secrete immunomodulatory signals and recruit lymphocytes in vitro. Genome-wide CRISPRi screens identified histone acetyltransferases or DNA methyltransferases driving schwannoma radiotherapy responses, including the epigenetic regulators KDM5C or KDM1A. CRISPRi and lymphocyte migration assays ± radiotherapy confirmed KDM5C drives schwannoma immune infiltration whereas KDM1A inhibits schwannoma immune infiltration. To define genomic mechanisms underlying epigenetic group identity, we performed pooled CRISPRi screening coupled with single-cell RNA sequencing (Perturb-seq) of 44 schwannoma markers. In parallel, we developed single nuclei profiling of chromatin accessibility through paired ATAC sequencing and RNA sequencing coupled with pooled CRISPRi screening (snARC-seq) of 54 epigenetic regulators identified by our genome-wide CRISPRi screen. Functional genomic approaches revealed the tyrosine phosphatase PTPRG as a regulator of survival, and KDM5C and KDM1A as regulators of inflammation. In summary, we report two epigenetic groups of schwannomas and mechanisms underlying epigenetic group identity using a new functional genomic technique allowing for simultaneous interrogation of single-cell epigenetic and gene expression changes in the context of genetic and therapeutic perturbations. These data elucidate a novel epigenetic mechanism of action of radiotherapy.

Irradiation-induced exosomal HMGB1 to confer radioresistance via the PI3K/AKT/FOXO3A signaling pathway in ESCC

BackgroundRadioresistance is a major cause of treatment failure in esophageal squamous cell carcinoma (ESCC) radiotherapy, and the underlying mechanisms of radioresistance are still unclear. Irradiation (IR) stimulates changes in tumor-derived exosome contents, which can be taken up by recipient cells, playing an important role in the proliferation, cell cycle and apoptosis of recipient cells. This study investigated the effect of IR-induced exosomal high mobility group box 1 (HMGB1) on radioresistance in ESCC cells.MethodsPlasma exosomes were isolated from 21 ESCC patients and 24 healthy volunteers, and the expression of HMGB1 was examined. Then, the therapeutic effect of radiotherapy was analyzed according to the different expression levels of plasma exosomal HMGB1 in ESCC patients. The uptake of exosomes by recipient cells was verified by immunofluorescence staining, and the localization of exosomes and HMGB1 in cells before and after IR was evaluated. The effects of IR-induced exosomes on cell proliferation, invasion, apoptosis, cell cycle distribution and radioresistance after HMGB1 knockdown were verified. Moreover, western blotting was used to measure changes in the expression of cyclin B1, CDK1, Bax, Bcl2, phosphorylated histone H2AX and the PI3K/AKT/FOXO3A pathway in the HMGB1-knockdown exosome group and the negative control group.ResultsThe expression of HMGB1 in ESCC plasma exosomes was significantly increased compared with that in healthy volunteers, and high expression of HMGB1 in plasma exosomes was associated with radioresistance (P = 0.016). IR-induced the release of exosomal HMGB1 and promoted proliferation and radioresistance in recipient cells, with a sensitization enhancement ratio (SER) of 0.906 and 0.919, respectively. In addition, IR-induced exosomal HMGB1 promotes G2/M phase arrest by regulating the proteins cyclin B1 and CDK1, cooperating with the proteins Bax and Bcl2 to reduce the apoptosis rate through the PI3K/AKT/FOXO3A signaling pathway, and participated in IR-induced DNA damage repair through γH2AX.ConclusionThese findings indicate that high expression of plasma exosomal HMGB1 is associated with an adverse radiotherapy response. IR-induced exosomal HMGB1 enhances the radioresistance of ESCC cells.

LncRNAs as biomarkers for predicting radioresistance and survival in cancer: a meta-analysis

The effect of long noncoding RNAs (lncRNAs) on the radiotherapy response has been gradually revealed. This systematic review and meta-analysis aimed to evaluate the association between the function and underlying mechanism of lncRNAs in regulating the radiosensitivity and radioresistance of different tumors. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated to estimate the effect of lncRNAs on cancer patient prognosis, including overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS) and progression-free survival (PFS). Collectively, 23 lncRNAs in 11 cancer types were enrolled. Of them, 13 lncRNAs were downregulated and related to radiosensitivity, 11 lncRNAs were upregulated and related to radioresistance, and 3 lncRNAs were upregulated and related to radiosensitivity in cancers. Furthermore, 17 microRNAs and 20 pathways were targeted by different lncRNAs and contributed to the cancer radiotherapy response in this meta-analysis. The individual pooled HRs (95% CIs) of downregulated radiation-resistant and upregulated radiation-resistant lncRNAs for OS were 0.49 (0.40–0.60) and 1.88 (1.26–2.79), respectively. Our results showed that lncRNAs could modulate tumor radioresistance or sensitivity by affecting radiation-related signaling pathways and serve as potential biomarkers to predict radiotherapy response.

194P A study of the treatment response of concomitant external beam radiotherapy (EBRT) and intracavitary brachytherapy in the management of locally advanced carcinoma of uterine cervix

194P A study of the treatment response of concomitant external beam radiotherapy (EBRT) and intracavitary brachytherapy in the management of locally advanced carcinoma of uterine cervix

Non-Small Cell Lung Cancer with Malignant Pleural Effusion May Require Primary Tumor Radiotherapy in Addition to Drug Treatment.

The impact of primary tumour radiotherapy on the prognosis for non-small-cell lung cancer (NSCLC) with controlled malignant pleural effusion (MPE-C) (MPE-C-NSCLC) is unclear. This study aimed to analyze the efficacy and safety of primary tumor radiotherapy in patients with MPE-C-NSCLC. A total of186 patients with MPE-C-NSCLC were enrolled and divided into two groups. The patients in the D group were treated with only drugs. Those in the RD group were treated with drugs plus primary tumour radiotherapy. The Kaplan-Meier method was used for survival analysis, and the Log rank test was used for between-group analysis and univariate prognostic analysis. The Cox proportional hazards model was used to perform multivariate analyses to assess the impacts of factors on survival. Propensity score matching (PSM) was matched based on clinical characteristics, systematic drug treatment and drug response to further adjust for confounding factors. The overall survival (OS) rates at 1, 2, and 3 years for the RD group and D group were 54.4%, 26.8%, and 13.3% and 31.1%, 11.5%, and 4.4%, respectively; the corresponding MSTs were 14 months and 8 months, respectively (χ 2=15.915, p<0.001). There was a significant difference in survival by PSM (p=0.027).Before PSM, multivariate analysis showed that metastasis status (organ≤3 and metastasis≤5), primary tumour radiotherapy, chemotherapy cycles≥4, and drug best response (CR+PR) were independent predictors of prolonged OS. After PSM, primary tumour radiotherapy and drug best response (CR+PR) were independent predictors of prolonged OS were still independent predictors of prolonged OS. There were no grade 4-5 radiation toxicities. For MPE-C-NSCLC, the response of systemic drug treatment plays a crucial role in survival outcomes, and we also should pay attention to primary tumour radiotherapy in addition to systematic drug treatment.

Transcriptomic Analysis of ATM Expression in Localized Prostate Cancer – Implications for Radiotherapy Treatment

<h3>Purpose/Objective(s)</h3> The prognostic impact and therapeutic implication of ATM (ataxia telangiectasia mutated) somatic and germline alterations have been previously characterized in prostate cancer. However, ATM expression, particularly in the context of radiotherapy (RT) for localized disease, has not been well documented. Herein, genomic expression analyses were performed to evaluate associations between ATM expression, biological pathways, clinical outcomes and RT treatment response. <h3>Materials/Methods</h3> Whole-transcriptome assays were used to interrogate 5,780 radical prostatectomy (RP) samples for ATM expression (5,000 from a prospective cohort was used to evaluate biological signatures and 780 samples from a retrospective cohort with long term follow-up data to evaluate ATM prognostic impact). Additionally, we assessed 245 patients (subset of the 780) who were treated with adjuvant or salvage RT after RP. A 1:1 matched cohort [n=98 treated with RT, n=98 with no RT] was generated to assess ATM expression in relation to RT response. We next investigated the relationship using Pearson's correlation tests between ATM expression and more than 200 genomic signatures, biological pathways, and a Genomic Classifier (GC) (molecular subtypes). ATM high, medium, and low were defined as the top 25%, middle 50%, and bottom 25% of ATM expression, respectively. The prognostic and predictive ability of ATM expression was examined for the metastasis-free survival (MFS) endpoint with hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox Proportional Hazard model. <h3>Results</h3> In the prospective cohort, ATM was significantly overexpressed in high GC patients (molecular surrogate for poor outcome) (p<0.0001). ATM high (top 25%) was associated with worse MFS (HR = 1.16, 95% CI: 1.51-1.96, p=0.002). ATM expression was highly correlated to signatures related to DNA repair, angiogenesis, immune cell infiltration and genomic instability and highly correlated to CDK2 and PARP1 genes (R>0.5, p<0.0001 for all). In patients treated with RT, ATM high was associated with worse MFS compared to lower ATM (10-year MFS 30% vs 61%; p=0.009), whereas in the patients treated without RT, ATM high was not significantly associated with worse MFS (10-year MFS 52% vs 66%; p=0.26) <h3>Conclusion</h3> Prostate cancer patients harboring high ATM expression by transcriptomic analysis had poorer outcomes with a significantly higher risk of metastasis. Given the worse outcomes, particularly in patients treated with RT, a high ATM expression may be a marker of resistance to DNA damaging agents. Additional studies are needed to elucidate further the predictive ability of ATM overexpression for RT personalization.

Metabolic biomarkers of radiotherapy response in plasma and tissue of an IDH1 mutant astrocytoma mouse model.

Astrocytomas are the most common subtype of brain tumors and no curative treatment exist. Longitudinal assessment of patients, usually via Magnetic Resonance Imaging (MRI), is crucial since tumor progression may occur earlier than clinical progression. MRI usually provides a means for monitoring the disease, but it only informs about the structural changes of the tumor, while molecular changes can occur as a treatment response without any MRI-visible change. Radiotherapy (RT) is routinely performed following surgery as part of the standard of care in astrocytomas, that can also include chemotherapy involving temozolomide. Monitoring the response to RT is a key factor for the management of patients. Herein, we provide plasma and tissue metabolic biomarkers of treatment response in a mouse model of astrocytoma that was subjected to radiotherapy. Plasma metabolic profiles acquired over time by Liquid Chromatography Mass Spectrometry (LC/MS) were subjected to multivariate empirical Bayes time-series analysis (MEBA) and Receiver Operating Characteristic (ROC) assessment including Random Forest as the classification strategy. These analyses revealed a variation of the plasma metabolome in those mice that underwent radiotherapy compared to controls; specifically, fumarate was the best discriminatory feature. Additionally, Nuclear Magnetic Resonance (NMR)-based 13C-tracing experiments were performed at end-point utilizing [U-13C]-Glutamine to investigate its fate in the tumor and contralateral tissues. Irradiated mice displayed lower levels of glycolytic metabolites (e.g. phosphoenolpyruvate) in tumor tissue, and a higher flux of glutamine towards succinate was observed in the radiation cohort. The plasma biomarkers provided herein could be validated in the clinic, thereby improving the assessment of brain tumor patients throughout radiotherapy. Moreover, the metabolic rewiring associated to radiotherapy in tumor tissue could lead to potential metabolic imaging approaches for monitoring treatment using blood draws.

Prospective Assessment of Diffusion-Weighted-MRI as a Biomarker of Treatment Response and Disease Control in Head and Neck Cancer

<h3>Purpose/Objective(s)</h3> To determine diffusion-weighted MRI (DWI) parameters associated with tumor response and local control (LC) in head and neck (HNC) patients treated with definitive radiation therapy (RT). <h3>Materials/Methods</h3> Eighty-seven HNC patients enrolled in an active prospective imaging study at MD Anderson Cancer Center were included in the analysis. Patients had MRIs prior to, at mid-RT, and post-treatment completion. Inclusion criteria include adult with histologic evidence of malignant head and neck neoplasm indicated for curative-intent treatment with RT with/without chemotherapy; good performance status (ECOG score 0-2); and with no contraindications to MRI. Patients were scanned using a full-body MRI scanner with two large four-channel flex phased-array coils. We used fat-suppressed T2-weighted turbo spin echo for tumor segmentation which was co-registered to respective DWIs for extraction of apparent diffusion coefficient (ADC) measurements. Sequence parameters were (TR/TE (ms); pixel size/slice thickness (mm); b-values (s/mm2)): T2-weighted (5280/80; 0.5/2; N/A), BLADE (5900/50; 2/4; 0 & 800), RESOLVE (9380/63; 2/4; 0 & 800). Treatment response was assessed at mid-RT and at 8-12 weeks post-RT using RECIST 1.1 criteria and was defined as: complete response (CR) vs non-complete response (non-CR). Pre-RT ADC was correlated with RT response (CR vs non-CR) at mid- and post-RT time points. Mann-Whitney test was used to compare ADC values between the mid-treatment CR group and the non-CR group. Recursive partitioning analysis (RPA) was done to identify ADC threshold associated with relapse. <h3>Results</h3> Fifty-nine patients with grossly visible primary tumor volume prior to RT start were included in this analysis. Patients' disease and treatment criteria are shown in Table 1. Pre-treatment ADC was not correlated with tumor response or oncologic outcomes (P>0.05). For patients with CR at the end of RT, there was a significant increase in mean ADC at mid-RT compared to baseline ((1.8 ± 0.29) × 10^–3 mm²/s <i>vs</i> (1.37 ± 0.22) × 10^–3 mm²/s, <i>p</i> <0.0001). However, patients with no-CR had no statistically significant increase (p>0.05). Median follow-up was 32 months. Patients with ≤106% delta ADC at mid-RT had significantly worse local control at 2-year compared to patients with higher delta ADC (48% vs 96%, <i>p</i> <0.0001). <h3>Conclusion</h3> Delta ADC changes is a strong predictor of local recurrence in head and neck cancer patients. Multi-institutional data is needed for validation of our results.

Improving Outcomes Prediction Using a Combination of MRI Wavelet Delta-Radiomic Textures and Clinical Biomarkers for MR-Guided Adaptive Radiation Therapy of Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> We have previously reported that wavelet delta radiomic features (WDRF) extracted from daily MRIs can predict treatment response of MRI-guided adaptive radiation therapy (MRgART) for pancreatic cancer. This study aims to investigate whether combining available clinical biomarkers with the WDRF would improve outcome prediction for pancreatic cancer treated with pre-operative MRgART. <h3>Materials/Methods</h3> This method was developed and demonstrated using 90 daily motion averaged MRI sets derived from 4D MRIs acquired during MRgART with concurrent chemotherapy for 18 pancreatic cancer patients treated in 5 SBRT fractions on a 1.5T MR-Linac, along with their CA19-9, CEA, metastatic status, and follow up data. For each daily MRI set, wavelet decompositions were applied a programming environment to provide a robust way for feature extraction and to overcome challenges with inter- and intra-patient MRI intensity variations. 438 WDRF were calculated from different decomposition levels. Good or bad response groups were defined based on pathological response or distant metastasis free progression, and 50% reduction in CA19-9. The time between the end of treatment and end points of death or presence of distant metastasis within 2 years were used to build progression free survival (PFS) model. Spearman correlations were applied to rule out redundant features. T-test and regression models were used to identify independent WDRFs with significant changes that correlate to response and to examine the effect of combining CA19-9, CEA, and WDRFs on response prediction. Concordance statistics was used to measure model effectiveness. A Cox analysis was performed to identify predictors of PFS and test the association of the combinations on PFS correlations. The effect of a decrease in CA19-9 or CEA levels during treatment versus failure of CA19-9 or CEA levels to normalize on PFS was examined. <h3>Results</h3> Spearman correlation showed that 67 WDRFs from different wavelet decomposition were not redundant and can be used for the analysis. 30 WDRF demonstrated opposite trends correlating to response. Of these, 8 WDRFs passed the t-test showing significant changes correlating to response by the 3rd or 4th fraction. CA199 and CEA were each correlated to 2 WDRFs. Increasing CA19-9, CEA levels during treatment were correlated to bad response. Incorporating CEA, CA19-9 with the significant WDRFs increased the concordance statistics from 0.65 to 0.96. The Cox multivariate analysis showed that a treatment related decrease in CA19-9 levels (p=0.0017), and 3 WDRFs (p=0.004-0.013) were independent predictors of PFS. The hazard ratio was reduced from 0.57, p=0.03 for using CA19-9 only to 0.163, p=0.004 for the combination of WDRFs and CA19-9. <h3>Conclusion</h3> Combining wavelet delta-radiomics features extracted from daily treatment MRIs with common clinical biomarkers improves outcome prediction for chemoradiation therapy of pancreatic cancer and may ultimately enable intensification of additional treatment to improve outcomes.