Enhanced Tumor Burden Research Articles

Abstract PO3-25-02: Circadian Rhythm Disruption Accelerates Aggressive Mammary Tumorigenesis by Altering Tumor Microenvironment

Abstract \Breast cancer is the most common cancer in women worldwide, leading to over 650,000 deaths worldwide. The circadian rhythm is a 24-hour biological rhythm that controls most cellular, hormonal, and behavioral processes in living organisms, which is why perturbation of these rhythms is linked to several devastating diseases such as cardiovascular diseases, diabetes, and cancer. In the mammary gland, circadian clocks regulate the rhythmic expression of numerous genes. Circadian rhythm disruption (CRD), which has been termed a "carcinogen" by the International Agency for Research in Cancer, is caused by different factors, one of them being shift work. Several epidemiological studies have revealed that women who work night shifts are predisposed to breast cancer. The aim of this study is to investigate the effect of circadian rhythm disruption on aggressive mammary tumorigenesis. To do this, we used genetically engineered mouse models of mammary tumors (HER2-tumor and triple-negative breast tumor, or TNBC). Chronic jetlag, which mimics shift work in mice and is known to cause CRD, was introduced in one group of mice by perturbing the normal light and dark cycles with an 8-hour advance every three days. Wheel-running, which is represented by an actogram, was used to confirm the circadian disruption in the CRD mice. CRD was found to accelerate tumor initiation with a significant increase in weight in the CRD group of mice. CRD enhanced tumor burden significantly compared to LD mice. Our results also showed high metastatic foci in the lungs of CRD mice compared to LD mice. A flow cytometry study showed a higher cancer stem cell population in CRD tumors. Mammosphere assays with tumor-derived cells showed that CRD increased the number and size of the mammospheres compared to the control tumors. The tumor cells were analyzed using single-cell RNA sequencing, which showed that CRD alters the tumor microenvironment by developing more immunosuppressive and "cold" tumors. The tumor-derived organoids (tumoroid) showed resistance to chemotherapeutics. Finally, bioinformatics analysis using single-cell RNA seq data from human breast tumors (TNBC, ER/PR, and HER2) showed that the malignant cells in TNBC tumors had a significantly higher circadian rhythm disrupted score (CRD score) compared to ER/PR tumors. Taken together, our data showed how circadian rhythm disruption affects TNBC tumorigenesis and drug response by altering the tumor microenvironment. Citation Format: Olajumoke Ogunlusi, Mrinmoy Sarkar, Tristan Nguyen, Devon Boland, James Cai, Arhit Chakrabarti, Bani Mallick, Alex Keene, Tapasree Roy Sarkar. Circadian Rhythm Disruption Accelerates Aggressive Mammary Tumorigenesis by Altering Tumor Microenvironment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-02.

NIMG-52. CORRELATION OF BIDIMENSIONAL AND VOLUMETRIC TUMOR SIZING IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Glioblastoma (GBM) is the most common malignant primary nervous system tumor and remains incurable with a poor prognosis despite current therapy. The standard for monitoring response to treatment, as defined by the Response Assessment in Neuro-Oncology (RANO) criteria, relies on a bidimensional (2D) measurement product of T1-gadolinium enhancing disease. However, due to the variability of bidimensional tumor characterization, there is considerable interest in volumetric segmentation to assess tumor burden, which could be implemented using machine learning models offering workflow automatization. METHODS In this study, we evaluate a commercially available automated tumor segmentation tool and correlate its volumetric output to the manual assessment of bidimensional 2D enhancing tumor burden by experts. MRI examinations during systemic treatment for two retrospective cohorts of patients with either newly diagnosed (nGBM) or recurrent GBM (rGBM) were assessed. The 2D diameter product in cm^2 of enhancing tumor was determined by blinded readers and volumetric segmentations in cm^3 were automatically generated. Spearman's correlation between the manual 2D and automated volume measurements was calculated for each cohort. RESULTS 315 patients with nGBM, and 482 with rGBM were evaluated, comprising 3073 total brain MRIs in the nGBM cohort and 2439 MRIs in the rGBM cohort. Spearman's correlation between the manual 2D and automated volumetric measurements was 0.7463 (0.730, 0.762) in the nGBM cohort and 0.8598 (0.849, 0.870) in the rGBM cohort. CONCLUSION Automated segmentation tools have the potential to revolutionize radiology workflows and increase sensitivity to subtle changes on imaging. However, the differential performance of this volumetric assessment confirms the need for further refinement and customization of such automated tools to account for tumor- and patient-specific factors.

Host obesity alters the ovarian tumor immune microenvironment and impacts response to standard of care chemotherapy

BackgroundThe majority of women with epithelial ovarian cancer (OvCa) are diagnosed with metastatic disease, resulting in a poor 5-year survival of 31%. Obesity is a recognized non-infectious pandemic that increases OvCa incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity mouse model wherein a significantly enhanced tumor burden was associated with a decreased M1/M2 tumor-associated macrophage ratio (Liu Y et al. Can, Res. 2015; 75:5046–57).MethodsThe objective of this study was to use pre-clinical murine models of diet-induced obesity to evaluate the effect of a high fat diet (HFD) on response to standard of care chemotherapy and to assess obesity-associated changes in the tumor microenvironment. Archived tumor tissues from ovarian cancer patients of defined body mass index (BMI) were also evaluated using multiplexed immunofluorescence analysis of immune markers.ResultsWe observed a significantly diminished response to standard of care paclitaxel/carboplatin chemotherapy in HFD mice relative to low fat diet (LFD) controls. A corresponding decrease in the M1/M2 macrophage ratio and enhanced tumor fibrosis were observed both in murine DIO studies and in human tumors from women with BMI > 30.ConclusionsOur data suggest that the reported negative impact of obesity on OvCa patient survival may be due in part to the effect of the altered M1/M2 tumor-associated macrophage ratio and enhanced fibrosis on chemosensitivity. These data demonstrate a contribution of host obesity to ovarian tumor progression and therapeutic response and support future combination strategies targeting macrophage polarization and/or fibrosis in the obese host.

Potential Value of Liver Enhancing Tumor Burden at CT to Predict Survival after Intra-arterial Treatment for Neuroendocrine Liver Metastases

HomeRadiology: Imaging CancerVol. 5, No. 2 PreviousNext Research HighlightsPotential Value of Liver Enhancing Tumor Burden at CT to Predict Survival after Intra-arterial Treatment for Neuroendocrine Liver MetastasesMohamed SolimanMohamed SolimanMohamed SolimanPublished Online:Mar 31 2023https://doi.org/10.1148/rycan.239008MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Highlighted ArticleAssouline J, Cannella R, Porrello G, et al. Volumetric Enhancing Tumor Burden at CT to Predict Survival Outcomes in Patients with Neuroendocrine Liver Metastases after Intra-arterial Treatment. Radiol Imaging Cancer 2023;5(1):e220051. doi: https://doi.org/10.1148/rycan.220051 Link, Google ScholarArticle HistoryPublished online: Mar 31 2023 FiguresReferencesRelatedDetailsRecommended Articles RSNA Education Exhibits RSNA Case Collection Vol. 5, No. 2 Metrics Altmetric Score PDF download

Volumetric Enhancing Tumor Burden at CT to Predict Survival Outcomes in Patients with Neuroendocrine Liver Metastases after Intra-arterial Treatment

Purpose To investigate whether liver enhancing tumor burden (LETB) assessed at contrast-enhanced CT indicates early response and helps predict survival outcomes in patients with multifocal neuroendocrine liver metastases (NELM) after intra-arterial treatment. Materials and Methods This retrospective study included patients with NELM who underwent intra-arterial treatment with transarterial embolization (TAE) or chemoembolization (TACE) between April 2006 and December 2018. Tumor response in treated NELM was evaluated by using the Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). LETB was measured as attenuation 2 SDs greater than that of a region of interest in the nontumoral liver parenchyma. Overall survival (OS); time to unTA(C)Eable progression, defined as the time from the initial treatment until the time when intra-arterial treatments were considered technically unfeasible, either not recommended by the multidisciplinary tumor board or until death; and hepatic and whole-body progression-free survival (PFS) were evaluated using multivariable Cox proportional hazards analyses, the Kaplan-Meier method, and log-rank test. Results The study included 119 patients (mean age, 60 years ± 11 [SD]; 61 men) who underwent 161 treatments. A median LETB change of -25.8% best discriminated OS (83 months in responders vs 51 months in nonresponders; P = .02) and whole-body PFS (18 vs 8 months, respectively; P < .001). A -10% LETB change best discriminated time to unTA(C)Eable progression (32 months in responders vs 12 months in nonresponders; P < .001) and hepatic PFS (18 vs 8 months, respectively; P < .001). LETB change remained independently associated with improved OS (hazard ratio [HR], 0.56), time to unTA(C)Eable progression (HR, 0.44), hepatic PFS (HR, 0.42), and whole-body PFS (HR, 0.47) on multivariable analysis. Neither RECIST nor mRECIST helped predict patient outcome. Conclusion Response according to LETB change helped predict survival outcomes in patients with NELM after intra-arterial treatments, with better discrimination than RECIST and mRECIST. Keywords: CT, Chemoembolization, Embolization, Abdomen/GI, Liver Supplemental material is available for this article. © RSNA, 2023.

Analysis of Tumor Burden as a Biomarker for Patient Survival with Neuroendocrine Tumor Liver Metastases Undergoing Intra-Arterial Therapies: A Single-Center Retrospective Analysis.

To assess the value of quantitative analysis of tumor burden on baseline MRI for prediction of survival in patients with neuroendocrine tumor liver metastases (NELM) undergoing intra-arterial therapies. This retrospective single-center analysis included 122 patients with NELM who received conventional (n = 74) or drug-eluting beads, (n = 20) chemoembolization and radioembolization (n = 28) from 2000 to 2014. Overall tumor diameter (1D) and area (2D) of up to 3 largest liver lesions were measured on baseline arterially contrast enhanced MR images. Three-dimensional quantitative analysis was performed using the qEASL tool (IntelliSpace Portal Version 8, Philips) to calculate enhancing tumor burden (the ratio between enhancing tumor volume and total liver volume). Based on Q-statistics, patients were stratified into low tumor burden (TB) or high TB. The survival curves were significantly separated between low TB and high TB groups for 1D (p < 0.001), 2D (p < 0.001) and enhancing TB (p = 0.008) measurements, with, respectively, 2.7, 2.6 and 2.2 times longer median overall survival (MOS) in the low TB group (p < 0.001, p < 0.001 and p = 0.008). Multivariate analysis showed that 1D, 2D, and enhancing TB were independent prognostic factors for MOS, with respective hazard ratios of 0.4 (95%CI: 0.2-0.6, p < 0.001), 0.4 (95%CI: 0.3-0.7, p < 0.001) and 0.5 (95%CI: 0.3-0.8, p = 0.003). The overall tumor diameter, overall tumor area, and enhancing tumor burden are strong prognostic factors of overall survival in patients withneuroendocrine tumor liver metastases undergoing intra-arterial therapies.

Loss of the aryl hydrocarbon receptor increases tumorigenesis in p53-deficient mice

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates cell fate via activation of a diverse set of genes. There are conflicting reports describing the role of AhR in cancer. AhR-knockout mice do not develop tumors spontaneously, yet the AhR can act as a tumor suppressor in certain contexts. Loss of tumor suppression by p53 is common in human cancer. To investigate AhR function in the absence of p53, we generated mice lacking both AhR and p53. Mice deficient for AhR and p53 had shortened lifespan, increased tumorigenesis, and an altered tumor spectrum relative to control mice lacking only p53. In addition, knockout of both AhR and p53 resulted in reduced embryonic survival and neonatal fitness. We also examined the consequences of loss of AhR in p53-heterozygous mice and observed a significantly reduced lifespan and enhanced tumor burden. These findings reveal an important role for the AhR as a tumor suppressor in the absence of p53 signaling and support the development of anti-cancer therapeutics that would promote the tumor suppressive actions of the AhR.

Abstract 975: Obesity-induced changes in the tumor microenvironment impact the response to chemotherapy and overall ovarian cancer metastatic success

Abstract Background The majority of women with epithelial ovarian cancer (OvCa) are diagnosed with metastatic disease, resulting in a poor 5-year survival of 31%. Obesity is a recognized epidemic that increases OvCa incidence, enhances metastatic success and reduces survival. We have previously demonstrated a link between obesity and OvCa metastatic success in a diet-induced obesity (DIO) mouse model where a significantly enhanced tumor burden was associated with a decreased M1/M2 tumor-associated macrophage (TAM) ratio (Liu Y et al. Can, Res. 2015; 75:5046-57). TAMs are the most abundant immune cell type in the ovarian tumor microenvironment and are generally categorized as M1-polarized (cytotoxic to tumor cells), or M2-polarized (growth promoting). For this study we sought to examine if a similar correlation between body mass index (BMI) and TAMs were also true for human ovarian cancer patients. Furthermore, we used the DIO mouse model to examine any potential effect of obesity on response to chemotherapy. Methods We analyzed high grade serous ovarian tumors from 6 normal weight patients (BMI 20-25), and 10 obese patients (BMI ≥35) for an in-depth analysis of immune cells using MultiOmyx™, an immunofluorescence (IF) multiplexing assay. After multiplexing FFPE sections with a custom panel of 13 immuno-oncology biomarkers, images were analyzed by applying the deep-learning based cell classification platform NeoLYTX.For the analysis of response to chemotherapy we used a DIO mouse model in which mice were fed a low-fat diet (LFD) vs high-fat diet (HFD) and then injected with ID8-Trp53-/- cells to establish tumor burden. Mice bearing equivalent tumor burden were treated with weight-adjusted standard of care chemotherapy. After sacrifice, remaining tumor burden was evaluated by quantitative fluorescence imaging. Results We found that the mean M1/M2 ratio in obese OvCa patients was nearly half (ratio=0.16) compared to patients who were normal weight (ratio=0.29), consistent with our previously published mouse data. Quantitation of residual tumor burden in the mouse model showed significantly reduced efficacy of chemotherapy (i.e., greater remaining tumor burden) in HFD mice (n=11/cohort). The M1/M2 TAM ratio in these mouse tumors is now under evaluation. Conclusions Our observations suggest that the negative impact of obesity on OvCa survival may be due in part to an increased M1/M2 TAM ratio and reduced response to chemotherapy. These data will be key to a more detailed understanding of the contribution of host obesity to ovarian tumor progression. Citation Format: Anna Juncker-Jensen, Yueying Liu, Tyvette S. Hilliard, Nicholas Stavrou, M Sharon Stack. Obesity-induced changes in the tumor microenvironment impact the response to chemotherapy and overall ovarian cancer metastatic success [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 975.

Optimization of the BCLC Staging System for Locoregional Therapy for Hepatocellular Carcinoma by Using Quantitative Tumor Burden Imaging Biomarkers at MRI.

Background Patients with intermediate- and advanced-stage hepatocellular carcinoma (HCC) represent a highly heterogeneous patient collective with substantial differences in overall survival. Purpose To evaluate enhancing tumor volume (ETV) and enhancing tumor burden (ETB) as new criteria within the Barcelona Clinic Liver Cancer (BCLC) staging system for optimized allocation of patients with intermediate- and advanced-stage HCC to undergo transarterial chemoembolization (TACE). Materials and Methods In this retrospective study, 682 patients with HCC who underwent conventional TACE or TACE with drug-eluting beads from January 2000 to December 2014 were evaluated. Quantitative three-dimensional analysis of contrast-enhanced MRI was performed to determine thresholds of ETV and ETB (ratio of ETV to normal liver volume). Patients with ETV below 65 cm3 or ETB below 4% were reassigned to BCLC Bn, whereas patients with ETV or ETB above the determined cutoffs were restratified or remained in BCLC Cn by means of stepwise verification of the median overall survival (mOS). Results This study included 494 patients (median age, 62 years [IQR, 56-71 years]; 401 men). Originally, 123 patients were classified as BCLC B with mOS of 24.3 months (95% CI: 21.4, 32.9) and 371 patients as BCLC C with mOS of 11.9 months (95% CI: 10.5, 14.8). The mOS of all included patients (including the BCLC B and C groups) was 15 months (95% CI: 12.3, 17.2). A total of 152 patients with BCLC C tumors were restratified into a new BCLC Bn class, in which the mOS was then 25.1 months (95% CI: 21.8, 29.7; P < .001). The mOS of the remaining patients (ie, BCLC Cn group) (n = 222; ETV ≥65 cm3 or ETB ≥4%) was 8.4 months (95% CI: 6.1, 11.2). Conclusion Substratification of patients with intermediate- and advanced-stage hepatocellular carcinoma according to three-dimensional quantitative tumor burden identified patients with a survival benefit from transarterial chemoembolization before therapy. © RSNA, 2022 Online supplemental material is available for this article.

T-Cell-Specific CerS4 Depletion Prolonged Inflammation and Enhanced Tumor Burden in the AOM/DSS-Induced CAC Model.

To better understand the role of sphingolipids in the multifactorial process of inflammatory bowel disease (IBD), we elucidated the role of CerS4 in colitis and colitis-associated cancer (CAC). For this, we utilized the azoxymethane/dextran sodium sulphate (AOM/DSS)-induced colitis model in global CerS4 knockout (CerS4 KO), intestinal epithelial (CerS4 Vil/Cre), or T-cell restricted knockout (CerS4 LCK/Cre) mice. CerS4 KO mice were highly sensitive to the toxic effect of AOM/DSS, leading to a high mortality rate. CerS4 Vil/Cre mice had smaller tumors than WT mice. In contrast, CerS4 LCK/Cre mice frequently suffered from pancolitis and developed more colon tumors. In vitro, CerS4-depleted CD8+ T-cells isolated from the thymi of CerS4 LCK/Cre mice showed impaired proliferation and prolonged cytokine production after stimulation in comparison with T-cells from WT mice. Depletion of CerS4 in human Jurkat T-cells led to a constitutively activated T-cell receptor and NF-κB signaling pathway. In conclusion, the deficiency of CerS4 in T-cells led to an enduring active status of these cells and prevents the resolution of inflammation, leading to a higher tumor burden in the CAC mouse model. In contrast, CerS4 deficiency in epithelial cells resulted in smaller colon tumors and seemed to be beneficial. The higher tumor incidence in CerS4 LCK/Cre mice and the toxic effect of AOM/DSS in CerS4 KO mice exhibited the importance of CerS4 in other tissues and revealed the complexity of general targeting CerS4.

Bronchial or Pulmonary Artery Chemoembolization for Unresectable and Unablatable Lung Metastases.

HomeRadiology: Imaging CancerVol. 3, No. 6 PreviousNext Research HighlightsFree AccessBronchial or Pulmonary Artery Chemoembolization for Unresectable and Unablatable Lung MetastasesMaximiliano KlugMaximiliano KlugMaximiliano KlugPublished Online:Nov 26 2021https://doi.org/10.1148/rycan.2021219023MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Take-Away Points■ Major Focus: A phase I clinical trial study prospectively evaluated the success rate and safety of transarterial chemoembolization (TACE) of bronchial or pulmonary arteries using ethiodized oil, mitomycin, and microspheres for treatment of unresectable and unablatable lung metastases.■ Key Results: Technical efficacy was 100% with no immediate major adverse events reported. Forty percent of patients showed partial metabolic response according to the PET Response Criteria in Solid Tumors (PERCIST).■ Impact: Lung TACE is a safe and technically achievable procedure with promising results for large and multifocal lung metastases with limited treatment options. Larger multicenter randomized clinical trials are needed to further evaluate safety and efficacy.Prognosis is poor for unresectable and unablatable lung metastases when they stop responding to systemic chemotherapy. Lung TACE of the pulmonary or bronchial arteries is an emerging treatment option for large and multifocal lung tumors, although response rate remains low. The authors hypothesize that the potential dual blood supply of lung tumors from bronchial or pulmonary arteries limits success of TACE.The single-center study prospectively enrolled patients with unresectable and unablatable lung, endobronchial, mediastinal, or pleural metastases from any primary tumor except lung cancer for which systemic chemotherapy failed. Nine of 10 patients had metastatic colorectal cancer. On the basis of pretreatment pulmonary and bronchial angiography, the authors performed chemoembolization with ethiodized oil, mitomycin, and microspheres through the artery that showed greater perfusion tumor enhancement at angiography. The study defined technical success by delivery of ethiodized oil and mitomycin into an artery supplying a target tumor, with safety assessment ending 6 weeks after the procedure. Using untreated tumors in a patient as an internal control, the team measured response to therapy by PERCIST and Response Evaluation Criteria in Solid Tumors (RECIST).The study reports that the technical success of intratumoral drug delivery was 100% with no severe adverse effects. However, both forced vital capacity and forced expiratory volume in 1 second decreased persistently through 4–6 weeks. Partial response rates after 4–6 weeks were 40% and 10% by PERCIST and RECIST, respectively. All colorectal metastases had bronchial artery supply, and tumor response by PERCIST correlated with concentration of ethiodized oil in a tumor.Although limited by small numbers of patients, the demonstrated efficacy and safety obtained and preliminary partial response rates encourage future larger clinical trials. Correctly identifying the vascular anatomy of lung metastases in unresectable and unablatable disease may be key for future improvements in TACE for lung metastases.Highlighted ArticleBoas FE, Kemeny NE, Sofocleous CT, et al. Bronchial or pulmonary artery chemoembolization for unresectable and unablatable lung metastases: a phase I clinical trial. Radiology 2021;301(2):474–484. doi: https://doi.org/10.1148/radiol.2021210213Highlighted ArticleBoas FE, Kemeny NE, Sofocleous CT, et al. Bronchial or pulmonary artery chemoembolization for unresectable and unablatable lung metastases: a phase I clinical trial. Radiology 2021;301(2):474–484. doi: https://doi.org/10.1148/radiol.2021210213 Link, Google ScholarArticle HistoryPublished online: Nov 26 2021 FiguresReferencesRelatedDetailsRecommended Articles Bronchial or Pulmonary Artery Chemoembolization for Unresectable and Unablatable Lung Metastases: A Phase I Clinical TrialRadiology2021Volume: 301Issue: 2pp. 474-484Chemoembolization for Lung Neoplasms: Exuberant Expectations versus Meticulous InvestigationRadiology2021Volume: 301Issue: 2pp. 485-486Survival and Toxicities after 90Y Transarterial Radioembolization of Metastatic Colorectal Cancer in the RESIN RegistryRadiology2022Volume: 305Issue: 1pp. 228-236Imaging Biomarkers of Tumor Response in Neuroendocrine Liver Metastases Treated with Transarterial Chemoembolization: Can Enhancing Tumor Burden of the Whole Liver Help Predict Patient Survival?Radiology2016Volume: 283Issue: 3pp. 883-894Prediction of Therapeutic Effect of Chemotherapy for NSCLC Using Dual-Input Perfusion CT Analysis: Comparison among Bevacizumab Treatment, Two-Agent Platinum-based Therapy without Bevacizumab, and Other Non-Bevacizumab Treatment GroupsRadiology2017Volume: 286Issue: 2pp. 685-695See More RSNA Education Exhibits Review of Different Underlying Causes of Life-Threatening HemoptysisDigital Posters2018Comprehensive Review of Hemoptysis: Imaging and TreatmentDigital Posters2018Hemoptysis: A Practical Guide to Understand Its Causes and TreatmentsDigital Posters2019 RSNA Case Collection Rasmussen aneurysmRSNA Case Collection2022Pulmonary pseudoaneurysmRSNA Case Collection2021Radioembolization of Liver Metastasis RSNA Case Collection2020 Vol. 3, No. 6 Metrics Altmetric Score PDF download

Identifying enhancement-based staging markers on baseline MRI in patients with colorectal cancer liver metastases undergoing intra-arterial tumor therapy.

To determine if three-dimensional whole liver and baseline tumor enhancement features on MRI can serve as staging biomarkers and help predict survival of patients with colorectal cancer liver metastases (CRCLM) more accurately than one-dimensional and non-enhancement-based features. This retrospective study included 88 patients with CRCLM, treated with transarterial chemoembolization or Y90 transarterial radioembolization between 2001 and 2014. Semi-automated segmentations of up to three dominant lesions were performed on pre-treatment MRI to calculate total tumor volume (TTV) and total liver volumes (TLV). Quantitative 3D analysis was performed to calculate enhancing tumor volume (ETV), enhancing tumor burden (ETB, calculated as ETV/TLV), enhancing liver volume (ELV), and enhancing liver burden (ELB, calculated as ELV/TLV). Overall and enhancing tumor diameters were also measured. A modified Kaplan-Meier method was used to determine appropriate cutoff values for each metric. The predictive value of each parameter was assessed by Kaplan-Meier survival curves and univariable and multivariable cox proportional hazard models. All methods except whole liver (ELB, ELV) and one-dimensional/non-enhancement-based methods were independent predictors of survival. Multivariable analysis showed a HR of 2.1 (95% CI 1.3-3.4, p = 0.004) for enhancing tumor diameter, HR 1.7 (95% CI 1.1-2.8, p = 0.04) for TTV, HR 2.3 (95% CI 1.4-3.9, p < 0.001) for ETV, and HR 2.4 (95% CI 1.4-4.0, p = 0.001) for ETB. Tumor enhancement of CRCLM on baseline MRI is strongly associated with patient survival after intra-arterial therapy, suggesting that enhancing tumor volume and enhancing tumor burden are better prognostic indicators than non-enhancement-based and one-dimensional-based markers. • Tumor enhancement of colorectal cancer liver metastases on MRI prior to treatment with intra-arterial therapies is strongly associated with patient survival. • Three-dimensional, enhancement-based imaging biomarkers such as enhancing tumor volume and enhancing tumor burden may serve as the basis of a novel prognostic staging system for patients with liver-dominant colorectal cancer metastases.

Integrated use of tumor AI volumetrics and advanced MRI to assess early response to Temferon in a phase 2 GBM trial: A novel paradigm.

e14041 Background: mRANO criteria form the basis for assessing treatment response in GBM clinical trials. mRANO measurements show variability due to limited sampling of the tumor morphology and reader estimations. Volumetrics may overcome limitations of linear measurements and improve our ability to detect changes reliably. Advanced MRI shed light on the mechanism of action and provide biomarkers, whose changes may precede any morphological alterations in the tumor. Methods: Six consecutive patients (3M, 3F, mean age 53.5 yrs) from an ongoing Phase-2 study on the effect of Temferon on recurrent GBM, were included and 3 consecutive MRI follow-up time points from each patient were entered in this interim analysis. The mRANO response status was determined by a central reader. Integrated volumetrics, two perfusion modalities (DSC/DCE) and diffusion analysis were performed on a proprietary platform after co-registering data in a common space to eliminate user bias and variability. Volumetrics and perfusion/diffusion biomarkers were estimated using state-of-the-art Artificial Intelligence (AI)-empowered algorithms. Statistical significance was set at p &lt; 0.001. Results: At the time of the interim analysis, 3 patients experienced stable disease (SD) / partial response (pR) and 3 patients had progressive disease (PD). The tumor volume had significant correlation (r = 0.89) with the SPDP but the SPDP showed monotonously biased overestimation of the tumor burden in the Bland-Altman analysis with mean difference = 886 (95%CI: 64-1708). Changes assessed by SPDP in the tumor burden during the treatment were underestimated for low volume tumor and underestimated for sizeable tumors compared with the volumetrics. The optimal threshold to predict tumor progression was 26% volume increase (sensitivity/specificity: 67/93%, AUC = 0.85), whereas there was no statistically significant threshold for SPDP. The perfusion fractional tumor volumes (FTV) with low and intermediately elevated rCBV showed strong correlation with the SPDP and enhancement volumetrics (r = 0.92-0.98). ROC analysis showed that 14% increase in the high perfusion tumor could significantly predict progression (sensitivity/specificity: 79/71%, AUC = 0.71). The responders showed significant increase in mean DWI values (11±0.3%) vs decrease (-4±0.05%) in non-responders. The mean rCBV and Vp values in responders showed decrease (-3±0.45% and -33±0.1%) and were increased in non-responders (25±0.1% and 51±0.66%). Conclusions: We demonstrated significant bias in estimating treatment response by means of mRANO compared to tumor volumetrics. Distinct patterns of changes in tumor perfusion, diffusion and FTV correlated highly with treatment response and enhancing tumor burden. Volumetrics and perfusion/diffusion composite biomarkers predicted accurately the response status in our patients. Clinical trial information: NCT03866109.

Role of 3D quantitative tumor analysis for predicting overall survival after conventional chemoembolization of intrahepatic cholangiocarcinoma

This study was designed to assess 3D vs. 1D and 2D quantitative tumor analysis for prediction of overall survival (OS) in patients with Intrahepatic Cholangiocarcinoma (ICC) who underwent conventional transarterial chemoembolization (cTACE). 73 ICC patients who underwent cTACE were included in this retrospective analysis between Oct 2001 and Feb 2015. The overall and enhancing tumor diameters and the maximum cross-sectional and enhancing tumor areas were measured on baseline images. 3D quantitative tumor analysis was used to assess total tumor volume (TTV), enhancing tumor volume (ETV), and enhancing tumor burden (ETB) (ratio between ETV and liver volume). Patients were divided into low (LTB) and high tumor burden (HTB) groups. There was a significant separation between survival curves of the LTB and HTB groups using enhancing tumor diameter (p = 0.003), enhancing tumor area (p = 0.03), TTV (p = 0.03), and ETV (p = 0.01). Multivariate analysis showed a hazard ratio of 0.46 (95%CI: 0.27–0.78, p = 0.004) for enhancing tumor diameter, 0.56 (95% CI 0.33–0.96, p = 0.04) for enhancing tumor area, 0.58 (95%CI: 0.34–0.98, p = 0.04) for TTV, and 0.52 (95%CI: 0.30–0.91, p = 0.02) for ETV. TTV and ETV, as well as the largest enhancing tumor diameter and maximum enhancing tumor area, reliably predict the OS of patients with ICC after cTACE and could identify ICC patients who are most likely to benefit from cTACE.

Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes

The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown. Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing invivo and invitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes. Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes. We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.

Combination total abdominal ultra-rapid flash irradiation and PD-1 inhibition provides enhanced tumor burden control in a preclinical ovarian cancer model

Objective: Ovarian cancer often presents with advanced-stage disease; however, despite surgery and chemotherapy, recurrence remains inevitable and prognosis poor. Advances in alternative targets including programmed cell death-1 (PD-1) inhibition show promise; however, clinical trials show modest response rates. Ovarian cancer is known to be radiosensitive, but use of total abdominal radiation is not utilized because of high abdominopelvic toxicity. Conventional radiotherapy is delivered at a dose rate of 3–4 Gy/minute, while our ultra-rapid FLASH radiotherapy system uses a linear accelerator to deliver dose rates of 200 Gy/second.

Regulation of invasion and peritoneal dissemination of ovarian cancer by mesothelin manipulation

Peritoneal dissemination is a particular form of metastasis typically observed in ovarian cancer and the major cause for poor patient’s outcome. Identification of the molecular players involved in ovarian cancer dissemination can offer an approach to develop treatment strategies to improve clinical prognosis. Here, we identified mesothelin (MSLN) as a crucial protein in the multistep process of peritoneal dissemination of ovarian cancer. We demonstrated that MSLN is overexpressed in primary and matched peritoneal metastasis of high-grade serous carcinomas (HGSC). Using several genetically engineered ovarian cancer cell lines, resulting in loss or gain of function, we found that MSLN increased cell survival in suspension and invasion of tumor cells through the mesothelial cell layer in vitro. Intraperitoneal xenografts established with MSLNhigh ovarian cancer cell lines showed enhanced tumor burden and spread within the peritoneal cavity. These findings provide strong evidences that MSLN is a key player in ovarian cancer progression by triggering peritoneal dissemination and provide support for further clinical investigation of MSLN as a therapeutic target in HGSC.

Wnt and Notch signaling govern self-renewal and differentiation in a subset of human glioblastoma stem cells.

Developmental signal transduction pathways act diversely, with context-dependent roles across systems and disease types. Glioblastomas (GBMs), which are the poorest prognosis primary brain cancers, strongly resemble developmental systems, but these growth processes have not been exploited therapeutically, likely in part due to the extreme cellular and genetic heterogeneity observed in these tumors. The role of Wnt/βcatenin signaling in GBM stem cell (GSC) renewal and fate decisions remains controversial. Here, we report context-specific actions of Wnt/βcatenin signaling in directing cellular fate specification and renewal. A subset of primary GBM-derived stem cells requires Wnt proteins for self-renewal, and this subset specifically relies on Wnt/βcatenin signaling for enhanced tumor burden in xenograft models. In an orthotopic Wnt reporter model, Wnthi GBM cells (which exhibit high levels of βcatenin signaling) are a faster-cycling, highly self-renewing stem cell pool. In contrast, Wntlo cells (with low levels of signaling) are slower cycling and have decreased self-renewing potential. Dual inhibition of Wnt/βcatenin and Notch signaling in GSCs that express high levels of the proneural transcription factor ASCL1 leads to robust neuronal differentiation and inhibits clonogenic potential. Our work identifies new contexts for Wnt modulation for targeting stem cell differentiation and self-renewal in GBM heterogeneity, which deserve further exploration therapeutically.

Quantitative Imaging Biomarkers for 90Y Distribution on Bremsstrahlung SPECT After Resin-Based Radioembolization.

Our purpose was to identify baseline imaging features in patients with liver cancer that correlate with 90Y distribution on postprocedural SPECT and predict tumor response to transarterial radioembolization (TARE). Methods: This retrospective study was approved by the institutional review board and included 38 patients with hepatocellular carcinoma (HCC) (n = 23; 18/23 men; mean age, 62.39 ± 8.62 y; 34 dominant tumors) and non-HCC hepatic malignancies (n = 15; 9/15 men; mean age, 61.13 ± 11.51 y; 24 dominant tumors) who underwent 40 resin-based TARE treatments (August 2012 to January 2018). Multiphasic contrast-enhanced MRI or CT was obtained before and Bremsstrahlung SPECT within 2 h after TARE. Total tumor volume (cm3) and enhancing tumor volume (ETV [cm3] and % of total tumor volume), and total and enhancing tumor burden (%), were volumetrically assessed on baseline imaging. Up to 2 dominant tumors per treated lobe were analyzed. After multimodal image registration of baseline imaging and SPECT/CT, 90Y distribution was quantified on SPECT as tumor-to-normal-liver ratio (TNR). Response was assessed according to RECIST1.1 and quantitative European Association for the Study of the Liver criteria. Clinical parameters were also assessed. Statistical tests included Mann-Whitney U, Pearson correlation, and linear regression. Results: In HCC patients, high baseline ETV% significantly correlated with high TNR on SPECT, demonstrating greater 90Y uptake in the tumor relative to the liver parenchyma (P < 0.001). In non-HCC patients, a correlation between ETV% and TNR was observed as well (P = 0.039). Follow-up imaging for response assessments within 1-4 mo after TARE was available for 23 patients with 25 treatments. The change of ETV% significantly correlated with TNR in HCC (P = 0.039) but not in non-HCC patients (P = 0.886). Additionally, Child-Pugh class B patients demonstrated significantly more 90Y deposition in nontumorous liver than Child-Pugh A patients (P = 0.021). Conclusion: This study identified ETV% as a quantifiable imaging biomarker on preprocedural MRI and CT to predict 90Y distribution on postprocedural SPECT in HCC and non-HCC. However, the relationship between the preferential uptake of 90Y to the tumor and tumor response after radioembolization could be validated only for HCC.

Utility of targeted deep sequencing for detecting circulating tumor DNA in pancreatic cancer patients

Targeted deep sequencing across broad genomic regions has been used to detect circulating tumor DNA (ctDNA) in pancreatic ductal adenocarcinoma (PDAC) patients. However, since most PDACs harbor a mutation in KRAS, sequencing of broad regions needs to be systemically compared to analyzing only KRAS mutations for PDAC. Using capture-based targeted deep sequencing, we detected somatic tumor mutations in 17 fine needle aspiration biopsy and 69 longitudinal cell-free DNA (cfDNA) samples from 17 PDAC patients. KRAS mutations were detected in 10 out of 17 pretreatment patient plasma samples. Next, interrogation of genetic alterations in matched primary tumor samples detected ctDNA in 12 of 17 pretreatment plasma samples and cfDNA sequencing across the 83 target genes identified ctDNA in 15 of 17 cases (88.2% sensitivity). This improved sensitivity of ctDNA detection resulted in enhanced tumor burden monitoring when we analyzed longitudinal plasma samples. We found that cfDNA sequencing detected the lowest mutant allelic fractions and number of variants when complete response or partial response to chemotherapy was achieved. We demonstrated that ctDNA levels measured by targeted deep sequencing sensitively indicate the presence of cancer and correlate well with clinical responses to therapy and disease progression in PDAC patients.