Imaging Biomarkers Of Treatment Response Research Articles

21 Early Apparent Diffusion Coefficient (ADC) Changes During Concurrent Chemoradiation: An Imaging Biomarker for Treatment Response and Recurrence Prediction in Glioblastoma

21 Early Apparent Diffusion Coefficient (ADC) Changes During Concurrent Chemoradiation: An Imaging Biomarker for Treatment Response and Recurrence Prediction in Glioblastoma

Clinical predictive factors and imaging biomarkers of treatment response to half dose PDT in patients with chronic central serous chorioretinopathy

PurposeTo determine the clinical and imaging biomarkers of the response to half-dose photodynamic therapy (HD-PDT) in patients with central serous chorioretinopathy (CSC) MethodsClinical records and baseline ophthalmic images of 67 chronic CSC patients who underwent HD-PDT were assessed. In addition to demographic data, optical coherence tomography (OCT), fluorescein angiography (FA) and fundus autofluorescence (FAF) images were analyzed for specific biomarkers. The patients were categorized to early responder and late responder based on the time needed for complete resolution of subretinal fluid after PDT (less than 1 month vs. more than 1 month). The baseline clinical and imaging biomarkers were compared between the two groups. ResultsSeventy-three eyes of 67 patients were included in the study. The mean response time to PDT was 1.63 ± 1.48 months with 82.2% (60/73) of eyes categorized as early responder. The mean response time to PDT in delayed-response group was 4.15±1.51 months. In multivariate analysis, delayed response to PDT was associated with lacking history of systemic corticosteroid consumption, lacking history of pretreatment with eplerenone or acetazolamide before PDT and presence of hyperreflective foci in baseline OCT images (all p values < 0.05). There was no association between final visual outcome and late response to PDT. ConclusionThe presence of inflammatory biomarkers such as hyperreflective foci in baseline OCT images might be indicative of resistance to PDT. Moreover, the effect of pretreatment with mineralocorticoid antagonist on the response to PDT in chronic CSC should be explored in future prospective studies.

Multi-center real-world data curation and assessment of tumor growth rate and overall survival in advanced NSCLC treated with PD-(L)1 immune checkpoint inhibitor therapy.

9124 Background: While Immune Checkpoint Inhibitors (ICI) have become the standard-of-care for advanced non-small cell lung cancer (NSCLC) for certain patient populations, durable responses only occur in a small subset of patients. Therefore, there is an unmet need to identify patients that will respond before and during treatment to optimize treatment strategies. Multiple studies have shown promise that quantitative imaging biomarkers can predict response to ICI therapy. Studies have also shown that tumor growth parameters derived from time series data can provide early indications of long-term response. However, most studies to date have investigated single institution or clinical trial datasets, which are inadequate to capture the broad spectrum of real-world diversity of ICI treatments. In this study, we aimed to build a generalizable, well-validated imaging biomarker for treatment response. Methods: We have curated a retrospective dataset including serial imaging data of 1,215 advanced NSCLC patients who received ICIs from nine institutions across the US and Europe, capturing the diversity of the imaging data, such as CT scanner models, image acquisition parameters, reconstruction algorithms, as well as diversity in patient population, performance status, and treatment settings. Expert lesion annotations and manual volumetric segmentations were performed on all visible lesions (ranging from 1-18 lesions per subject, totaling 6,441 lesions) across the serial imaging data (ranging from 1-18 follow-up scans per subject), which enables lesion and organ-specific tumor burden assessment. We stratified overall survival based on volumetric response and tumor growth rate using a model defined by the sum of exponential growth ( g) and decay ( d), vol(t) = vol(0)*(egt + e-dt -1). Results: Survival analysis showed that the 3-month volumetric response (N = 875) was significantly associated with overall survival (OS) for the lowest quartile (Q1; log-rank p-value, P = 2.1e-4) and highest quartile (Q4; P = 9.8e-8) compared to the middle quartiles (Q2+Q3). The median overall survival (OS) stratified by the volumetric response was 547.7, 450.9, and 332.0 days in the Q1, Q2+Q3, Q4 quadrants, respectively. Among patients having a minimum of 2 follow-up scans in the first 18 weeks (N = 264), we found that patients with the tumor growth parameter ( g) in the highest quartile had significantly lower OS compared to the patients in the Q2+Q3 quadrants (P = 7.2e-5). Conclusions: Our results demonstrate the potential of large multi-center real-world imaging datasets in investigating novel early response assessment methodologies, such as volumetric tumor burden quantification and tumor growth modeling. In our further work, we will investigate response patterns at individual lesion levels and correlations with overall patient-level response.

Quantitative Airway Assessment of Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) on CT as a Novel Biomarker.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) occurs due to abnormal proliferation of pulmonary neuroendocrine cells. We hypothesized that performing a quantitative analysis of airway features on chest CT may reveal differences to matched controls, which could ultimately help provide an imaging biomarker. A retrospective quantitative analysis of chest CTs in patients with DIPNECH and age matched controls was carried out using semi-automated post-processing software. Paired segmental airway and artery diameters were measured for each bronchopulmonary segment, and the airway:artery (AA) ratio, airway wall thickness:artery ratio (AWTA ratio) and wall area percentage (WAP) calculated. Nodule number, size, shape and location was recorded. Correlation between CT measurements and pulmonary function testing was performed. 16 DIPNECH and 16 control subjects were analysed (all female, mean age 61.7 +/- 11.8 years), a combined total of 425 bronchopulmonary segments. The mean AwtA ratio, AA ratio and WAP for the DIPNECH group was 0.57, 1.18 and 68.8%, respectively, compared with 0.38, 1.03 and 58.3% in controls (p &lt; 0.001, &lt;0.001, 0.03, respectively). DIPNECH patients had more nodules than controls (22.4 +/- 32.6 vs. 3.6 +/- 3.6, p = 0.03). AA ratio correlated with FVC (R2 = 0.47, p = 0.02). A multivariable model incorporating nodule number, AA ratio and AWTA-ratio demonstrated good performance for discriminating DIPNECH and controls (AUC 0.971; 95% CI: 0.925-1.0). Quantitative CT airway analysis in patients with DIPNECH demonstrates increased airway wall thickness and airway:artery ratio compared to controls. Quantitative CT measurement of airway wall thickening offers a potential imaging biomarker for treatment response.

Longitudinal Assessment of Gross Tumor Volume in Abdominal and Pelvic Patients Undergoing MR-Guided Online Adaptive Radiotherapy as a Predictive Biomarker of Treatment Response

<h3>Purpose/Objective(s)</h3> MR-guided radiotherapy (MRgRT) provides longitudinal MR images during RT, and enables the evaluation of potential imaging biomarkers of treatment response (TR). We investigated whether interfraction tumor volumetric changes correlated with ultimate radiographic response. <h3>Materials/Methods</h3> 131 patients underwent daily adaptive MRgRT of the pancreas (n=71), adrenal (n=27), abdominal lymph node (LN) (n=19), and pelvic LN (n=14) to a median of 50 Gy/5 fractions (fxs). For each adaptive fx, the simulation GTV was compared to the daily GTV on the 0.35 T TRUFI MR. GTV change (ΔGTV) was quantified as the % difference in GTV of the adapted fx compared to simulation. To ensure robustness, a minimum ΔGTV > ±1 cc was required for TR-correlation on post-RT diagnostic MR. Patients were categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD), using RECIST criteria, and TR was correlated to fx with the largest ΔGTV. <h3>Results</h3> Median follow up was 22.5 months. Numerically (not statistically significant) the largest interfraction ΔGTV for the entire cohort was observed at fx 3 (14.2%) compared to 6.8, 10.2, 8.9, and 13.1% for fxs 1, 2, 4, and 5, respectively. For pancreas, adrenal, abdominal LN, and pelvic LN, the median ΔGTV at fx 3 (ΔGTV_fx3) was -5.1, 20.8, 27.5, and 3.4%, respectively; meaning GTV increased, on average, for all sites except pancreas. ΔGTV_fx3 as a function of TR is displayed in the Table. ΔGTV_fx3 for pancreas and pelvic LN was <10%. For adrenals achieving post-RT CR, PR, SD, larger ΔGTV_fx3 were observed, with median of 23.8, 20.8, and 26.3%, respectively, with extreme case of 41% increase in a patient achieving a subsequent CR. For PD adrenal lesions, the ΔGTV_fx3 is 0. These findings putatively suggest an acute SBRT-related inflammatory response resulting in subsequent disease stability or regression. In contrast, for abdominal LN, no such significant ΔGTV_fx3 is noted for CR, PR, or SD, but for PD, the ΔGTV_fx3 increases substantially to 39.1%_. <h3>Conclusion</h3> Daily adaptive MRgRT enabled interfraction tracking of ΔGTV that was retrospectively correlated to TR. Numerically, we observed the greatest ΔGTV at fx 3. However, this change was seen primarily in adrenal and abdominal nodal lesions, and not other sites. The significance of this change is non-uniform, in that for adrenal lesions, responders were more likely to have volumetric increase, whereas for abdominal LN, progressors were more likely to have volumetric increase. These preliminary findings are being rigorously tested through a retrospective, multi-observer blinded contouring exercise, and also being extended to other disease sites, prior to formulating a clinically actionable hypothesis.

Image-Based Evaluation of Irradiation Effects in Brain Tissues by Measuring Absolute Electrical Conductivity Using MRI.

Simple SummaryNon-invasive quantification of radiation-induced damage is an important factor in radiation therapy to maximize radiation dose to cancer cells while minimizing damage to surrounding healthy tissue. Development of imaging biomarkers to assess post-RT effects accurately at an early stage is important for better prognosis and to individualize the management of brain tumors. Recent MR-based electrical conductivity imaging provides novel contrast information based on the concentration and mobility of ions constituting tissue and can exhibit high sensitivity in quantifying the therapeutic effect of ionizing radiation used in cancer treatment. This study suggests that the change in conductivity at different doses can provide a way to quantify the response of the tissue to irradiation, and the variation in conductivity with the elapsed time shows potential as a tool to monitor the therapeutic effect of radiation.Radiation-induced injury is damage to normal tissues caused by unintentional exposure to ionizing radiation. Image-based evaluation of tissue damage by irradiation has an advantage for the early assessment of therapeutic effects by providing sensitive information on minute tissue responses in situ. Recent magnetic resonance (MR)-based electrical conductivity imaging has shown potential as an effective early imaging biomarker for treatment response and radiation-induced injury. However, to be a tool for evaluating therapeutic effects, validation of its reliability and sensitivity according to various irradiation conditions is required. We performed MR-based electrical conductivity imaging on designed phantoms to confirm the effect of ionizing radiation at different doses and on in vivo mouse brains to distinguish tissue response depending on different doses and the elapsed time after irradiation. To quantify the irradiation effects, we measured the absolute conductivity of brain tissues and calculated relative conductivity changes based on the value of pre-irradiation. The conductivity of the phantoms with the distilled water and saline solution increased linearly with the irradiation doses. The conductivity of in vivo mouse brains showed different time-course variations and residual contrast depending on the irradiation doses. Future studies will focus on validation at long-term time points, including early and late delayed response and evaluation of irradiation effects in various tissue types.

92418 Molecular imaging of the tumor microenvironment to predict response to combination treatment with immunotherapy in triple negative breast cancer

ABSTRACT IMPACT: Insights from this project will provide clinical guidance in treatment of immunotherapy in triple negative breast cancer and identify early imaging biomarkers of treatment response. OBJECTIVES/GOALS: Significant research that addresses monitoring and predicting patient response of triple negative breast cancer (TNBC) to immunotherapy is needed. Using positron emission tomography (PET) imaging to probe the tumor microenvironment (hypoxia, T-cell activation), we aim to predict early response to immunotherapy for in mouse models of TNBC tumors. METHODS/STUDY POPULATION: Female Balb/c mice with 4T1-luciferase mammary carcinoma cell tumors were administered paclitaxel (PTX; 10 mg/kg), anti-PD1 (200 µg), both, or vehicle (saline) intraperitoneally. Treatment was given on days 0, 2, and 5 for cohort 1 (n=16) who underwent granzyme B specific (GZP) PET imaging (T-cell activation) and days 0, 2, 5, and 8 for cohort 2 (n=12) who underwent [18F]-fluoromisonidazole (FMISO)-PET imaging (hypoxia). Bioluminescence (BLI) imaging and caliper measurements were performed to track tumor size changes at multiple timepoints and tumors were collected for histological validation on day 20. Mean standard uptake value (SUVmean) was calculated as percent of day 0, and statistical analyses were performed with unpaired t-tests and Wilcoxon-rank sum tests. RESULTS/ANTICIPATED RESULTS: Non-responders to treatment had a significantly higher tumor volume compared to responders starting on day 6 (p&lt;0.05). Although no significant differences in BLI between control and single-agent therapies were found, BLI data revealed that treatment with combination PTX and anti-PD1 significantly decreased viability signal between days 3 and 6 (p=0.04). SUVmean from GZP-PET was over 250% higher in responders compared to non-responders by day 6 (p=0.03). SUVmean from FMISO-PET was 80% less in responders compared to nonresponders, indicating less tumor hypoxia (p=0.04). DISCUSSION/SIGNIFICANCE OF FINDINGS: Non-invasive PET imaging of the tumor microenvironment can provide data on T cell activation and hypoxic response predicting response to combination immunotherapy and chemotherapy. Utilizing advanced imaging to understand biologically distinct features of the TNBC tumor microenvironment can aid in personalizing anti-cancer therapies.

Association between background parenchymal enhancement and tumor response in patients with breast cancer receiving neoadjuvant chemotherapy

PurposeTo analyze the relationships between background parenchymal enhancement (BPE) of the contralateral healthy breast and tumor response after neoadjuvant chemotherapy (NAC) in women with breast cancer. Materials and methodsA total of 228 women (mean age, 47.6 years±10 [SD]; range: 24–74 years) with invasive breast cancer who underwent NAC were included. All patients underwent breast magnetic resonance imaging (MRI) before and after NAC and 127 patients underwent MRI before, during (after the 4th cycle of NAC) and after NAC. Quantitative semi-automated analysis of BPE of the contralateral healthy breast was performed. Enhancement level on baseline MRI (baseline BPE) and MRI after chemotherapy (final BPE), change in enhancement rate between baseline MRI and final MRI (total BPE change) and between baseline MRI and midline MRI (early BPE change) were recorded. Associations between BPE and tumor response, menopausal status, tumor phenotype, NAC type and tumor stage at diagnosis were searched for. Pathologic complete response (pCR) was defined as the absence of residual invasive cancer cells in the breast and ipsilateral lymph nodes. ResultsNo differences were found in baseline BPE, final BPE, early and total BPE changes between pCR and non-pCR groups. Early BPE change was higher in non-pCR group in patients with stages 3 and 4 breast cancers (P=0.019) and in human epidermal growth factor receptor 2 (HER2)-negative patients (P=0.020). ConclusionEarly reduction of BPE in the contralateral breast during NAC may be an early predictor of loss of tumor response, showing potential as an imaging biomarker of treatment response, especially in women with stages 3 or 4 breast cancers and in HER2 – negative breast cancers.

PH-weighted amine chemical exchange saturation transfer echoplanar imaging (CEST-EPI) as a potential early biomarker for bevacizumab failure in recurrent glioblastoma.

The objective of the current study was to explore the efficacy of using pH-weighted amine CEST-EPI as a potential non-invasive imaging biomarker for treatment response and/or failure in recurrent GBM patients treated with bevacizumab. A total of 11 patients with recurrent GBM treated with bevacizumab were included in this prospective study. CEST-EPI, perfusion MRI, and standardized anatomic MRI were obtained in patients before and after bevacizumab administration. CEST-EPI measures of magnetization transfer ratio asymmetry (MTRasym) at 3ppm were used for pH-weighted imaging contrast. Multiple measures were examined for their association with progression-free survival (PFS). Tumor acidity, measured with MTRasym at 3ppm, was significantly reduced in both contrast enhancing and non-enhancing tumor after bevacizumab (p = 0.0002 and p < 0.00001, respectively). The reduction in tumor acidity in both contrast enhancing and non-enhancing tumor was linearly correlated with PFS (p = 0.044 and p = 0.00026, respectively). In 9 of the 11 patients, areas of residual acidity were localized to areas of tumor recurrence, typically around 2 months prior to radiographic progression. Univariate (p = 0.006) and multivariate Cox regression controlling for age (p = 0.009) both indicated that change in tumor acidity (ΔMTRasym at 3ppm) was a significant predictor of PFS. This pilot study suggests pH-weighted amine CEST MRI may have value as a non-invasive, early imaging biomarker for bevacizumab treatment response and failure. Early decreases MTRasym at 3.0ppm in recurrent GBM after bevacizumab may be associated with better PFS. Residual or emerging regions of acidity may colocalize to the site of tumor recurrence.

Decreased background parenchymal enhancement of the contralateral breast after two cycles of neoadjuvant chemotherapy is associated with tumor response in HER2-positive breast cancer.

Background Several recent studies have focused on the association between background parenchymal enhancement (BPE) and tumor response to neoadjuvant chemotherapy (NAC), but early prediction of tumor response based on BPE has yet not been investigated. Purpose To retrospectively investigate whether changes in the BPE of the contralateral breast following NAC could help predict tumor response in early stage HER2-positive breast cancer. Material and Methods Data from 71 patients who were diagnosed with unilateral HER2 positive breast cancer and then underwent NAC with trastuzumab before surgery were analyzed retrospectively. Two experienced radiologists independently categorized the patients' levels of BPE of the contralateral breast into four categories (1 = minimal, 2 = mild, 3 = moderate, 4 = marked) at baseline and after the second cycle of NAC. After undergoing surgery, 34 patients achieved pathologic complete response (pCR) and 37 patients had residual disease (non-pCR). The association between BPE and histopathologic tumor response was analyzed. Result The level of BPE was higher in premenopausal than post-menopausal women both at baseline and after the second cycle of NAC ( P < 0.005). A significant reduction in BPE ( P < 0.001) was observed after the second NAC cycle; however, a more obvious decrease in BPE was identified in premenopausal relative to post-menopausal women ( P = 0.041). No significant association was identified between pCR and baseline BPE ( P = 0.287). However, after the second NAC cycle, decreased BPE was significantly associated with pCR ( P = 0.003). Conclusion For HER2-positive patients, changes in BPE may serve as an additional imaging biomarker of treatment response at an early stage.

DCE- and DW-MRI as early imaging biomarkers of treatment response in a preclinical model of triple negative breast cancer.

This work evaluates quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRI) parameters as early biomarkers of response in a preclinical model of triple negative breast cancer (TNBC). The standard Tofts' model of DCE-MRI returns estimates of the volume transfer constant (Ktrans ) and the extravascular extracellular volume fraction (ve ). DW-MRI returns estimates of the apparent diffusion coefficient (ADC). Mice (n=38) were injected subcutaneously with MDA-MB-231. Tumors were grown to approximately 275mm3 and sorted into the following groups: saline controls, low-dose Abraxane (15mg/kg) and high-dose Abraxane (25mg/kg). Animals were imaged at days zero, one and three. On day three, tumors were extracted for immunohistochemistry. The positive percentage change in ADC on day one was significantly higher in both treatment groups relative to the control group (p<0.05). In addition, the positive percentage change in Ktrans was significantly higher than controls (p<0.05) on day one for the high-dose group and on days one and three for the low-dose group. The percentage change in tumor volume was significantly different between the high-dose and control groups on day three (p=0.006). Histology confirmed differences at day three through reduced numbers of proliferating cells (Ki67 staining) in the high-dose group (p=0.03) and low-dose group (p=0.052) compared with the control group. Co-immunofluorescent staining of vascular maturity [using von Willebrand Factor (vWF) and α-smooth muscle actin (α-SMA)] indicated significantly higher vascular maturation in the low-dose group compared with the controls on day three (p=0.03), and trending towards significance in the high-dose group compared with controls on day three (p=0.052). These results from quantitative imaging with histological validation indicate that ADC and Ktrans have the potential to serve as early biomarkers of treatment response in murine studies of TNBC.

CT texture analysis in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: A potential imaging biomarker for treatment response and prognosis.

PurposeTo evaluate the association of computed tomography (CT) texture features of locally advanced rectal cancer with neoadjuvant chemoradiotherapy (CRT) response and disease-free survival (DFS).Methods and findingsThe institutional review board approved this retrospective study. 95 patients who received neoadjuvant CRT, followed by surgery, for locally advanced rectal cancer were included. Texture features (entropy, uniformity, kurtosis, skewness, and standard deviation) were assessed in pretreatment CT images and obtained without filtration and with Laplacian of Gaussian spatial filter of various filter values (1.0, 1.5, 2.0, and 2.5). Dworak pathologic grading was used for treatment response assessment. Independent t-test was used to compare each texture feature between the treatment responder and non-responder groups. DFS was assessed with Kaplan-Meier method, and differences were compared with log-rank test. Cox proportional hazards models were constructed to predict prognosis based on stage, age, and each texture feature. Treatment responders (n = 32) showed significantly lower entropy, higher uniformity, and lower standard deviation in no filtration, fine (1.0), and medium (1.5) filter values. Entropy, uniformity, and standard deviation without filtration showed significant difference in DFS in Kaplan-Meier analysis (P = 0.015, 0.025, and 0.038). Homogeneous texture features (≤ 6.7 for entropy, > 0.0118 for uniformity, and ≤ 28.06 for standard deviation) were associated with higher DFS. Entropy, uniformity, and standard deviation were independent texture features in predicting DFS (P = 0.017, 0.03, and 0.036)ConclusionsHomogeneous texture features are associated with better neoadjuvant CRT response and higher DFS in patients with locally advanced rectal cancer.

Abstract 2873: Imaging tumor heterogeneity after multikinase inhibitor therapy in rat hepatocellular carcinoma

Abstract Purpose To assess tumor tissue perfusion and vascular permeability through multiparametric functional imaging, and to evaluate their correspondence with histopathologic parameters of necrosis and hypoxia in a rat model of hepatocellular carcinoma treated with a multikinase inhibitor. Materials and Methods Rat hepatoma McA-RH7777 cells were implanted in the left liver lobe of nineteen male Buffalo rats. Exactly 2 weeks after tumor inoculation, the animals were randomly assigned to remain untreated (n=10) or to receive a daily dose of 7.5 mg/kg sorafenib by oral gavage (n=9) for 2 additional weeks. T2-weighted spin-echo magnetic resonance imaging (MRI), dynamic contrast-enhanced (DCE) and contrast-enhanced ultrasound (CEUS) were performed weekly. All tumors were harvested 4 weeks post-implantation &amp;gt;90 minutes after injecting 60mg/kg pimonidazole. Tissue sections were stained for hematoxylin-eosin and pimonidazole for quantitative assessment of necrosis and hypoxia, respectively. Differences between treatment groups were assessed using the Mann-Whitney test, and the correlation of imaging and histopathology parameters was determined by Spearman correlation analysis. Results In spite of the relatively low dose and short treatment duration, the response to sorafenib therapy was characterized by a significantly higher median tumor necrosis (60 vs 15%, P &amp;lt; 0.0001) and increased tumor tissue hypoxia (35 vs 18.5% pimonidazole binding, P &amp;lt; 0.0001). Similarly, the sorafenib regimen caused a substantial decrease in vascular permeability, measured by DCE-MRI Ktrans (P = 0.002) as well as reduction in tumor perfusion evaluated by CEUS peak enhancement (PE) (P =0.043). Our findings show a strong correlation between the two histopathologic parameters we assessed, tumor tissue necrosis and hypoxia (r = 0.645, P=0.002). Furthermore, our results demonstrate significant correlation of functional imaging parameters of vascular permeability, namely DCE-MRI Ktrans and DCE-MRI normalized initial area under the curve (NIAUC), with histopathologic tissue hypoxia (r=-0.663, P= 0.002, and r= -0.512, P=0.029, respectively). In contrast, histopathologic tumor necrosis appears more strongly correlated with a functional imaging parameter of tumor perfusion, specifically, CEUS PE (r = -0.547, P = 0.028). Conclusion Tumors exhibited wide heterogeneity in vascular perfusion and hypoxia after treatment. Interestingly, functional MRI parameters appear to correlate more strongly with tissue oxygenation, whereas functional CEUS parameters correlate with tumor viability. Novel predictive imaging biomarkers of treatment response may be developed through further analyses of spatial tumor heterogeneity in our animal model. Citation Format: Nina M. Muñoz, Adeeb A. Minhaj, Kiersten L. Maldonado, Charles Kingsley, Hideyuki Nishiofuku, Keith A. Michel, Andrea C. Cortes, James A. Bankson, Asif Rashid, Rony Avritscher. Imaging tumor heterogeneity after multikinase inhibitor therapy in rat hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2873. doi:10.1158/1538-7445.AM2017-2873

Whole-body MRI quantitative biomarkers are associated significantly with treatment response in patients with newly diagnosed symptomatic multiple myeloma following bortezomib induction

ObjectivesTo evaluate whole-body MRI (WB-MRI) parameters significantly associated with treatment response in multiple myeloma (MM).MethodsTwenty-one MM patients underwent WB-MRI at diagnosis and after two cycles of chemotherapy. Scans acquired at 3.0 T included T2, diffusion-weighted-imaging (DWI) and mDixon pre- and post-contrast. Twenty focal lesions (FLs) matched on DWI and post-contrast mDixon were selected for each time point. Estimated tumour volume (eTV), apparent diffusion coefficient (ADC), enhancement ratio (ER) and signal fat fraction (sFF) were derived. Clinical treatment response to chemotherapy was assessed using conventional criteria. Significance of temporal parameter change was assessed by the paired t test and receiver operating characteristics/area under the curve (AUC) analysis was performed. Parameter repeatability was assessed by interclass correlation (ICC) and Bland–Altman analysis of 10 healthy volunteers scanned at two time points.ResultsFifteen of 21 patients responded to treatment. Of 254 FLs analysed, sFF (p < 0.0001) and ADC (p = 0.001) significantly increased in responders but not non-responders. eTV significantly decreased in 19/21 cases. Focal lesion sFF was the best discriminator of treatment response (AUC 1.0). Bone sFF repeatability was excellent (ICC 0.98) and better than bone ADC (ICC 0.47).ConclusionWB-MRI derived focal lesion sFF shows promise as an imaging biomarker of treatment response in newly diagnosed MM.Key Points• Bone signal fat fraction using mDixon is a robust quantifiable parameter• Fat fraction and ADC significantly increase in myeloma lesions responding to treatment• Bone lesion fat fraction is the best discriminator of myeloma treatment response

Phase III randomized trial of image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) for locoregionally advanced cervical cancer: The INTERTECC-3 trial.

TPS5600 Background: Cervical cancer is a leading cause of cancer death in women worldwide. Image-guided bone marrow-sparing intensity modulated radiation therapy (IG-BMS-IMRT) has shown potential to reduce acute toxicity of chemoradiotherapy and improve chemotherapy delivery in phase I and II trials (Mell LK, Sirák I, Wei L, et al. Bone Marrow-sparing IMRT With Concurrent Cisplatin For Stage IB-IVA Cervical Cancer: An International Multicenter Phase II Clinical Trial (INTERTECC-2). Int J Radiat Oncol Biol Phys 2017;97:536-545. Mell LK, Saenz CC, Yashar CM, et al. Phase I Trial of Bone Marrow Sparing IMRT With Concurrent Cisplatin and Gemcitabine in Stage IB-IVA Cervical Cancer (abstr.) Int J Radiat Oncol Biol Phys 2016; 96: S14.). Methods: INTERTECC-3 is a randomized phase III trial designed to test the effect of IG-BMS-IMRT on progression-free survival (PFS) for women with unresected FIGO stage IB-IVA cervical carcinoma (clinicaltrials.gov #NCT01554397). It presently involves centers in the U.S., Czech Republic, U.K., India, Japan, and China. Women are randomized 3:2 to either (A) IG-BMS-IMRT or (B) standard chemoradiation, with 6 cycles of concurrent cisplatin (40 mg/m2) weekly in both arms. Secondary objectives are to compare overall survival, treatment-related toxicity, disease recurrence, quality of life, chemotherapy delivery, and radiation quality assurance. Planning objectives require maintaining pelvic marrow and active marrow mean doses &lt; 27 Gy and &lt; 28.5 Gy respectively. Correlative studies involve longitudinal collection of magnetic resonance restriction spectrum imaging and 18F-fluorothydimine positron emission tomography scans to assess imaging biomarkers of treatment response in select patients. 415 women will be enrolled to determine if IG-BMS-IMRT improves the median PFS from 3.2 to 5.0 years with 80% power and alpha = 0.05. INTERTECC-3 opened in the U.S. and Czech Republic in 2016. To date, 17 patients have been randomized. The trial will be activated at additional international sites in late 2017 and 2018. We are seeking to recruit sites who wish to collaborate. Clinical trial information: NCT01554397.

A Pilot Study of Quantitative MRI Parametric Response Mapping of Bone Marrow Fat for Treatment Assessment in Myelofibrosis.

Myelofibrosis (MF) is a hematologic neoplasm arising as a primary disease or secondary to other blood malignancies. Both primary and secondary MF develop progressive fibrosis of bone marrow, displacing normal hematopoietic cells to other organs and disrupting normal production of mature blood cells. Activation of JAK2 signaling in hematopoietic stem cells commonly causes MF, and ruxolitinib, a drug targeting this pathway, is the preferred treatment for many patients. However, current measures of disease status in MF do not necessarily predict response to treatment with ruxolitinib or other drugs. Bone marrow biopsies are invasive and prone to sampling error, while measurements of spleen volume only indirectly reflect status of bone marrow. Toward the goal of developing an imaging biomarker for treatment response in MF, we present preliminary results from a prospective clinical study evaluating parametric response mapping (PRM) of quantitative Dixon MRI bone marrow fat fraction maps in four MF patients treated with ruxolitinib. PRM allows voxel-wise identification of temporal changes in quantitative imaging readouts, in this case bone marrow fat. We identified heterogeneous responses of bone marrow fat among patients and within different bone marrow sites in the same patient. Changes in bone marrow fat fraction also were discordant with reductions in spleen volume, the standard imaging metric for treatment response. This study provides initial support for PRM analysis of quantitative MRI of bone marrow fat to monitor therapy in MF, setting the stage for larger studies to further develop and validate this method as a complementary imaging biomarker.

TU‐G‐BRA‐09: MR Elastography as a Predictor of Therapeutic Response: Assessment in Non‐Hodgkin's Lymphoma (NHL)

Purpose:To develop magnetic resonance elastography (MRE) as a noninvasive imaging biomarker of treatment response in cancer and to evaluate its prognostic potential for assessing chemotherapy response in non‐Hodgkin's lymphoma (NHL).Methods:A small animal cancer MRE methodology was developed which included a custom‐built 4 cm, 8‐channel receive‐only coil and an electromechanical driver capable of producing shear waves at a frequency of 800 Hz attached to an MRI‐compatible needle inserted in tissue. MRE reproducibility was evaluated in tumor phantoms and in vivo mouse experiments. Tumor shear stiffness was monitored following a single chemotherapy treatment in a murine xenograft of NHL to determine the biomechanical effect of an initial therapy response followed by tumor regrowth. The effect of an increased chemotherapy dose on the resulting decrease in tumor shear stiffness was quantified. In vivo evaluation of the feasibility of this potential biomarker was performed on three patients with NHL prior to and 2 weeks after chemotherapy treatment.Results:Tumor phantom models and in vivo measurements demonstrated excellent shear stiffness reproducibility with a standard deviation of ±3%. In the murine model, tumor shear stiffness and volume changes following chemotherapy treatment corresponded to periods of response and subsequent tumor regrowth. Shear stiffness alterations demonstrated a dose dependency with a decrease of 15% and 25% for the low and high dose group respectively compared to an increase of 7% in an untreated control group. In three patients with NHL, tumor shear stiffness decreased by an average of 38% within 2 weeks of chemotherapy treatment.Conclusion:These data demonstrate that MRE is a potentially sensitive biomarker of disease stage and response to therapy in cancer. The results demonstrate that MRE‐derived shear stiffness measurements are sensitive to chemotherapy response and disease progression in vivo, and are the first human application of MRE as a noninvasive assessment of therapy response.Funding provided by the Mayo Clinic Center for Individualized Medicine, Imaging Biomarker Discovery Program and the Mayo Graduate School.

In pursuit of neuroimaging biomarkers to guide treatment selection in major depressive disorder: a review of the literature.

Over the last few decades, neuroimaging techniques have advanced the identification of structural, functional, and neurochemical brain abnormalities that are associated with the increased risk, clinical course, and treatment outcomes of major depressive disorder (MDD). This paper reviews specific neuroimaging abnormalities that, on the basis of early studies, may discriminate between MDD patients who do or do not respond to current therapeutic modalities, such as antidepressants, cognitive behavioral therapy, or novel therapies. Differences in gray matter volume, white matter coherence, brain activity via structural and functional magnetic resonance imaging techniques, and concentrations of specific brain metabolites (as measured with magnetic resonance spectroscopy), are potential biomarkers discussed in this review. Given the heterogeneity of MDD, larger, multisite studies with increased statistical power will be needed to identify more precise imaging biomarkers of treatment response in MDD.

Quantitative total bone imaging (QTBI) in patients with metastatic castration-resistant prostate cancer (CRPC) using NaF PET/CT.

180 Background: CRPC is frequently associated with the development of osseous metastases. While imaging allows treatment response determination in soft tissue metastasis, its application in bony metastasis is limited to staging. Methods: QTBI is an innovative tool that allows extraction of comprehensive functional information in all osseous metastases, as well as treatment response in individual lesions, using 18F-Sodium Fluoride (NaF) PET/CT. We completed a multi-center trial assessing the performance characteristics (test-retest) and responsiveness of QTBI as an imaging biomarker of treatment response in men with metastatic CRPC to bone treated with either a taxane-based or androgen-signaling pathway directed therapy. Results: 54 patients have been enrolled from three academic centers. Potential imaging biomarkers of treatment response have been identified. Here we present initial data regarding the inter-lesional response heterogeneity and implications. Conclusions: Changes in SUVmax, SUVtotal, and SUVmean reflect quantifiable PET measurements that are complementary, but may have different meaning depending on the treatment administered (cytotoxic vs cytostatic). Relying on one measure alone can be misleading, particularly when assessing treatment response. For example, some lesions may experience a decrease in SUVmax, while simultaneously having an increase in SUVtotal. This implies that the therapy decreased the max functional activity of the lesion, but the overall functional burden of the lesion increased analogous to “slowing down” progression. This is in contrast with lesions that decrease (increase) in both SUVmax and SUVtotal, which would imply decreased activity and burden (increased activity and burden). We will show data representative of the above along with clinical outcomes in support of this conclusion, as well as the implications of treatment response heterogeneity in the clinical outcome. In summary, QTBI provides a unique tool in understanding the dynamics of treatment response, allowing newer trial designs that can explore combination, sequence, and the issue of continuing treatment beyond progression with existing therapies. Clinical trial information: NCT01516866.

Automated Tracking of Quantitative Assessments of Tumor Burden in Clinical Trials

There are two key challenges hindering effective use of quantitative assessment of imaging in cancer response assessment: 1) Radiologists usually describe the cancer lesions in imaging studies subjectively and sometimes ambiguously, and 2) it is difficult to repurpose imaging data, because lesion measurements are not recorded in a format that permits machine interpretation and interoperability. We have developed a freely available software platform on the basis of open standards, the electronic Physician Annotation Device (ePAD), to tackle these challenges in two ways. First, ePAD facilitates the radiologist in carrying out cancer lesion measurements as part of routine clinical trial image interpretation workflow. Second, ePAD records all image measurements and annotations in a data format that permits repurposing image data for analyses of alternative imaging biomarkers of treatment response. To determine the impact of ePAD on radiologist efficiency in quantitative assessment of imaging studies, a radiologist evaluated computed tomography (CT) imaging studies from 20 subjects having one baseline and three consecutive follow-up imaging studies with and without ePAD. The radiologist made measurements of target lesions in each imaging study using Response Evaluation Criteria in Solid Tumors 1.1 criteria, initially with the aid of ePAD, and then after a 30-day washout period, the exams were reread without ePAD. The mean total time required to review the images and summarize measurements of target lesions was 15% (P < .039) shorter using ePAD than without using this tool. In addition, it was possible to rapidly reanalyze the images to explore lesion cross-sectional area as an alternative imaging biomarker to linear measure.We conclude that ePAD appears promising to potentially improve reader efficiency for quantitative assessment of CT examinations, and it may enable discovery of future novel image-based biomarkers of cancer treatment response.