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Sex differences, tumor vascularity, and blood flow seen on multiecho dynamic contrast–based MRI scans enabled prediction of treatment response and overall survival in patients with rectal cancer. Background: MRI is the standard tool for rectal cancer staging. However, more precise diagnostic tests that can assess biologic tumor features decisive for treatment outcome are necessary. Tumor perfusion and hypoxia are two important features; however, no reference methods that measure these exist in clinical use. Purpose: To assess the potential predictive and prognostic value of MRI-assessed rectal cancer perfusion, as a surrogate measure of hypoxia, for local treatment response and survival. Materials and Methods: In this prospective observational cohort study, 94 study participants were enrolled from October 2013 to December 2017 (ClinicalTrials.gov: NCT01816607). Participants had histologically confirmed rectal cancer and underwent routine diagnostic MRI, an extended diffusion-weighted sequence, and a multiecho dynamic contrast agent–based sequence. Predictive and prognostic values of dynamic contrast-enhanced, dynamic susceptibility contrast (DSC), and intravoxel incoherent motion MRI were investigated with response to neoadjuvant treatment, progression-free survival, and overall survival as end points. Secondary objectives investigated potential sex differences in MRI parameters and relationship with lymph node stage. Statistical methods used were Cox regression, Student t test, and Mann-Whitney U test.Results: A total of 94 study participants (mean age, 64 years ± 11 [standard deviation]; 61 men) were evaluated. Baseline tumor blood flow from DSC MRI was lower in patients who had poor local tumor response to neoadjuvant treatment (96 mL/min/100 g ± 33 for ypT2–4, 120 mL/min/100 g ± 21 for ypT0–1; P = .01), shorter progression-free survival (hazard ratio = 0.97; 95% confidence interval: 0.96, 0.98; P < .001), and shorter overall survival (hazard ratio = 0.98; 95% confidence interval: 0.98, 0.99; P < .001). Women had higher blood flow (125 mL/min/100 g ± 27) than men (74 mL/min/100 g ± 26, P < .001) at stage 4. Volume transfer constant and plasma volume from dynamic contrast-enhanced MRI as well as ΔR2* peak and area under the curve for 30 and 60 seconds from DSC MRI were associated with local malignant lymph nodes (pN status). Median area under the curve for 30 seconds was 0.09 arbitrary units (au) ± 0.03 for pN1–2 and 0.19 au ± 0.12 for pN0 (P = .001). Conclusion:Low tumor blood flow from dynamic susceptibility contrast MRI was associated with poor treatment response in study participants with rectal cancer.

BackgroundIn colorectal cancer, the inflamed tumour microenvironment with its angiogenic activities is immune- tolerant and incites progression to liver metastasis. We hypothesised that angiogenic and inflammatory factors in serum samples from patients with non-metastatic rectal cancer could inform on liver metastasis risk.MethodsWe measured 84 angiogenic and inflammatory markers in serum sampled at the time of diagnosis within the population-based cohort of 122 stage I–III patients. In a stepwise manner, the statistically strongest proteins associated with time to development of liver metastasis were analysed in the corresponding serum samples from 273 stage II–III rectal cancer patients in three independent cohorts.ResultsWe identified the soluble form of the costimulatory immune checkpoint receptor cluster of differentiation molecule 40 (sCD40) as a marker of liver metastasis risk across all patient cohorts—the higher the sCD40 level, the shorter time to liver metastasis. In patients receiving neoadjuvant treatment, the sCD40 value remained an independent variable associated with progression to liver metastasis along with the local treatment response. Of note, serum sCD40 was not associated with progression to lung metastasis.ConclusionsCirculating sCD40 is a marker of liver metastasis risk in rectal cancer and may be developed for use in clinical practice.

Purpose: Cancer immune therapy has revolutionized patient outcome for the small mCRC subgroup with highly immunogenic disease. The majority of mCRC cases, however, are MSS with inherently low susceptibility to immune therapy. In our ongoing METIMMOX study (NCT03388190), MSS-mCRC patients are randomized to oxaliplatin-based immunogenic chemotherapy followed by ICI (experimental study arm) or the oxaliplatin-based standard-of-care (control arm). A subgroup of experimental arm patients has obtained durable major partial or complete responses. Such remarkable outcomes call for biomarkers that may help identifying MSS-mCRC patients who will benefit from such sequential therapy. Experimental procedures: Study enrollment began August 2018. Patients with unresectable, previously untreated MSS-mCRC have been randomized to the Nordic FLOX regimen (standard-of-care) or repeat sequential 2 FLOX cycles and 2 cycles of nivolumab (240 mg Q2W). At analysis October 2020, 48 patients were evaluable for progression-free survival (PFS). Serum collected at baseline and after the first 2 FLOX and 2 nivolumab cycles were analyzed for 42 immune factors with the Luminex multiplex immunoassay. The Significance Analysis for Microarrays method was applied to select the most significant proteins. Diffusion-weighted magnetic resonance imaging (DW-MRI) of the liver was performed at baseline and after the first 2 FLOX cycles. Using a b-value of 1000 s/mm2, the intensity ratio of a representative metastatic lesion relative to normal parenchymal tissue in the liver was calculated at each recording. Results: At this early time of analysis, with median follow-up of 8.6 (range, 1-21) months, median PFS for the entire groups of control and experimental arm patients was identical (6.4 and 6.6 months, respectively). We selected 13 experimental arm patients with long (median 13.6 months) or short (median 5.6 months) PFS for the serum protein analysis and 9 patients with liver DW-MRI. High serum CD40L levels (> median 47.6 ng/ml) at baseline or CD23 levels (> median 15.7 ng/ml) after the first 2 FLOX and 2 nivolumab cycles were both associated with improved PFS (p < 0.001 and p < 0.007; log-rank test). The baseline DW-MRI intensity of the peripheral hyperintense rim of the metastatic lesion (2.0- to 2.8-fold higher than the corresponding parenchymal value) diminished towards the parenchymal intensity (1.2- to 1.6-fold higher) after the first 2 FLOX cycles in patients with longer PFS than the median for all study patients. The rim intensity did not change in patients with short PFS. Conclusions: Three potential response markers in serum or at DW-MRI (one at baseline, one following the induction immunogenic chemotherapy, and one following the subsequent ICI) were identified for MSS-mCRC at this early time of the METIMMOX study conduct. Citation Format: Anne Hansen Ree, Sebastian Meltzer, Kine M. Bakke, Hanne M. Hamre, Christian Kersten, Eva Hofsli, Marianne Grønlie Guren, Halfdan Sorbye, Christin Johansen, Anne Negård, Kathrine Røe Redalen, Kjersti Flatmark. Immunogenic chemotherapy and immune checkpoint inhibition (ICI) in microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): Biomarkers indicative of durable treatment response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 522.

Background and purpose We investigated how features relating to pelvic cavity anatomy and tumor hemodynamic factors may influence systemic failure in rectal cancer. Materials and methods Rectal cancer patients (207 women, 343 men), who had been prospectively enrolled onto six cohorts and given curative-intent therapy, were analyzed for the first metastatic event. In one of the cohorts, the diameter of the inferior mesenteric vein (IMV) was assessed on diagnostic abdominal computed tomography images (n = 113). Tumor volume (n = 193) and histologic response to neoadjuvant therapy (n = 445) were recorded from diagnostic magnetic resonance images and surgical specimens, respectively. Results More women than men developed lung metastasis (p = 0.037), while the opposite was the case for liver metastasis (p = 0.040). Wider IMV diameter correlated with larger tumor volume (r = 0.481, p < 0.001) and male sex (p < 0.001). Female sex was the only adverse prognostic factor for lung metastasis. When sex, tumor volume, and histologic response were taken into consideration, poor tumor response remained the only determinant for liver metastasis (p = 0.002). Conclusions In a diverse rectal cancer population given curative-intent treatment, women and men had different outcome with regard to the primary metastatic site. Tumor hemodynamic factors should be considered in rectal cancer risk stratification. (C) 2019 The Author(s). Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Background Dynamic contrast‐based MRI and intravoxel incoherent motion imaging (IVIM) MRI are both methods showing promise as diagnostic and prognostic tools in rectal cancer. Both methods aim at measuring perfusion‐related parameters, but the relationship between them is unclear. Purpose To investigate the relationship between perfusion‐ and permeability‐related parameters obtained by IVIM‐MRI, T1‐weighted dynamic contrast‐enhanced (DCE)‐MRI and T2*‐weighted dynamic susceptibility contrast (DSC)‐MRI. Study Type Prospective. Subjects In all, 94 patients with histologically confirmed rectal cancer. Field Strength/Sequence Subjects underwent pretreatment 1.5T clinical procedure MRI, and in addition a study‐specific diffusion‐weighted sequence (b = 0, 25, 50, 100, 500, 1000, 1300 s/mm2) and a multiecho dynamic contrast‐based echo‐planer imaging sequence. Assessment Median tumor values were obtained from IVIM (perfusion fraction [f], pseudodiffusion [D*], diffusion [D]), from the extended Tofts model applied to DCE data (Ktrans, kep, vp, ve) and from model free deconvolution of DSC (blood flow [BF] and area under curve). A subgroup of the excised tumors underwent immunohistochemistry with quantification of microvessel density and vessel size. Statistical Test Spearman's rank correlation test. Results D* was correlated with BF (rs = 0.47, P < 0.001), and f was negatively correlated with kep (rs = –0.31, P = 0.002). BF was correlated with Ktrans (rs = 0.29, P = 0.004), but this correlation varied extensively when separating tumors into groups of low (rs = 0.62, P < 0.001) and high (rs = –0.06, P = 0.68) BF. Ktrans was negatively correlated with vessel size (rs = –0.82, P = 0.004) in the subgroup of tumors with high BF. Data Conclusion We found an association between D* from IVIM and BF estimated from DSC‐MRI. The relationship between IVIM and DCE‐MRI was less clear. Comparing parameters from DSC‐MRI and DCE‐MRI highlights the importance of the underlying biology for the interpretation of these parameters. Level of Evidence: 2 Technical Efficacy: Stage 1 © 2019 The Authors. his is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Background: In locally advanced rectal cancer (LARC), responses to preoperative treatment are highly heterogeneous and more accurate diagnostics are likely to enable more individualised treatment approaches with improved responses. We investigated the potential of diffusion-weighted magnetic resonance imaging (DW MRI), with quantification of the apparent diffusion coefficient (ADC) and perfusion fraction (F), as well as volumetry from T2-weighted (T2W) MRI, for prediction of therapeutic outcome. Material and methods: In 27 LARC patients receiving neoadjuvant chemotherapy (NACT) before chemoradiotherapy (CRT), T2W- and DW MRI were obtained before and after NACT. Tumour volumes were delineated in T2W MRI and ADCs and Fs were estimated from DW MRI using a simplified approach to the intravoxel incoherent motion (IVIM) model. Mean tumour values and histogram analysis of whole-tumour heterogeneity were correlated with histopathologic tumour regression grade (TRG) and 5-year progression-free survival (PFS). Results: At baseline, high tumour F predicted good tumour response (TRG1-2) (AUC = 0.79, p = 0.01), with a sensitivity of 69% and a specificity of 100%. The combination of F and tumour volume (Fpre/Vpre) gave the highest prediction of poor tumour response (AUC = 0.93, p

The liver is the most frequent metastatic site in colorectal cancer (CRC), and relevant orthotopic in vivo models are needed to study the efficacy of anticancer drugs in the metastatic setting. A challenge when utilizing such models is monitoring tumor growth during the experiments. In this study, experimental liver metastases were established in nude mice by splenic injection of the CRC cell lines HT29 and HCT116, and the mice were treated with the antiangiogenic drug aflibercept. Tumor growth was monitored using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). Aflibercept treatment was well tolerated and resulted in increased animal survival in HCT116, but not in HT29, while inhibited tumor growth was observed in both models. Treatment efficacy was monitored with high precision using MRI, while BLI detected small-volume disease with high sensitivity, but was less accurate in end-stage disease. Apparent diffusion coefficient (ADC) values obtained by diffusion weighted MRI (DW-MRI) were highly predictive of treatment response, with increased ADC corresponding well with areas of necrosis observed by histological evaluation of aflibercept-treated xenografts. The results showed that the efficacy of the antiangiogenic drug aflibercept varied between the two models, possibly reflecting unique growth patterns in the liver that may be representative of human disease. Non-invasive imaging, especially MRI and DW-MRI, can be used to effectively monitor tumor growth and treatment response in orthotopic liver metastasis models.

BACKGROUND: The liver is the most frequent metastatic site in colorectal cancer (CRC), and relevant in vivo models are needed to study the efficacy of anticancer drugs in this setting. Aflibercept, targeting vascular endothelial growth factors A and B and placental growth factor, is one of the most recently approved antiangiogenic agents for treatment of metastatic CRC. In the present work, the efficacy of aflibercept was investigated in experimental models of liver metastases in nude mice and growth progression was monitored using non-invasive imaging. METHODS: Liver metastases were established in mice by intrasplenic injection of CRC cell lines HCT116 and HT29 transfected with luciferase. Magnetic resonance imaging (MRI) (7T) and bioluminescent imaging (IVIS spectrum) were used to monitor tumor growth. Aflibercept was delivered intraperitoneally. To further characterize treatment response in metastatic tumors, diffusion-weighted (DW)-MR images were obtained. At termination tumors were sampled for histopathologic analysis. RESULTS: Mice bearing HCT116 xenografts responded well to treatment and a significant increase in survival compared to vehicle treated animals was observed (p< 0.001), in addition to decreased tumor burden. No increase in survival was observed upon aflibercept treatment in HT29 xenografts (p = 0.155), whereas in one of two experiments performed a significant reduction in tumor volume was observed, suggesting that there was a slight response to treatment. T2-weighted MRI was used to quantify tumor volume by manual delineation using the OsiriX software. MRI-assessed tumor volumes correlated well with tumor weight at the time of termination, while for bioluminescence measurements no such correlation was observed. In contrast, bioluminescence was a sensitive detection method early in the experiments when MRI did not show liver tumor. DW-MRI was obtained and apparent diffusion coefficient (ADC) tumor maps were calculated using the nordicIce software. A slight increase in ADC values was observed for HT29 tumors while there was a large increase in ADC values for HCT116 tumors after treatment with aflibercept. This corresponded well with histologic evaluation of tumors, showing increased necrosis in HCT116 tumors, but not in HT29 tumors. CONCLUSION: Our results demonstrate efficacy of aflibercept in an orthotopic model of liver metastases in CRC. MRI could be used to monitor treatment efficacy with high precision, while bioluminescence measurement could detect small-volume disease with high sensitivity, but was less specific in high-volume disease. Interestingly, ADC values obtained from DW-MRI were highly predictive of treatment response by clearly visualizing and quantifying tumor necrosis. Citation Format: Karianne G. Fleten, Kine M. Bakke, Andreas Abildgaard, Gunhild M. Mælandsmo, Katrine Røe Redalen, Kjersti Flatmark. Diffusion-weighted MRI can predict response to aflibercept in in vivo models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4218.