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Radiomics objectively quantifies image information through numerical metrics known as features. In this study, we investigated the stability of magnetic resonance imaging (MRI)-based radiomics features in rectal cancer using both anatomical MRI and quantitative MRI (qMRI), when different methods to define the tumor volume were used. Second, we evaluated the prognostic value of stable features associated to 5-year progression-free survival (PFS) and overall survival (OS). On a 1.5 T MRI scanner, 81 patients underwent diagnostic MRI, an extended diffusion-weighted sequence with calculation of the apparent diffusion coefficient (ADC) and a multiecho dynamic contrast sequence generating both dynamic contrast-enhanced and dynamic susceptibility contrast (DSC) MR, allowing quantification of K trans , blood flow (BF) and area under the DSC curve (AUC). Radiomic features were extracted from T2w images and from ADC, K trans , BF and AUC maps. Tumor volumes were defined with three methods; machine learning, deep learning and manual delineations. The interclass correlation coefficient (ICC) assessed the stability of features. Internal validation was performed on 1000 bootstrap resamples in terms of discrimination, calibration and decisional benefit. For each combination of image and volume definition, 94 features were extracted. Features from qMRI contained higher prognostic potential than features from anatomical MRI. When stable features (> 90% ICC) were compared with clinical parameters, qMRI features demonstrated the best prognostic potential. A feature extracted from the DSC MRI parameter BF was associated with both PFS ( p  = 0.004) and OS ( p  = 0.004). In summary, stable qMRI-based radiomics features was identified, in particular, a feature based on BF from DSC MRI was associated with both PFS and OS.

Biological heterogeneity and low inherent immunogenicity are two features that greatly impact therapeutic management and outcome in colorectal cancer. Despite high local control rates, systemic tumor dissemination remains the main cause of treatment failure and stresses the need for new developments in combined-modality approaches. While the role of adaptive immune responses in a small subgroup of colorectal tumors with inherent immunogenicity is indisputable, the challenge remains in identifying the optimal synergy between conventional treatment modalities and immune therapy for the majority of the less immunogenic cases. In this context, cytotoxic agents such as radiation and certain chemotherapeutics can be utilized to enhance the immunogenicity of an otherwise immunologically silent disease and enable responsiveness to immune therapy. In this review, we explore the immunological characteristics of colorectal cancer, the effects that standard-of-care treatments have on the immune system, and the opportunities arising from combining immune checkpoint-blocking therapy with immune-modulating conventional treatments.

Background Recent reports have demonstrated that the entire mitochondrial genome can be secreted in extracellular vesicles (EVs), but the biological attributes of this cell-free mitochondrial DNA (mtDNA) remain insufficiently understood. We used next-generation sequencing to compare plasma EV-derived mtDNA to that of whole blood (WB), peripheral blood mononuclear cells (PBMCs), and formalin-fixed paraffin-embedded (FFPE) tumor tissue from eight rectal cancer patients and WB and fresh-frozen (FF) tumor tissue from eight colon cancer patients. Methods Total DNA was isolated before the mtDNA was enriched by PCR with either two primer sets generating two long products or multiple primer sets (for the FFPE tumors), prior to the sequencing. mtDNA diversity was assessed as the total variant number, level of heteroplasmy (mutant mtDNA copies mixed with wild-type copies), variant distribution within the protein-coding genes, and the predicted functional effect of the variants in the different sample types. Differences between groups were compared by paired Student’s t -test or ANOVA with Dunnett’s multiple comparison tests when comparing matched samples from patients. Mann–Whitney U test was used when comparing differences between the cancer types and patient groups. Pearson correlation analysis was performed. Results In both cancer types, EV mtDNA presented twice as many variants and had significantly more low-level heteroplasmy than WB mtDNA. The EV mtDNA variants were clustered in the coding regions, and the proportion of EV mtDNA variants that were missense mutations (i.e., estimated to moderately affect the mitochondrial protein function) was significantly higher than in WB and tumor tissues. Nonsense mutations (i.e., estimated to highly affect the mitochondrial protein function) were only observed in the tumor tissues and EVs. Conclusion Taken together, plasma EV mtDNA in CRC patients exhibits a high degree of diversity. Trial registration ClinicalTrials.gov: NCT01816607 . Registered 22 March 2013.

Background We reported previously that rectal cancer patients given curative-intent chemotherapy, radiation, and surgery for non-metastatic disease had enhanced risk of metastatic progression and death if circulating levels of 25-hydroxyvitamin D [25(OH) D] were low. Here we investigated whether the association between the vitamin D status and prognosis pertains to the general, unselected population of rectal cancer patients. Methods Serum 25(OH) D at the time of diagnosis was assessed in 129 patients, enrolled 2013–2017 and representing the entire range of rectal cancer stages, and analyzed with respect to season, sex, systemic inflammation, and survival. Results In the population-based cohort residing at latitude 60°N, 25(OH) D varied according to season in men only, who were overrepresented among the vitamin D-deficient (< 50 nmol/L) patients. Consistent with our previous findings, the individuals presenting with T4 disease had significantly reduced 25(OH) D levels. Low vitamin D was associated with systemic inflammation, albeit with distinct modes of presentation. While men with low vitamin D showed circulating markers typical for the systemic inflammatory response (e.g. , elevated erythrocyte sedimentation rate), the corresponding female patients had elevated serum levels of interleukin-6 and the chemokine (C-X-C motif) ligand 7. Despite disparities in vitamin D status and the potential effects on disease attributes, significantly shortened cancer-specific survival was observed in vitamin D-deficient patients irrespective of sex. Conclusion This unselected rectal cancer cohort confirmed the interconnection of low vitamin D, more advanced disease presentation, and poor survival, and further suggested it may be conditional on disparate modes of adverse systemic inflammation in men and women. Trial registration ClinicalTrials.gov NCT01816607 ; registration date: 22 March 2013.

Background Following curative-intent neoadjuvant therapy in locally advanced rectal cancer, metastatic progression is still dominant. We investigated if patients’ circulating 25-hydroxyvitamin D [25(OH)D] levels were associated with outcome. Methods Serum 25(OH)D concentration was assessed by liquid chromatography-mass spectrometry in samples collected from 84 patients at baseline, completion of the neoadjuvant therapy, and treatment evaluation before surgery, and analyzed with respect to season, disease presentation, and treatment effects. Results In the cohort of patients residing at latitude 58–62°N, baseline 25(OH)D differed significantly over the seasons, with highest measures (mean of 71.2 ± 5.6 nmol/L) in summer and lowest (48.7 ± 4.5 nmol/L) in spring, and changed over the three-month neoadjuvant period till response evaluation solely owing to season. The patient subgroup with slightly reduced performance status, anemia, and T4 disease that did not respond to the neoadjuvant therapy (ypT4 cases), had significantly lower baseline 25(OH)D (below 50 nmol/L) than T4 cases with response (ypT0–3) and T2–3 cases (above 60 nmol/L). Compared to the T4 patients with levels above 50 nmol/L, regarded as sufficient for a healthy bone status, those presenting levels below had significantly heightened risk of disease progression (mainly metastasis) and death, with hazard ratio of 3 and 17, respectively, on adjustment for age, sex, body mass index, and season. Conclusion Rectal cancer T4 cases had high risk of metastatic progression and death if circulating 25(OH)D levels were insufficient but obtained short-term and long-term outcome to neoadjuvant treatment no worse than patients with T2–3 disease when 25(OH)D was sufficient. Trial registration ClinicalTrials.gov NCT00278694 ; registration date: 16 January 2006, retrospective to enrollment of the first 10 patients of the current report.

Colorectal cancer (CRC) is the third most common type of cancer worldwide. The link between inflammation and CRC is well established. Elevated levels of C-reactive protein (CRP) upon diagnosis is a known negative prognostic factor for CRC patients. Monomeric CRP (mCRP) has been demonstrated in tissues of several diseases associated with inflammation, including colon cancer (CC). mCRP possesses proinflammatory properties and is a possible mediator of tumor-promoting inflammation. This study aimed to detect and quantify circulating mCRP and assess potential correlations with clinical CRP and intra-tumoral mCRP in CC patients. Forty patients treated for stage II-III CC between 2012 and 2015 at Sorlandet Hospital, Norway, were included in the study. Twenty patients had CRP level <10 mg/l and 20 patients had CRP ≥10 mg/l, measured routinely at diagnosis (clinical CRP). EDTA plasma was used for mCRP detection by enzyme-linked immunosorbent assay (ELISA; n = 40) and mass spectrometry (MS; n = 20) (MS data are available via ProteomeXchange with identifier PXD046746). Tumor mCRP abundance was classified into three categories by reference scoring, using an antigen-retrieval technique on formalin-fixed paraffin-embedded tissue samples (n = 29). Circulating mCRP levels were detectable by both ELISA and MS. Median mCRP level measured by ELISA was 2.55 ng/mL, while the MS analysis detected 19.02 ng/mL. Both analyses exhibited significant correlations with clinical CRP (ELISA, = 0.012; MS, < 0.001). Intra-tumoral mCRP correlated with circulating mCRP measured by MS ( < 0.001) and with clinical CRP ( < 0.001). To the authors' knowledge, this is the first report of mCRP in the circulation of cancer patients. By employing two different analytical methods, mCRP was reliably detected in CC patients. Patients with elevated circulating mCRP measured by MS had higher intra-tumoral mCRP abundance. The interesting correlation of circulating and intra-tumoral mCRP levels may represent another facet of the interplay between local and systemic inflammation in CC patients.

Background The cellular metabolism undergoes reprogramming during the metastatic process. We hypothesised that serum metabolites at the time of primary tumour diagnosis might identify rectal cancer patients prone to metastatic progression. Methods One hundred twenty-three rectal cancer patients from a prospective observational biomarker study were followed up to 5 years after study entry. We have assessed metabolites in serum sampled at the time of diagnosis by 1 H-nuclear magnetic resonance spectroscopy, using the internal reference trimethylsilylpropanoic acid for quantification. Results Here we show that patients who develop overt metastatic disease more than 6 months after the primary tumour diagnosis have elevated serum levels (Kruskal-Wallis test) of alanine ( P  = 0.005), lactate ( P  = 0.023), pyruvate ( P  = 0.041) and citrate ( P  = 0.007) compared to those without metastases at the 5-year follow-up or with metastases already 6 months or sooner after the cancer diagnosis. Patients with serum citrate above 0.24 mmol/L have poorer progression-free survival compared to those with levels below ( P  < 0.001; log-rank test). Conclusions We observe a distinct serum metabolite profile, in particular involving citrate to the best of our knowledge shown for the first time clinically, in rectal cancer patients at heightened risk of metastasis already when the primary tumour is diagnosed, offering insights into the metabolism of metastatic progression. Plain Language Summary Cancer cells need energy and building blocks, such as amino acids and lipids, when growing. This is particularly important when the cancer cells are spreading to other organs in the body, named metastasis. Metastatic spread is a common cause of death from bowel cancer. We analysed metabolites (energy and building block proteins) in the blood from 123 patients with bowel cancer and found that patients who later developed metastasis had other levels of blood metabolites than patients who never were diagnosed with metastasis. In particular, we found higher levels of four specific metabolites: lactate, pyruvate, alanine and citrate. These findings may enable more precise diagnosis of bowel cancer at risk of spread to other organs and may help us better understand why metastasis occurs. Bakke, Bousquet et al. identify serum metabolite biomarkers at the time of primary tumour diagnosis in rectal cancer participants prone to metastatic progression. These individuals show higher serum metabolites of alanine, lactate, pyruvate, and citrate compared to those without metastatic progression.

The tumour microenvironment (TME) constitution is decisive for cancer outcome and is manifested in diffusion‐weighted (DW) magnetic resonance imaging (MRI). We hypothesized that the TME metabolic state is reflected by mitochondrial DNA (mtDNA) secreted in extracellular vesicles (EVs) and examined whether plasma EV‐mtDNA variants may divulge MRI‐assessed TME attributes of rectal cancer aggressiveness. On the diagnostic MRI scans from 60 rectal cancer patients, the apparent diffusion coefficient (ADC) was calculated on DW images (n = 29), and tumour volume (n = 57) and extramural vascular invasion (EMVI; all patients) were determined on anatomical images. Plasma EVs (all patients) were isolated by size exclusion chromatography and verified for EV features. The EV‐mtDNA was sequenced along with mtDNA in whole blood (WB; normal tissue) to calculate the EV/WB‐mtDNA total variant number (TVN) and heteroplasmic variant number (HVN)—as a proxy for TME intracellular mtDNA variants expelled in EVs. Low EV/WB‐mtDNA TVN and HVN, indicative of hampered clearance of mutated mtDNA via EVs, were associated with low ADC (high TME cell density; p = 0.018, p = 0.005) and a large tumour volume (p = 0.002, p = 0.003). Likewise, low EV/WB‐mtDNA TVN and HVN were associated with positive EMVI (tumour infiltration in blood vessels; p = 0.002, p = 0.003) and histologic ypN stage 1–2 (lymph nodes with tumour cells surviving radiotherapy; p = 0.002, p = 0.005), both indicators of high tumour aggressiveness. High cellular density may hamper the clearance of pathogenic tumour mtDNA variants by EVs and thus promote rectal cancer aggressiveness. Trial Registration: ClinicalTrials.gov: NCT01816607. Registered 22 March 2013, https://clinicaltrials.gov/ct2/show/NCT01816607

Background We evaluated first-line treatment of metastatic microsatellite-stable colorectal cancer with short-course oxaliplatin-based chemotherapy alternating with immune checkpoint blockade. Methods Patients were randomly assigned to chemotherapy (the FLOX regimen; control group) or alternating two cycles each of FLOX and nivolumab (experimental group). Radiographic response assessment was done every eight weeks with progression-free survival (PFS) as the primary endpoint. Cox proportional-hazards regression models estimated associations between PFS and relevant variables. A post hoc analysis explored C-reactive protein as signal of responsiveness to immune checkpoint blockade. Results Eighty patients were randomised and 38 in each group received treatment. PFS was comparable—control group: median 9.2 months (95% confidence interval (CI), 6.3–12.7); experimental group: median 9.2 months (95% CI, 4.5–15.0). The adjusted Cox model revealed that experimental-group subjects aged ≥60 had significantly lowered progression risk ( p  = 0.021) with hazard ratio 0.17 (95% CI, 0.04–0.76). Experimental-group patients with C-reactive protein <5.0 mg/L when starting nivolumab ( n  = 17) reached median PFS 15.8 months (95% CI, 7.8–23.7). One-sixth of experimental-group cases (all KRAS/BRAF -mutant) achieved complete response. Conclusions The investigational regimen did not improve the primary outcome for the intention-to-treat population but might benefit small subgroups of patients with previously untreated, metastatic microsatellite-stable colorectal cancer. Trial registration ClinicalTrials.gov number, NCT03388190 (02/01/2018).

BackgroundImmune checkpoint blockade (ICB) results in radiologic tumour response dynamics that differ from chemotherapy efficacy measures and require an early signal of clinical utility.MethodsPreviously untreated, unresectable microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC) patients were randomly assigned to the oxaliplatin-based Nordic FLOX regimen (control arm) or repeat sequential two FLOX cycles and two ICB cycles (experimental arm). The radiologic response was assessed every 8 weeks. In this post hoc analysis, we explored early target lesion (TL) dynamics as indicator of ICB responsiveness. Progression-free survival (PFS) was the primary endpoint.ResultsUsing a landmark analysis approach, we categorised experimental-arm patients into ≥10% (N = 19) or <10% (N = 16) TL reduction at the first post-baseline response assessment. Median PFS for the groups was 16.0 (95% confidence interval (CI), 12.3–19.7) and 3.9 months (95% CI, 2.3–5.5), respectively, superior and inferior (both P < 0.01) to the median PFS of 9.8 months (95% CI, 4.9–14.7) for control arm patients (N = 31).ConclusionsRadiologic TL reduction of ≥10% at the first post-baseline response assessment identified patients with ICB-responsive metastatic MSS/pMMR-CRC. This pragmatic measure may be used to monitor patients in investigational ICB schedules, enabling early treatment adaptation for unresponsive cases.Trial registrationClinicalTrials.gov number, NCT03388190 (02/01/2018).