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The genomic profiling of circulating tumor cells (CTCs) in the bloodstream should provide clinically relevant information on therapeutic efficacy and help predict cancer survival. However, the molecular characterization of CTCs has so far proven extremely difficult. A variety of technologies have been developed for CTC isolation, but so far the impact on the genomic assessment of CTCs has not been fully evaluated. To fill this gap, here we contrasted the genomic profiles of CTC pools recovered from blood samples obtained from four metastatic colorectal cancer (mCRC) patients using three different enrichment strategies (CellSearch, Parsortix, and FACS). Our results suggest clear differences in the mutational burden of CTC pools depending on the enrichment method used, with all evaluated methods returning a somewhat limited representation of the mutational spectrum of individual tumors, potentially due to allelic dropout during whole-genome amplification. Nevertheless, the CTC pools from Parsortix, and in part, CellSearch, showed diversity estimates, mutational signatures and drug-suitability scores remarkably close to the ones found in matching primary tumor samples. In contrast, FACS CTC pools were substantially enriched in apparent sequencing artifacts, which led to much higher estimates of genomic diversity. Although CTC genomics still faces technical challenges, our results suggest that CTC-derived metrics can reflect the diversity scores seen in primary tumor lesions thus highlighting the utility of CTCs to assess the heterogeneity status of individual tumors, and to help clinicians prioritize drugs in mCRC.

CA19-9 serum has been suggested as a marker of unresectability but different cut-off levels have been published. A cut-off of 500 U/ml is currently considered in an international consensus as biological criteria of borderline resectable pancreatic adenocarcinoma. To evaluate whether serum CA19-9 threshold of 500 U/ml could be adequate predictor of resectability in pancreatic adenocarcinoma. Multicenter, observational, prospective study performed in Spain including 203 patients diagnosed with pancreatic adenocarcinoma. 43 (21.2%) cases were resectable and 160 (78.8%) unresectable. Among the 176 preoperative CA19-9 available values, 98 (58.3%) were ≤ 500 U/ml and 73 (42.7%) > 500 U/ml. Resectability rate in those patients with CA19-9 ≤ 500 U/ml was 60% while it was found to be 18% when CA19-9 > 500 U/ml. Statistical model to predict resectability based on CA19-9 provide an AUC of 0.6618 (95% CI 0.53–0.83) when only CA19-9 values > 500 U/ml are studied. Serum levels of CA19-9 higher than 500 U/ml are indicative of unresectable disease, however reduced sensitivity and specificity lead to a limited clinical applicability for resectability.

Simple Summary The development of colorectal cancer (CRC) is influenced by the environment, genetics and microbiota. Microbiome and metabolome analyses allowed for the finding of factors and markers associated with adenoma and CRC risk, but the interaction of host genomics with those omic layers remains unclear. Thus, our aim is to add host genome information to find new factors and markers associated with adenoma and CRC risk or to propose biological mechanisms involved in the risk. We found interactions between different omic layers that could be biologically relevant, and the three layers gave complementary information to predict adenoma and CRC risk. Our findings will help to find new markers for adenoma and CRC risk and to analyze biological mechanisms involved in adenoma and CRC development. Abstract Background: Colorectal cancer (CRC), a major health concern, is developed depending on environmental, genetic and microbial factors. The microbiome and metabolome have been analyzed to study their role in CRC. However, the interplay of host genetics with those layers in CRC remains unclear. Methods: 120 individuals were sequenced and association analyses were carried out for adenoma and CRC risk, and for selected components of the microbiome and metabolome. The epistasis between genes located in cholesterol pathways was analyzed; modifiable risk factors were studied using Mendelian randomization; and the three omic layers were used to integrate their data and to build risk prediction models. Results: We detected genetic variants that were associated to components of metabolome or microbiome and adenoma or CRC risk (e.g., in LINC01605, PROKR2 and CCSER1 genes). In addition, we found interactions between genes of cholesterol metabolism, and HDL cholesterol levels affected adenoma (p = 0.0448) and CRC (p = 0.0148) risk. The combination of the three omic layers to build risk prediction models reached high AUC values (>0.91). Conclusions: The use of the three omic layers allowed for the finding of biological mechanisms related to the development of adenoma and CRC, and each layer provided complementary information to build risk prediction models.

Background and Aims The development programm UNIFI has shown promising results of ustekinumab in ulcerative colitis [UC] treatment which should be confirmed in clinical practice. We aimed to evaluate the durability, effectiveness, and safety of ustekinumab in UC in real life. Methods Patients included in the prospectively maintained ENEIDA registry, who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score [PMS]>2], were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at Week 16. Results A total of 95 patients were included. At Week 16, 53% of patients had response [including 35% of patients in remission]. In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at Weeks 24 and 52, respectively; 36% of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at Week 16, 63% at Week 56, and 59% at Week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. Conclusions Ustekinumab is effective in both the short and the long term in real life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.