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Colorectal cancer remains the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide [...].Colorectal cancer remains the third most commonly diagnosed malignancy and the second leading cause of cancer-related death worldwide [...].

BackgroundPreoperative colonic stenting for malignant large bowel obstruction (MLBO), also called bridge to surgery (BTS), is considered a great substitute treatment for emergency resection (ER) in the left-sided colon. However, its efficacy in the right-sided colon remains controversial. This systematic review and meta-analysis aimed to compare the postoperative short-term outcomes between BTS and ER for right-sided MLBO.MethodsA comprehensive electronic literature search throughout December 2020 was performed to identify studies comparing short-term outcomes between BTS and ER for right-side MLBO. The main outcome measures were postoperative complications and mortality rates. A meta-analysis was performed using a fixed-effect or a random-effect method to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs).ResultsSeven studies were included in this meta-analysis, comprising 5136 patients, of whom 1662 (32.4%) underwent BTS and 3474 (67.6%) underwent ER. This meta-analysis demonstrated that BTS resulted in reductions in postoperative complications (OR = 0.78; 95% CI: 0.66–0.92) and mortality (OR = 0.51; 95% CI: 0.28–0.92) than ER.ConclusionThe results of this meta-analysis indicate that BTS for right-sided MLBO confers preferable short-term outcomes as well as for left-sided. This suggests that BTS results in a reduction of postoperative complications and mortality for right-sided MLBO than ER.

BackgroundThe self-expanding metallic stent (SEMS) provides effective decompression for patients with malignant large bowel obstruction (MLBO); however, mechanical damage to malignant cells from insertion may negatively affect prognosis, similar to surgical manipulation, and its oncological safety is unclear. We examined mechanical damage from SEMS placement using circulating cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA).MethodsBetween 1 November 2014 and 30 June 2017, 35 MLBO patients were analyzed, comprising 25 SEMS patients and 10 transanal decompression tube (TDT) patients (control). Blood samples were collected before and after decompression on days 0, 1, 3, and 7. cfDNA, ctDNA, white blood cells, C-reactive protein, and lactate dehydrogenase were analyzed.ResultsThe clinical success rates of SEMS and TDT were 88 and 90%, respectively (p = 1.0). The cfDNA concentration on day 7 was significantly higher in the SEMS group than in the TDT group (992 vs. 308 ng/mL; p = 0.005). A significant increase in ctDNA was observed in the SEMS group compared with the TDT group (83% vs. 22%; p = 0.002). The cfDNA concentration showed strong positive correlations with ctDNA and lactate dehydrogenase (R2 = 0.838 and 0.593, respectively), and a weak positive correlation with C-reactive protein (R2 = 0.263).ConclusionsDespite equivalent clinical success rates, SEMS placement increased plasma levels of cfDNA and ctDNA by tumor manipulation, but TDT did not. Colonic stenting showed oncological risk in terms of molecular analysis.

A significant association exists between the gut microbiome and colorectal carcinogenesis, as well as cancer progression. It has been reported that Escherichia coli (E. coli) containing polyketide synthetase (pks) island contribute to colorectal carcinogenesis by producing colibactin, a polyketide‐peptide genotoxin. However, the functions of pks+ E. coli in initiation, proliferation, and metastasis of colorectal cancer (CRC) remain unclear. We investigated the clinical significance of pks+ E. coli to clarify its functions in CRC. This study included 413 patients with CRC. Pks+ E. coli of tumor tissue and normal mucosal tissue were quantified using droplet digital PCR. Pks+ E. coli was more abundant in Stages 0–I tumor tissue than in normal mucosal tissue or in Stages II–IV tumor tissue. High abundance of pks+ E. coli in tumor tissue was significantly associated with shallower tumor depth (hazard ratio [HR] = 5.0, 95% confidence interval [CI] = 2.3–11.3, p < 0.001) and absence of lymph node metastasis (HR = 3.0, 95% CI = 1.8–5.1, p < 0.001) in multivariable logistic analyses. Pks+ E. coli‐low and ‐negative groups were significantly associated with shorter CRC‐specific survival (HR = 6.4, 95% CI = 1.7–25.6, p = 0.005) and shorter relapse‐free survival (HR = 3.1, 95% CI = 1.3–7.3, p = 0.01) compared to the pks+ E. coli‐high group. Pks+ E. coli was abundant in Stages 0–I CRC and associated with CRC prognosis. These results suggest that pks+ E. coli might contribute to carcinogenesis of CRC but might not be associated with tumor progression. Polyketide synthetase (pks)‐positive Escherichia coli (pks+ E. coli), which has been reported to contribute to colorectal carcinogenesis, is more abundant in Stage I tumors than normal mucosal tissue and Stages II–IV tumors. Furthermore, a high level of pks+ E. coli in tumor tissue is associated with a favorable prognosis of prognosis in multivariable Cox regression analysis.

Liquid biopsy using circulating tumor DNA (ctDNA) is useful for precision medicine and molecular‐guided oncology; however, its sensitivity is insufficient. We focused on DNA in extracellular vesicles (evDNA) as a new target for liquid biopsy and investigated its sensitivity. This observational study included 334 Stage I–IV colorectal cancer patients. evDNAs and ctDNAs were extracted from plasma collected before surgery. KRAS mutation status was analyzed using droplet digital PCR. One hundred and forty‐eight patients had KRAS mutations in tumor tissues, and 186 patients had no KRAS mutations. In Stage II (Stage II 37.8% vs. 13.3%, p = 0.015) or III (Stage III 43.1% vs. 13.6%, p = 0.001) patients, sensitivities to detect KRAS mutations using evDNA were higher than those using ctDNA. Surprisingly, evDNA identified KRAS mutations in 13.8% of patients who lacked them in tumor tissue samples. Among Stage III patients, those with higher concentrations of evDNA had significantly poorer relapse‐free survival compared with those who had lower concentrations of evDNA (p = 0.043). The use of evDNA improved the identification rate of KRAS mutations. By using evDNA, KRAS mutations were identified in more than 10% of patients without KRAS mutations in their tumor tissues. The concentration of evDNA can be a prognostic factor for Stage III colorectal cancer patients. DNA in the circulating extracellular vesicle (evDNA) has superior potential for detecting KRAS mutations compared with circulating tumor DNA, possibly because evDNA comprises very long, undamaged DNA strands. The analysis using evDNA demonstrated that heterogeneity related to KRAS exists at a higher frequency than we had anticipated. Furthermore, it was suggested that colorectal cancer patients with higher levels of evDNA may have a poorer prognosis.

We recruited 56 colorectal cancer patients and compared the mutational spectrum of tumor tissue DNA, circulating cell‐free DNA (ccfDNA) and circulating tumor cell (CTC) DNA (ctcDNA) to evaluate the potential of liquid biopsy to detect heterogeneity of cancer. Tumor tissue DNA, ccfDNA, and ctcDNA were extracted from each patient and analyzed using next‐generation sequencing (NGS) and digital PCR. To maximize yields of CTC, three antibodies were used in the capture process. From 34 untreated patients, 53 mutations were detected in tumor tissue DNA using NGS. Forty‐seven mutations were detected in ccfDNA, including 20 not detected in tissues. Sixteen mutations were detected in ctcDNA, including five not detected in tissues. In 12 patients (35.3%), mutations not found in tumor tissues were detected by liquid biopsy: nine (26.5%) in ccfDNA only and three (8.8%) in ctcDNA only. Combination analysis of the two liquid biopsy samples increased the sensitivity to detect heterogeneity. From 22 stage IV patients with RAS mutations in their primary tumors, RAS mutations were detected in 14 (63.6%) ccfDNA and in eight (36.4%) ctcDNA using digital PCR. Mutations not detected in primary tumors can be identified in ccfDNA and in ctcDNA, indicating the potential of liquid biopsy in complementing gene analysis. Combination analysis improves sensitivity. Sensitivity to detect cancer‐specific mutations is higher in ccfDNA compared with ctcDNA. Cancer is a heterogeneous disease. We compared the mutational spectrum of tumor tissue DNA, circulating cell‐free DNA, and circulating tumor cell DNA in colorectal cancer patients using next‐generation sequencing and digital PCR. Results showed the potential of liquid biopsy samples to provide a complementary role in genetic analysis.

Background Fibroblast growth factor receptor 4 (FGFR4) is overexpressed in up to 50% of pancreatic ductal adenocarcinoma (PDAC) cases. BLU9931, a selective FGFR4 inhibitor, exerts cytotoxic effects on PDAC cells and induces cellular senescence. This study aimed to investigate the effects of BLU554, another selective FGFR4 inhibitor, whose efficacy and safety in hepatocellular carcinoma has been proven in clinical trials, on PDAC cell lines. Methods BLU554 was applied to PDAC cell lines, and cytotoxicity in PK-1 and T3M-4 cells was assessed by counting viable cells. BLU554-induced senescence was detected using γH2AX immunocytochemical staining; qualitative polymerase chain reaction (qPCR) analysis of CDKN1A, LMNB1 , and senescence-associated secretory phenotype (SASP) factors; transmission electron microscopy of lysosomal structures and numbers; and the senescence-associated-β-galactosidase assay. In addition, we assessed whether dasatinib and quercetin, two representative senolytic agents, could reduce the viability of BLU554-treated cells, using an ATP assay. Results BLU554 suppressed the growth of PK-1 and T3M-4 cells, which express high FGFR4 levels, with a stronger effect in T3M-4 cells. Cellular senescence, which can be triggered by chemotherapy-induced stress, was induced in both PK-1 and T3M-4 cells, as evidenced by elevated γH2AX expression. Treatment with BLU554 increased the number of PDAC cells exhibiting lysosomal enzyme activity abnormalities, as indicated by SA-β-galactosidase staining. The number of PDAC cells showing lysosomal morphological alterations, observed under transmission electron microscopy, also increased. Increased CDKN1A and decreased LMNB1 mRNA levels, combined with changes in the expression of SASP factors, further confirmed the induction of cellular senescence. Application of the senolytic drugs dasatinib or quercetin significantly reduced the viability of BLU554-treated cells, which are associated with increased malignancy. Conclusions This two-step strategy may represent a novel therapeutic approach for the treatment of therapy-resistant PDAC through senescence induction and subsequent senolysis.

Oncogenic RAS mutations are negative biomarkers of response to epidermal growth factor receptor (EGFR) blockade. RAS mutations are usually detected in biopsies of primary colorectal tumors. However, the genomic profiles of primary tumors and metastases are not always concordant, and chemotherapeutic agents can alter the tumor molecular landscape. Cell-free DNA (cfDNA) is a novel tool to detect molecular heterogeneity. This study evaluated the clinical utility of cfDNA to predict primary or secondary resistance to EGFR blockade in patients with metastatic colorectal cancer. Thirty metastatic colorectal cancer patients without RAS and BRAF mutations were prospectively enrolled and treated with cytotoxic agents and EGFR blockade as first-line therapy. cfDNA was analyzed for the presence of RAS, BRAF, and EGFR (S492R) point mutations before initiating chemotherapy and every 2 months during chemotherapy. The analysis was performed in 223 plasma samples from all 30 patients. Of the 30 patients, five had RAS mutations in their cfDNA before starting chemotherapy and did not respond. Twenty-four of the remaining 25 patients without cfDNA RAS mutations had a response. Twenty of the 24 responders developed secondary resistance and cfDNA RAS mutations were found in 17 of the 20. cfDNA BRAF mutations were found in seven, and EGFR mutations were found in eight of the 20 patients. Emerging RAS, BRAF, and EGFR mutations occurred in patients with primary and secondary resistance to EGFR blockade. The detection of these mutations in cfDNA is a promising approach to predict treatment response and secondary resistance.

Objective Anchorage-independent growth is a critical feature of cancer cells, reflecting their ability to survive and proliferate without attachment to the extracellular matrix. Spheres—cancerous masses formed in a three-dimensional (3D) anchorage-independent culture—contain a high level of cancer stem cells. This anchorage-independent proliferative capacity closely relates to tumorigenicity, anoikis resistance, and metastatic capability. Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous group comprising epithelial and mesenchymal features, and these subtypes exhibit different biological characteristics in 3D cultures. This study examines whether these PDAC subtypes differ in their anchorage-independent proliferative capability at the single-cell level. Methods Eight PDAC cell lines, including five epithelial-type and three mesenchymal-type lines, were cultured as single cells in poly (2-methacryloyloxyethyl phosphorylcholine) (MPC) polymer–coated low-attachment microwell plates, and time-lapse imaging was performed every 15 min for 60 h. Results Three phenotypes were observed: non-proliferating single cells, cells dividing into two, and those forming clusters of three or four cells. In single-cell analysis, KP4 and MIA PaCa-2 mesenchymal PDAC cells exhibited a high number of cells proliferating into two or more cells. Conclusion These findings suggest that mesenchymal PDAC cells exhibit greater anchorage-independent proliferative capability, reflecting their aggressive biological behavior.

Background Neoadjuvant chemotherapy (NAC) is gaining attention as a treatment for advanced colorectal cancer owing to its potential to improve surgical outcomes and prognosis. However, reliable biomarkers to predict the response to NAC are lacking. We aimed to investigate the predictive value of cell-free DNA (cfDNA) integrity index for NAC response, using machine learning to compensate for the small cohort size. Methods This retrospective study included 31 locally advanced colorectal cancer patients who underwent NAC and surgery at the Nippon Medical School Hospital between 2016 and 2020. Blood samples were collected pre-post-NAC to assess cfDNA levels using quantitative polymerase chain reaction. The cfDNA integrity index was calculated based on the ratio of long to short fragments in the long-interspersed element-1 repeat sequence. Statistical analyses, including random forest modeling, were performed to evaluate the predictive value of the cfDNA integrity index for treatment response. Results Of the 31 patients, 19 (61.3%) were classified as responders and 12 (38.7%) as non-responders. The post-NAC cfDNA integrity index was significantly different between the groups ( P  = 0.002, odds ratio = 16.0). Random forest analysis identified changes in the cfDNA integrity index as the most important predictor of NAC response (%IncMSE: 15.79; IncNodePurity: 2.21), while sex, age, tumor site, and pre-NAC cfDNA levels were not significant predictors. Conclusions Variability in the cfDNA integrity index shows promise as a biomarker for predicting NAC efficacy in colorectal cancer.