Asimina Koulouridi

Background: The optimal duration of adjuvant chemotherapy for stage III colorectal cancer (CRC) remains uncertain following the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) trial collaboration, while the prognostic role of liquid biopsy biomarkers in this setting is unclear. We evaluated the clinical relevance of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) in patients receiving three or six months of adjuvant chemotherapy. Methods: In this prospective, single-center study, 173 patients with resected stage III CRC received adjuvant fluorouracil, leucovorin and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) for three or six months. Peripheral blood samples were collected at baseline and during treatment. CTCs were assessed using immunofluorescence and reverse-transcription quantitative polymerase chain reaction, while baseline ctDNA was assessed using an exploratory tumour-agnostic analysis of molecular association, in a patients’ subgroup. Associations with disease-free survival (DFS) and overall survival (OS) were evaluated. Results: Baseline CTCs were detected in 45.1% of patients and were associated with shorter DFS. CTC levels decreased after three months of CAPOX treatment but increased between three and six months in selected subgroups. Kaplan–Meier analyses showed no significant DFS or OS differences by regimen or treatment duration. LEF1, MAPK1, and AXIN1 showed nominal survival associations that did not remain significant after false discovery rate (FDR) adjustment. Conclusions: CTC assessment showed associations with clinical outcomes, whereas exploratory baseline ctDNA analysis identified nominal molecular associations that did not remain significant after FDR adjustment. These findings require prospective validation and do not establish specific genomic prognostic biomarkers or comparative efficacy between treatment durations or regimens.

Febrile neutropenia (FN) is a common but serious complication encountered in patients with cancer and is associated with significant morbidity and mortality. In this prospective study, 63 patients with solid tumors under chemotherapy or immunotherapy were admitted to the hospital due to febrile neutropenia, confirmed through clinical or microbiological documentation. The aim of this study was to provide a comprehensive overview of the epidemiological and microbiological characteristics of hospitalized neutropenic patients with solid tumors undergoing treatment. Additionally, we aimed to assess the duration of neutropenia and identify factors influencing patient outcomes. The median age of patients was 71 ± 10.2 years, most of which were males (66.7%), and the primitive tumor location was the lung (38.1%), with most patients (82.5%) being at disease stage IV. The median duration of neutropenia was three days (range 1–10), and, notably, mucositis was significantly associated with neutropenia lasting ≥3 days (p = 0.012). Patients with lung cancer (38.1%) and patients with stage IV disease (82.5%) presented a higher risk of FN, although these differences did not reach statistical significance. The site of infection was identifiable in 55.6% of patients, with positive cultures detected in 34.9% and positive blood cultures (BC) drawn in 17.5% of cases. Gram-positive bacteria were the predominant causative agents in BC (63.6%), with Staphylococci being the most prevalent among them (66.7%). The median duration of hospitalization was nine days (range, 3–43 days), and most patients showed improvement or cure of infection (16.9% and 74.6%, respectively). Among recorded risk factors, the Eastern Cooperative Oncology Group (ECOG) performance status (PS) appears to be statistically significant. Patients with an impaired PS score (2–4) experienced worse outcomes and higher likelihood of mortality (p = 0.004). Regarding the outcome, a longer duration of neutropenia was also statistically significant (p = 0.050). Of the patients, 12.7% ultimately succumbed to their conditions, with 37.5% attributed to infections. FN is a common yet serious complication in solid tumor patients. Adequate knowledge of the predictors of mortality and the microbiological causes are of utmost importance to allow accurate diagnosis and prompt treatment as they significantly influence patient outcomes.

Colorectal cancer (CRC) remains a major public health issue. The detection of parameters that affect CRC prognosis is of great significance. KRAS mutations, play a crucial role in tumorigenesis with a strong predictive value. KRAS-mutated stage-IV CRC patients gain no benefit of the anti-EGFR therapy. The KRAS G12C mutation subtype is under investigation for treatment regimens. The present study aimed to detect various RAS mutations in a cohort of 578 RAS-mutated CRC patients; 49% of them had de novo metastatic disease; 60% were male; 71.4% had left-sided tumors; and 94.6% had a good performance status. KRAS mutations were detected in 93.2% of patients, with KRAS G12D being the most common subtype (30.1%). KRAS mutations presented shorter progression-free (PFS) and overall survival (OS), compared with NRAS mutations, although not significantly (PFS: 13.8 vs. 18.5 months; p = 0.552; OS: 53.1 vs. 60.9 months; p = 0.249). KRAS G12D mutations presented better OS rates (p = 0.04). KRAS G12C mutation, even though not significantly, presented worse PFS and OS rates. KRAS exon 3 and 4 mutations presented different PFS and OS rates, although these were not significant. Concluding, KRAS G12D and G12C mutations lead to better and worst prognosis, respectively. Further studies are warranted to validate such findings and their possible therapeutic implication.

Over the last few years, immunotherapy has been considered as a key player in the treatment of solid tumors. Immune checkpoint inhibitors (ICIs) have become the breakthrough treatment, with prolonged responses and improved survival results. ICIs use the immune system to defeat cancer by breaking the axes that allow tumors to escape immune surveillance. Innate and adaptive immunity are involved in mechanisms against tumor growth. The gut microbiome and its role in such mechanisms is a relatively new study field. The presence of a high microbial variation in the gut seems to be remarkably important for the efficacy of immunotherapy, interfering with innate immunity. Metabolic and immunity pathways are related with specific gut microbiota composition. Various studies have explored the composition of gut microbiota in correlation with the effectiveness of immunotherapy. Colorectal cancer (CRC) patients have gained little benefit from immunotherapy until now. Only mismatch repair-deficient/microsatellite-unstable tumors seem to respond positively to immunotherapy. However, gut microbiota could be the key to expanding the use of immunotherapy to a greater range of CRC patients.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death due to its high metastatic potential. This study aimed to investigate the detection and heterogeneity of circulating tumor cells (CTCs) and the microsatellite instability (MSI) status in advanced CRC patients prior to any systemic front-line treatment. Peripheral whole blood was obtained from 198 patients. CTCs were detected using double immunofluorescence and a real time-polymerase chain reaction assay; whereas MSI status was evaluated using fragment analysis. Median age of the patients was 66 years, 63.1% were males, 65.2% had a colon/sigmoid tumor location and 90.4% had a good performance status (PS). MSI-High status was detected in 4.9% of the patients; 33.3%, 56.1% and 8.6% patients had at least one detectable CEACAM5⁺/EpCAM⁺, CEACAM5⁺/EpCAM⁻ and CEACAM5⁻/EpCAM⁺ CTC, respectively, and 9.1% of the patients had CEACAM5mRNA-positive CTCs. Following multivariate analysis, age, PS and MSI were confirmed as independent prognostic factors for decreased time to progression, whereas age, PS and CTC presence were confirmed as independent prognostic factors for decreased overall survival. In conclusion, our data support the use of CEACAM5 as a dynamic adverse prognostic CTC biomarker in patients with metastatic CRC and MSI-High is considered an unfavorable prognostic factor in metastatic CRC patient tumors.

Vitamin D deficiency has been associated with increased colorectal cancer (CRC) incidence risk and mortality. Vitamin D mediates its action through the binding of the vitamin D receptor (VDR), and polymorphisms of the VDR might explain these inverse associations. The aim of the study was the investigation of the relevance of rs731236; Thermus aquaticus I (TaqI), rs7975232; Acetobacter pasteurianus sub. pasteurianus I (ApaI), rs2228570; Flavobacterium okeanokoites I (FokI) and rs1544410, Bacillus stearothermophilus I (BsmI) polymorphisms of the VDR gene to colorectal carcinogenesis (CRC) and progression. Peripheral blood was obtained from 397 patients with early operable stage II/III (n = 202) and stage IV (n = 195) CRC. Moreover, samples from 100 healthy donors and 40 patients with adenomatous polyps were also included as control groups. Genotyping in the samples from patients and controls was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). A significant association was revealed between all four polymorphisms and cancer. Individuals with homozygous mutant (tt, aa, ff or bb) genotypes were more susceptible to the disease (p < 0.001). All of the mutant genotypes detected were also significantly associated with stage IV (p < 0.001), leading to significantly decreased survival (p < 0.001). Moreover, all four polymorphisms were significantly associated with KRAS (Kirsten ras oncogene) mutations and Toll-like receptor (TLR2, TLR4 and TLR9) genetic variants. In multivariate analysis, tt, aa and ff genotypes emerged as independent factors associated with decreased overall survival (OS) (p = 0.001, p < 0.001 and p = 0.001, respectively). The detection of higher frequencies of the VDR polymorphisms in CRC patients highlights the role of these polymorphisms in cancer development and progression.

Dysbiosis has been associated with various diseases and is of major health importance. Dysbiosis leads to microbial translocation, which is the passage of microorganisms, their fragments, or their metabolites from the intestinal lumen into the blood circulation and other sites. The aim of the study was to determine whether microbial translocation occurs in stage II/III-IV colorectal cancer (CRC) patients. The aim was also to evaluate the usefulness of blood PCR for diagnosis of such translocation and correlate the presence of toll-like receptor/vitamin D receptor (TLR/VDR) gene polymorphisms with microbial DNA fragments detected in the blood of CRC patients. Three hundred and ninety-seven CRC patients enrolled in the study. Peripheral blood DNA was analyzed using PCR for the amplification of genomic DNA encoding 16S rRNA, the β-galactosidase gene of Escherichia coli, glutamine synthase gene of Bacteroides fragilis, and 5.8S rRNA of Candida albicans. Significantly higher rates of all microbial fragments, but E. coli, detected were observed in the CRC patients (p < 0.001); such detection of all four microbial fragments was also significantly associated with the metastatic disease (p < 0.001), leading to shorter survival rates (p < 0.001). Tumor location in the right colon also significantly correlated with shorter survival (p = 0.016). Individuals with homozygous mutant alleles of TLR/VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. The detection of microbial DNA fragments in CRC patients highlighted the role of these microbes in cancer development, progression, and patients’ survival.