Clinical value of sequential circulating tumor DNA analysis using next-generation sequencing and epigenetic modifications for guiding thermal ablation for colorectal cancer metastases: a prospective study.

INTRODUCTION: While thermal ablation is now a standard treatment option for oligometastatic colorectal cancer patients, selecting those who will benefit most from locoregional therapies remains challenging. This proof-of-concept study is the first to assess the feasibility of routine testing of ctDNA before and after thermal ablation with curative intent, analyzed by next-generation sequencing (NGS) and methylation specific digital droplet PCR (ddPCR). Our prospective study primary objective was to assess the prognostic value of ctDNA before thermal ablation. METHODS: This single-center prospective study from November 2021 to June 2022 included colorectal cancer patients referred for curative-intent thermal ablation. Cell-free DNA was tested at different time points by next-generation sequencing and detection of WIF1 and NPY genes hypermethylation using ddPCR. The ctDNA was considered positive if either a tumor mutation or hypermethylation was detected; recurrence-free survival was used as the primary endpoint. RESULTS: The study enrolled 15 patients, and a total of 60 samples were analyzed. The median follow-up after ablation was 316 days, and median recurrence-free survival was 250 days. CtDNA was positive for 33% of the samples collected during the first 24 h. The hazard ratio for progression according to the presence of baseline circulating tumor DNA was estimated at 0.14 (CI 95%: 0.03-0.65, p = 0.019). The dynamics are provided, and patients with no recurrence were all negative at H24 for ctDNA. DISCUSSION: This study shows the feasibility of routine testing of ctDNA before and after thermal ablation with curative intent. We report that circulating tumor DNA is detectable in patients with low tumor burden using 2 techniques. This study emphasizes the potential of ctDNA for discerning patients who are likely to benefit from thermal ablation from those who may not, which could shape future referrals. The dynamics of ctDNA before and after ablation shed light on the need for further research and larger studies.

Is laparoscopic approach as treatment of large gastric GIST acceptable?

AIM: Laparoscopic surgery is widely used for small gastric gastrointestinal stromal tumors (GISTs) (≤ 5 cm) but remains a controversial approach for larger gastric GISTs (> 5 cm). This study aims to compare short- and long-term outcomes of laparoscopic resection in comparison with open resection for gastric GISTs measuring over 5 cm. METHOD: All patients receiving surgery for gastric GIST > 5 cm between 2000 and 2021 in a single tertiary hospital were included. Data were collected from prospectively maintained records. Kaplan-Meier method and log rank test were used to compare survival outcomes. RESULTS: Among 108 included patients, 59 patients had minimally invasive (MI) surgery (54.6%) whereas 49 patients had open surgery (46.4%). The rate of overall postoperative morbidity was 14.8% and the median length was significantly shorter in the MI group [4 (range 2-30) vs. 7 (range 4-33) days; P = 0.007]. The overall R0 resection rate was 98.2% and the rate of tumor rupture was 13%, not different between the two groups. Recurrence occurred in 24% of the whole population without any difference between groups (20.3% vs. 28.7%, p = 0.31). Minimally invasive surgery was not found as a negative prognostic disease-free survival factor. CONCLUSION: Laparoscopic surgery could be a safe and feasible alternative to open surgery in large gastric GIST, bringing the benefits of minimally invasive surgery without compromising oncologic results.

MSI colorectal cancer, all you need to know.

Colorectal cancer management has been dramatically impacted by molecular profiling these last years. Among these molecular subgroups, patients with microsatellite instability (MSI) are of particular interest, owing to the prognostic and predictive value of this tumor biomarker. This review article explains the molecular abnormalities underlying MSI phenotype and the consequences of such molecular abnormalities on carcinogenesis, genetic instability and immune infiltration. It details the diagnostic methods for identifying MSI colorectal cancer patients and describes how the prognostic and theranostic values of this marker are impacting treatment decision-making for these patients in 2022.

Voltage-Gated Sodium Channel NaV1.5 Controls NHE-1-Dependent Invasive Properties in Colon Cancer Cells.

Colorectal cancer (CRC) is the second leading cause of death worldwide, with 0.9 million deaths per year. The metastatic stage of the disease is identified in about 20% of cases at the first diagnosis and is associated with low patient-survival rates. Voltage-gated sodium channels (NaV) are abnormally overexpressed in several carcinomas including CRC and are strongly associated with the metastatic behavior of cancer cells. Acidification of the extracellular space by Na+/H+ exchangers (NHE) contributes to extracellular matrix degradation and cell invasiveness. In this study, we assessed the expression levels of pore-forming α-subunits of NaV channels and NHE exchangers in tumor and adjacent non-malignant tissues from colorectal cancer patients, CRC cell lines and primary tumor cells. In all cases, SCN5A (gene encoding for NaV1.5) was overexpressed and positively correlated with cancer stage and poor survival prognosis for patients. In addition, we identified an anatomical differential expression of SCN5A and SLC9A1 (gene encoding for NHE-1) being particularly relevant for tumors that originated on the sigmoid colon epithelium. The functional activity of NaV1.5 channels was characterized in CRC cell lines and the primary cells of colon tumors obtained using tumor explant methodologies. Furthermore, we assessed the performance of two new small-molecule NaV1.5 inhibitors on the reduction of sodium currents, as well as showed that silencing SCN5A and SLC9A1 substantially reduced the 2D invasive capabilities of cancer cells. Thus, our findings show that both NaV1.5 and NHE-1 represent two promising targetable membrane proteins against the metastatic progression of CRC.