Targeting lysine-specific demethylase 1 (KDM1A/LSD1) impairs colorectal cancer tumorigenesis by affecting cancer cells stemness, motility, and differentiation.

Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A also known as LSD1), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC samples, KDM1A overexpression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted multi-omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype, supporting the role of KDM1A in CRC cells stemness maintenance. Also, KDM1A silencing resulted in up-regulation of miR-506-3p, previously reported to play a tumor-suppressive role in CRC. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A impacts CRC progression in several non-overlapping ways, and therefore it represents a promising epigenetic target to prevent tumor relapse.

Laparoscopic resection of splenic flexure colon cancers: a retrospective multi-center study with 117 cases.

The objective is to investigate the short- and long-term outcomes of laparoscopic resections of splenic flexure colon cancers in three Italian high-volume centers. The laparoscopic resection of splenic flexure colon cancers is a challenging procedure and has not been completely standardized, mainly due to the technical difficulty, the arduous identification of major blood vessels, and the problems associated with anastomosis construction. In this retrospective cohort observational study, a consecutive series of patients treated in three Italian high-volume centers with elective laparoscopic resection of the splenic flexure for cancer is analyzed. The observational period was from January 2008 to August 2017. Patient demographics and clinical features, operative data, and short- and long-term outcomes were prospectively recorded in a specific database and were retrospectively analyzed. During the observation period, 117 patients were selected. Conversion to open surgery was necessary in 15 patients (12.8%). Of 102 complete laparoscopic procedures, multi-visceral resection was performed in 13 cases (12.7%). Postoperative surgical complications occurred in 13 patients (12.7%), with 3 cases of anastomotic leak (2.9%) and 3 cases of re-operation (2.9%). The postoperative mortality in this population was null. The 5-year overall survival rate was 84.3%, and the 5-year disease-free survival rate was 87.8%. Laparoscopic resection of the splenic flexure is feasible and safe in high-volume centers. Compared to the results of other laparoscopic colonic resections, the short- and long-term outcomes are similar, but the conversion rate is higher.

Intracorporeal Versus Extracorporeal Anastomosis for Laparoscopic Resection of the Splenic Flexure Colon Cancer: A Multicenter Propensity Score Analysis.

PURPOSE: The aim of this study is to compare the short and long-term outcomes of intracorporeal anastomosis (IA) versus extracorporeal anastomosis (EA) during laparoscopic resection of splenic flexure for cancer, in 3 high-volume Italian centers. MATERIALS AND METHODS: A retrospective analysis was conducted on a multicenter database of a consecutive series of patients who underwent an elective laparoscopic resection of the splenic flexure for colon cancer in 3 high-volume centers between January 2008 and August 2017. Propensity score matching analysis was performed to overcome patients' selection bias between the 2 surgical techniques. Data on patients' demographics, operative details, short-term and long-term outcomes were prospectively recorded. RESULTS: In total, 102 patients were selected. After propensity score match, 72 patients were compared: 36 for the IA group, 36 for the EA group. The IA group showed a significantly shorter median time to first flatus, time to first stool, time to oral feeding, and time to discharge, as well as significantly lower incidence of postoperative severe surgical complications, especially in terms of wound infections, and of incisional hernia (IH).Risk factors for IH on logistic regression were longer operative time, EA, longer incision, postoperative blood transfusions, and longer specimen. CONCLUSIONS: The IA in laparoscopic resection of the splenic flexure is feasible and safe in terms of short-term and long-term outcomes. Major advantages are shorter time to first flatus and first stool, complete oral feeding and time to discharge, with minor incidence of severe surgical complications, such as wound infection, and lower incidence of IH.

Metachronous solitary left adrenal gland metastasis of right colon cancer treated with laparoscopic approach.

AIM: Adrenal gland metastasis are the second most common type of adrenal mass lesions after adenomas and they could be related to numerous malignancies; Literature shows that adrenal metastasis deriving from colorectal cancer are very rare. MATERIAL OF THE STUDY: A 71-year old - male patient, treated two years before with right colectomy and adjuvant chemotherapy for right colon cancer, came to our attention after the diagnosis at follow up, of a left adrenal gland mass; CT scan and CT - PET did not show other pathological findings. RESULTS: The patient underwent left adrenalectomy with trans-peritoneal laparoscopic approach: the definitive histological examination diagnosed metastatic tissue of colonic cancer in left adrenal gland. CONCLUSIONS: Adrenal gland metastases are common clinical entities, but which of them arise starting from colonic cancer are very rare and they are generally discovered about 1 year after the first diagnosis of cancer. Early diagnosis, laparoscopic radical excision when feasible and eventual adjuvant radio-chemotherapy are actually the proper clinical management of adrenal gland metastases finalized to better outcomes in terms of longer survival rate and quality of life. KEY WORDS: Adrenal gland, Colorectal cancer, Laparoscopic, Metastasis.