Molecular Deciphering of Colorectal Cancer: Exploring Molecular Classifications and Analyzing the Interplay among Molecular Biomarkers MMR/MSI, KRAS, NRAS, BRAF and CDX2 - A Comprehensive Literature Review.

Background: Colorectal cancer (CRC) exhibits molecular and morphological diversity, involving genetic, epigenetic alterations, and disruptions in signaling pathways. This necessitates a comprehensive review synthesizing recent advancements in molecular mechanisms, established biomarkers, as well as emerging ones like CDX2 for enhanced CRC assessment. Material and Methods: This review analyzes the last decade's literature and current guidelines to study CRC's molecular intricacies. It extends the analysis beyond traditional biomarkers to include emerging ones like CDX2, examining their interaction with carcinogenic mechanisms and molecular pathways, alongside reviewing current testing methodologies. Results: A multi-biomarker strategy, incorporating both traditional and emerging biomarkers like CDX2, is crucial for optimizing CRC management. This strategy elucidates the complex interaction between biomarkers and the tumor's molecular pathways, significantly influencing prognostic evaluations, therapeutic decision-making, and paving the way for personalized medicine in CRC. Conclusions: This review proposes CDX2 as an emerging prognostic biomarker and emphasizes the necessity of thorough molecular profiling for individualized treatment strategies. By enhancing CRC treatment approaches and prognostic evaluation, this effort marks a step forward in precision oncology, leveraging an enriched understanding of tumor behavior.

Safety and Efficacy of Simultaneous Resection of Gastric Carcinoma and Synchronous Liver Metastasis-A Western Center Experience.

Background and objectives: Gastric cancer (GC) is often diagnosed in the metastatic stage. Palliative systemic therapy is still considered the gold standard, even for patients with resectable oligometastatic disease. The aim of the current study is to assess the potential benefit of up-front gastric and liver resection in patients with synchronous resectable liver-only metastases from GC (LMGC) in a Western population. Materials and Methods: All patients with GC and synchronous LMGC who underwent gastric resection with or without simultaneous resection of LMs between January 1997 and December 2016 were selected from the institutional records. Those with T4b primary tumors or with unresectable or more than three LMs were excluded from the analysis. All patients who underwent emergency surgery for hemorrhagic shock or gastric perforation were also excluded. Results: Out of 28 patients fulfilling the inclusion criteria, 16 underwent simultaneous gastric and liver resection (SR group), while 12 underwent palliative gastric resection (GR group). The median overall survival (OS) of the entire cohort was of 18.81 months, with 1-, 3- and 5-year OS rates of 71.4%, 17.9% and 14.3%, respectively. The 1-, 3- and 5-year OS rates in SR group (75%, 31.3% and 25%, respectively) were significantly higher than those achieved in GR group (66.7%, 0% and 0%, respectively; p = 0.004). Multivariate analysis of the entire cohort revealed that the only independent prognostic factor associated with better OS was liver resection (HR = 3.954, 95% CI: 1.542-10.139; p = 0.004). Conclusions: In a Western cohort, simultaneous resection of GC and LMGC significantly improved OS compared to patients who underwent palliative gastric resection.

The Impact of Postoperative Complications on Survival after Simultaneous Resection of Colorectal Cancer and Liver Metastases.

BACKGROUND: The aim of this study was to investigate the impact of postoperative complications on the long-term outcomes of patients who had undergone simultaneous resection (SR) of colorectal cancer and synchronous liver metastases (SCLMs). METHODS: We conducted a single-institution survival cohort study in patients with SR, collecting clinical, pathological, and postoperative complication data. The impact of these variables on overall survival (OS) and disease-free survival (DFS) was compared by log rank test. Multivariate Cox regression analysis identified independent prognostic factors. RESULTS: Out of 243 patients, 122 (50.2%) developed postoperative complications: 54 (22.2%) major complications (Clavien-Dindo grade III-V), 86 (35.3%) septic complications, 59 (24.2%) hepatic complications. Median comprehensive complication index (CCI) was 8.70. Twelve (4.9%) patients died postoperatively. The 3- and 5-year OS and DFS rates were 60.7%, 39.5% and 28%, 21.5%, respectively. Neither overall postoperative complications nor major and septic complications or CCI had a significant impact on OS or DFS. Multivariate analysis identified the N2 stage as an independent prognostic of poor OS, while N2 stage and four or more SCLMs were independent predictors for poor DFS. CONCLUSION: N2 stage and four or more SCLMs impacted OS and/or DFS, while CCI, presence, type, or grade of postoperative complications had no significant impact on long-term outcomes.

Embryologic Origin of the Primary Tumor and RAS Status Predict Survival after Resection of Colorectal Liver Metastases.

Background and objectives. In colorectal cancers, the embryologic origin of the primary tumor determines important molecular dissimilarities between right-sided (RS) and left-sided (LS) carcinomas. Although important prognostic differences have been revealed between RS- and LS-patients with resected colorectal liver metastases (CLMs), it is still unclear if this observation depends on the RAS mutational status. To refine the impact of primary tumor location (PTL) on the long-term outcomes of patients with resected CLMs, the rates of overall survival (OS), relapse-free survival (RFS) and survival after recurrence (SAR) were compared between RS- vs. LS-patients, according to their RAS status. Material and Methods. All patients with known RAS status, operated until December 2019, were selected from a prospectively maintained database, including all patients who underwent hepatectomy for histologically-proven CLMs. A log-rank test was used to compare survival rates between the RS- vs. LS-group, in RAS-mut and RAS-wt patients, respectively. A multivariate analysis was performed to assess if PTL was independently associated with OS, RFS or SAR. Results. In 53 patients with RAS-mut CLMs, the OS, RFS and SAR rates were not significantly different (p = 0.753, 0.945 and 0.973, respectively) between the RS and LS group. In 89 patients with RAS-wt CLMs, the OS and SAR rates were significantly higher (p = 0.007 and 0.001, respectively) in the LS group vs. RS group, while RFS rates were similar (p = 0.438). The multivariate analysis performed in RAS-wt patients revealed that RS primary (p = 0.009), extrahepatic metastases (p = 0.001), N-positive (p = 0.014), age higher than 65 (p = 0.002) and preoperative chemotherapy (p = 0.004) were independently associated with worse OS, while RS location (p < 0.001) and N-positive (p = 0.007) were independent prognostic factors for poor SAR. Conclusions. After resection of CLMs, PTL had no impact on long-term outcomes in RAS-mut patients, while in RAS-wt patients, the RS primary was independently associated with worse OS and SAR.

Prognostic Value of Lymph Node Ratio in Patients with Resected Synchronous Colorectal Liver Metastases and Less Than 12 Examined Lymph Nodes.

BACKGROUND: Recent studies suggest that lymph node ratio (LNR) has significantly better prognostic power than N-status in patients with colorectal cancer, in particular when the number of evaluated lymph nodes (LNs) was insufficient. The aim of this study was to assess the prognostic value of LNR in patients with resected synchronous colorectal liver metastases (SCLMs) and less than 12 examined LNs. METHODS: A prospectively maintained database of patients with resected SCLMs was queried for patients with less than 12 LNs evaluated at the time of surgery. X-tile software was used to determine the LNR cutoff value able to divide the patients in two subgroups with distinct prognosis. Overall survival (OS) and disease-free survival (DFS) rates were compared by log-rank test. A multivariate Cox regression analysis identified independent prognostic factors. RESULTS: A cutoff LNR value of 0.22 divided patients into Low-LNR group (35 patients) and High-LNR group (36 patients). Both OS and DFS rates were significantly higher in Low-LNR group than those in High-LNR group. Independent predictors of poor OS were High-LNR (HR: 2.841, 95% CI: 1.480-5.453, p value = 0.002), bilobar SCLMs (HR: 2.253, 95% CI: 1.144-4.437, p value = 0.019) and lack of adjuvant chemotherapy (HR: 2.702, 95% CI: 1.448-5.043, p value = 0.002), while the only independent predictor of poor DFS was High-LNR (HR: 2.531, 95% CI: 1.259-5.090, p value = 0.009). CONCLUSIONS: LNR > 0.22 was independently associated with poor OS and DFS in patients with resected SCLMs and less than 12 evaluated LNs.

Resection of Concomitant Hepatic and Extrahepatic Metastases from Colorectal Cancer - A Worthwhile Operation?

Background: The benefit of hepatic resection in case of concomitant colorectal hepatic and extrahepatic metastases (CHEHMs) is still debatable. The purpose of this study is to assess the results of resection of hepatic and extrahepatic metastases in patients with CHEHMs in a high-volume center for both hepatobiliary and colorectal surgery and to identify prognostic factors that correlate with longer survival in these patients. METHOD: It was performed a retrospective analysis of 678 consecutive patients with liver resection for colorectal cancer metastases operated in a single Centre between April 1996 and March 2016. Among these, 73 patients presented CHEHMs. Univariate analysis was performed to identify the risk factors for overall survival (OS) in these patients. Results: There were 20 CHMs located at the lymphatic node level, 20 at the peritoneal level, 12 at the ovary and lung level, 12 presenting as local relapses and 9 other sites. 53 curative resections (R0) were performed. The difference in overall survival between the CHEHMs group and the CHMs group is statistically significant for the entire groups (p 0.0001), as well as in patients who underwent R0 resection (p 0.0001). In CHEHMs group, the OS was statistically significant higher in patients who underwent R0 resection vs. those with R1/R2 resection (p=0.004). Three variables were identified as prognostic factors for poor OS following univariate analysis: 4 or more hepatic metastases, major hepatectomy and the performance of operation during first period of the study (1996 - 2004). There was a tendency toward better OS in patients with ovarian or pulmonary location of extrahepatic disease, although the difference was not statistically significant. CONCLUSION: In patients with concomitant hepatic and extrahepatic metastases, complete resection of metastatic burden significantly prolong survival. The patients with up to 4 liver metastases, resectable by minor hepatectomy benefit the most from this aggressive onco-surgical management.

Comparative Analysis between Simultaneous Resection and Staged Resection for Synchronous Colorectal Liver Metastases - A Single Center Experience on 300 Consecutive Patients.

Introduction: In synchronous colorectal liver metastases (SCLMs), simultaneous resection (SR) of the primary tumor and liver metastases has not gained wide acceptance. Most authors prefer staged resections (SgR), especially in patients presenting rectal cancer or requiring major hepatectomy. Methods: Morbidity, mortality, survival rates and length of hospital stay were compared between the two groups of patients (SR vs. SgR). A subgroup analysis was performed for patients with similar characteristics (e.g. rectal tumor, major hepatectomy, bilobar metastases, metastatic lymph nodes, preoperative chemotherapy). Results: Between 1995 and 2016, SR was performed in 234 patients, while 66 patients underwent SgR. Comparative morbidity (41% vs. 31.8%, respectively, p = 0.1997), mortality (3.8% vs. 3%, respectively, p = 1) and overall survival rates (85.8%, 51.3% and 30% vs. 87%, 49.6% and 22.5%, at 1-, 3- and 5-years, respectively, p = 0.386) were similar between the SR and SgR group. Mean hospital stay was significantly shorter in patients undergoing SR than SgR (15.11 ‚+- 8.60 vs. 19.42 ‚+- 7.36 days, respectively, p 0.0001). The characteristics of SR and SgR groups were similar, except the following parameters: rectal tumor (34.1% vs. 19.7%, respectively, p = 0.0245), metastatic lymph nodes (68.1% vs. 86.3%, respectively, p = 0.0383), bilobar liver metastases (22.6% vs. 37.8%, respectively, p = 0.0169), major hepatectomies (13.2% vs. 30.3%, respectively, p= 0.0025) and neo-adjuvant chemotherapy (13.2% vs. 77.2%, respectively, p 0.0001). A comparative analysis of morbidity, mortality and survival rates between SR and SgR was performed for subgroups of patients presenting these parameters. In each of these subgroups, SR was associated with similar morbidity, mortality and survival rates compared with SgR (p value 0.05). CONCLUSION: In patients with SCLMs, SR provides similar short-term and long-term outcomes as SgR, with a shorter hospital stay. Therefore, in most patients with SCLMs, SR might be considered the treatment of choice.