Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.

The aim of this study is to externally validate the original borderline resectability (BR) category for predicting overall survival (OS) in hepatocellular carcinoma (HCC) following resection and to assess whether incorporating the tumor burden score (TBS) and other clinical factors could enhance predictive accuracy.

A recent Japanese expert panel introduced a new HCC classification scheme: resectable (R), borderline resectable 1 (BR1), and borderline resectable 2 (BR2).

Patients undergoing curative-intent hepatectomy for HCC (2000-2023) were classified as R, BR1, and BR2 using the original BR and a novel TBS-BR category. The TBS-BR category replaces BR's categorical tumor morphology factors with the continuous TBS (TBS² = [maximum tumor diameter]² + [number of tumors]²). Multivariable analysis identified oncologic, morphometric, and patient-level factors associated with OS, which were incorporated into an online predictive tool.

Among 1766 patients, the original BR category grouped 1504 (85.2%) as R, 249 (14.1%) as BR1, and 13 (0.7%) as BR2. Utilizing the TBS-BR category, patients were reclassified as TBS-BR R (n = 684, 38.7%), BR1 (n = 1009, 57.1%), and BR2 (n = 73, 4.1%). Both the original and TBS-BR categories correlated with 5-year OS (original: 65.1%, 48.2%, 46.4%; TBS-BR: 70.8%, 58.3%, 40.0%; P < 0.001 for both; area under the curve: 0.54 vs 0.58). On multivariable analysis, TBS-BR1 (hazard ratio [HR]: 1.59 [1.20-2.09]; P = 0.001), TBS-BR2 (HR: 2.45 [1.47-4.07]; P < 0.001, reference: TBS-BR R), American Society of Anesthesiologists (ASA) class >2 (HR: 1.40 [1.09-1.80]; P = 0.007), albumin-bilirubin (ALBI) score (HR: 1.51 [1.21-1.88]; P < 0.001), and log α-fetoprotein (AFP) (HR: 1.07 [1.03-1.11]; P < 0.001) were independently associated with OS. A TBS-BR composite model based on these factors (TBS-BR category, ASA class, ALBI score, and log AFP) was developed and made available online (https://makbn.shinyapps.io/BRHCC/). The model's area under the receiver operating characteristic at 5 years (0.70) outperformed both the original BR (0.57) and Barcelona Clinic Liver Cancer classification (0.64).

The TBS-BR composite model, integrating tumor morphology (TBS), tumor biology (log AFP), overall physical status (ASA class), and liver function (ALBI score) demonstrated superior predictive accuracy for OS compared with the original BR and Barcelona Clinic Liver Cancer classifications.

Perioperative chemotherapy has emerged as a critical component in managing resectable colorectal liver metastases (CRLM), aiming to improve long-term survival, although data supporting its use remains controversial. This narrative review explores the current state of perioperative chemotherapy in patients with resectable CRLM, focusing on its role in different oncological risk categories. The review highlights ongoing controversies, such as optimal patient selection and the role of post- versus preoperative treatment in specific scenarios.

To explore the value of preoperative CT-based morphological heterogeneity (MH) for predicting local tumor disease-free survival (LTDFS) and progression-free survival (PFS) in patients with colorectal cancer liver metastases (CRLM).

The latest CT data of 102 CRLM patients were retrospectively analyzed. The morphological score of each liver metastasis was obtained, and the morphological heterogeneity difference (MHD) was calculated. The receiver operating characteristic (ROC) curve was drawn, and the cutoff value was found. The Kaplan-Meier method was used to draw survival curves of patients with or without MH. The Cox regression analysis was used to build the model with MH and clinical characteristics for predicting PFS.

In 78 patients without MH, median PFS was 9.0 months (95% CI:6.5-11.5), while in 24 patients with MH, median PFS was 6.0 months (95% CI:4.0-8.1), indicating that MH significantly affected PFS (p = 0.001). MH affected PFS in both the chemotherapy group and the chemotherapy combined with targeted therapy group (p = 0.005, p = 0.043). MH, preoperative carcinoembryonic antigen (CEA) and chemotherapy after surgery were independent predictors for postoperative PFS in patients with CRLM.

Preoperative CT-based MH had good efficacy for predicting LTDFS and PFS of CRLM patients after surgical resection, regardless of preoperative treatment. MH is one of the independent predictors of PFS.

The combination of preoperative chemotherapy and surgical treatment has been shown to significantly enhance the prognosis of colorectal cancer with liver metastases (CRLM) patients. Nevertheless, as a result of variations in clinicopathological parameters, the prognosis of this particular group of patients differs considerably. This study aimed to develop and evaluate Cox proportional risk regression model and competing risk regression model using two patient cohorts. The goal was to provide a more precise and personalized prognostic evaluation system.

We collected information on individuals who had a pathological diagnosis of colorectal cancer between 2000 and 2019 from the Surveillance, Epidemiology, and End Results (SEER) Database. We obtained data from patients who underwent pathological diagnosis of colorectal cancer and got comprehensive therapy at the hospital between January 1, 2010, and June 1, 2022. The SEER data collected after screening according to the inclusion and exclusion criteria were separated into two cohorts: a training cohort (training cohort) and an internal validation cohort (internal validation cohort), using a random 1:1 split. Subgroup Kaplan-Meier (K-M) survival analyses were conducted on each of the three groups. The data that received following screening from the hospital were designated as the external validation cohort. The subsequent variables were chosen for additional examination: age, gender, marital status, race, tumor site, pretreatment carcinoembryonic antigen level, tumor size, T stage, N stage, pathological grade, number of tumor deposits, perineural invasion, number of regional lymph nodes examined, and number of positive regional lymph nodes. The primary endpoint was median overall survival (mOS). In the training cohort, we conducted univariate Cox regression analysis and utilized a stepwise regression approach, employing the Akaike information criterion (AIC) to select variables and create Cox proportional risk regression models. We evaluated the accuracy of the model using calibration curve, receiver operating characteristic curve (ROC), and area under curve (AUC). The effectiveness of the models was assessed using decision curve analysis (DCA). To evaluate the non-cancer-related outcomes, we analyzed variables that had significant impacts using subgroup cumulative incidence function (CIF) and Gray's test. These analyses were used to create competing risk regression models. Nomograms of the two models were constructed separately and prognostic predictions were made for the same patients in SEER database.

This study comprised a total of 735 individuals. The mOS of the training cohort, internal validation cohort, and QDU cohort was 55.00 months (95%CI 46.97-63.03), 48.00 months (95%CI 40.65-55.35), and 68.00 months (95%CI 54.91-81.08), respectively. The multivariate Cox regression analysis revealed that age, N stage, presence of perineural infiltration, number of tumor deposits and number of positive regional lymph nodes were identified as independent prognostic risk variables (p < 0.05). In comparison to the conventional TNM staging model, the Cox proportional risk regression model exhibited a higher C-index. After controlling for competing risk events, age, N stage, presence of perineural infiltration, number of tumor deposits, number of regional lymph nodes examined, and number of positive regional lymph nodes were independent predictors of the risk of cancer-specific mortality (p < 0.05).

We have developed a prognostic model to predict the survival of patients with synchronous CRLM who undergo preoperative chemotherapy and surgery. This model has been tested internally and externally, confirming its accuracy and reliability.

This study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection.

An international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS).

R1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21).

R1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

Background/Objectives: Adipophilin (ADP) is a protein associated with lipid droplets, and its expression is related to poor prognosis in certain cancers. However, its impact on the survival of patients with colorectal liver metastases (CRLMs) remains unclear. This study investigated the impact of ADP expression on long-term survival following hepatectomy in patients with CRLM. Methods: We retrospectively analyzed 102 consecutive patients who underwent hepatectomy between 2006 and 2022. ADP expression was examined in resected specimens through immunohistochemical staining using tissue microarrays. Long-term outcomes for ADP-positive (n = 51) and ADP-negative (n = 51) groups were compared with Kaplan-Meier survival analysis. Results: We found significantly decreased 5-year recurrence-free survival (RFS) and overall survival (OS) rates for ADP-positive patients relative to ADP-negative patients (29.4% versus 52.1%, respectively; p = 0.001 and 43.7% versus 72.2%, respectively; p = 0.003). Moreover, multivariate Cox hazards analysis demonstrated that patients with ADP-positive CRLM had a worse prognosis after hepatectomy than those with ADP-negative CRLM, as reflected by both RFS (HR 2.46, 95% CI 1.39-4.36, p = 0.002) and OS (HR: 2.89, 95% CI 1.43-5.85, p = 0.003). Conclusions: ADP expression had a significant prognostic impact on the survival of patients with CRLM following liver resection and may aid in optimal treatment planning.

Oncological hepatic surgery carries the possibility to perform vascular reconstructions for advanced tumours with vessel invasion since surgery often represents the only potentially curative approach for these tumours. An extended review was conducted in an attempt to understand and clarify the latest trends in hepatectomies with vascular resections. We searched bibliographic databases including PubMed, Scopus, references from bibliographies and Cochrane Library. Information and outcomes from worldwide clinical trials were collected from qualified institutions performing hepatectomies with vascular resection and reconstruction. Careful patient selection and thorough preoperative imaging remain crucial for correct and safe surgical planning. A literature analysis shows that vascular resections carry different indications in different diseases. Despite significant advances made in imaging techniques and technical skills, reports of hepatectomies with vascular resections are still associated with high postoperative morbidity and mortality. The trend of complex liver resection with vascular resection is constantly on the increase, but more profound knowledge as well as further trials are required. Recent technological developments in multiple fields could surely provide novel approaches and enhance a new era of digital imaging and intelligent hepatic surgery.

(1) Background: Liver metastases (LM) are the leading cause of death in colorectal cancer (CRC) patients. Despite advancements, relapse rates remain high and current prognostic nomograms lack accuracy. Our objective is to develop an interpretable neoadjuvant algorithm based on mathematical models to accurately predict individual risk, ensuring mathematical transparency and auditability. (2) Methods: We retrospectively evaluated 86 CRC patients with LM treated with neoadjuvant systemic therapy followed by complete surgical resection. A comprehensive analysis of 155 individual patient variables was performed. Logistic regression (LR) was utilized to develop the predictive model for relapse risk through significance testing and ANOVA analysis. Due to data limitations, gradient boosting machine (GBM) and synthetic data were also used. (3) Results: The model was based on data from 74 patients (12 were excluded). After a median follow-up of 58 months, 5-year relapse-free survival (RFS) rate was 33% and 5-year overall survival (OS) rate was 60.7%. Fifteen key variables were used to train the GBM model, which showed promising accuracy (0.82), sensitivity (0.59), and specificity (0.96) in predicting relapse. Similar results were obtained when external validation was performed as well. (4) Conclusions: This model offers an alternative for predicting individual relapse risk, aiding in personalized adjuvant therapy and follow-up strategies.

Metastatic colorectal cancer (mCRC) is a major cause of cancer-related death, with a 5-year relative overall survival of up to 20%. The liver is the most common site of distant metastasis in colorectal cancer (CRC), with about 50% of CRC patients metastasizing to their liver over the course of their disease. Complete liver resection is the primary modality of treatment for resectable colorectal cancer liver metastasis (CRLM), with an overall 5-year survival rate of up to 58%. However, only 15% to 20% of patients with CRLM are deemed suitable for resection at presentation. For unresectable diseases, the median survival of patients remains low even with the best chemotherapy. In recent decades, the management of CRLM has continued to evolve with the expansion of resection criteria, novel targeted systemic therapies, and improved locoregional therapies. However, due to the heterogeneity of the CRC patient population, the optimal evaluation of treatment options for CRLM remains complex. Therefore, effective management requires a multidisciplinary team to help define resectability and devise a personalized treatment approach, from the initial diagnosis to the final treatment.

Colorectal cancer (CRC) is a significant public health challenge, with 5-fluorouracil (5-FU) resistance being a major obstacle to effective treatment. Despite advancements, resistance to 5-FU remains formidable due to complex mechanisms such as alterations in drug transport, evasion of apoptosis, dysregulation of cell cycle dynamics, tumor microenvironment (TME) interactions, and extracellular vesicle (EV)-mediated resistance pathways. Traditional chemotherapy often results in high toxicity, highlighting the need for alternative approaches with better efficacy and safety. Phytochemicals (PCs) and EVs offer promising CRC therapeutic strategies. PCs, derived from natural sources, often exhibit lower toxicity and can target multiple pathways involved in cancer progression and drug resistance. EVs can facilitate targeted drug delivery, modulate the immune response, and interact with the TME to sensitize cancer cells to treatment. However, the potential of PCs and engineered EVs in overcoming 5-FU resistance and reshaping the immunosuppressive TME in CRC remains underexplored. Addressing this gap is crucial for identifying innovative therapies with enhanced efficacy and reduced toxicities. This review explores the multifaceted mechanisms of 5-FU resistance in CRC and evaluates the synergistic effects of combining PCs with 5-FU to improve treatment efficacy while minimizing adverse effects. Additionally, it investigates engineered EVs in overcoming 5-FU resistance by serving as drug delivery vehicles and modulating the TME. By synthesizing the current knowledge and addressing research gaps, this review enhances the academic understanding of 5-FU resistance in CRC, highlighting the potential of interdisciplinary approaches involving PCs and EVs for revolutionizing CRC therapy. Further research and clinical validation are essential for translating these findings into improved patient outcomes.

A large proportion of patients with colorectal cancer (CRC) presents with synchronous colorectal liver metastases (sCRLM) at diagnosis. Surgical approaches for patients with sCRLM have evolved over the past decades. Simultaneous resection (SR) of CRC and sCRLM for selected patients has emerged as a safe and efficient alternative approach to traditional staged resections.

A comprehensive review of the literature was performed using MEDLINE/PubMed and Web of Science databases with the end of search date October 30, 2023. The MeSH terms "simultaneous resections" and "combined resections" in combination with "colorectal liver metastases," "colorectal cancer," "liver resection," and "hepatectomy" were searched in the title and/or abstract.

SRs aim to achieve maximal tumor clearance, minimizing the risk of disease progression and optimizing the potential for long-term survival. Improvements in perioperative care, advances in surgical techniques, and a better understanding of patient selection criteria have collectively contributed to reducing morbidity and mortality associated with these complex procedures. Several studies have demonstrated that SR are associated with reduced overall length of stay and lower costs with comparable morbidity and long-term outcomes. In light of these outcomes, the proportion of patients undergoing SR for CRC and sCRLM has increased substantially over the past 2 decades.

For patients with sCRLM, SR represents an attractive alternative to the traditional staged approach and should be selectively used; however, the decision on whether to proceed with a simultaneous versus staged approach should be individualized based on several patient- and disease-related factors.

The use of preoperative or "neoadjuvant" chemotherapy (NAC) has long been controversial for resectable colorectal liver metastases (CRLM). The European Society of Medical Oncology (ESMO) 2023 guidelines on metastatic colorectal cancer (CRC) indicate a combination of surgical/technical and oncologic/prognostic criteria as the two determinants for allocating patients to NAC or upfront hepatectomy. However, surgical and technical criteria have evolved, and oncologic prognostic criteria date from the pre-modern chemotherapy era and lack prospective validation. The traditional literature is interpreted as not supporting the use of NAC because several studies fail to demonstrate a benefit in overall survival (OS) compared to upfront surgery; however, OS may not be the most appropriate endpoint to consider. Moreover, the commonly quoted studies against NAC contain many limitations that may explain why NAC failed to demonstrate its value. The query of the recent literature focused primarily on other aspects than OS, such as surgical technique, the impact of side effects of chemotherapy, the histological growth pattern of metastases, or the detection of circulating tumor DNA, shows data that support a more widespread use of NAC. These should prompt a critical reappraisal of the use of NAC, leading to a more precise selection of patients who could benefit from it.

The aim of this study was to identify the heterogeneous and homogeneous prognostic factors associated with distant metastasis to the liver, lung, bone, and brain in colorectal cancer (CRC) patients and then construct nomograms to predict the prognosis.

CRC patients registered in the surveillance, epidemiology, and end results database between 2010 and 2017 were included. A Cox regression model was used to analyse homogeneous and heterogeneous prognostic factors, and Kaplan‒Meier analysis was performed to estimate overall survival (OS). Predictive nomograms were constructed, and their performance was evaluated with C-indexes, calibration curves and the area under the receiver operating characteristic (ROC) curve (AUC).

A total of 37,641 patients with distant metastasis to the liver, lung, bone, and brain were included. The median survival times of patients with liver metastasis, lung metastasis, bone metastasis, and brain metastasis were 12.00 months (95% CI 11.73-12.27 months), 10.00 months (95% CI 9.60-10.41 months), 5.00 months (95% CI 4.52-5.48 months), and 3.00 months (95% CI 2.28-3.72 months), respectively. An older age, higher N stage, elevated carcinoembryonic antigen level, no surgery at the primary site and no/unknown treatment with chemotherapy were identified as homogeneous prognostic factors for the four types of metastases. The calibration curves, C-indexes and AUCs exhibited good performance for predicting the OS of patients with distant metastases to the liver, lung, bone, and brain.

CRC patients with distant metastasis to the liver, lung, bone, and brain exhibited homogeneous and heterogeneous prognostic factors, all of which were associated with shorter survival. The nomograms showed good accuracy and may be used as tools for clinicians to predict the prognosis of CRC patients with distant metastasis.

Gemcitabine, cisplatin, and S-1 chemotherapy was superior to gemcitabine and cisplatin chemotherapy for progression-free survival and overall survival for unresectable and recurrent biliary tract cancer in a randomized phase III trial (KHBO1401). This study aimed to evaluate the outcome of conversion surgery after chemotherapy in biliary tract cancer patients (ancillary study, KHBO1401-3C).

A total of 246 patients were enrolled in KHBO1401. We compared progression-free and overall survivals between the conversion surgery and non-conversion surgery groups.

Eight patients (3.3%) underwent conversion surgery with chemotherapy, seven of whom were diagnosed with unresectable disease and one with recurrence. Six and two patients received gemcitabine, cisplatin, and S-1 chemotherapy as well as gemcitabine and cisplatin chemotherapy, respectively. Three patients in the conversion surgery group who received gemcitabine, cisplatin, and S-1 chemotherapy showed no disease progression and survived without postoperative chemotherapy. Preoperative carbohydrate antigen 19-9 (CA19-9) level was a prognostic factor for conversion surgery. After correcting for immortal time bias, 1-year progression-free survival rates in the conversion surgery and non-conversion surgery groups were 50.0% and 19.0%, respectively (hazard ratio 0.343, 95% confidence interval 0.286-0.843, p = 0.0092). One-year overall survival rates in the conversion surgery and non-conversion surgery groups were 87.5% and 56.0%, respectively (hazard ratio 0.222, 95% confidence interval 0.226-0.877, p = 0.0197).

Conversion surgery might be an option for the treatment of unresectable and recurrent biliary tract cancer in patients with normal preoperative CA19-9 level.

Open combined resections of colorectal primary tumors and synchronous liver metastases have become common in selected cases. However, evidences favoring a minimally invasive (MIS) approach are still limited. The aim of this study is to evaluate the outcomes of MIS vs. open synchronous liver and colorectal resections.

384 cases of synchronous colorectal and liver resections performed at one institution were identified during the study period. MIS vs open approach were compared after a propensity score matching; surgical outcomes were analyzed.

MIS cases featured longer operative time (399 vs 300 min, p < 0.001), fewer blood loss (200 vs 500 ml, p = 0.003), and shorter hospitalization (median LOS 4 vs 6 days, p = 0.001). No difference was observed between the two groups for use of Pringle maneuver (p = 0.083), intraoperative blood transfusion (p = 0.061), achievement of negative colorectal (p = 0.176) and liver margins (p = 1.000), postoperative complications (p = 1.000) and significant (Clavien-Dindo ≥ 3a) complications (p = 0.817), delay of adjuvant therapy due to complications (p = 0.555), 30- and 90-day mortality.

Synchronous colorectal and liver metastases resections via a minimally-invasive approach in high-volume centers with appropriate expertise result in significantly lower blood loss and length of stay despite longer operative time in comparison to open, with no oncological inferiority.

The role of paraaortic lymph node dissection (PALND) in colorectal cancer (CRC) has been less evaluated than surgical treatments for other distant metastases. We evaluated surgical outcomes after PALND and identified prognostic factors.

The medical records of patients who underwent PALND for paraaortic lymph node metastasis (PALNM) were reviewed retrospectively. All patients were categorized into the M1a group (isolated PALNM, n = 27), and the M1bc group (distant metastases other than PALNM, n = 26). Three severity factors (PALNM-SF: number of harvested paraaortic lymph nodes [hLN], ≥14; number of metastatic paraaortic lymph nodes [mLN], ≥5; and lymph nodes ratio [mLN/hLN], ≥0.5) were defined to determine their effects on survival.

The 5-year overall survival (OS) of the M1a and M1bc groups were 61.1% and 6.4%, respectively (P = 0.0013). The 5-year disease-free survival (DFS) of the M1a group was 47.4%, and the 3-year DFS of the M1bc group was 9.1% (P < 0.001). Patients with 2 or more PALNM-SFs showed worse OS than those with 1 PALNM-SF (P = 0.017). In multivariate analysis, M1bc (non-isolated PALNM) was the only significant factor for survival. In the M1a group, patients with 2 or more PALNM-SFs showed significantly worse survival than those with a single PALNM-SF. In multivariate analysis, 2 or more PALNM-SF was a significant factor for survival.

PALND for CRC provided favorable outcomes in the survival of an isolated PALNM, although this was uncertain for non-isolated PALNMs. The PALNM-SFs helped assess the prognosis after PALND.

We sought to assess the overall benefit of laparoscopic versus open hepatectomy for treatment of colorectal liver metastases (CRLMs) using the win ratio, a novel methodological approach.

CRLM patients undergoing curative-intent resection in 2001-2018 were identified from an international multi-institutional database. Patients were paired and matched based on age, number and size of lesions, lymph node status and receipt of preoperative chemotherapy. The win ratio was calculated based on margin status, severity of postoperative complications, 90-day mortality, time to recurrence, and time to death.

Among 962 patients, the majority underwent open hepatectomy (n=832, 86.5%), while a minority underwent laparoscopic hepatectomy (n=130, 13.5%). Among matched patient-to-patient pairs, the odds of the patient undergoing laparoscopic resection "winning" were 1.77 [WR: 1.77, 95% confidence interval (CI): 1.42-2.34]. The win ratio favored laparoscopic hepatectomy independent of low (WR: 2.94, 95% CI: 1.20-6.39), medium (WR: 1.56, 95% CI: 1.16-2.10) or high (WR: 7.25, 95% CI: 1.13-32.0) tumor burden, as well as unilobar (WR: 1.71, 95% CI: 1.25-2.31) or bilobar (WR: 4.57, 95% CI: 2.36-8.64) disease. The odds of "winning" were particularly pronounced relative to short-term outcomes (i.e., 90-day mortality and severity of postoperative complications) (WR: 4.06, 95% CI: 2.33-7.78).

Patients undergoing laparoscopic hepatectomy had 77% increased odds of "winning". Laparoscopic liver resection should be strongly considered as a preferred approach to resection in CRLM patients.

Bilobar liver metastases from colorectal cancer pose a challenge for obtaining a satisfactory oncological outcome with an adequate future liver remnant. This study aimed to assess the clinical and pathological determinants of overall survival and recurrence-free survival among patients undergoing surgical clearance of bilobar liver metastases from colorectal cancer.

A retrospective international multicentre study of patients who underwent surgery for bilobar liver metastases from colorectal cancer between January 2012 and December 2018 was conducted. Overall survival and recurrence-free survival at 1, 2, 3 and 5 years after surgery were the primary outcomes evaluated. The secondary outcomes were duration of postoperative hospital stay, and 90-day major morbidity and mortality rates. A prognostic nomogram was developed using covariates selected from a Cox proportional hazards regression model, and internally validated using a 3:1 random partition into derivation and validation cohorts.

A total of 1236 patients were included from 70 centres. The majority (88 per cent) of the patients had synchronous liver metastases. Overall survival at 1, 2, 3 and 5 years was 86.4 per cent, 67.5 per cent, 52.6 per cent and 33.8 per cent, and the recurrence-free survival rates were 48.7 per cent, 26.6 per cent, 19.2 per cent and 10.5 per cent respectively. A total of 25 per cent of patients had recurrent disease within 6 months. Margin positivity and progressive disease at liver resection were poor prognostic factors, while adjuvant chemotherapy in margin-positive resections improved overall survival. The bilobar liver metastases from colorectal cancer-overall survival nomogram was developed from the derivation cohort based on pre- and postoperative factors. The nomogram's ability to forecast overall survival at 1, 2, 3 and 5 years was subsequently validated on the validation cohort and showed high accuracy (overall C-index = 0.742).

Despite the high recurrence rates, overall survival of patients undergoing surgical resection for bilobar liver metastases from colorectal cancer is encouraging. The novel bilobar liver metastases from colorectal cancer-overall survival nomogram helps in counselling and informed decision-making of patients planned for treatment of bilobar liver metastases from colorectal cancer.

Routine treatment with preoperative systemic chemotherapy (CTx) in patients with colorectal liver metastases (CRLM) remains controversial due to lack of consistent evidence demonstrating associated survival benefits. This study aimed to determine the effect of preoperative CTx on overall survival (OS) compared to surgery alone and to assess hospital and oncological network variation in 5-year OS.

This was a population-based study of all patients who underwent liver resection for CRLM between 2014 and 2017 in the Netherlands. After 1:1 propensity score matching (PSM), OS was compared between patients treated with and without preoperative CTx. Hospital and oncological network variation in 5-year OS corrected for case-mix factors was calculated using an observed/expected ratio.

Of 2820 patients included, 852 (30.2%) and 1968 (69.8%) patients were treated with preoperative CTx and surgery alone, respectively. After PSM, 537 patients remained in each group, median number of CRLM; 3 [IQR 2-4], median size of CRLM; 28 mm [IQR 18-44], synchronous CLRM (71.1%). Median follow-up was 80.8 months. Five-year OS rates after PSM for patients treated with and without preoperative chemotherapy were 40.2% versus 38.3% (log-rank P = 0.734). After stratification for low, medium, and high tumour burden based on the tumour burden score (TBS) OS was similar for preoperative chemotherapy vs. surgery alone (log-rank P = 0.486, P = 0.914, and P = 0.744, respectively). After correction for non-modifiable patient and tumour characteristics, no relevant hospital or oncological network variation in five-year OS was observed.

In patients eligible for surgical resection, preoperative chemotherapy does not provide an overall survival benefit compared to surgery alone.

No well-performing nomogram has been developed specifically to predict individual-patient cancer-specific survival (CSS) and overall survival (OS) among patients with resectable colorectal liver metastasis (CRLM) who undergo simultaneous resection of primary and hepatic lesions without neoadjuvant chemotherapy (NAC). We aim to investigate the prognosis of patients with resectable CRLM undergoing simultaneous resection of primary and hepatic lesions without NAC.

Data of patients with CRLM in the Surveillance, Epidemiology and End Results Program (cohort, n = 225) were collected as the training set, and data of patients with CRLM treated at the National Cancer Center (cohort, n = 180) were collected as the validation set. The prognostic value of the clinicopathological parameters in the training cohort was assessed using Kaplan‒Meier curves and univariate and multivariate Cox proportional hazards models, and OS and CSS nomograms integrated with the prognostic variables were constructed. Calibration analyses, receiver operating characteristic (ROC) curves, and decision curve analyses (DCAs) were then performed to evaluate the performance of the nomograms.

There was no collinearity among the collected variables. Three factors were associated with OS and CSS: the pretreatment carcinoembryonic antigen (CEA) concentration, pathologic N (pN) stage, and adjuvant chemotherapy (each p < 0.05). OS and CSS nomograms were constructed using these three parameters. The calibration plots revealed favorable agreement between the predicted and observed outcomes. The areas under the ROC curves were approximately 0.7. The DCA plots revealed that both nomograms had satisfactory clinical benefits. The ROC curves and DCAs also confirmed that the nomogram surpassed the tumor, node, and metastasis staging system.

The herein-described nomograms containing the pretreatment CEA concentration, pN stage, and adjuvant chemotherapy may be effective models for predicting postoperative survival in patients with CRLM.

Patients with resectable colorectal liver metastases (CLM) are treated with surgery alone, surgery and posthepatectomy chemotherapy, or prehepatectomy chemotherapy and surgery. The optimal approach in terms of survival is unclear. We compared survival in the three treatment groups using inverse probability of treatment weighting (IPTW) analysis.

Data from patients undergoing initial CLM resection in 2005-2018 were obtained from a prospectively maintained database. Our group treated resectable CLM with surgery alone but gradually adopted post- and prehepatectomy chemotherapy for patients with CLM number ≥5 after 2015. IPTW analysis was employed to adjust the characteristics of the three groups.

Of the 439 patients meeting the inclusion criteria, 175 underwent surgery alone, 135 underwent surgery and posthepatectomy chemotherapy, and 129 underwent prehepatectomy chemotherapy and surgery. After the IPTW adjustment, the demographic and clinicopathological characteristics were well balanced. The IPTW analysis revealed that the recurrence-free survival was better in patients undergoing surgery and posthepatectomy chemotherapy than in patients undergoing surgery alone (median recurrence-free survival, 1.3 years vs 0.7 years; P = .018). Overall survival was not significantly different between the three treatment approaches.

Posthepatectomy but not prehepatectomy chemotherapy prolongs the time to recurrence after curative-intent resection of CLM.

The liver is the most common site of metastases in patients with colorectal cancer. Colorectal liver metastases (CRLMs) are the result of molecular mechanisms that involve different cells of the liver microenvironment. The aberrant activation of Wingless/It (Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium, but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymal-epithelial transition interactions. In liver microenvironment, metastatic cells can also survive and adapt through dormancy, which makes them less susceptible to pro-apoptotic signals and therapies. Treatment of CRLMs is challenging due to its variability and heterogeneity. Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been re-cognized in chemoresistance. At the state of art, there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie. In this review, current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered. In addition, an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.

Liver resection is the only curative treatment for colorectal liver metastasis. The identification of predictive factors leads to personalize patient management to enhance their long-term outcomes. This population-based study aimed to characterize factors associated with, and survival impact of patients who received hepatectomy for colorectal liver metastasis.

A retrospective cohort study of all the hepatectomies for colorectal liver metastasis performed at third-level hospital of Spain (2010-2018) was conducted. The Kaplan-Meier method was used for survival analyses. Multivariable Cox and regression models were used to determine prognostic factors associated with overall survival.

The 5-year overall survival and disease-free survival were 42 and 33%, respectively. Survival analysis showed that metastasis features (number, largest size, distribution, and extrahepatic disease) and postsurgical factors (transfusion, major complications, and positive margin resection), as well as non-mutated KRAS, showed a significant association with survival. Otherwise, on multivariate analysis, only 5 independent risk factors were identified: major size metastasis >4 cm, RAS mutation, positive margin resection, intraoperative transfusion, and major complications.

According to our findings, major size metastasis >4 cm, intraoperative transfusion, and major postoperative complications continue to be traditional prognostic factors. Meanwhile, the KRAS biomarker has a powerful impact as a survival prognostic factor.

Neoadjuvant therapy (NAT) for advanced colorectal cancer (ACRC) is a kind of well-evidenced therapy, yet a portion of ACRC patients have poor therapeutic response. To date, no suitable biomarker used for assessing NAT efficacy has been reported. Here, we collect 72 colonoscopy biopsy tissue specimens from ACRC patients before undergoing NAT and investigate the relationship between HOXA13 expression and NAT efficacy. The results show that HOXA13 expression in pretreated tumor specimens is negatively associated with tumor regression ( P<0.001) and progression-free survival ( P<0.05) in ACRC patients who underwent NAT. Silencing of HOXA13 or its regulator HOTTIP significantly enhances the chemosensitivity of colorectal cancer (CRC) cells, leading to an increase in cell apoptosis and the DNA damage response (DDR) to chemotherapeutic drug treatment. In contrast, HOXA13 overexpression causes a significant increase in chemoresistance in CRC cells. In summary, we find that the HOTTIP/HOXA13 axis is involved in regulating chemotherapeutic sensitivity in CRC cells by modulating the DDR and that HOXA13 serves as a promising marker for NAT efficacy prediction in ACRC patients.

The inflammatory response to tumor has been proven to be closely related to the prognosis of colorectal cancer. Neutrophil to lymphocyte ratio (NLR) is a widely available inflammatory biomarker that may have prognostic value for patients with colorectal liver metastasis (CRLM).

To assess the role of NLR as a prognostic factor of survival and tumor recurrence in patients with CRLM.

A systematic literature search of PubMed, Cochrane Library and clinicaltrials.gov was conducted by two independent researchers in order to minimize potential errors and bias. Conflicts were discussed and settled between three researchers. Studies including patients undergoing different types of medical interventions for the treatment of CRLM and evaluating the correlation between pretreatment NLR and disease-free survival (DFS) and overall survival (OS) were included in the review. Nineteen studies, involving 3283 patients matched our inclusion criteria.

In the studies included, NLR was measured before the intervention and the NLR thresholds ranged between 1.9 and 7.26. Most studies used 5 as the cut-off value. Liver metastases were treated with hepatectomy with or without chemotherapy regimens in 13 studies and with radiofrequency ablation, radioembolization, chemoembolization or solely with chemotherapy in 6 studies. High NLR was associated with decreased OS and DFS after liver resection or other medical intervention. Moreover, high NLR was associated with poor chemosensitivity. On the contrary, CRLM patients with low pretreatment NLR demonstrated improved OS and DFS. NLR could potentially be used as a predictive factor of survival and tumor recurrence in patients with CRLM treated with interventions of any modality, including surgery, chemotherapy and ablative techniques.

NLR is an inflammatory biomarker that demonstrates considerable prognostic value. Elevated pretreatment NLR is associated with poor OS and DFS in patients with CRLM who are submitted to different treatments.

Liver resection for malignant tumors should respect oncological margins while ensuring safety and improving the quality of life, therefore tumor staging, underlying liver disease and performance status should all be attentively assessed in the decision process. The concept of parenchyma-sparing liver surgery is nowadays used as an alternative to major hepatectomies to address deeply located lesions with intricate topography by means of complex multiplanar parenchyma-sparing liver resections, preferably under the guidance of intraoperative ultrasound. Regenerative liver surgery evolved as a liver growth induction method to increase resectability by stimulating the hypertrophy of the parenchyma intended to remain after resection (referred to as future liver remnant), achievable by portal vein embolization and liver venous deprivation as interventional approaches, and portal vein ligation and associating liver partition and portal vein ligation for staged hepatectomy as surgical techniques. Interestingly, although both strategies have the same conceptual origin, they eventually became caught in the never-ending parenchyma-sparing liver surgery vs. regenerative liver surgery debate. However, these strategies are both valid and must both be mastered and used to increase resectability. In our opinion, we consider parenchyma-sparing liver surgery along with techniques of complex liver resection and intraoperative ultrasound guidance the preferred strategy to treat liver tumors. In addition, liver volume-manipulating regenerative surgery should be employed when resectability needs to be extended beyond the possibilities of parenchyma-sparing liver surgery.

Depending on the patient's constitution, the biological conditions of the primary tumor, the metastases and the liver function and perfusion, a variety of therapeutic options are available. The basis of metastatic surgery of the liver is partial liver resection. Multimodal therapies with local and systemic approaches are used in functionally or oncologically borderline situations. They are intended to improve long-term success and allow curative treatment in more patients. In recent years, for isolated lesions that cannot be removed by partial liver resection, an R0 situation is achieved in selected patients by liver transplantation with good long-term success. The large number of treatment options and the increasing individualization of therapy require treatment planning in the interdisciplinary tumor board. Also, in view of promising studies, for example, in the field of liver transplantation as well as regional therapy methods, the range of treatment options has not yet been exhausted.

Previous reports showed an increased risk of infectious complications when liver radiofrequency ablation (RFA) is performed simultaneously to colorectal resection. The aim of this study was to compare early and long-term outcomes of simultaneous versus staged strategy.

Data from colorectal cancer liver metastases consecutively treated by surgery of the primary tumor with an associated liver RFA procedure between January 1, 2010 and January 31, 2020. Patients were divided into two groups: RFA performed during colorectal surgery (simultaneous) or in a different moment (staged). Patients were manually matched (1:1) to minimize influence of known covariates.

Seventy-two patients were included. After matching, there was no difference between the two groups in morbidity or mortality. Hospital stay was 2 days shorter in the simultaneous group.

Early or long-term outcomes were identical between the two strategies. The simultaneous strategy was associated with a shorter duration of hospitalization although not significant. Simultaneous colorectal resection and liver RFA is safe and must be included in surgeons' armamentarium.