There is still debate over how reviewing oncological histories and addressing appropriate therapies in multidisciplinary team (MDT) discussions may affect patients’ overall survival (OS). The aim of this study was to describe MDT outcomes for a single cancer center’s patients affected by colorectal liver metastases (CRLMs). From 2010 to 2020, a total of 847 patients with CRLMs were discussed at our weekly MDT meeting. Patients’ characteristics and MDT decisions were analyzed in two groups: patients receiving systemic therapy (ST) versus patients receiving locoregional treatment (LRT). Propensity-score matching (PSM) was run to reduce the risk of selection bias. The median time from MDT indication to treatment was 27 (IQR 13–51) days. The median OS was 30 (95%CI = 27–34) months. After PSM, OS for patients undergoing LRT was 51 (95%CI = 36–64) months compared with 15 (95%CI = 13–20) months for ST patients (p < 0.0001). In this large retrospective study, the MDT discussions were useful in providing the patients with all available locoregional options. Full article

Quantitative analysis of Tumor Microenvironment (TME) provides prognostic and predictive information in several human cancers but, with few exceptions, it is not performed in daily clinical practice since it is extremely time-consuming. We recently showed that the morphology of Tumor Associated Macrophages (TAMs) correlates with outcome in patients with Colo-Rectal Liver Metastases (CLM). However, as for other TME components, recognizing and characterizing hundreds of TAMs in a single histopathological slide is unfeasible. To fasten this process, we explored a deep-learning based solution. We tested three Convolutional Neural Networks (CNNs), namely UNet, SegNet and DeepLab-v3, with three different segmentation strategies, semantic segmentation, pixel penalties and instance segmentation. The different experiments are compared according to the Intersection over Union (IoU), a metric describing the similarity between what CNN predicts as TAM and the ground truth, and the Symmetric Best Dice (SBD), which indicates the ability of CNN to separate different TAMs. UNet and SegNet showed intrinsic limitations in discriminating single TAMs (highest SBD $61.34\pm 2.21$), whereas DeepLab-v3 accurately recognized TAMs from the background (IoU $89.13\pm 3.85$) and separated different TAMs (SBD $79.00\pm 3.72$). This deep-learning pipeline to recognize TAMs in digital slides will allow the characterization of TAM-related metrics in the daily clinical practice, allowing the implementation of prognostic tools. Full article

The aim of this study was to assess safety, efficacy and survival outcomes of repeat thermal ablation as compared to repeat partial hepatectomy in patients with recurrent colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study of two cohorts, repeat thermal ablation versus repeat partial hepatectomy, analyzed 136 patients (100 thermal ablation, 36 partial hepatectomy) and 224 tumors (170 thermal ablation, 54 partial hepatectomy) with recurrent CRLM from May 2002 to December 2020. The primary and secondary endpoints were overall survival (OS), distant progression-free survival (DPFS) and local tumor progression-free survival (LTPFS), estimated using the Kaplan–Meier method, and complications, analyzed using the chi-square test. Multivariable analyses based on Cox proportional hazards model were used to account for potential confounders. In addition, subgroup analyses according to patient, initial and repeat local treatment characteristics were performed. In the crude overall comparison, OS of patients treated with repeat partial hepatectomy was not statistically different from repeat thermal ablation (p = 0.927). Further quantification of OS, after accounting for potential confounders, demonstrated concordant results for repeat local treatment (hazard ratio (HR), 0.986; 95% confidence interval (CI), 0.517–1.881; p = 0.966). The 1-, 3- and 5-year OS were 98.9%, 62.6% and 42.3% respectively for the thermal ablation group and 93.8%, 74.5% and 49.3% for the repeat resection group. No differences in DPFS (p = 0.942), LTPFS (p = 0.397) and complication rate (p = 0.063) were found. Mean length of hospital stay was 2.1 days in the repeat thermal ablation group and 4.8 days in the repeat partial hepatectomy group (p = 0.009). Subgroup analyses identified no heterogeneous treatment effects according to patient, initial and repeat local treatment characteristics. Repeat partial hepatectomy was not statistically different from repeat thermal ablation with regard to OS, DPFS, LTPFS and complications, whereas length of hospital stay favored repeat thermal ablation. Thermal ablation should be considered a valid and potentially less invasive alternative for small-size (0–3 cm) CRLM in the treatment of recurrent new CRLM. While, the eagerly awaited results of the phase III prospective randomized controlled COLLISION trial (NCT03088150) should provide definitive answers regarding surgery versus thermal ablation for CRLM. Full article

Purpose: To evaluate immune cell infiltration, the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) expression and their prognostic value in a series of mismatch proficient (pMMR) CRC with matched liver and lung metastases. Methods: Formalin-fixed paraffin-embedded tissue sections stained for CD3, CD8, PD-L1 and PD-1 from 113 primary CRC tumours with 105 liver and 59 lung metastases were analyzed. The amount of CD3 and CD8 positive lymphocytes were combined as immune cell score (ICS). Comparative analyses on immune contexture were performed both between the primary tumour and matched metastases and between the metastatic sites. Results: In liver metastases, immune cell infiltration was increased in general compared to primary tumours but did not correlate case by case. On the contrary, ICS between lung metastases and primary tumours correlated well, but the expression of PD-1/PD-L1 was increased in lung metastases. The proportion of tumours with high ICS together with PD-L1-positivity almost doubled in metastases (39%) compared to primary tumours (20%). High ICS (compared to lowest) in patient’s least immune-infiltrated metastasis was an independent prognostic marker for disease-specific (HR 9.14, 95%CI 2.81–29.68) and overall survival (HR 6.95, 95%CI 2.30–21.00). Conclusions: Our study confirms the prognostic value of high ICS in least immune-infiltrated metastases in pMMR CRC patients. Major differences observed in immune contexture between primary tumours and metastases may have significance for treatment strategies for patients with advanced CRC. Full article

Background: Stereotactic body radiotherapy (SBRT) is a recognized treatment for colorectal cancer (CRC) metastases. We postulated that local responses could be improved by SBRT with a concomitant radiosensitizing agent (irinotecan). Methods: RADIOSTEREO-CAMPTO was a prospective multi-center phase 2 trial investigating SBRT (40–48 Gy in 4 fractions) for liver and/or lung inoperable CRC oligometastases (≤3), combined with two weekly intravenous infusions of 40 mg/m² Irinotecan. Primary outcome was the objective local response rate as per RECIST. Secondary outcomes were early and late toxicities, EORTC QLQ-C30 quality of life, local control and overall survival. Results: Forty-four patients with 51 lesions (liver = 39, lungs = 12) were included. Median age was 69 years (46–84); 37 patients (84%) had received at least two prior chemotherapy treatments. Median follow-up was 48.9 months. One patient with two lung lesions was lost during follow-up. Assuming maximum bias hypothesis, the objective local response rate in ITT was 86.3% (44/51—95% CI: [76.8–95.7]) or 82.4% (42/51—95% CI: [71.9–92.8]). The observed local response rate was 85.7% (42/49—95% CI: [75.9–95.5]). The 1 and 2-year local (distant) progression-free survivals were 84.2% (38.4%) and 67.4% (21.3%), respectively. The 1 and 2-year overall survivals were 97.5% and 75.5%. There were no severe acute or late reactions. The EORTC questionnaire scores did not significantly worsen during or after treatment. Conclusions: SBRT with irinotecan was well tolerated with promising results despite heavily pretreated patients. Full article

Colorectal liver metastases (CRLM) are the major cause of death in patients with colorectal cancer (CRC). The cornerstone treatment of CRLM is surgical resection. Post-operative morbidity and mortality are mainly linked to an inadequate future liver remnant (FLR). Nowadays preoperative portal vein embolization (PVE) is the most widely performed technique to increase the size of the future liver remnant (FLR) before major hepatectomies. One method recently proposed to increase the FLR is liver venous deprivation (LVD), but its oncological impact is still unknown. The aim of this study is to report first short- and long-term oncological outcomes after LVD in patients undergoing right (or extended right) hepatectomy for CRLM. Seventeen consecutive patients undergoing LVD between July 2015 and May 2020 before an (extended) right hepatectomy were retrospectively analyzed from an institutional database. Post-operative and follow-up data were analyzed and reported. Primary outcomes were 1-year and 3-year overall survival (OS) and hepatic recurrence (HR). Postoperative complications occurred in 8 patients (47%). No deaths occurred after surgery. HR occurred in 9 patients (52.9%). 1-year and 3-year OS were 87% (95% confidence interval [CI]: ±16%) and 60.3%, respectively (95% CI: ±23%). Median Disease-Free Survival (DFS) was 6 months (CI 95%: 4.7–7.2). With all the limitations of a retrospective study with a small sample size, LVD showed similar oncological outcomes compared to literature reports for Portal Vein Embolization (PVE). Full article

Pedicle clamping (PC) during liver resection for colorectal metastases (CRLM) is used to reduce blood loss and allogeneic blood transfusion (ABT). The effect on long-term oncologic outcomes is still under debate. A retrospective analysis of the impact of PC on ABT-demand regarding overall (OS) and recurrence-free survival (RFS) in 336 patients undergoing curative resection for CRLM was carried out. Survival analysis was performed by both univariate and multivariate methods and propensity-score (PS) matching. PC was employed in 75 patients (22%). No increased postoperative morbidity was monitored. While the overall ABT-rate was comparable (35% vs. 37%, p = 0.786), a reduced demand for more than two ABT-units was observed (p = 0.046). PC-patients had better median OS (78 vs. 47 months, p = 0.005) and RFS (36 vs. 23 months, p = 0.006). Multivariate analysis revealed PC as an independent prognostic factor for OS (HR = 0.60; p = 0.009) and RFS (HR = 0.67; p = 0.017). For PC-patients, 1:2 PS-matching (N = 174) showed no differences in the overall ABT-rate compared to no-PC-patients (35% vs. 40%, p = 0.619), but a trend towards reduced transfusion requirement (>2 ABT-units: 9% vs. 21%, p = 0.052; >4 ABT-units: 2% vs. 11%, p = 0.037) and better survival (OS: 78 vs. 44 months, p = 0.088; RFS: 36 vs. 24 months; p = 0.029). Favorable long-term outcomes and lower rates of increased transfusion demand were observed in patients with PC undergoing resection for CRLM. Further prospective evaluation of potential oncologic benefits of PC in these patients may be meaningful. Full article

Colorectal cancer (CRC) is the third most common cancer worldwide and has a high rate of metastatic disease which is the main cause of CRC-related death. Oligometastatic disease is a clinical condition recently included in ESMO guidelines that can benefit from a more aggressive locoregional approach. This review focuses the attention on colorectal liver metastases (CRLM) and highlights recommendations and therapeutic locoregional strategies drawn from the current literature and consensus conferences. The different percutaneous therapies (radiofrequency ablation, microwave ablation, irreversible electroporation) as well as trans-arterial approaches (chemoembolization and radioembolization) are discussed. Ablation margins, the choice of the imaging guidance as well as characteristics of the different ablation techniques and other technical aspects are analyzed. A specific attention is then paid to the increasing role of biomarkers (in particular molecular profiling) and their role in the selection of the proper treatment for the right patient. In conclusion, in this review an up-to-date state of the art of the application of locoregional treatments on CRLM is provided, highlighting both technical aspects and the role of biomarkers, two sides of the same coin. Full article

Hepatic resection has been widely accepted as the first choice for the treatment of colorectal metastases. Liver surgery has been recognized as a major abdominal procedure; it exposes patients to a high risk of perioperative adverse events. Decision sharing and the multimodal approach to the patients’ management are the two key items for a safe outcome, even in such a high-risk surgery. This review aims at addressing the main perioperative issues (preoperative evaluation; general anesthesia and intraoperative fluid management and hemodynamic monitoring; intraoperative metabolism; administration policy for blood-derivative products; postoperative pain control; postoperative complications), in particular, from the anesthetist’s point of view; however, only an alliance with the surgery team may be successful in case of adverse events to accomplish a good final outcome. Full article

Colorectal cancer (CRC) is the third most prevalent malignancy and the second most common cause of death in the US. Liver is the most common site of colorectal metastases. About 13% of patients with colorectal cancer have liver metastasis on initial presentation and 50% develop them during the disease course. Although systemic chemotherapy and immunotherapy are the mainstay treatment for patients with metastatic disease, for selected patients with predominant liver metastasis, liver-directed approaches may provide prolonged disease control when combined with systemic treatments. Hepatic artery infusion pump (HAIP) chemotherapy is an approach which allows direct infusion of chemotherapeutic into the liver and is especially useful in the setting of multifocal liver metastases. When combined with systemic chemotherapy, HAIP improves the response rate, provides more durable disease control, and in some patients leads to successful resection. To ensure safety, use of HAIP requires multidisciplinary collaboration between interventional radiologists, medical oncologists, hepatobiliary surgeons and treatment nurses. Here, we review the benefits and potential risks with this approach and provide our single institution experience on two CRC patients successfully treated with HAIP in combination with systemic chemotherapy. We provide our recommendations in adopting this technique in the current era for patient with colorectal liver metastases. Full article

Colorectal cancer (CRC) is one of the most common cancers in western countries. Its mortality rate varies greatly, depending on the stage of the disease. The main cause of CRC mortality is metastasis, which most commonly affects the liver. The role of tumor microenvironment in tumor initiation, progression and metastasis development has been widely studied. In this review we summarize the role of the tumor microenvironment in the liver pre-metastatic niche formation, paying attention to the distant cellular crosstalk mediated by exosomes. Moreover, and based on the prognostic and predictive capacity of alterations in the stromal compartment of tumors, we describe the role of tumor microenvironment cells and related liquid biopsy biomarkers in the delivery of precise medication for metastatic CRC. Finally, we evaluate the different clinical strategies to prevent and treat liver metastatic disease, based on the targeting of the tumor microenvironment. Specifically, targeting angiogenesis pathways and regulating immune response are two important research pipelines that are being widely developed and promise great benefits. Full article

Prognostic studies are increasingly providing new tools to stratify colo-rectal liver metastasis patients into clinical subgroups, with remarkable implications in terms of clinical management and therapeutic choice. Here, the strengths and hurdles of current prognostic tools in colo-rectal liver metastasis are discussed. Alongside more classic histopathological parameters, which capture features related to the tumor component, such as tumor invasion, tumor growth pattern and regression score, we will discuss immune mediators, which are starting to be considered important features. Their objective quantification has shown significant results in prognostication studies, with most of the work focused on adaptive immune cells, namely T cells. As for macrophages, they are only starting to be appreciated and we will present recent advances in evaluation of macrophage morphological features. Deeper knowledge acquired by multiparametric analyses is rapidly uncovering the variety of immune players that should be assessed. The future projection is to implement deep-learning histopathological tools and to integrate histopathological and immune metrics in multiparametric scores, with the ultimate objective to achieve a deeper resolution of the tumor features and their relevance for colo-rectal liver metastasis. Full article

(1) Background: colorectal liver metastases (CRLM) are the most common extra-lymphatic metastases in colorectal cancer; however, few patients are fit for curative surgery. Microwave ablation (MWA) showed promising outcomes in this cohort of patients. This systematic review and pooled analysis aimed to analyze the oncological results of MWA for CRLM. (2) Methods: Following PRISMA guidelines, PubMed, Scopus, EMBASE, Google Scholar, Science Direct, and the Wiley Online Library databases were searched for reports published before January 2021. We included papers assessing MWA, treating resectable CRLM with curative intention. We evaluated the reported MWA-related complications and oncological outcomes as being recurrence-free (RF), free from local recurrence (FFLR), and overall survival rates (OS). (3) Results: Twelve out of 4822 papers (395 patients) were finally included. Global RF rates at 1, 3, and 5 years were 65.1%, 44.6%, and 34.3%, respectively. Global FFLR rates at 3, 6, and 12 months were 96.3%, 89.6%, and 83.7%, respectively. Global OS at 1, 3, and 5 years were 86.7%, 59.6%, and 44.8%, respectively. A better FFLR was reached using the MWA surgical approach at 3, 6, and 12 months, with reported rates of 97.1%, 92.7%, and 88.6%, respectively. (4) Conclusions: Surgical MWA treatment for CRLM smaller than 3 cm is a safe and valid option. This approach can be safely included for selected patients in the curative intent approaches to treating CRLM. Full article