• Humans
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/surgery
• Colorectal Neoplasms/mortality
• Liver Neoplasms/surgery
• Liver Neoplasms/secondary
• Liver Neoplasms/genetics
• Liver Neoplasms/mortality
• Proto-Oncogene Proteins p21(ras)/genetics
• Male
• Female
• Hepatectomy
• Middle Aged
• Aged
• Margins of Excision
• Mutation
• Disease-Free Survival
• Retrospective Studies
• Prognosis
• Aged, 80 and over
• Adult

• (MeSHterms) hepatectomy
• Colorectal neoplasms
• Metastasectomy
• Propensity score

• LiverMetSurvey
• colorectal cancer
• downsizing
• hepatectomy
• irresectable hepatic metastases
• liver metastases
• liver resection
• neo-adjuvant chemotherapy
• onco-surgical approach
• preoperative chemotherapy
• real-world evidence

• Colorectal cancer
• Hepatectomy
• Liver metastasis
• Parenchyma-sparing
• Vessel skeletonization

• ACR–ABS–ACNM–ASTRO–SIR–SNMMI
• Radioembolization
• SIRT
• TARE
• Yttrium-90

The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.

A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.

We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4⁺ T cell, CD8⁺ T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.

SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.

• Anti‐epidermal growth factor receptor therapy
• Colorectal cancer
• Drug resistance
• Transcriptional alterations
• Tumor immune cell infiltration

Liver metastasis is the most common form of distant metastasis in colorectal cancer and is a key factor for prognosis in patients with colorectal cancer. Surgery may be the only way to cure colorectal liver metastases. This paper mainly summarizes the latest progress in surgical treatment of colorectal liver metastases, including how to increase resection rate of liver metastases with neoadjuvant therapy or staged hepatectomy, the effect of surgical margin on the prognosis of patients, the timing of surgery in patients with synchronous colorectal liver metastasis, the impact of laparoscopic hepatectomy of liver metastases, the application of liver transplantation in patients with colorectal liver metastases, etc, with an aim to help develop an optimal treatment for patients with colorectal liver metastases through combination of surgical innovations with individualized treatment, thereby improving patients' disease-free survival and overall survival.

• Colorectal liver metastasis
• Surgery
• Prognosis

• Conversion surgery
• Induction chemotherapy
• Stage IV gastric cancer

• Colorectal cancer
• Hepatic arterial infusion
• Liver metastases
• Oxaliplatin
• Targeted therapy

• Colorectal cancer
• Hepatic arterial infusion
• Liver metastases
• Liver resection
• Oxaliplatin
• Randomized trial

• Colorectal liver metastasis (CRLM)
• liver resection
• liver targeted therapy
• liver transplantation
• systemic chemotherapy

Colorectal cancer is the third most common cancer in men and the second most common in women worldwide. Almost a third of the patients has or will develop liver metastases. Neoadjuvant chemotherapy (NAC) has recently become nearly systematic prior to surgery of colorectal livers metastases (CRLMs). The response to NAC is evaluated by radiological imaging according to morphological criteria. More recently, the response to NAC has been evaluated based on histological criteria of the resected specimen. The most often used score is the tumor regression grade (TRG), which considers the necrosis, fibrosis, and number of viable tumor cells.

To analyze the predictive factors of the histological response, according to the TRG, on CRLM surgery performed after NAC.

From January 2006 to December 2013, 150 patients who had underwent surgery for CRLMs after NAC were included. The patients were separated into two groups based on their histological response, according to Rubbia-Brandt TRG. Based on their TRG, each patient was either assigned to the responder (R) group (TRG 1, 2, and 3) or to the non-responder (NR) group (TRG 4 and 5). All of the histology slides were re-evaluated in a blind manner by the same specialized pathologist. Univariate and multivariate analyses were performed.

Seventy-four patients were classified as responders and 76 as non-responders. The postoperative mortality rate was 0.7%, with a complication rate of 38%. Multivariate analysis identified five predictive factors of histological response. Three were predictive of non-response: More than seven NAC sessions, the absence of a radiological response after NAC, and a repeat hepatectomy (P < 0.005). Two were predictive of a good response: A rectal origin of the primary tumor and a liver-first strategy (P < 0.005). The overall survival was 57% at 3 yr and 36% at 5 yr. The disease-free survival rates were 14% at 3 yr and 11% at 5 yr. The factors contributing to a poor prognosis for disease-free survival were: No histological response after NAC, largest metastasis > 3 cm, more than three preoperative metastases, R1 resection, and the use of a targeted therapy with NAC (P < 0.005).

A non-radiological response and a number of NAC sessions > 7 are the two most pertinent predictive factors of non-histological response (TRG 4 or 5).

• Colorectal liver metastasis
• Tumor regression grade
• Neoadjuvant chemotherapy
• Liver surgery
• Histological response
• Hepatectomy

Liver surgery for the treatment of colorectal liver metastases is the standard treatment in a dynamic surgical field with many variables that should be considered in a curative intent scenario. Hepatectomy for colorectal liver metastases has undergone constant changes over the last 30 years, including indications until the need for rescue procedures of recurrent and advanced diseases as well as minimally invasive surgery. These advancements in liver surgery have not only resulted from overall improvements in the surgical field but have also resulted from a better understanding of the biological behavior of the disease, liver regeneration, and homeostasis during and after surgery. Improvements in anesthesiology, intensive care medicine, radiology, and surgical devices have correlated with further advancements of hepatectomies. Moreover, changes are still forthcoming, and both fields of augmented reality and artificial intelligence will likely have future contributions in this field in regard to both diagnoses and the planning of procedures. The aim of this editorial is to emphasize several aspects that have contributed to the paradigm shifts in colorectal liver metastases surgery over the last three decades as well as to discuss the factors concerning patient selection and the technical aspects of liver surgery. Finally, this editorial will highlight the promising new features of this surgery for diagnoses and treatments in this field.

• Colorectal liver metastases
• Cancer
• Hepatectomy
• Liver
• Surgery
• Oncology

The purpose of this study was to investigate whether any texture features show a correlation with intrahepatic tumor growth before the metastasis is visible to the human eye.

Eight male C57BL6 mice (age 8–10 weeks) were injected intraportally with syngeneic MC-38 colon cancer cells and two mice were injected with phosphate-buffered saline (sham controls). Small animal magnetic resonance imaging (MRI) at 4.7 T was performed at baseline and days 4, 8, 12, 16, and 20 after injection applying a T2-weighted spin-echo sequence. Texture analysis was performed on the images yielding 32 texture features derived from histogram, gray-level co-occurrence matrix, gray-level run-length matrix, and gray-level size-zone matrix. The features were examined with a linear regression model/Pearson correlation test and hierarchical cluster analysis. From each cluster, the feature with the lowest variance was selected.

Tumors were visible on MRI after 20 days. Eighteen features from histogram and the gray-level-matrices exhibited statistically significant correlations before day 20 in the experiment group, but not in the control animals. Cluster analysis revealed three distinct clusters of independent features. The features with the lowest variance were Energy, Short Run Emphasis, and Gray Level Non-Uniformity.

Texture features may quantitatively detect liver metastases before they become visually detectable by the radiologist.

• Colorectal neoplasms
• Computer-assisted image processing
• Liver
• Magnetic resonance imaging (MRI)
• Neoplasm micrometastases

• gastrointestinal cancer
• hypermutation
• immune checkpoint inhibitor
• microsatellite instability
• precision medicine

• R01 CA160688 NCI NIH HHS

To evaluate the impact of targeted agents in stage II-III rectal cancer undergoing neoadjuvant concurrent chemoradiation therapy (CCRT).

A retrospective study was performed in 124 consecutive patients with clinically T₃N_0-2M₀-staged rectal cancer incorporating targeted agents in CCRT.

Pathologic complete response was detected in 34.2% (n=26) of bevacizumab+FOLFOX-treated patients (n=76), which was significantly higher (p=0.019, post-hoc statistical power =35.87%) than that (n=10, 20.8%) of the cetuximab+FOLFOX-treated patients (n=48). Patients receiving cetuximab+FOLFOX therapy tended to develop severe liver toxicity (91.7%, n=44 versus 17.1%, n=13, p<0.0001), as evaluated by morphologic grading of hepatic steatosis and sinusoidal dilatation in laparoscopy. In the 57 patients with morphologically severe liver toxicity, 36 (63.2%) retained a normal liver function; for the remaining 21 patients with an abnormal liver function, the abnormality was self-limited in 19 patients, whereas 2 cetuximab–treated patients progressed to hepatic failure and mortality. A subset analysis within bevacizumab+FOLFOX-treated patients with either wild-type (n=36) or mutant (n=40) K-ras status indicated K-ras status did not significantly influence the treatment outcomes.

The addition of bevacizumab instead of cetuximab to FOLFOX in the neoadjuvant settings for T₃N_0-2M₀-staged rectal cancer could induce a promising rate of pathologic complete response and lesser hepatotoxicity.

• CCRT
• bevacizumab
• cetuximab
• rectal cancer
• total mesorectal excision

• Advanced (joint) multidisciplinary team
• ablation
• centralization
• surgery
• synchronous colorectal liver metastases
• systemic therapy

• Bevacizumab
• Colorectal liver metastases
• Hepatotoxicity
• Liver resection
• Oxaliplatin
• Sinusoidal obstruction syndrome

Resectability of colorectal liver metastasis (CRLM) depends on major vascular involvement and is affected by chemotherapy-induced liver injury. Parenchyma-sparing with combined resection and reconstruction of involved vessels may expand the indications and safety of hepatectomy.

Of 92 patients who underwent hepatectomy for CRLM, 15 underwent major vascular resection and reconstruction. The reconstructed vessels were the portal vein (PV) in five cases, the major hepatic vein (HV) in nine cases, and the inferior vena cava in six cases.

All PV reconstructions were direct anastomoses. The HV was reconstructed with an autologous inferior mesenteric venous patch or an external iliac vein interposition graft. Total hepatic vascular exclusion was performed for six patients. Of nine patients with HV reconstruction, three had tumors involving all three major HVs, in whom the left HV was reconstructed as an only vein after extended right hepatectomy. In another six patients, multiple bilobar tumors or tumors in the liver that had chemotherapy-induced injury involved one or two HVs. Parenchyma-sparing by reconstruction of the HV was performed to secure the residual liver function. The patients with vascular reconstruction had an operative time of 462 ± 111 min and a blood loss of 1278 ± 528 mL. No complication classified as Clavien–Dindo 3 or more developed. The median hospital stay was 17 days (range 8–26 days). The cumulative 5-year survival rate for all the patients was 54.6 %, with no significant difference according to vascular reconstruction.

Parenchyma-sparing hepatectomy combined with vascular reconstruction is a useful option to avoid major hepatectomy among various procedures for resection of CRLM with major vascular invasion.

• Adjuvant therapy
• Combination therapy
• Liver resection
• Metastatic colorectal cancer
• Surgery

• Adjuvant surgery
• Chemotherapy
• Conversion therapy
• Gastric cancer
• Stage IV gastric cancer

• cetuximab
• chronotherapy
• colorectal cancer
• hepatectomy
• hepatic artery infusion
• liver metastases

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Camptothecin/analogs & derivatives
• Camptothecin/therapeutic use
• Cetuximab/therapeutic use
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• Disease-Free Survival
• Female
• Fluorouracil/therapeutic use
• Hepatectomy
• Hepatic Artery
• Humans
• Infusions, Intra-Arterial
• Irinotecan
• Liver/pathology
• Liver/surgery
• Liver Neoplasms/drug therapy
• Liver Neoplasms/mortality
• Liver Neoplasms/secondary
• Liver Neoplasms/surgery
• Male
• Middle Aged
• Organoplatinum Compounds/therapeutic use
• Oxaliplatin
• Proto-Oncogene Proteins p21(ras)/genetics
• Treatment Outcome

• Ablation
• Borderline
• Borderline-resectable
• Colorectal cancer
• Colorectal liver metastases
• Future liver remnant
• Hepatectomy
• Hepatic arterial infusion pump
• Liver resection
• Portal veinembolization
• Systemic chemotherapy
• Two-stage hepatectomy

• P30 CA008748 NCI NIH HHS

• Cetuximab
• Colorectal
• Indian study
• Liver metastases
• mCRR

• Colorectal cancer
• Multidisciplinary team management
• Surgery
• Synchronous colorectal liver metastases
• Systemic therapy

• Bile leak
• Hepatectomy
• Post hepatectomy liver failure
• Venous thromboembolism

• liver sinusoid
• oxaliplatin
• scoring

• Chemotherapy
• Colorectal cancer
• Refractory
• Salvage therapy
• Targeted therapy

• Aged
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/mortality
• Colorectal Neoplasms/pathology
• DNA Mutational Analysis
• DNA, Neoplasm/genetics
• Disease Progression
• Female
• Follow-Up Studies
• Humans
• Japan/epidemiology
• Liver Neoplasms/diagnosis
• Liver Neoplasms/genetics
• Liver Neoplasms/secondary
• Male
• Microsatellite Instability
• Mutation
• Polymerase Chain Reaction
• Prognosis
• Proto-Oncogene Proteins/genetics
• Proto-Oncogene Proteins/metabolism
• Proto-Oncogene Proteins B-raf/genetics
• Proto-Oncogene Proteins p21(ras)
• Retrospective Studies
• Survival Rate/trends
• ras Proteins/genetics
• ras Proteins/metabolism

• capecitabine plus oxaliplatin (XELOX) chemotherapy
• colon cancer
• liver metastasis
• liver resection
• panitumumab

• Cetuximab
• Colorectal cancer
• Hepatectomy
• Liver metastases