Treatment Of Colorectal Cancer Metastases Research Articles

Atovaquone inhibits colorectal cancer metastasis by regulating PDGFRβ/NF-κB signaling pathway

BackgroundColorectal cancer is a common malignant tumour. Invasive growth and distant metastasis are the main characteristics of its malignant biological behaviour, and they are also the primary factors leading to death in colon cancer patients. Atovaquone is an antimalarial drug, and its anticancer effect has recently been demonstrated in several cancer models in vitro and in vivo, but it has not been examined in the treatment of colorectal cancer.MethodsTo elucidate the effect of atovaquone on colorectal cancer. We used RNA transcriptome sequencing, RT‒PCR and Western blot experiments to examine the expression of NF-κB (p-P65), EMT-related proteins and related inflammatory factors (IL1B, IL6, CCL20, CCL2, CXCL8, CXCL6, IL6ST, FAS, IL10 and IL1A). The effect of atovaquone on colorectal cancer metastasis was validated using an animal model of lung metastases. We further used transcriptome sequencing, the GCBI bioinformatics database and the STRING database to predict relevant target proteins. Furthermore, pathological sections were collected from relevant cases for immunohistochemical verification.ResultsThis study showed that atovaquone could inhibit colorectal cancer metastasis and invasion in vivo and in vitro, inhibit the expression of E-cadherin protein, and promote the protein expression of N-cadherin, vimentin, ZEB1, Snail and Slug. Atovaquone could inhibit EMT by inhibiting NF-κB (p-P65) and related inflammatory factors. Further bioinformatics analysis and verification showed that PDGFRβ was one of the targets of atovaquone.ConclusionIn summary, atovaquone can inhibit the expression of NF-κB (p-P65) and related inflammatory factors by inhibiting the protein expression of p-PDGFRβ, thereby inhibiting colorectal cancer metastasis. Atovaquone may be a promising drug for the treatment of colorectal cancer metastasis.

Activin and Hepatocyte Growth Factor Promotes Colorectal Cancer Stemness and Metastasis through FOXM1/SOX2/CXCR4 Signaling.

Cancer stem cells (CSCs) are believed to drive tumor development and metastasis. Activin and hepatocyte growth factor (HGF) are important cytokines with the ability to induce cancer stemness. However, the effect of activin and HGF combination treatment on CSCs is still unclear. In this study, we sequentially treated colorectal cancer cells with activin and HGF and examined CSC marker expression, self-renewal, tumorigenesis, and metastasis. The roles of forkhead box M1 (FOXM1) and sex-determining region Y-box 2 (SOX2), two stemness-related transcription factors, in activin/HGF-induced aggressive phenotype were explored. Activin and HGF treatment increased the expression of CSC markers and enhanced sphere formation in colorectal cancer cells. The tumorigenic and metastatic capacities of colorectal cancer cells were enhanced upon activin and HGF treatment. Activin and HGF treatment preferentially promoted stemness and metastasis of CD133+ subpopulations sorted from colorectal cancer cells. FOXM1 was upregulated by activin and HGF treatment, and the knockdown of FOXM1 blocked activin/HGF-induced stemness, tumorigenesis, and metastasis of colorectal cancer cells. Similarly, SOX2 was silencing impaired sphere formation of activin/HGF-treated colorectal cancers. Overexpression of SOX2 rescued the stem cell-like phenotype in FOXM1-depleted colorectal cancer cells with activin and HGF treatment. Additionally, the inhibition of FOXM1 via thiostrepton suppressed activin/HGF-induced stemness, tumorigenesis and metastasis. Sequential treatment with activin and HGF promotes colorectal cancer stemness and metastasis through activation of the FOXM1/SOX2 signaling. FOXM1 could be a potential target for the treatment of colorectal cancer metastasis.

Differences in tissue-associated bacteria between metastatic and non-metastatic colorectal cancer.

Accumulated evidence indicates that the intestinal microbiota plays crucial roles in the initiation and progression of colorectal cancer (CRC). However, the effects of the tissue-associated microbiota on CRC metastasis are poorly defined. The aim of this study was to explore the differences in bacteria between metastatic and non-metastatic CRC tissues and identify potential bacterial species that associate with CRC metastasis. 16S rDNA amplicon high-throughput sequencing was used to test the intestinal tissue-associated microbiota in patients with metastatic CRC (n = 48) and non-metastatic CRC (n = 44). The microbial diversity and differential species were analysed by standard microbiological methods, and then the differential bacteria were confirmed by qPCR. Receiver operating characteristic (ROC) curves were plotted to evaluate the ability of the differential bacteria in predicting the metastasis of CRC. In addition, the microbial compositions of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were analysed. The α- or β-diversity of microbial community between the metastatic and non-metastatic CRC groups did not exhibit significant differences. However, some bacterial abundances between two groups showed significant differences. At the phylum level, Bacteroidota and Desulfobacterota were significantly higher in the metastatic group than in the non-metastatic group, while Proteobacteria was significantly decreased in the metastatic group. At the genus level, Bacteroides (mainly composed of Bacteroides fragilis and Bacteroides uniformis) was significantly higher in the metastatic group than in the non-metastatic group, while Streptococcus and Escherichia-Shigella were significantly decreased. The ROC curves of the selected bacteria showed area under the curve (AUC) values ranging from 0.598 to 0.69; when CEA and the selected bacteria were combined, the AUC values increased from 0.678 to 0.705. In addition, the bacterial composition of tumor-adjacent tissues from the metastatic and non-metastatic CRC groups were also different, and the differential bacteria were consistent with those between metastatic and non-metastatic CRC tumor tissues. The bacterial composition of tumor and tumor adjacent tissue from the metastatic CRC group was different from that of the non-metastatic CRC group; in particular, Bacteroides was increased, and Streptococcus was decreased. These findings are helpful to further reveal the mechanism of CRC metastasis and provide new ideas for the clinical diagnosis and treatment of CRC metastasis.

Markers of inflammation in invasive treatment of coloractal cancer liver metastases

Background. In 25–30% of patients with colorectal cancer (CRC) who have no visible signs of metastasis at the time of surgery, metastases are detected within 5 years. Among the options for local treatment of metastatic liver lesions in patients with CRC, various resection options and minimally invasive methods, in particular radiofrequency ablation (RFA), occupy a prominent place. The inflammatory response caused by surgery is a factor that can negatively affect the course of tumor disease. The inflammatory responses of the body, as well as markers for their evaluation and prognosis in the treatment of CRC metastases, have not yet been sufficiently studied. Purpose – to study the dynamics of inflammatory markers in the invasive treatment of colorectal cancer liver metastases to select the most informative markers for assessing and predicting the degree of inflammatory response. Materials and methods. Clinical and laboratory examination was carried out in 18 patients with CRC during the treatment of metastases in the liver, adenocarcinoma was determined in all patients during histological examination. The examination was carried out in three stages: the day before RFA or resection, on days 3 and 14 after the intervention. Serum levels of insulin and IL-6 were measured using an enzyme-linked immunosorbent assay, and levels of C-reactive protein and ferritin were determined using an automatic biochemical analyser. Results and discussion. Markers of inflammation in patients with CRC with liver metastases after invasive intervention were identified. A significant increase in the levels of circulating C-reactive protein (CRP), IL-6 and ferritin was detected along with an increase in the insulin resistance index (HOMA-IR) on day 3 after RFA and resection. The increase in IL-6 was 2-fold higher and the HOMA-IR index was 1.5-fold higher after resection compared with RFA. Patients after RFA showed an approach of indicators to baseline values on day 14 of the study, while CRP, ferritin, IL-6 and insulin levels in patients after resection decreased by only 20–30% at the same time same period. This is consistent with other studies. In particular, elevated CRP levels are considered as a risk factor for the appearance and progression of CRC.There is also evidence that in patients with operable CRC, preoperative IL-6 levels affect the risk of recurrence. Strong evidence suggests that ferritin is a key mediator of immune dysregulation through direct immunosuppressive and pro-inflammatory effects. The accumulated data from the literature and our own results suggest the role of CRP, IL-6 and ferritin in postoperative inflammatory states as mediators and biomarkers of the further course of CRС, since their appearance identifies patients with a high risk of mortality, and timely or preventive correction of the inflammatory response improves their survival. Conclusions. The results of the study show that the most informative markers of the level of inflammatory response after RFA or surgical resection are the levels of C-reactive protein, IL-6 and ferritin. Moderate inflammatory reaction is shown in the early stages after RFA and pronounced and longer-lasting reaction after surgical treatment. Prediction, assessment of the degree of inflammatory reaction and the feasibility of anti-inflammatory therapy in the early stages after intervention can be determined by the complex of immunological, haematological and biochemical markers studied by us.

Current and potential treatment of colorectal cancer metastasis to bone

BackgroundColorectal cancer (CRC) with subsequent bone metastasis is associated with a poor prognosis compared with patients who do not develop bone metastasis. However, metastasis in bone is rare, contrasted with more common locations such as the liver and lungs. As a result, the treatment methods targeting CRC bone lesions are limited. This review aims to compile information regarding current and potential medical and surgical treatment methods for colorectal cancer with specific regard to bone metastasis. MethodsA computer-based literature review of animal- and human-based studies was conducted using multiple database searches. Case reports were excluded. ResultsPreliminary findings demonstrate that treatments specifically targeting bone metastasis due to colorectal cancer are categorized by local vs. systemic treatment. The primary goals are the alleviation of skeletal-related events and improvement in quality of life. Current options include: chemotherapy, radiation, monoclonal antibodies, and surgery. Emerging options include intratumoral mellitin, MRgFUS, and bone microenvironment targeting. ConclusionTreatment of CRC metastasis to bone is necessary to slow down metastatic progression, alleviate symptoms, and improve quality of life. With a possible rise in bone metastasis due to increased overall CRC survival rates, more clinical trials should be performed to address this growing concern.

Time for a lead-time definition? Author response to 'Why the length of recurrence free survival or "lead-times" can be misleading. Comment on: Callesen LB, Takacova T, Hamfjord J, et al. Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis'.

Time for a lead-time definition? Author response to 'Why the length of recurrence free survival or "lead-times" can be misleading. Comment on: Callesen LB, Takacova T, Hamfjord J, et al. Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis'.

Why the length of recurrence-free survival or 'lead-times' can be misleading. Comment on: Callesen LB, Takacova T, Hamfjord J, et al. Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis.

Why the length of recurrence-free survival or 'lead-times' can be misleading. Comment on: Callesen LB, Takacova T, Hamfjord J, et al. Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis.

The Biological Effect of Small Extracellular Vesicles on Colorectal Cancer Metastasis

Colorectal cancer (CRC) is a malignancy that seriously threatens human health, and metastasis from CRC is a major cause of death and poor prognosis for patients. Studying the potential mechanisms of small extracellular vesicles (sEVs) in tumor development may provide new options for early and effective diagnosis and treatment of CRC metastasis. In this review, we systematically describe how sEVs mediate epithelial mesenchymal transition (EMT), reconfigure the tumor microenvironment (TME), modulate the immune system, and alter vascular permeability and angiogenesis to promote CRC metastasis. We also discuss the current difficulties in studying sEVs and propose new ideas.

The Incredible Potential of Exosomes as Biomarkers in the Diagnosis of Colorectal Cancer.

Colorectal cancer (CRC) is common cancer that is one of the leading causes of cancerrelated deaths around the world. The creation of new biomarkers for this disease is an important public health strategy for lowering the disease's mortality rate. According to new research, exosomes may be important sources of biomarkers in CRC. Exosomes are nanometer-sized membrane vesicles (30-200 nm) secreted by normal and cancer cells that transport RNA and proteins between cells and are thought to help with intercellular communication. Exosomes have been linked to CRC initiation and progression, and some differentially expressed RNAs and proteins in exosomes have been identified as potential cancer detection candidates. As a result, studying the relationship between exosomes and CRC may aid in the development of new biomarkers for the disease. This article discusses the importance of exosomes as biomarkers in the diagnosis of CRC, as well as their use in the treatment of CRC metastasis, chemoresistance, and recrudescence. The benefits and drawbacks of using exosomes as tumour markers are also discussed.

Jianpi Jiedu Recipe inhibits colorectal cancer liver metastasis via regulating ITGBL1-rich extracellular vesicles mediated activation of cancer-associated fibroblasts

BackgroundExtracellular vesicles (EVs) contribute greatly to the formation of pre-metastatic niche and tumor metastasis. Our previous study has revealed that tumor-derived ITGBL1 (integrin beta- like 1)-rich EVs activate fibroblasts through the NF-κB signaling to promote colorectal cancer (CRC) metastasis. Targeting ITGBL1-loaded EVs may be a new and effective therapy for treating CRC metastasis. Simultaneously, our preliminary clinical trial has demonstrated that Jianpi Jiedu Recipe (JPJDR) was an ideal alternative traditional Chinese medicine for the prevention and treatment of CRC metastasis. However, the underlying mechanism of JPJDR in the prevention of CRC metastasis is not clear. In this study, we will investigate the regulatory effect of JPJDR on ITGBL1 levels in CRC-derived EVs, and to detect how JPJDR regulate ITGBL1-rich EVs mediated activation of fibroblasts to inhibit CRC metastasis. MethodsEVs derived from CRC cells with/without JPJDR treatment were obtained by ultracentrifugation, following by characterization with electron microscopy, LM10 nanoparticle characterization system and western blot. The migration and growth of CRC cells were tested by transwell assay, wound healing assay and colony formation assay. The effect of JPJDR on the fibroblasts-activation associated inflammatory factors including IL-6, IL-8 and α-SMA was detected by real-time PCR. The levels of IL-6, IL-8 and α-SMA in the cell culture supernatant were detected by ELISA. The protein expressions of TNFAIP3, ITGBL1, p-NF-κB, IκBα and β-actin were detected by western blot. Liver metastasis model in mice was established by injecting MC38 single cell suspension into the spleen of mice to observe the effect of JPJDR on CRC liver metastasis. Immunohistochemistry were applied to detect the expression of ITGBL1 and TNFAIP3 in the liver metastatic tissues. Tissue immunofluorescence detection was performed to observe the regulatory effect of JPJDR on the ITGBL1-NF-κB signaling pathway. Cancer-associated fibroblasts (CAFs) in the liver metastatic tissues were sorted and characterized by platelet-derived growth factor receptor β (PDGFRβ) with flow cytometry, following by the detection of inflammatory factors including IL-6, IL-8 and α-SMA using real-time PCR. ResultsJPJDR reduced the ITGBL1 levels in CRC cells-derived EVs. JPJDR inhibited the migration and growth of CRC cells via regulating ITGBL1-rich EVs mediated fibroblasts activity. Mechanically, JPJDR decreased fibroblasts activation by regulating ITGBL1-rich EVs mediated TNFAIP3-NF-κB signaling. Further in vivo experiments demonstrated that JPJDR reduced CRC liver metastasis by regulating ITGBL1-rich EVs secretion from CRC and blocked the fibroblasts activation by regulating ITGBL1-TNFAIP3- NF-κB signaling. ConclusionOur research demonstrated that JPJDR preventd CRC liver metastasis via down-regulating CRC-derived ITGBL1-loaded EVs mediated activation of CAFs, providing the experimental evidence for the clinical application of JPJDR in the prevention and treatment of CRC metastasis. More importantly, our study confirmed the great benefits of therapeutic targeting the EVs-mediated metastasis and warranted future clinical validation.

Small Particle DEBIRI TACE as Salvage Therapy in Patients with Liver Dominant Colorectal Cancer Metastasis: Retrospective Analysis of Safety and Outcomes.

The aim of this study was to examine the safety and efficacy of 40 µm and 75 µm calibrated irinotecan-eluting beads (DEBIRI-TACE) for the treatment of colorectal cancer metastases. We conducted a retrospective review of 36 patients with unresectable liver metastases from colorectal cancer who were treated with DEBIRI-TACE between 2017 to 2020. Patients who received at least one session of DEBIRI were included in our analysis. A total of 105 DEBIRI sessions were completed. 86% of patients (n = 31) underwent one round of treatment, 14% of patients (n = 5) underwent two distinct rounds of treatment. The majority of patients were discharged the next day (92%, n = 33 patients) with no 30-day post-DEBIRI mortality. Five high-grade adverse events occurred, including longer stay for pain management (n = 2), postembolization syndrome requiring readmission (n = 2), and liver abscess (n = 1). The average survival from diagnosis of metastatic disease was 33.3 months (range 11–95, median 28). Nine of 36 patients are still alive (December 2020) and have an average follow-up time of 36.8 months from T0 (range 12–63, median 39). Small particle DEBIRI is safe and well-tolerated in the salvage setting, with outcomes comparable to that of larger bead sizes.

Circulating DNA in patients undergoing loco-regional treatment of colorectal cancer metastases: a systematic review and meta-analysis.

Loco-regional treatment strategies of colorectal cancer (CRC) metastases are evolving, but biological markers that can benefit patients and assist physicians in clinical decisions are lacking. The primary objective of this systematic review and meta-analysis is to investigate the current knowledge on circulating DNA and its clinical utility in predicting outcomes in patients undergoing loco-regional treatment of CRC metastases. A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials was conducted on March 22, 2022. We included studies on patients undergoing loco-regional treatment of CRC metastases reporting the predictive or prognostic value of circulating DNA in the blood. Hazard ratios (HR) were pooled in separate random-effects meta-analyses to investigate if pre- or post-ablation measurements of circulating DNA were associated with survival. The risk of bias was assessed according to the Quality in Prognosis Studies tool. Twenty-eight studies with 2868 patients were included, of which 16 studies were eligible for meta-analyses. As expected in this new research field, a majority of included studies (n = 21/28) had a high risk of bias in at least one domain. Circulating DNA above the cutoff in a plasma sample taken before loco-regional treatment was associated with a short recurrence-free survival [pooled HR = 2.8, 95% confidence interval (CI) 1.4-5.7, n = 162] and overall survival (pooled HR = 4.7, 95% CI 1.1-20.6, n = 105). Circulating DNA above the cutoff in a plasma sample taken after loco-regional treatment was associated with a short recurrence-free survival (pooled HR = 4.5, 95% CI 3.4-6.1, n = 569) and overall survival (pooled HR = 7.5, 95% CI 2.0-27.3, n = 161). There was limited data on the association between dynamics in circulating DNA and outcome. Measurements of circulating DNA can be valuable when selecting and monitoring patients undergoing loco-regional treatment of CRC metastases. Studies designed to investigate the true clinical utility of circulating DNA in the context of various ablation modalities are warranted.The review has been registered at PROSPERO (ID: CRD42022320032).

Colorectal cancer metastases to the lungs: outcomes of surgical treatment and prognostic factors

Objective: to evaluate short-term and long-term outcomes of surgical treatment for colorectal cancer metastases to the lungs and to analyze factors affecting the efficacy of surgery. Materials and methods. This study included 211 patients with colorectal cancer metastases to the lungs treated between 1994 and 2014. We enrolled patients with resectable or conventionally resectable metastases (according to chest computed tomography evaluated by a thoracic surgeon); the exclusion criteria were as follows: multiple primary tumors and age more than 85 years. We assessed the type of surgeries, frequency of R0 resections, incidence of postoperative complications, overall survival, and progression-free survival. Results. One hundred and sixty-two patients out of 211 (76.8 %) have undergone atypical lung resection. Forty-nine patients (23.2 %) have undergone pneumonectomy, bilobectomy, or lobectomy. The majority of patients (96.2 %) have had R0 resection, whereas 2.9 % of study participants have had R1 or R2 resections. One patient has undergone a trial surgery. Clinically significant postoperative complications were observed in 4 (2 %) patients; postoperative mortality was 0.5 % (1 case). The five-year overall survival rate was 52.7 %; the 5-year progression-free survival rate was 45.8 %. Development of metastases within 24 months after primary surgery was found to be a significant factor negatively affecting overall survival (hazard ratio 0.347; 95 % confidence interval 0.227–0.53; р <0.0001). Conclusions. Surgical treatment is currently the only truly effective treatment, which can improve long-term survival of patients with colorectal cancer metastases to the lungs; the best treatment results are achieved in patients with a relapse-free interval of more than 24 months.

Neutrophil extracellular traps blockade in combination with PD-1 inhibition in treatment of colorectal cancer metastasis.

e16002 Background: Immune checkpoint inhibitors (ICIs) are currently approved for microsatellite instability-high metastatic colorectal cancer (mCRC) however reported objective response rate to monotherapy range between 28-52%. Neutrophil Extracellular Traps (NETs), an extracellular network of DNA and proteins expelled by neutrophils into the tumor microenvironment, promote CRC metastasis by inducing potent immunosuppressive effects. We hypothesize that targeting this network may improve response rates to immune checkpoint therapy. The purpose of our study is to investigate the effect of combination DNase I treatment, a NET depleting agent, and PD-1 blockade in mCRC progression. Methods: Subcutaneous MC38 (MSI-H adenocarcinoma of the colon) tumors were established in 6-week-old mice. Treatment was initiated six days after tumor inoculation with daily intraperitoneal (i.p) injections of DNase I followed by i.p anti-PD-1 treatment administered every 3 days. Animals were divided into treatment groups: control, DNase alone, anti-PD-1 alone and combination of DNase I with anti-PD-1 (n = 6 mice/ group). Results: Tumors were successfully established after 6 days of inoculation. These tumors expressed high neutrophil infiltration and NETs. To determine the effects of combination therapy on tumor progression, we measured tumor volume and time to progression (TTP). We found that mice treated with combination DNase I and anti-PD-1 had significantly lower mean tumor volume compared to anti-PD-1 alone (1372.68mm3 vs 2193.20 mm3, p-value = 0.043). TTP was higher in the combination group compared to anti-PD-1 treatment alone (median time to progression 22 vs 17 days, p-value = 0.004). Next we sought to determine the mechanism behind this effect by investigating if NETs blockade modulated the tumor microenvironment. We found that treatment with DNase I decreased exhaustion of CD8+ T-cells in the tumor compared to no treatment. Conclusions: Targeting NETs in combination with immune checkpoint inhibition may be an option to improve response rate to immune checkpoint inhibitors through decreasing exhausted CD8+ T-cells.

Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression.

Aims: We aimed to measure the abundance of Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) tissues from patients and to uncover the function of this bacterium in colorectal tumor metastasis.Methods: We collected metastatic and non-metastatic CRC tissues to analyze F. nucleatum abundance. Cells were incubated with F. nucleatum or chloroquine (CQ) or were transfected with CARD3-targeting siRNA; the expression of mRNAs and proteins was then measured. CRC cells stably transfected with shRNA-luc were mixed with F. nucleatum and intravenously injected into BALB/cJ mice. APCMin/+, CARD3-/-and CARD3wt C57BL mice were given F. nucleatum; some mice were given azoxymethane (AOM) and dextran sodium sulfate (DSS).Results: F. nucleatum was abundant in CRC tissues from patients with metastasis. F. nucleatum infection increased CRC cell motility and upregulated the expression of CARD3, LC3-II, Beclin1 and Vimentin, and downregulated the expression of E-cadherin and P62 in CRC cells. These effects were attenuated by treatment with CQ, siCARD3 or both. APCMin/+ mice gavaged with F. nucleatum developed more aggressive tumors than control mice. After AOM/DSS administration, the colorectums of CARD3-/- mice had fewer tumors than those of control mice. Tumors from CARD3-/- mice had lower levels of LC3-II and Beclin1 and higher levels of P62 than those from control mice. BALB/cJ mice injected with both CT26-luc cells and F. nucleatum formed more metastases than control mice. CQ treatment, CARD3 knockdown or both reduced the ability of CT26-luc cells to form metastases in vivo.Conclusions: F. nucleatum is enriched in CRC tissues from patients with metastasis. F. nucleatum orchestrates CARD3 and autophagy to control CRC metastasis. Measuring and targeting F. nucleatum and its associated pathways will yield approaches for the prevention and treatment of CRC metastasis.

ColotypeR gene signature predicts response to cetuximab in colorectal cancer metastases.

599 Background: The consensus molecular subtypes (CMS1-4) partition primary colorectal cancer (CRC) into subgroups with distinct molecular characteristics. We previously reported a 20-genes ColotypeR-CMS signature that accurately defines CMS subtypes for primary CRC tumor samples. The utility of CMS subtyping in defining response to treatment of CRC metastases remains to be established. Here, we report the ability of ColotypeR scores to predict differential response to cetuximab among CMS subtypes in CRC metastases. Methods: The role of ColotypeR-CMS signature scores was assessed in CRC metastasis samples (GSE5851, N = 68, Affymetrix microarray) in predicting response to cetuximab. Progression-free survival (PFS) was the primary endpoint. The predictive significance of ColotypeR-CMS scores relative to KRAS mutation status was also studied using multivariate Cox proportional hazards models. Results: ColotypeR-CMS scores were computed in GSE5851 using the algorithm developed in primary tumor samples. Higher values of ColotypeR-CMS CMS2 score were significantly predictive of longer PFS (p = 5 x 10-5for the score test in Cox proportional hazards model; hazard ratio 0.20 (95%CI 0.09-0.44) in CRC metastases samples (GSE5851, N = 68) treated with cetuximab. PFS was independent of CMS1,3, 4 scores. KRAS wild type tumors had significantly longer PFS (p = 0.01; hazard ratio 0.49 (95%CI 0.28-0.86). In multivariate survival analysis, ColotypeR-CMS CMS2 score added to the significance of KRAS status (p = 0.012) and ColotypeR-CMS CMS2 score was predictive of longer PFS in KRAS wild type tumors (p = 0.009; hazard ratio 0.20 (95%CI 0.06-0.69)). Conclusions: We showed that in CRC metastasis samples, the ColotypeR CMS2 score was highly predictive of sensitivity to cetuximab treatment, while no increase in PFS was observed for higher values of CMS1, 3, 4 scores.

Applicability of 3D printing in the planning of complex liver surgery (LIV3DPRINT)

Introduction: Three-dimensional (3D) printing has gained popularity in medicine in the last decade. Hepatic resections are challenging operations due to the complex nature of the liver anatomy, so 3D printing is a promising new tool for surgical planning. Mehtods: Complex hepatic tumors (bilobar disease, infiltration of suprahepatic veins or two-stage resection or intrahepatic vascular reconstruction). A CT and / or MRI was performed preoperatively to document the tumor distribution, estimate the remaining volume of the future liver and identify tumor-vessel relationships. In all patients, a 3D digital image reconstruction and a 3D printing model were performed. Results: A 3D digital image reconstruction and a 3D printing model were performed in a total of 10 patients. In 6 of them an ALPPS was performed (3 due to hepatic metastasis of colorectal ca, 1 hepatocellular carcinoma, 1 intrahepatic cholangiocarcinoma and 1 Klastkin tumor), in 1 patient an extended right hepatectomy with Roux-en-Y hepaticojejunostomy for Klatskin tumor, in 1 patient a right hepatectomy for intrahepatic cholangiocarcioma, in 1 patient an exploratory laparotomy for assessment of response to neoadjuvant treatment of colorectal cancer metastasis, and in 1 patient a renal venal graft in right suprahepatic metastasis of colorectal cancer. Conclusions: Surgeons reported greater confidence with the use of the 3D model for the identification of the intrahepatic and extrahepatic structure, segmentation and specific tumor extension. At the same time, they highlighted its applicability in the teaching of students and residents as well as its usefulness in the information of the patient.

Multiregion whole-exome sequencing of matched primary and metastatic tumors revealed genomic heterogeneity and suggested polyclonal seeding in colorectal cancer metastasis

Distant metastasis accounts for 90% of deaths from colorectal cancer (CRC). Genomic heterogeneity has been reported in various solid malignancies, but remains largely under-explored in metastatic CRC tumors, especially in primary to metastatic tumor evolution. We conducted high-depth whole-exome sequencing in multiple regions of matched primary and metastatic CRC tumors. Using a total of 28 tumor, normal, and lymph node tissues, we analyzed inter- and intra-individual heterogeneity, inferred the tumor subclonal architectures, and depicted the subclonal evolutionary routes from primary to metastatic tumors. CRC has significant inter-individual but relatively limited intra-individual heterogeneity. Genomic landscapes were more similar within primary, metastatic, or lymph node tumors than across these types. Metastatic tumors exhibited less intratumor heterogeneity than primary tumors, indicating that single-region sequencing may be adequate to identify important metastasis mutations to guide treatment. Remarkably, all metastatic tumors inherited multiple genetically distinct subclones from primary tumors, supporting a possible polyclonal seeding mechanism for metastasis. Analysis of one patient with the trio samples of primary, metastatic, and lymph node tumors supported a mechanism of synchronous parallel dissemination from the primary to metastatic tumors that was not mediated through lymph nodes. In CRC, metastatic tumors have different but less heterogeneous genomic landscapes than primary tumors. It is possible that CRC metastasis is, at least partly, mediated through a polyclonal seeding mechanism. These findings demonstrated the rationale and feasibility for identifying and targeting primary tumor-derived metastasis-potent subclones for the prediction, prevention, and treatment of CRC metastasis.

The role of preoperative chemotherapy for colorectal cancer metastases in the liver with the lack of RAS mutations

Colorectal cancer (CRC) is one of the most common malignancies, occupying the third place in the world among malignant tumors morbidity rate and the 4th place on the causes of death. Every year in the world there are diagnosed more than 1.3 millions of new cases of the disease. The mortality rate continues to be one of the most common causes in the structure of cancer incidence. In Russia, each year there are diagnosed more than 60 thousands of new cases of colorectal cancer. For the last time the incidence increased by 11%, out of them more than 17 thousands patients show newly diagnosed distant metastases. In the absolute majority of cases metastases in the liver are firstly detected in 2-3 years. Liver is the organ- the most commonly affected by metastases. Methods of medicinal treatment of CRC metastases are of great importance and allowed to greatly improve the life expectancy of patients. Median overall survival (OS) is 35-40 months. The one of the last achievement of the modern drug therapy of metastatic CRC was the appearance of the preparation Cetuximab. Blocking of the KRAS gene is a key compartment of the signaling pathways that transmit extracellular growth signals from the surface of the cell to the nucleus. Further signals are transmitted via the cascade into the cellular nucleus, regulating cell growth, proliferation, angiogenesis, invasion and metastasis. Results of the research of PRIME, PEAK and FIRE-3 confirm the advantage of supplement ofpanitumumab or cetuximab to chemotherapy regimens FOLFOX or FOLFIRI in patients with wild-type Ras.

Surgical Treatment of Colorectal Cancer Metastases

Surgical Treatment of Colorectal Cancer Metastases