Establishment And Validation Of The Nomogram Model For Patient With Lum
To explore factors influencing the prognosis of LuM patients, we performed univariate and multivariate Cox proportional hazard regression analyses with CSS and OS as final outcomes, respectively. In the univariate analysis, age, primary site, N stage, lymph node positive rate, bone metastasis and brain metastasis were significantly different in CSS and OS. Gender was only associated with CSS, whereas race was correlated with OS. Multivariate analysis showed that male might be a beneficial factor in CSS compared to female, while race was not significantly different with OS. Primary tumors in the ascending colon, transverse colon, and splenic regions of the colon, patients with age> 65, higher rate of lymph node positive, and combined brain metastasis were common risk factors for both CSS and OS .3). Based on these results, we developed 2 nomogram models to predict 1-, 3-, and 5-years CSS 2) and OS ,3), respectively. The C-index for the CSS-predicted nomogram model was 0.719 and for the OS-predicted nomogram model was 0.700 . The calibration curves for CSS and OS at 1-, 3-, and 5-years presented the comparison between the prediction probability of the models and the actual observation results. The prediction curves were all close to the 45° line, indicating that the models had predictive performance .
Section : Tumour Characterisation And Biomarkers In Colorectal Cancer
The development of liver resection for CRLM has stimulated attempts to identify prognostic factors to aid in patient selection. Such factors have included primary CRC characteristics , CRLM characteristics , and other factors such as CEA, presence of additional extra-hepatic disease, and time interval between the emergence of CRC and CRLMs. The limitations of individual factors in prognostication prompted their combination to produce risk scores such as the Fong score, however even this was found wanting in terms of prognostication. It seems likely that the prognostic shortcomings of clinical criteria reflect the fact that they are merely surrogate markers for the underlying molecular biological markers that truly determine tumour biology.
Although a detailed account of current CRC biomarkers is beyond the scope of this review, the following summaries and Figure âFigure11 give an impression of some of the key CRC oncogenic pathways 1A) and the biomarkers KRAS, NRAS, BRAF, TP53, PIK3CA, APC, and Mismatch Repair Deficiency , chosen for their prominence, and also because they inform the rationale for current chemotherapy and biological targeting treatments .
Role Of Circulating Tumor Cells In Crlm
Patient-derived CTCs has been shown to bear all the functional attributes of CSCs. The markers expressed by CTCs are similar to the cancer niche, which are conducive to liver metastasis., CD133+CD44â+âCD54â+âcellular subpopulation of CTCs has a prognostic value in CRLM, especially in the survival of CRLM who did not receive surgical treatment for metastasis. Patient-derived CTCs lines are tumorigenic in subcutaneous xenografts and are also able to colonize the liver after intrasplenic injection. Drug test by in vitro culture of CTCs may facilitate access to personalized medicine. TAMs regulated JAK2/STAT3 signaling pathway by secreting IL6, thereby inhibiting miR-506-3p expression and promoting FoxQ1 expression. CTC cells then produced CCL2 to recruit more TAMs. TAMs and CTC both interacted to promote the occurrence of metastasis. These findings suggest targeting strategies against CTC clusters may be effective in the treatment of liver metastases.
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Treatment Options For Colorectal Cancer With Liver Metastasis
Hello, Im Mary Mulcahy from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Liver metastasis is the most common site of metastases for colorectal cancer. Standard treatment involves systemic chemotherapy with multidrug agents and often biologic agents in addition, either a VEGF or an EGFR inhibitor. In a small number of cases, immunotherapy may be beneficial. For liver-only disease, we try to incorporate liver resection when possible. However, of all patients with metastatic disease to the liver, about 80% arent amenable to any surgical intervention or local ablative therapy intervention. For those, were seeking out other treatments to enhance the effects of the chemotherapy on liver-only metastasis. Right now, the standard of care therapy is multiagent systemic chemotherapy with a biologic agent. When theres disease confined to a small area, to a lobe, or perhaps multilobar disease, some of it may be amenable to surgical resection or ablative therapy. However, the majority of these cases arent.
Transcript edited for clarity.
Youll Need A Strong Treatment Team
Should colon cancer spread to your liver, get the advice of a multidisciplinary team of surgeons and oncologists ASAP, Dr. Polite says. Colon cancer is one of the few cancers where even in patients with metastatic disease, we can sometimes cut out that disease and still achieve a long-term cure for patients, he says. So early consultation with a team that specializes in colon cancer and has surgeons dedicated to liver surgery is an important first step. They can determine if surgery could remove your tumors, which means fewer damaging effects of chemotherapy on the still-healthy parts of your liver, he explains.
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Radiation Based Therapies For Unresectable Crlm
In addition to chemotherapy in all its forms, unresectable CRLM may be treated by radiation either by selective internal radiotherapy or stereotactic body radiotherapy .
Selective internal radiation therapy: The blood supply of metastatic liver tumours is predominantly arterial, in contrast to that of hepatocytes which is mostly portal venous. This, together with significant arterial neovascularisation in the tumour bed, provides the physiological underpinning of SIRT, which achieves tumour destruction by delivery of radioactive microspheres via its arterial supply. Ytrium-90, which undergoes beta decay, is the most commonly used radionuclide used to label microspheres, on account of favourable penetration characteristics: Mean and maximal penetration are 2.5 and 10 mm respectively, thus delivering maximal irradiation to the tumour whilst sparing surrounding parenchyma. Currently glass and resin-based versions of the sphere are commercially available. A newer sphere which employs Holmium-166 rather than Ytrium-90 is also available and being evaluated.
In the context of colorectal liver metastases, interest in SIRT originated from studies done in patients with unresectable liver or liver dominant metastases who had proved refractory to conventional chemotherapy. These studies suggested response to SIRT in the face of prior chemo refractory status, and in some reports, significantly improved OS in patients who responded to SIRT.
The Role Of Circrnas In Liver Metastasis Of Colorectal Cancer
The role and mechanism of circRNA in tumor is one of the recent research hotspots. In 2013, Jeck detected more than 25,000 circRNAs in human fibroblasts.68 They realized that circRNA is widespread in the human body and may play an important role in the spectrum of human diseases. CircRNA is a special type of endogenous non-coding RNA whose 3end and 5end are connected to form a closed covalent ring structure. This structure makes circRNA more stable and highly conserved. Since circRNA has one or more miRNA binding sites, it can reduce the activity of miRNA by binding to miRNA, weaken the inhibitory effect of miRNA on target genes, thereby regulating the expression of related target genes, and ultimately leading to increased production of messenger RNA. The biological effect is strengthened, this is the competitive-binding mechanism, and this effect is called miRNA sponge. At the same time, circRNA can combine with specific proteins to form RNA-protein complexes, thereby affecting protein translation and regulating protein functions.
The Main Mechanism of circRNAs Regulation in CRLM
Diagnosis Can Involve A Range Of Tests
When youre diagnosed with colon cancer, you get a CT scan to stage the cancer to see if its localized to colon, which were hoping for, or if it has spread, explains Dr. Abrams. Then a biopsy usually needs to be done to confirm that. In the case of a colon cancer recurrence in the liver, the cancer is usually found during routine follow-up testing, he says. That follow-up involves a blood test for the tumor marker carcinoembryonic antigen . If your CEA rises, that may trigger a CT scan that could discover a cancer recurrence in the liver, he says.
The Role Of Mirnas In Liver Metastasis Of Colorectal Cancer
MiRNA is a class of highly conserved, 1825 nucleotides long endogenous single-stranded non-coding small molecule RNA.69 MiRNA exists widely in eukaryotes, and it does not have an open reading frame and does not encode proteins, but miRNA has the characteristics of clustering and can be co-expressed with related genes.70 In tumors, miRNA usually plays the role of tumor genes or tumor suppressor genes in the occurrence and development of tumors.71 Onco-miRNA such as miR-21 and miR-10b have oncogene-like functions and are positively correlated with tumorigenesis. Their overexpression or continuous activation will directly lead to tumorigenesis and development.72,73 Suppressor-miRNA such as miR-15/16 and Let-7 have the function similar to tumor suppressor gene. It has a negative correlation with tumorigenesis, and its down-regulation or inactivation will directly lead to tumorigenesis and development.74,75
The Main Mechanism of miRNAs Regulation in CRLM
Thus, many miRNAs have been found in CRLM, and the related mechanisms of their regulation of CRLM are gradually becoming clear. It is believed that miRNA will play an important role in the diagnosis and treatment of CRLM.
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Treating Colon Cancer That Has Spread To The Liver: A Team Approach
Adrian Gerard Murphy, M.B. B.C.H. B.A.O., M.B.B.Ch., Ph.D.
If you or a loved one has a colon cancer diagnosis, there is also the chance that the cancer will spread to other organs, most commonly the liver. However, according to Dr. Richard Burkhart, a Johns Hopkins cancer surgeon and researcher, advancements in the treatment of liver tumors caused by colon cancer have improved survival rates drastically. In fact, 40-60 percent of patients treated for isolated colon cancer liver metastasis are still alive five years after treatment.
At Johns Hopkins, researchers such as Dr. Burkhart are conducting clinical trials to find ways to slow or prevent the spread of colon cancer. These trials, coupled with a multidisciplinary, or team, approach using molecular testing, surgical techniques, chemotherapy and radiation, have greatly improved life expectancy for patients in the last 10 years.
When Surgery Isnt Possible
If surgery isnt recommended, there are other potential treatments that may be used either alone or in combination. These include:
- Ablation: Ablation involves using an ultrasound to place a needlelike probe into the tumor. Then, radio waves can be used to heat the probe, killing the surrounding cancer cells.
- Radiation therapy:Stereotactic radiosurgery can be used to deliver a large amount of radiation to a small, specific area of the liver. Whole liver radiation is less common and is mostly used as a part of palliative care.
- Chemotherapy:Chemotherapy uses drugs that target the growth and division of cancer cells. It may be given orally or by an IV and can help to kill the cancer cells or slow down their growth.
- Targeted therapy: Targeted therapy hones in on specific markers on cancer cells. Targeted therapy, either alone or with chemotherapy, may be used to treat CRC liver metastases. Some examples of targeted therapy drugs that may be used are:
Overall, the outlook can depend on many factors, including the specific characteristics of the cancer, how much of the liver is affected, and whether it has spread to other places. Your age and overall health also play a role.
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The Role Of Lncrnas In Liver Metastasis Of Colorectal Cancer
In 2002, Japanese researchers first put forward the concept of lncRNA, which refers to non-coding RNA with a length of more than 200 nt.84 Until 2007, a highly expressed functional lncRNA gene of 2.2 kb was found for the first time in breast cancer, proving the role of lncRNA in tumorigenesis and development.85
LncRNA has a 5- cap structure and a 3- terminal polyadenylate tail, and its gene structure is similar to that of mRNA.86 LncRNA can act as the sponge of microRNA and adsorb some specific microRNA, in the way of bait so as to regulate the expression of some microRNA target genes. The lncRNA with this function is also known as ceRNA .87 At the same time, because the expression of most long non-coding genes is transcribed by RNA polymerase II , the specific expression of these genes in tissues and developmental stages indicates that the transcription of these genes is strictly regulated, so people can infer the state of chromatin according to the expression of lncRNA. In addition, lncRNA can also regulate tumor suppression or oncogene expression. Many studies have shown that lncRNA has a variety of other effect mechanisms, it can be used as signal molecules, bait molecules and guiding, functional scaffolds, but also can interact with other biomolecules to form a certain module structure to exert its biological function.88,89 It can be seen that LncRNA is closely related to the occurrence and development of tumors.90
The Main Mechanism of lncRNAs Regulation in CRLM
Taking Care Of Yourself
You go through a lot when you have cancer. Rest, exercise, and managing stress can help. It’s also important to eat well during your treatment. It may be harder now for your body to absorb nutrients from food. Work with a dietitian to make sure you get enough calories and nutrition. Ask your doctor for a referral.
Make sure you get the emotional support you need during this time, too. Friends, family members, social workers, and therapists can all be a big help. They may not be sure what to offer, so let them know what would be helpful. Ask them to listen when youâve had a tough day or to do something fun with you when you have the energy for it.
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Surgery For Colon And Liver Tumors
MSK surgeons can often remove tumors in both the colon and the liver during the same procedure. This can reduce pain and shorten recovery time. If the cancer is advanced, chemotherapy and radiation therapy are sometimes used to shrink tumors before surgery. MSK surgeons operate on several hundred people with liver metastasis each year.
In some cases, a colostomy will be necessary. For this procedure, a surgeon cuts the colon above the level of the cancer and attaches the end to a surgical opening in the belly. Waste is collected from this opening and stored in a bag attached to the skin.
Treatment Of Unresectable Metastases
Isolated hepatic perfusion is an optional regional treatment that offers a highdose of chemotherapy, biological agents, and hyperthermia by means of a recirculationcircuit of vascular perfusion as treatment of hepatic metastasis. A study was conducted ofIHP with tumor necrosis factor plus Melphalan, or IHP with Melphalan alone, Floxuridine ininfusion, and Leucovorin in patients with advanced hepatic metas-tases from colorectalcancer that were unresectable or recurrent. It was concluded that IHP can be performedwith low morbidity and that it possesses great antitumor activity with clinical relevancein patients with hepatic metastasis from colorectal cancer that are unresectable orrecurrent.56 About 10 to 25% ofpatients with isolated metastases in the liver are candidates for resection due toanatomical limitations , inadequatefunctional-liver reserve, or comorbidities. The hepatic metastases of colorectal cancerare defined as resectable when it is anticipated that these can be completely resected,when there is adequate vascular flow , preserved bile drainage, andadequate hepatic volume. For cases that are unresectable, local therapy is the bestchoice due to that it increases the survival rate.57
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Ablation Techniques For Crlm
The observation of long term survival after resection of colorectal liver metastases, and evidence suggesting that locoregional resection is oncologically equivalent to major anatomical resection has prompted interest in minimally invasive ablative techniques which might achieve similar results to non-anatomical resection with less morbidity. Radiofrequency ablation and microwave ablation have been investigated in the context of a variety of liver tumours including colorectal liver metastases.
Radiofrequency ablation: RFA delivers alternating electrical current to cause ionic agitation, with the resulting heat generation causing denaturation and coagulation of the targeted tissue.
The benefit of radiofrequency ablation over systemic chemotherapy alone was suggested by the European Organisation for Research and Treatment of Cancer 40004 CLOCC trial comparing systemic chemotherapy alone to chemotherapy combined with RFA +/- resection for patients with inoperable CRLM, which showed a significantly improved progression-free survival for patients treated with RFA in the initial analysis and at 9.7 years of median follow up.
Meta-analyses have nevertheless assessed the efficacy of RFA in comparison to liver resection.
In terms of the efficacy of MWA in comparison to chemotherapy alone, no randomised studies have been carried out.
Key Molecules And Signaling Pathway Driving Liver Metastasis
Various signaling pathways and factors may be involved in the process of CRLM, including hepatocyte growth factor/câMet signaling pathway, phosphatase of regenerating liver , Notch pathway, TGFÎ² signaling, Tyrosine kinase c-MET signaling, tumor-associated calcium signal transducer 2 , L1 cell adhesion molecule , metastasis-related gene 1 , S100 family proteins and other pathways. There are multiple intersections between these molecular mechanisms driving CRLM.
HGF/c-Met signaling pathway
The association between C-Met and CRC was even stronger due to c-MET being identified as a transcriptional target of colon cancer MACC1. MACC1 promotes proliferation, invasion, and HGF-induced scattering of CRC cells in cell culture and tumor growth and metastasis in mouse models. In advanced metastatic CRC patients, MACC1 and c-Met were both upregulated. MACC1, a new detectable biomarker in cancer, is also an independent prognostic factor for the recurrence after liver resection of CRC metastasis.
HGF/c-Met signaling promoted metastasis of cancer cells by regulating a diverse downstream prometastatic effector molecules, via Ras-MAPK/ERK, PI3K/AKT signaling, JAK2/STAT3 signaling. MACC1, KPNB1 and FOXC2 could transactivate the expression of c-MET.
CRLM and PRL3
PRL3 promoted metastasis of cancer cells by regulating a diverse downstream prometastatic effector molecule, via NF-ÎºB pathway, AKT, STAT3, EGFR, IL-8 and CCL26.
CRLM and Notch pathway
Fig. 6Fig. 7
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