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Abstract Aim This study aimed to evaluate the expression levels of miR-99b and miR-135b in peritoneal carcinoma and liver metastases associated with Colorectal Cancer (CRC), assess their association with the intracellular signaling pathway proteins Kirsten Rat Sarcoma Virus (KRAS) and Akt, and investigate their effects on survival. Materials and methods Changes in the KRAS gene and Akt proteins, expression levels of miR-99b and miR-135b, and factors affecting survival were compared between colorectal cancer-associated peritoneal carcinomatosis and liver metastasis. Results The expression levels of miR-99b and miR-135b and the immunohistochemical grade classification score of Akt were higher in colorectal cancer, peritoneal carcinomatosis, and liver metastasis than in normal tissues (p< 0.05). MiR-99b expression was highest in CRC, whereas miR-135b expression was highest in peritoneal carcinomatosis (p< 0.05). The expression level of miR-99b decreased and that of miR-135b increased in peritoneal and liver metastases compared with that in the tumor tissue. MiR-99b, Akt, and recurrence were risk factors that affected the overall survival rate in the model of clinical predictions (p= 0.045, p= 0.006, and p= 0.012, respectively). Conclusion While the expression of miR-99b was highest in the primary tumor, its decrease in liver metastasis and peritoneal carcinomatosis suggests that miR-99b has a protective effect against liver metastasis and peritoneal carcinomatosis. However, the detection of miR-135b expression was highest in peritoneal carcinomatosis and liver metastasis compared with that in the colorectal cancer tissues suggesting that it facilitates peritoneal carcinomatosis and liver metastasis. Furthermore, miR-99b, KRAS mutations, and Akt are risk factors for the overall survival of colorectal cancer.
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This report described one case of applying liver transplantation (LT) in for liver metastases of unresectable rectal cancer.The recipient had multiple intrahepatic metastases upon a diagnosis of colorectal cancer.FOLFOX chemotherapy plus bevacizumab targeted therapy were offered after a resection of primary lesion.Two years later, intrahepatic metastases expanded while no extrahepatic metastasis or in situ recurrence was noted.After LT, tacrolimus + sirolimus immunosuppression regimen and chemotherapy of rhatitrexed were prescribed.Tumor recurred at 3 years after LT and the survival time was 6 years.For patients with unresectable liver metastases of colorectal cancer, LT in the absence of orthotopic recurrence and other distant metastases may improve patient quality-of-life and achieve better outcomes.
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The histopathological growth pattern (HGP) of colorectal cancer liver metastasis (CRLM) is correlated with the prognosis of patients. Patients with desmoplastic HGP have a better prognosis. The latest international scoring guidelines have modified the cut-off value of HGP, and divides it into two types: complete desmoplastic HGP and incomplete desmoplastic HGP. However, the relationship between the HGPs and the treatment response to systemic treatment is still unclear. It is necessary to develop non-invasive methods to evaluate changes in HGP during treatment in the future. This paper reviews the new scoring consensus and clinical applications of HGP in CRLM.
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Objective:To explore the predictive value of ultrasound-based radiomics for liver metastasis in pancreatic neuroendocrine tumors (pNEN).Methods:A retrospective analysis was conducted on clinical, pathological, and ultrasound data of 269 pNEN patients confirmed by pathology at Tianjin Medical University Cancer Institute and Hospital from January 2012 to June 2022, including 94 patients with liver metastasis and 175 without liver metastasis. The regions of interest (ROI) were delineated on the maximum diameter section of the tumor using ITKSNAP software, and radiomics features were extracted using Pyradiomics. Radiomics features with an intra-group correlation coefficient greater than 0.90 were retained, and the optimal features were selected using the maximum relevance minimum redundancy (MRMR) algorithm. The dataset was randomly divided into a training set and a validation set in a ratio of 7∶3, and the random forest algorithm (Rfs) was used to predict pNEN liver metastasis. Three models were constructed, including the clinical ultrasound model, the radiomics model, and the comprehensive model that combined clinical ultrasound and radiomics features. The predictive performance of different models for pNEN liver metastasis was analyzed using the ROC curve, and the predictive performance of different models was compared using the Delong test.Results:A total of 874 features were extracted from the ROI, and 12 highly robust radiomics features were retained for model construction based on inter- and intra-observer correlation grading and feature selection. The area under curve(AUC), sensitivity, specificity, and accuracy of the radiomics model, the clinical ultrasound model, and the comprehensive model for predicting liver metastasis in pNEN patients were 0.800, 0.574, 0.789, 0.714; 0.780, 0.596, 0.874, 0.777; and 0.890, 0.694, 0.874, 0.810, respectively. The Delong test showed that the comprehensive model had the best predictive performance, with an AUC superior to that of radiomics model ( Z=3.845, P=0.000 12) and clinical ultrasound model ( Z=3.506, P=0.000 45). Conclusions:The radiomics model based on ultrasound has good performance in predicting liver metastasis in pNEN, and the comprehensive model that combines clinical ultrasound and radiomics features can further improve the predictive performance of the model.
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Objective:To investigate the clinicopathological characteristics and prognostic factors of pancreatic cancer patients with liver metastasis.Methods:The clinical data of 67 pancreatic cancer patients with liver metastases who received first treatment in Department of Oncology of the First Affiliated Hospital of Naval Medical University between July 2012 and June 2016 were retrospectively analyzed. The relationship between patient survival time and the clinicopathological characteristics including patients' age, gender, tumor location, physical activity status score, tumor markers, number of distant metastatic organs, radiotherapy at the primary site, first-line chemotherapy regimen, number of cycles of first-line chemotherapy received, and liver metastases undergoing transcatheter arterial chemoembolization (TACE) was analyzed. Kaplan-Meier curves were plotted to reveal survival time in pancreatic cancer patients with liver metastases, and univariate and multifactorial COX proportional risk regression models were used to analyze independent prognostic risk factors for pancreatic cancer patients with liver metastases.Results:All patients were followed up until December 31, 2018, and all 67 patients died. The results of univariate analysis showed that patients with positive tumor marker, number of distant metastatic organs ≥2, number of cycles of first-line chemotherapy ≤2, no radiotherapy to the primary site and no TACE had shorter survival than those with negative tumor marker, one distant metastatic organ, number of cycles of first-line chemotherapy ≥3, with radiotherapy to the primary site and TACE, and all the differences were statistically significant (all P values <0.05). The results of multifactorial analysis showed that positive tumor markers ( HR=0.567, 95% CI 0.332-0.954, P=0.031), number of distant metastatic organs ≥2 ( HR=0.581, 95% CI 0.353-0.977, P=0.039), number of first-line chemotherapy cycles ≤2( HR=1.890, 95% CI 1.155-3.121, P=0.013) and primary foci without radiotherapy ( HR=0.414, 95% CI 0.231-0.732, P=0.002) were the independent prognostic risk factors for pancreatic cancer patients with liver metastasis. Conclusions:The prognosis of pancreatic cancer patients with liver metastasis is affected by multiple factors, among which positive tumor markers, more distant metastatic organs, no radiotherapy at the primary site and fewer first-line chemotherapy cycles are independent prognostic risk factors for pancreatic cancer with liver metastasis.
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Small intestinal medullary carcinoma (MC) is a newly recognized subclass of small intestinal carcinomas and is an exceptional entity for this site. A search of the literature for similar cases arising in the small intestine revealed only six previously reported cases. Here we present a case of MC arising in the jejunum of a 65-year-old male. The patient presented to the emergency with features of perforation peritonitis with liver metastasis and no known predisposing factors like inflammatory bowel disease and celiac disease. Studies conducted on this tumor's colonic counterpart have shown microsatellite instability (MSI) and B-type Raf kinase (BRAF) mutations; however, few exceptions are known. Also, this subtype of carcinoma is known to have a better prognosis than its other histological subtypes.
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Objective:To investigate the clinical efficacy and prognosis of simultaneous resection of synchronous colorectal liver metastasis in patients admitted in different phases.Methods:The retrospective cohort study was conducted. The clinicopathological data of 346 patients who underwent simultaneous resection of synchronous colorectal liver metastasis in the First Affiliated Hospital of Naval Medical University (Changhai Hospital of Shanghai) from January 2000 to April 2021 were collected. There were 217 males and 129 females, aged (58±12)years. Patients under-went simultaneous resection of synchronous colorectal liver metastasis. Observation indicators: (1) clinicopathological features of patients with synchronous colorectal liver metastasis in 2000?2010 and 2011?2021; (2) surgical and postoperative situations of patients with synchronous colorectal liver metastasis in 2000?2010 and 2011?2021; (3) analysis of prognosis of patients with synchro-nous colorectal liver metastasis in 2000?2010 and 2011?2021. Follow-up was conducted using telephone interview or outpatient examination to detect survival of patients. The follow-up was performed once every 3 months, including blood routine test, liver and kidney function test, car-cinoembryonic antigen (CEA) test, CA19-9 test, abdominal B-ultrasound examination, and once every 6 months, including chest computed tomography (CT) plain scan, liver magnetic resonance imaging (MRI) and/or CT enhanced scan, abdominal or pelvic MRI and/or CT enhanced scan, within postoperative 2 year. The follow-up was performed once every 6?12 months within postoperative 2?5 years including above reexaminations. Electronic colonoscopy was performed once a year after operation. The follow-up was up to November 12, 2021. Measurement data with normal distribution were represented as Mean± SD, and comparison between groups was conducted using the t test. Measurement data with skewed distuibution were represented as M(range). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the rank sum test. Kaplan-Meier method was used to calculate survival rates and draw survival curves, and Log-Rank test was used to conduct survival analysis. Results:(1) Clinicopathological features of patients with synchronous colorectal liver metastasis in 2000?2010 and 2011?2021. Of the 346 patients, 59 cases underwent simultaneous resection within 2000?2010 and 287 cases underwent simultaneous resection within 2011?2021. The gender (males and females), cases with or without fundamental diseases, cases with the number of lymph nodes harvested in primary lesion as <12 or ≥12, the tumor diameter of primary lesion, the tumor diameter of liver metastasis lesion, the number of liver metastasis lesions, cases with or without preoperative treatment, cases with or without postoperative treatment, cases with adjuvant therapy as perioperative treatment, surgery or other treatment were 47, 12, 36, 23, 19, 40, (5.5±2.4)cm, (2.1±0.7)cm, 1.6±0.5, 59, 0, 16, 16, 0, 16, 43 in patients admitted in 2000?2010, respectively. The above indicators in patients admitted in 2011?2021 were 170, 117, 121, 166, 58, 229, (4.2±2.0)cm, (3.0±2.0)cm, 1.9±1.4, 208, 79, 34, 235, 74, 29, 184, respectively. There were significant differences in the above indicators between patients admitted in 2000?2010 and 2011?2021 ( χ2=8.73, 7.02, 4.07, t= 4.40, ?6.04, ?3.10, χ2=21.05, 28.82, 26.68, P<0.05). (2) Surgical and postoperative situations of patients with synchronous colorectal liver metastasis in 2000?2010 and 2011?2021. Cases with surgical methods as complete open surgery or laparoscopy combined with open surgery, the operation time, time to postoperative initial liquid food intake, cases with or without postoperative complications, cases with postoperative duration of hospital stay as ≤10 days or >10 days were 58, 1, (281±57)minutes, (5±1)days, 33, 26, 14, 45 in patients admitted in 2000?2010, respec-tively. The above indicators in patients admitted in 2011?2021 were 140, 147, (261±82)minutes, (3±1)days, 233, 54, 198, 89, respectively. There were significant differences in the above indicators between patients admitted in 2000?2010 and 2011?2021 ( χ2=49.04, t=2.24, 7.53, χ2=17.56, 26.02, P<0.05). There was no death in the 346 patients. (3) Analysis of prognosis of patients with synchro-nous colorectal liver metastasis in 2000?2010 and 2011?2021. Of the 346 patients, 295 cases were followed up for 47(range, 1?108)months. Of the 29 patients admitted in 2000?2010 who were followed up, there were 27 cases died. The median survival time, 1-, 3-, 5-year overall survival rates, 1-, 3-, 5-year disease free survival rates of patients admitted in 2000?2010 were 18.0 months (95% confidence interval as 12.7?23.3 months), 82.8%, 11.5%, 3.8%, 53.6%, 8.3%, 4.2%, respec-tively. Of the 266 patients admitted in 2011?2021 who were followed up, there were 109 cases died. The median survival time, 1-, 3-, 5-year overall survival rates, 1-, 3-, 5-year disease free survival rates of patients admitted in 2011?2021 were 54.0 months (95% confidence interval as 38.1?70.4 months), 93.3%, 61.8%, 47.0%, 68.2%, 33.7%, 28.3%, respectively. There were significant differences in overall survival rate and disease free survival rate between patients admitted in 2000?2010 and 2011?2021 ( χ2=47.57, 9.17, P<0.05). Conclusions:With the increase of the operation volume of simultaneous resection of synchronous colorectal liver metastasis, the operation time, time to postoperative initial liquid food intake, postoperative duration of hospital stay and postoperative complications have significantly decreased, while the overall survival rate and disease free survival rate have significantly increased.
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Colorectal cancer is one of the most common malignant tumors, liver metastasis is the main factor affecting the prognosis of patients with colorectal cancer. Exosomes as lipid bilayer microvesicles widely existing in a variety of biological fluids, can promote the occurrence and development of colorectal cancer liver metastasis by inducing M2 macrophage polarization, regulating the activity of cancer-associated fibroblasts and enhancing drug resistance of tumor cells, plays an important role in the diagnosis, treatment and prognosis of colorectal cancer liver metastasis. To explore the mechanism of exosomes in colorectal cancer liver metastasis and related treatment progress, in order to find new drug targets to improve the prognosis of patients.
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Objective To investigate the clinicopathological significance of PDC in liver metastases and analyze the correlation of PDC between liver metastases and primary lesions. Methods Retrospective analysis of 72 matched cases of colorectal cancer with liver metastases was performed. The PDC in primary tumor and liver metastatic lesion was interpreted synchronously, and then the relationship between PDC in liver metastasis and clinicopathological parameters was analyzed based on the correlation of PDC between primary and metastatic lesions. In addition, PDC were interpreted in accordance with Uenos' standard. Results Among the 72 cases of liver metastasis of colorectal cancer, the number of G1, G2, and G3 graded by PDC was 28, 24, and 20, respectively. The PDC in liver metastatic lesion was correlated with tumor budding in liver metastatic lesion and PDC grade of primary lesion. No significant correlation with the size and number of liver metastatic lesion, the site, WHO grade, depth of invasion, lymph node metastasis, vascular invasion or tumor budding of the primary lesion was observed. Conclusion A positive correlation is found between liver metastasis of colorectal adenocarcinoma and PDC grade of primary tumor. Evaluating the PDC grade of primary tumor may provide a reference for the risk of liver metastasis.
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Objective: To investigate the ultrasonographic features and clinical pathological of liver metastasis in patients with melanoma. Methods: Thirteen patients with liver metastasis from melanoma treated in Tianjin Medical University Cancer Institute and Hospital from 2013 to 2019 were selected, and their ultrasonographic and clinicopathological characteristics were analyzed retrospectively. Results: Eleven of the 13 patients had multiple liver lesions. The maximum diameter of the lesions was (5.89±2.73) cm. Five cases of lesions were mixed echo (3 cases with high melanin content), 4 cases of lesions were hyperechoic (3 cases with low melanin content), 3 cases of lesions were hypoechoic (all with high melanin content), 1 case of lesions were equal echo (with high melanin content). The lesions in 11 patients had clear boundaries, while other 2 patients lacked the clear borders. Cystic areas were present in the lesions of 3 patients. Six cases had irregular lesions (lobulated), and 7 cases had regular lesions (round, oval). There were acoustic halos around the lesion in 9 cases and smooth and uneven acoustic halos in 5 cases. The results of immunohistochemistry showed that 11 cases were positive for S-100, HMB45 and Melan-A. One patient was not tested for HMB45, while S-100 and Melan-A were positive. One patient did not undergo Melan-A test, while S-100 and HMB45 were positive. Conclusion: Most of the liver metastases of melanoma are mixed echo or hyperechoic, most of them are nodular with clear boundaries combined with vocal halo, and a few of the lesions have cystic areas.
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Humans , Liver Neoplasms/secondary , MART-1 Antigen , Melanins , Melanoma/pathology , Retrospective StudiesABSTRACT
Objective:To investigate the workflow, efficacy and safety of MR-Linac in liver malignancies.Methods:Clinical data of 15 patients with hepatocellular carcinomas (HCC) or liver metastases treated with MR-Linac between November 2019 and July 2021 were retrospectively analyzed. The workflow of MR-Linac was investigated and image identification rate was analyzed. Patients were followed up for response and toxicity assessment.Results:Fifteen patients (6 HCC, 8 liver metastases from colorectal cancer, 1 liver metastasis from breast cancer) were enrolled. A total of 21 lesions were treated, consisting of 10 patients with single lesion, 4 patients with double lesions and 1 patient with triple lesions. The median tumor size was 2.4 cm (0.8-9.8 cm). The identification rate for gross tumor volume (GTV) in MR-Linac was 13/15. Although GTV of two patients were unclearly displayed in MR-Linac images, the presence of adjacent blood vessel and bile duct assisted the precise registration. All the patients were treated with stereotactic body radiation therapy (SBRT). For HCC, the median fraction dose for GTV or planning gross tumor volume (PGTV) was 6 Gy (5-10 Gy) and the median number of fractions was 9(5-10). The median total dose was 52 Gy (50-54 Gy) and the median equivalent dose in 2 Gy fraction (EQD 2Gy) at α/ β= 10 was 72 Gy (62.5-83.3 Gy). For liver metastases, the median fraction dose for GTV or PGTV was 5 Gy (5-10 Gy) and the median number of fractions was 10(5-10). The median total dose was 50 Gy (40-50 Gy) and the median EQD 2Gy at α/ β=5 was 71.4 Gy (71.4-107.1 Gy). At 1 month after SBRT, the in-field objective response rate (ORR) was 8/13 and the disease control rate was 13/13. At 3-6 months after SBRT, the in-filed ORR was increased to 6/6. During the median follow-up of 4.0 months (0.3-11.6), 4-month local progression-free survival, progression-free survival and overall survival were 15/15, 11/15 and 15/15, respectively. Toxicities were mild and no grade 3 or higher toxicities were observed. Conclusions:MR-Linac provides a platform with high identification rates of liver lesions. Besides, the presence of adjacent blood vessel and bile duct also assists the precise registration. It is especially suitable for liver malignancies with promising local control and well tolerance.
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Surgery is recognized as the core treatment for colorectal liver metastasis (CRLM), while its recurrence rate remains relatively high, even for resectable CRLM. This hints that the efficacy of treatment involves not only technological factors of surgery, but also biological behavior of tumor. For resectable CRLM, neoadjuvant therapy is beneficial to eliminate the micro-metastasis, reduce postoperative recurrence rate, screen tumor biological behavior and improve prognosis. However, questions about which kind of CRLM patients fits for neoadjuvant therapy and what regimen should be used are still debatable. This paper reviews stratified management of resectable CRLM, choice of neoadjuvant regimen, especially the application value of targeted therapy, based on the latest guidelines and studies.
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Humans , Colorectal Neoplasms/surgery , Hepatectomy , Liver Neoplasms/surgery , Neoadjuvant Therapy , Neoplasm Recurrence, Local/surgeryABSTRACT
RATIONALE@#The liver is the most common site of metastasis from colorectal cancer. Curative intent liver metastasectomy has shown improvement in overall survival. This manuscript will present the long-term oncologic outcomes of hepatic metastasectomy for colorectal cancer with resectable liver metastasis.@*METHODS@#Data of patients with resectable liver metastases from colorectal cancer who underwent hepatic resection at the Philippine General Hospital over a 10-year period was reviewed. The primary outcome investigated was overall survival.@*RESULTS@#Thirty patients were included in the study. The median overall survival was 20 months, with a 2-year and 5-year overall survival rate of 40% and 6.67% respectively. Eleven (36.67%) patients had disease recurrence, with a median disease-free survival of 16 months. A significant difference in survival was seen between patients with synchronous and metachronous liver metastasis (20.38 and 36.78 months respectively, p=0.0393) and in patients given adjuvant chemotherapy at any time in relation to the occurrence of the liver metastases versus patients who did not receive any adjuvant treatment (34.08 and 18.59 months respectively, p=0.0349). Trends towards improved overall survival were seen in patients 50 years old or less (36.86 versus 21.78 months, p=0.0837) and in patients with a clinical risk score of 2 or less (29.65 versus 19.62 months, p=0.1823), which may show significance in a higher powered study@*CONCLUSION@#Improved overall survival was observed among patients with colorectal liver metastases undergoing hepatic metastasectomy compared to no liver resection.
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Metastasectomy , PhilippinesABSTRACT
Objective:To explore the survival status of rectal cancer patients with liver metastasis after receiving different treatments and its influencing factors.Methods:The clinicopathological characteristics, treatment methods and survival of 211 rectal cancer patients with liver metastasis who received different treatments in Shanxi Provincial Cancer Hospital from January 2012 to December 2016 were retrospectively analyzed. Cox proportional hazards regression model was used to analyze the related factors affecting the prognosis of patients.Results:The median overall survival (OS) time of 211 rectal cancer patients with liver metastasis was 19 months (1-115 months), and the 1-, 3- and 5-year OS rates were 66%, 22% and 10%. The OS of rectal cancer patients with metachronous liver metastasis was better than that of rectal cancer patients with simultaneous liver metastasis ( χ2 = 17.225, P < 0.01). The OS of patients with primary tumor resection was better than that of patients without primary tumor resection ( χ2 = 69.54, P < 0.01). Among patients with primary tumor resection, the OS of patients with untreated liver metastasis was worse than that of patients with interventional treatment of liver metastasis ( χ2 = 7.311, P = 0.007). Among the patients without primary tumor resection, the OS of patients with chemotherapy alone was better than that of untreated patients ( χ2 = 4.123, P = 0.042). The OS of patients with primary tumor resection and untreated liver metastasis and patients with primary tumor resection and liver metastasis intervention therapy was better than that of patients with chemotherapy alone (both P < 0.01). The results of Cox regression analysis showed that the differentiation degree of primary tumor, liver metastasis and carbohydrate antigen 199 level at diagnosis were independent factors influencing the survival of rectal cancer patients with liver metastasis (all P < 0.01). Conclusion:For patients with diagnosed rectal cancer, even if there is liver metastasis before surgery, active surgical resection of the primary tumor and local treatment of liver metastasis can still improve the survival.
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Oligometastasis is an intermediate status between the locally advanced and wide spread disease. Patients with oligometastasis may obtain long-term survival after local treatment. Stereotactic body radiation therapy (SBRT) can deliver radical ablative doses in a small number of fractions, which is a highly precise local ablation therapy. Approximately half of patients diagnosed with colorectal cancer (CRC) will develop metastases, with the liver and lung as the most common site of involvement. In this article, the safety, local efficacy and prognostic factors of SBRT for liver and lung oligometastases from CRC were illustrated. The highlights of SBRT implementation were also discussed. SBRT is safe and effective for oligometastases from CRC under respiratory motion management and robust quality assurance.
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Liver is the most important metastatic target organ of colorectal cancer. Nearly 50% of colorectal patients are found to have liver metastasis during the course of the disease, including 25% of colorectal patients undergoing simultaneous liver metastasis and the other 25% undergoing metachronous liver metastasis. Liver metastasis is the main cause of death for colorectal patients and the prevention and treatment of colorectal cancer liver metastasis is the top priority to overcome the disease. Active surgical treatment can bring survival benefits to colorectal patients. The authors analyze and summarize the multidisciplinary treatment of colorectal liver metastasis in the department of organ transplantation of First Affiliated Hospital of Kunming Medical University to discuss the hepatectomy strategy of colorectal liver metastasis.
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Liver metastasis is not rare during the course of neuroendocrine neoplasms.The methods for treating neuroendocrine neoplasm with liver metastasis(NENLM)are diversifying,which exposes the limitations of the early therapeutic response assessment based on only morphological changes.The emerging imaging biomarkers can sensitively describe changes in response to treatment from the functional level,providing new ideas for the therapeutic response evaluation of NENLM.In this paper,we reviewed the status quo and the latest research progress of imaging assessment for early therapeutic response of NENLM,aiming to provide reference for assessing the response and further exploring the treatment-related biomarkers.
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Humans , Diagnostic Imaging , Liver Neoplasms/diagnostic imaging , Neoplasm Metastasis , Neuroendocrine Tumors/diagnostic imagingABSTRACT
Liver is the most common metastatic site for colorectal cancer (CRC), there is no satisfied approach to treat CRC liver metastasis (CRCLM). Here, we investigated the role of a polycomb protein BMI-1 in CRCLM. Immunohistochemical analysis showed that BMI-1 expression in liver metastases was upregulated and associated with T4 stage, invasion depth and right-sided primary tumor. Knockdown