Tumor-free Survival Time Research Articles

Role of Oncostatin M in Exercise-Induced Breast Cancer Prevention.

Moderate-to-vigorous-intensity physical activity decreases the risk of breast cancer. The muscle-derived cytokine (myokine), oncostatin M (OSM), has been shown to decrease breast cancer cell proliferation. We hypothesized that OSM is involved in physical activity-induced breast cancer prevention, and that OSM antibody (Anti-OSM) administration would mitigate the effect of physical activity in a rat model of mammary carcinoma. Female Sprague Dawley rats were injected with 50 mg/kg N-methyl-N-nitrosourea to induce mammary carcinogenesis. During the 20-week study, rats were exercise trained (EX) or remained sedentary (SED). Additional groups were treated with Anti-OSM antibody (SED + Anti-OSM and EX + Anti-OSM) to explore the impact of OSM blockade on tumor latency. Exercise training consisted of treadmill acclimation and progressive increases in session duration, speed, and grade, until reaching 30 min/day, 20 m/min at 15% incline. Experimentally naïve, age-matched, female rats also completed an acute exercise test (AET) with time course blood draws to evaluate OSM plasma concentrations. Relative tumor-free survival time was significantly longer in EX animals (1.36 ± 0.39) compared to SED animals (1.00 ± 0.17; p = 0.009), SED + Anti-OSM animals (0.90 ± 0.23; p = 0.019), and EX + Anti-OSM animals (0.93 ± 0.74; p = 0.004). There were no significant differences in relative tumor latency between SED, SED + Anti-OSM, or EX + Anti-OSM animals. Following the AET, OSM plasma levels trended higher compared to baseline OSM levels (p = 0.080). In conclusion, we observed that exercise-induced delay of mammary tumor development was mitigated through Anti-OSM administration. Thus, future studies of the OSM mechanism are required to lay the groundwork for developing novel chemo-prevention strategies in women who are unable or unwilling to exercise.

SURGICAL TREATMENT FOR ADVANCED COLORECTAL CANCER WITH ABDOMINAL WALL INVASION AND IMPLANTATION

Abstract Aim The prognosis of abdominal wall invasion and implantation from colorectal cancer (CRC) is not good. With radical resection and abdominal wall reconstruction (AWR) technique, locally advanced CRC patients with resectable abdominal wall invasion and implantation may achieve longer tumor-free survival time and an improved quality of life. Methods 15 patients were retrospectively analyzed. All patients underwent preoperative three-dimensional visualization reconstruction of the abdominal wall and evaluation with a multidisciplinary team (MDT). Patient information, including tumor size, defect size, operation time, intraoperative bleeding, length of hospital stays, and other factors, was collected. Results All 15 locally advanced CRC patients with abdominal wall invasion and implantation underwent radical abdominal wall tumor resection followed by AWR. The average tumor dimension and abdominal wall defects after resection were 98.13 ± 71.70 and 270.07 ± 101.95 cm2 respectively; and accurate abdominal wall classification and zoning were obtained for all patients. The average operation time was 431.7 ± 189.2 min, and the average blood loss was 513.3 ± 244.6 ml. The incidence of incisional hernia and CRC recurrence were 6.0% and 13.3%, respectively. Conclusions With comprehensive preoperative evaluation, results of radical resection of abdominal wall invasion and implantation in locally advanced CRC patients is satisfactory and safe.

EGLN1: A Biomarker of Poor Prognosis of Cervical Cancer and a Target of Treatment.

Objective: To conduct bioinformatics analysis on the prognostic effect, mechanism of action, and drug sensitivity of Egl-9 family hypoxia-inducible factor 1 (EGLN1) expression on cervical cancer. Methods: Bioinformatics were obtained from Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), and the human cancer metastasis database (HCMDB), and the effect of EGLN1 expression level on the prognosis of cervical cancer was comprehensively analyzed. The protein-protein interaction network was constructed by Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the possible mechanism of EGLN1 affecting the prognosis of cervical cancer was discussed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, Gene Set Cancer Analysis (GSCALite) was used to predict sensitive drugs online. Results: The higher the expression level of EGLN1, the shorter the tumor-free survival time and overall survival time of cervical cancer. The higher the stage of cervical cancer, the higher the expression level of EGLN1. The expression of EGLN1 affects the degree of immune infiltration, the variation of somatic copy number, and the level of N6-methyladenosine (m6A) modification in cervical cancer. COX regression model suggested that EGLN1 was an independent prognostic factor of cervical cancer. Conclusions: The high expression of EGLN1 in cervical cancer is an independent risk factor for the prognosis of cervical cancer, which affects the prognosis of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) through different signal pathways. It is expected to be used to predict the sensitive anticancer drugs for the treatment of cervical cancer.

Immunotherapy for hepatocellular carcinoma: molecular pathogenesis and clinical research progress

Abstract The treatment of hepatocellular carcinoma (HCC) is advancing rapidly in the 21st century. Although there are various treatment methods, the most promising breakthrough seems to be in immunotherapy. Recent guidelines from the American Society of Clinical Oncology and the European Association for the Study of the Liver have recommended immunotherapies with strong antitumor effects for HCC treatment. Emerging systemic therapeutic strategies, such as immune checkpoint inhibitors combined with targeted therapy or local treatment, are among the most promising for improving overall and tumor-free survival times in patients with HCC. This review analyzes the molecular mechanisms of existing immune checkpoint inhibitors, vaccines, and chimeric antigen receptor–T cells; summarizes the latest progress in relevant clinical research; and outlines future trends and opportunities for HCC immunotherapy.

Adjuvant treatment of canine splenic hemangiosarcoma with autologous dendritic cell therapy - a prospective, randomized double-blind study

Canine splenic hemangiosarcomas (HSA) are malignant mesenchymal tumors with a high tendency for metastasis. Median survival times after splenectomy followed by adjuvant chemotherapy usually range between 5 and 8 months. The aim of this prospective randomized double-blinded study was to examine the efficacy of a commercially available dendritic cell therapy (PetBioCell) following splenectomy. In addition, possible side effects of this therapy were evaluated. Twenty-one dogs with histologically confirmed splenic HSA without metastasis (stages I or II) were included in the study. Ten dogs received the dendritic cell therapy, and 11 dogs received a placebo. Injections were administered according to the manufacturer's instructions monthly for the first 3 months and then every 3 months until death. Survival times and toxicoses of both groups were compared. Follow-up data were available for all 21 patients; the observation period ranging until euthanasia or metastasis-related death. One patient that had received the dendritic cell therapy was euthanized due to prostatitis and experienced the longest survival time (668 days). One dog in the placebo-group lived for 448 days after splenectomy. The median survival times in the dendritic cell therapy and the placebo group amounted to 74 and 126 days, respectively. There was no significant difference in tumor-free interval (t(18) = 1.4, p = 0.911) and survival times (t(19) = -0.094, p = 0.463) between the 2 groups. Toxicoses reported in both groups were mild and self-limiting. Immunotherapy using autologous, immature and unprimed dendritic cells according to the PetBioCell method failed to show efficacy on tumor-free interval and survival time in the presented dog population with splenic hemangiosarcoma.

Malignant germ cell tumor of fallopian tube with rhabdomyosarcoma: a case report and literature review

BackgroundMixed germ cell tumors originating from the fallopian tubes are rarely reported, and high-grade rhabdomyosarcoma with differentiated components is even less common. The non-specific clinical manifestations of this tumor are prone to misdiagnosis, and there is still controversy over the treatment plan for this rare differentiated type, and there are limited reports on the prognosis of related diseases.Case presentationHere, we report a 34-year-old woman who presented to our hospital with abdominal pain for two weeks and aggravated for two days. After completing relevant examinations, she underwent transabdominal resection of large tubal masses on the left side of the tube + pelvic lymph node dissection + abdominal paraaortic lymph node dissection + right ovarian cyst excision + greater omentectomy + multipoint peritoneal biopsy. hematoxylin–eosin (H&E) and immunohistochemical (IHC) staining were performed on the surgically resected specimens to further determine the type and nature of the tumor, and 3 cycles of Bleomycin + Etoposide + Cisplatonum (BEP) chemotherapy and 1 cycle of EP(Etoposide + Cisplatonum) chemotherapy were given after surgery.ConclusionUp to now, regular follow-up of the patient's tumor markers and imaging showed no abnormalities, the general condition is good, and the tumor free survival time has reached 24 months.

Efficacy and prognostic factors of repeated hepatectomy for postoperative intrahepatic recurrence of hepatocellular carcinoma undergoing initial hepatectomy.

Postoperative recurrence of hepatocellular carcinoma (HCC) is associated with low survival rates. While HCC treatment options have expanded substantially, they are accompanied by several challenges. This study assessed the outcomes of repeated hepatectomy (RH) for postoperative intrahepatic recurrence of HCC among patients undergoing initial hepatectomy (IH) as well as independent risk factors for HCC recurrence among patients undergoing repeated hepatectomy (RH). Clinical data from 84 patients undergoing both IH and RH and 66 recurrent HCC patients who had received radiofrequency ablation (RFA) from July 2011 to September 2017 were retrospectively reviewed. The following groups were compared: (1) RH Group A (n = 84), (2) IH Group (n = 84, same individuals as RH Group A), (3) RH Group B (n = 45/84 from RH Group A), and (4) RFA Group (n = 66). The clinical pathology and operative characteristics of the patients in RH Group A were compared to those in the IH Group. Meanwhile, the clinical pathology and pre- and post-treatment features of the patients in RH Group B were compared to those in the RFA Group. The tumor-free survival time was compared between patients in RH Group A and the IH Group as well as between patients in RH Group B and the RFA Group. The independent risk factors for the 1-year postoperative tumor-free survival of RH Group A patients were investigated using univariate and multivariate analysis. Measures of clinical pathology, including AFP, Child-Pugh score, HBV-DNA, tumor number, liver cirrhosis, tumor differentiation, surgical approach, and TNM stage differed significantly between patients in RH Group A and the IH Group (all P < 0.05), with the exception of tumor number and tumor size (both P > 0.05). No significant differences were found in these measures between the patients in RH Group B and the RFA Group (all P > 0.05). While patients in the RH Group A had a longer operation time than those in the IH Group (4.35 ± 1.25 h vs. 3.55 ± 0.92 h, P < 0.001), the level of intraoperative bleeding was similar (400.00 ± 199.25 ml vs. 359.40 ± 213.37 ml, P = 0.204). RH Group B patients had a longer hospitalization time than those in the RFA Group (6.5 ± 0.8 d vs. 5.5 ± 1.1 d, P < 0.001), however, the difference in hospitalization costs was not statistically significant (29,009 ± 3,806 CNY vs. 29,944 ± 3,752 CNY, P = 0.202). Five-day post-operative serum biomarker levels, including direct bilirubin (DB) and albumin (ALB), were significantly higher in RH Group B than in the RFA Group (all P < 0.05), with the exception of ALT, AST, and total bilirubin (TB) (all P > 0.05). Patients in RH Group A had a lower tumor-free survival time than those in the IH Group (median: 12 vs. 22 months, P < 0.001), and patients in the RH Group B had a significantly higher tumor-free survival time than those in the RFA group (median: 15 months vs. 8 months, P < 0.001). Age ≥50 y, Child-Pugh class A, and negative HBV-DNA were independent risk factors that positively impacted the 1-year postoperative tumor-free survival rate of postoperative intrahepatic recurrent HCC patients undergoing RH (P < 0.001, respectively). Due to the potential of harm related to relapse of recurrent HCC for cancer patients, RH is a superior option. RH could offer better outcomes for recurrent HCC patients undergoing IH. Compared with lesion pathology, the better target organ of the liver will be key to ameliorating tumor-free survival for recurrent HCC patients undergoing RH.

Abstract P004: Targeting the RXR pathway for the prevention of triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive cancer that lacks expression of the estrogen receptor (ER), progesterone receptor, and Erb-B2 receptor tyrosine kinase 2. TNBC patients exhibit a poor prognosis, even if treated with chemotherapy. Although studies using selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have shown that breast cancer prevention is feasible, these drugs do not prevent ER-negative or TNBC tumors. It has been shown by our laboratory and others that retinoid X receptor (RXR)-specific ligands (rexinoids) can prevent breast cancers that are both ER-positive and ER-negative in mice. In our previous studies in MMTV-erbB2 mice, IRX-4204, a fourth generation rexinoid, prevented the development of most HER2/erbB2-positive tumors in these mice. For this study, we hypothesized that by targeting RXR pathway, we can prevent the development of triple negative, BRCA1-mutant mammary tumors in mice. To test the hypothesis, we treated MMTV-Cre/BRCA1co/co/p53+/- mice prior to their developing tumors with IRX-4204 to determine whether this RXR agonist effectively prevents triple-negative breast tumors. Methods: We tested the tumor preventative effect of IRX-4204 using the established MMTV-Cre/BRCA1co/co/p53+/- mouse model. These mice were produced by breeding MMTV-Cre/BRCA1co/co/p53+/- males and MMTV-Cre/BRCA1co/co/p53+/+ females, and female pups were PCR genotyped. All mice were separated into 4 groups: 1) sesame oil control, 2) IRX-4204 (10 mg/kg), 3) IRX-4204 (20 mg/kg) and 4) 9-cis-UAB-30 (5 mg/kg). All treatments were given by oral gavage, five days a week from 4 months of age. Mice were observed daily for tumor formation and toxicity. The percentage of tumor free mice were recorded, from which tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the Log-rank test. Results: In MMTV-Cre/BRCA1co/co/p53+/- mice, IRX-4204 reduced tumor incidence and was associated with an increase in median tumor free survival time from 209 days to 336 days at 10 mg/kg dose (p=0.005). At the higher dose (20 mg/kg) IRX-4204 also delayed tumor formation with median tumor free survival from 209 days to 260 days (p=0.039). The rexinoid 9-cis-UAB 30 also significantly delayed tumor formation in MMTV-Cre/BRCA1co/co/p53+/- mice with median survival from 209 days to 270 days (p=0.04). Long term treatment of IRX-4204 was not associated with any toxicity. Conclusion: RXR agonist IRX-4204 delayed ER-negative mammary tumor formation in BRCA1co/co; MMTV-Cre; p53+/- mice. Based on our results, IRX-4204 is an effective cancer preventive drug without observed toxicity. Our results suggest that studies with reduced IRX-4204 dose alone or in combination with other targeted therapies such as selective estrogen receptor modulators are warranted. In the future, clinical trials of the IRX-4204 should be considered for the prevention of breast cancer in high-risk patients. (Supported by NCI-PREVENT contract to P. Brown and A. Mazumdar HHSN26100008). Citation Format: Cassandra Moyer, Jamal Hill, Darian Coleman, Shizuko Sei, Altaf Mohammed, Martin Sanders, Powel Brown, Abhijit Mazumdar. Targeting the RXR pathway for the prevention of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P004.

Clinical Significance of TUBGCP4 Expression in Hepatocellular Carcinoma.

We aim to investigate the expression and clinical significance of the tubulin gamma complex-associated protein 4 (TUBGCP4) in hepatocellular carcinoma (HCC). The mRNA expression of TUBGCP4 in HCC tissues was analyzed using The Cancer Genome Atlas (TCGA) database. Paired HCC and adjacent nontumor tissues were obtained from HCC patients to measure the protein expression of TUBGCP4 by immunohistochemistry (IHC) and to analyze the relationship between TUBGCP4 protein expression and the clinicopathological characteristics and the prognosis of HCC patients. We found that TUBGCP4 mRNA expression was upregulated in HCC tissues from TCGA database. IHC analysis showed that TUBGCP4 was positively expressed in 61.25% (49/80) of HCC tissues and 77.5% (62/80) of adjacent nontumor tissues. The Chi-square analysis indicated that the positive rate of TUBGCP4 expression between HCC tissues and the adjacent nontumor tissues was statistically different (P < 0.05). Furthermore, we found that TUBGCP4 protein expression was correlated with carbohydrate antigen (CA-199) levels of HCC patients (P < 0.05). Further, survival analysis showed that the overall survival time and tumor-free survival time in the TUBGCP4 positive group were significantly higher than those of the negative group (P < 0.05), indicating that the positive expression of TUBGCP4 was related to a better prognosis of HCC patients. COX model showed that TUBGCP4 was an independent prognostic factor for HCC patients. Our study indicates that TUBGCP4 protein expression is downregulated in HCC tissues and has a relationship with the prognosis of HCC patients.

LINC01285 promotes proliferation and metastasis of colorectal cancer cells by regulating epithelial-mesenchymal transition

To clarify the mechanism by which LINC01285 regulates proliferation and migration of colorectal cancer (CRC) cells and the clinical implications. We analyzed the expression of LINC01285 in CRC tissues and normal tissues using data from Starbase public database. We also examined the expression levels of LINC01285 in 70 pairs of CRC and adjacent tissue samples collected from our center and in different CRC cell lines using RT-qPCR, and analyzed the correlation of LINC01285 expression with the clinicopathological parameters and tumor-free survival time of the patients. In CRC cell lines (SW620 and HT-29), the changes in cell proliferation, apoptosis, metastasis and epithelial-mesenchymal transition (EMT) phenotype following LINC01285 knockdown were analyzed using CCK-8 assay, flow cytometry, Transwell assay and Western blotting. The TCGA-COAD transcriptome sequencing data obtained from the Starbasev3.0 public database revealed a significantly higher expression level of LINC01285 in CRC tissues than in adjacent tissues (P=0.00016), which was verified by RT-qPCR results of the clinical samples (P=0.0002). In CRC patients, the expression level of LINC01285 was closely correlated with histological differentiation of the tumor (P=0.036), T classification (P=0.000), lymph node metastasis (P=0.001), TNM stage (P=0.000), Duke stage (P=0.009) and relapse-free survival (P=0.0102). In SW620 and HT-29 cells, which expressed significantly higher levels of LINC01285 than normal colorectal mucosal cells (P < 0.001), LINC01285 knockdown significantly inhibited cell proliferation (P < 0.001), increased early apoptosis, late apoptosis and total apoptosis rates (P < 0.05), suppressed cell migration and invasion (P < 0.001), upregulated the expression of E-cadherin (P < 0.001), and downregulated the expression of N-cadherin (P < 0.001). The expression level of LINC01285, which modulates the EMT pathway to regulate the proliferation, apoptosis and metastasis of CRC cells, is closely correlated with the prognosis of CRC patients.

Abstract 919: APOBEC3 promotes tumor progression, squamous differentiation and metastasis in bladder cancer mouse model

Abstract Bladder cancer is the sixth most common type of cancer in the United States. In 2021, there are an estimated 83,730 new cases and 17,200 deaths from bladder cancer. Only about 15% of patients with metastatic disease survive past five years. The apolipoprotein B mRNA editing enzyme catalytic subunit 3B (APOBEC3B) is overexpressed in bladder tumors compared to corresponding healthy tissues. This enzyme catalyzes the conversion of cytidine to uracil playing an important physiologic role in restricting viral replication. When aberrantly over-expressed, APOBEC3B can damage single-stranded DNA present during DNA replication and transcription, resulting in an increased tumor mutational burden. Strikingly, APOBEC mutagenesis accounts for 70% of all single-nucleotide variants found in bladder cancer. Despite the strong evidence of APOBEC mutagenesis in bladder cancer, the effects of APOBEC3B on the disease progression remain unclear. To address this question, we generated the UPPA (urothelial specific over-expression of mouse Apobec3 along with Pten and p53 knock-out) and control UPP mouse models to interrogate the role Apobec3 in bladder cancer progression. Apobec3 over-expression shortened tumor latency in the UPPA model with the median tumor free survival time of 43.3 weeks compared to 53.6 weeks in the UPP model. Histological analysis showed that bladder epithelial cells in the UPPA mice underwent squamous differentiation which is associated with aggressive disease in human. Additionally, immunofluorescence analysis showed up-regulation of krt6a (a squamous marker) in UPPA urothelium compared to a complete lack of krt6a signal in the urothelium of UPP mice. Necropsy revealed the presence of metastatic nodules in lung, liver and peritoneum in UPPA mice. Cell lines derived from a matched pair of UPPA primary tumor and peritoneal metastatic tumor formed lung and liver nodules in wild-type C57BL/6J mice via tail vein injection. Our results so far suggest that Apobec3 promotes tumor progression, squamous differentiation and metastasis. Additional work utilizing bladder organoids and scRNAseq are underway to unravel the mechanism by which Apobec3 promotes these observed phenotypes. Currently, single-cell RNAseq analysis on primary UPPA tumor demonstrated high degree to T cell infiltration. Approximately 60% of cells sequenced were annotated as T-cells and natural killer T-cells by SingleR. We treated mice bearing UPPA primary bladder tumors with anti-PD-1 antibody and observed significant tumor growth inhibition. Citation Format: Andrew S. Truong, Mi Zhou, Michael S. Sturdivant, John D. Raupp, Ujjawal Manocha, William Y. Kim. APOBEC3 promotes tumor progression, squamous differentiation and metastasis in bladder cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 919.

Efficacy of Lipid Nanoparticle-Loaded Sorafenib Combined with Hepatic Artery Chemoembolization in the Treatment of Primary Hepatocellular Carcinoma Complicated with Microvascular Invasion.

This work was to evaluate the therapeutic effect of lipid nanoparticle-loaded sorafenib combined with transcatheter artery chemoembolization (TACE) in patients with primary hepatocellular carcinoma (HC) complicated with microvascular invasion (MVI). In this work, 102 patients with primary HC combined with MVI after radical resection were divided into 4 groups according to different treatment methods. Experimental group 1 was treated with lipid nanoparticle-loaded sorafenib combined with TACE treatment group; experimental group 2 was treated with lipid nanoparticle-loaded sorafenib treatment group; experimental group 3 was TACE treatment group; control group was postoperative routine nursing group. Sorafenib lipid nanoparticles were prepared. The basic information, operation, MVI degree, tumor recurrence, and survival time of patients in each group were recorded and compared to evaluate the therapeutic effect of combined way. No great difference was found in MVI grade, average age, sex ratio, preoperative tumor markers, tumor size, number of patients with liver cirrhosis, operation time, and intraoperative bleeding among the four groups (P > 0.05). In addition, the tumor free survival time (TFST), overall survival time (OST), and postoperative 1-year and 2-year survival rates of patients in test group 1 were greatly higher than those in single mode treatment group and control group (P < 0.05). In summary, sorafenib nanoparticles combined with TACE can improve the survival status of patients after resection and delay the time of postoperative tumor recurrence.

The mediating role of self-efficacy in the association between perceived stigma and psychosocial adjustment: a cross-sectional study among nasopharyngeal cancer survivors.

This study aims to examine the levels of and associations between perceived stigma, self-efficacy, and psychosocial adjustment (PA) among nasopharyngeal carcinoma (NPC) survivors, and to identify the mediating role of self-efficacy between stigma and PA and explore the influencing factors of PA. A cross-sectional survey was conducted and 307 NPC survivors were recruited by convenience sampling method in Southern China from July 2019 to January 2020. Data analyses were performed with the SPSS WIN 25.0 program and PROCESS macro version 3.3. Stigma and self-efficacy were positively associated with PA among Chinese NPC survivors. Tumor-free survival time, late toxicities (fatigue, dizziness and headache, and hearing loss), stigma, and self-efficacy entered the final regression model and explained 55.9% of the variance of PA. The total and direct effects of stigma on PA and its subscales were significant (p<0.05). Positive indirect effects were found for stigma on PA via self-efficacy (point estimate=0.159, SE=0.032, 95% CI [0.102 to 0.229]). Stigma and self-efficacy are significantly associated with PA, and self-efficacy is also a mediating variable between stigma and PA among NPC survivors. Medical staff could improve the PA of NPC survivors by alleviating their stigma, enhancing their self-efficacy, and relieving their late toxicities (fatigue, dizziness and headache, and hearing loss).

Molecular mechanism of CK19 involved in the regulation of postoperative recurrence of HBV-associated primary hepatocellular carcinoma in Guangxi.

BackgroundCytokeratin 19 (CK19/KRT19) is a marker of biliary epithelial cells and hepatic progenitor cells, which can be expressed in some hepatocellular carcinoma (HCC). However, its role in the occurrence, development, and recurrence of hepatitis B virus (HBV)-associated HCC remains to be clarified. This study is to analyze the relationship between the expression of CK19 protein and clinicopathological factors, as well as the effect of positive CK19 expression on the prognosis of HCC patients.MethodsSmall interfering RNA (siRNA) transfection was used to silence CK19 in MHCC-97H and Hep-3B. Real time polymerase chain reaction (qPCR), immunohistochemistry (IHC), and flow cytometry were used to detect the effects of CK19 silencing on cell function. High-throughput sequencing was used to explore the potential molecular mechanism of CK19 positive expression of HCC.ResultsIn 24 patients with HCC, CK19 was only expressed in cancer tissues, regardless of primary or recurrent tumors, and the positive expression rate of recurrent tumors was higher than that of primary tumors. The HCC participants with positive primary CK19 expression had a shorter tumor-free survival time. Silencing of the CK19 gene in MHCC-97H and Hep-3B attenuated the migration and invasion ability of MHCC-97H, increased the G2 phase cell content of MHCC-97H and Hep-3B, and increased the proportion of apoptosis. High-throughput sequencing results suggested that changes in the function of the cell cycle regulating genes, drug, and carcinogenic metabolism might be the potential pathways of CK19 in regulating the biological behavior of HCC.ConclusionsAmong HBV-related recurrent HCC, the positive rate of CK19 expression in recurrent HCC tumors was higher, and the tumor-free survival time of HCC patients with positive CK19 expression in primary HCC was shorter. After silencing of the CK19 gene, the migration and invasion ability of HCC cells were weakened, the content of G2-M cell cycle cells was increased, the invasion and migration of HCC cells were inhibited, and apoptosis was promoted. Changes in the function of the cell cycle regulating genes and the regulation of drug and carcinogenic metabolites-related pathways may be the pathways through which CK19 affects the biological behavior of HCC.

The ratio of preoperative alpha-fetoprotein level to total tumor volume as a prognostic factor of hepatocellular carcinoma after liver transplantation.

To evaluate the effect of preoperative serum alpha-fetoprotein(AFP) level to total tumor volume (TTV) ratio as a prognostic marker on predicting the tumor recurrence and overall survival time of patients with hepatocellular carcinoma (HCC) after liver transplantation.One-hundred eight patients with HCC who underwent liver transplantation in Beijing Chaoyang Hospital from April 2013 to October 2017 were studied. Divided into AFP/TTV≤2 group and AFP/TTV>2 group by the best cut-off score calculated by receiver operation characteristic curve, the clinical and pathological data of the patients in two groups were compared to explore the relationship between AFP/TTV and tumor recurrence together with the prognosis of HCC patients after liver transplantation. Risk factors of early tumor recurrence and poor prognosis of HCC in patients after liver transplantation were studied by multivariate regression analysis. Kaplan-Meier survival analysis was used to compare the tumor-free survival and overall survival between the two groups of patients.In 108 patients, 47 patients have AFP/TTV≤2 while 61 patients have AFP/TTV>2. Patients in AFP/TTV≤2 group have longer tumor-free survival time and overall survival time compared with patients in AFP/TTV>2 group. The age, total bilirubin level, serum AFP level, TTV, portal vein tumor thrombus and AFP/TTV (all P < .05) of patient with HCC are closely related to poor prognosis after liver transplantation. Multivariate regression analysis showed that have portal vein tumor thrombus (hazard ratio [HR] = 2.345, P < .05), TTV≥65.5 cm3 (HR = 2.701, P < .05) and AFP/TTV > 2 (HR = 4.624, P < .05) are independent risk factors for poor prognosis of patients with HCC after liver transplantation while TTV≥65.5 cm3 (HR = 2.451, P < .05) and AFP/TTV > 2 (HR = 4.257, P < 0.05) were independent risk factors for tumor recurrence at the same time.The tumor recurrence and the prognosis of patients with HCC after liver transplantation is affected by many factors. AFP/TTV ratio has important predictive value for the tumor recurrence and the prognosis of patients with HCC after liver transplantation. AFP/TTV>2 is an independent risk factor for both early tumor recurrence and poor prognosis of patients with HCC after liver transplantation.

Laparoscopic Surgery for Gallbladder Neuroendocrine Carcinoma: a Case Series and Literature Review

Gallbladder neuroendocrine carcinomas (GB-NECs) are a group of rare and heterogeneous neoplasms. There are few reports regarding laparoscopic surgery for GB-NEC cases diagnosed at advanced stage. Three patients, two females and one male, were admitted to our hospital. Two patients had the chief complaint of upper quadrant pain and one patient was found to have gallbladder occupation during a routine health checkup. No patient complained of jaundice, weight loss, or carcinoid syndrome–related symptoms including diarrhea, edema, flushing, and wheezing. Contrast-enhanced computed tomography (CT) examination showed local wall thickening of the gallbladder. In addition, one patient showed focal liver parenchymal invasion, and none of the three patients’ preoperative imaging examination revealed lymph node (LN) metastases. All three patients underwent laparoscopic radical cholecystectomy according to intraoperative frozen pathological examination, and they were diagnosed as GB-NEC based on postoperative pathology and immunohistochemistry. TNM stages of these patients were IIIA (T3N0M0), IIIB (T3N1M0), and IVB (T3N2M0), respectively. Chromogranin A (CgA) and synaptophysin (Syn) were positive in all cases. No patient encountered postoperative bleeding, bile leakage, abdominal abscess, gastrointestinal fistulas, or pulmonary complication. Two patients underwent postoperative chemotherapy with two cycles and seven cycles of etoposide plus cisplatin, respectively. Another patient did not receive postoperative chemotherapy due to his poor general condition. The overall survival time of the three patients was 4.6 months, 16.8 months, and 8.5 months, respectively. All three patients presented with liver and/or bile duct recurrence after surgery with a tumor-free survival time of 2.3 months, 3.3 months, and 3.0 months, respectively. Laparoscopic surgery may be considered a potential treatment for advanced GB-NEC in selected patients. However, further studies are needed to investigate the tumor-free survival benefit of laparoscopic surgery, and whether expanding the resection scope could reduce postoperative recurrence.

The Association of Single-Nucleotide Polymorphism rs13181 in ERCC2 with Risk and Prognosis of Nasopharyngeal Carcinoma in an Endemic Chinese Population.

ObjectiveWe examined whether the single-nucleotide polymorphism (SNP) rs13181 in the gene encoding excision repair cross complementation group 2 (ERCC2) is associated with the risk and prognosis of nasopharyngeal carcinoma (NPC).MethodsSNPs at rs13181 were genotyped in 439 NPC patients (NPC group) and 431 age- and gender-matched cancer-free controls (control group) from a region of China where NPC is endemic, and frequencies of GG, GT and TT genotypes were compared between the two groups in the case–control study. In a subset of 365 NPC cases, SNPs were examined for potential correlation with tumor-free survival time (TFS) and overall survival (OS).ResultsRelative to NPC risk with a TT genotype, NPC risk was similar with GT + GG genotypes (OR 1.052, 95% CI 0.656–1.688), after adjusting for gender, age, smoking history, and immunoglobin A against Epstein-Barr virus capsid antigen (EBV-VCA-IgA) status. Univariate analysis showed that the GG or GT genotype was associated with significantly worse TFS (p<0.001) and OS (p=0.010) than the TT genotype. Prognosis was significantly worse for men than for women (TFS, p=0.045; OS, p=0.031), for T3–T4 classification than for T1–T2 (TFS, p=0.009; OS, p=0.007), for N3 than for N0+N1+N2 (TFS, p<0.001; OS, p<0.001). Based on multivariate analysis, independent risk factors for poor TFS were GG or GT genotype (HR 2.629, 95% CI 1.625–4.254, p<0.001), T3–T4 classification (HR 2.146, 95% CI 1.244–3.701, p=0.006) and N3 (HR 2.527, 95% CI 1.574–4.059, p<0.001). GG or GT genotype (HR 2.217, 95% CI 1.283–3.832, p=0.004), gender (HR 1.989, 95% CI 1.046–3.785, p=0.036), T3–T4 (HR 2.431, 95% CI 1.306–4.526, p=0.005) and N3 (HR 2.693, 95% CI 1.637–4.432, p<0.001) were independent risk factors for poor OS.ConclusionThe rs13181 SNP in ERCC2 does not appear to be associated with NPC risk, but it may serve as an independent prognostic factor for NPC recurrence and death.

Analysis of Differentially Expressed Proteins Involved in miR-449a for Hepatocellular Carcinoma by iTRAQ Proteomics.

To investigate the relationship between down-regulation of miR-449a and prognosis of hepatocellular carcinoma (HCC) and to elucidate the potential target proteins of miR-449a. The expression of miR-449a in 142 HCC tissues was detected by RT-PCR. The correlation between down-regulation of miR-449a and prognosis of HCC was statistically analyzed during clinical follow-up. The Bel-7042 HCC cell line in miR-449a-mimic and miR-449a-inhihbitor model was used, and the potential target protein of miR-449a was screened by isobaric tags for relative and absolute quantitation (iTRAQ) technology. miR-449a was significantly down-regulated in HCC tissues, which was significantly associated with post-operative metastasis (p < 0.0001) and recurrence (p < 0.0001). The median overall survival time in the low-expression group of miR-449a was significantly lower than that of the high-expression group (19 months vs. 37 months, p = 0.001). In addition, the tumor-free survival time of the low-expression group was significantly lower than that of the high-expression group (14 months vs. 24 months, p = 0.001). iTRAQ analysis screened out 137 differential proteins, among which 88 were up-regulated and 49 were down-regulated. GO clustering, KEGG pathway, and STRING analysis were performed, suggesting that these differential proteins have complicated functions, such as ATP binding, metal ion binding, RNA binding, human papillomavirus infection, and Epstein-Barr virus infection. miR-449a was negatively correlated with HCC prognosis. The differential proteins screened by iTRAQ can provide the basis for studying the target proteins regulated by miR-449a and understanding the pathogenesis of HCC.

Circulating tumor cells and CXCR4 in the prognosis of hepatocellular carcinoma.

BackgroundThis study was to determine circulating tumor cells (CTCs) and the expression of CXC chemokine receptor type 4 (CXCR4) in primary hepatocellular carcinoma (HCC) and the relationships with prognosis.MethodsWe used an advanced CanPatrolTM CTC-enrichment technique to collect CTCs for isolation and characterization from blood samples. The RNA in situ hybridization (RNA-ISH) method, which is based on branched DNA (bDNA) signal amplification technology, was used to determine the expression of CXCR4 according to epithelial-mesenchymal transition (EMT) markers in 99 patients with primary liver cancer in blood samples pre-operatively. The relationship between the EMT markers and HCC was determined.ResultsThe positive rates of CTCs and CXCR4 were 89.9% and 58.8%, respectively. CTCs were positively correlated with the Barcelona clinic liver cancer (BCLC) staging, tumor diameter and number, envelope, microsatellite damage, portal vein thrombosis, alpha-fetoprotein (AFP), and hepatitis B DNA, and negatively correlated with Edmondson grade. There were significant differences in the expression of CXCR4 between interstitial CTCs and mixed CTCs. A total of 99 patients underwent CTCs testing prior to surgery. The tumor-free survival time of HCC patients with interstitial CTCs <1 (13.3 months) was significantly longer than patients with interstitial CTCs ≥1 (5.0 months) pre-operatively.ConclusionsCTC-positivity was shown to be associated with HCC and can be used as an independent prognostic factor for HCC. High CXCR4 protein expression was more common in mixed CTCs.

Overexpression of KLF5 is associated with poor survival and G1/S progression in pancreatic cancer.

Despite improvements in surgical procedures and comprehensive therapies, pancreatic cancer remains one of the most aggressive and deadly human malignancies. It is therefore necessary to determine which cellular mediators associate with prognosis in pancreatic cancer so as to improve the treatment of this disease. In the present study, mRNA array and immunohistochemical analyses showed that KLF5 is highly expressed in tissue samples from three short-surviving patients with pancreatic cancer. Survival analysis using data from The Cancer Genome Atlas showed that patients highly expressing KLF5 exhibited shorter overall and tumor-free survival times. Mechanistically, KLF5 promoted expression of E2F1, cyclin D1 and Rad51, while inhibiting expression of p16 in pancreatic cancer cells. Finally, flow cytometric analyses verified that KLF5 promotes G1/S progression of the cell cycle in pancreatic cancer cells. Collectively, these findings demonstrate that KLF5 is an important prognostic biomarker in pancreatic cancer patients, and they shed light on the molecular mechanism by which KLF5 stimulates cell cycle progression in pancreatic cancer.