Comprehensive analysis of KLF2 as a prognostic biomarker associated with fibrosis and immune infiltration in advanced hepatocellular carcinoma.

PURPOSE: Most Hepatocellular carcinoma (HCC) patients are in advanced or metastatic stage at the time of diagnosis. Prognosis for advanced HCC patients is dismal. This study was based on our previous microarray results, and aimed to explore the promising diagnostic and prognostic markers for advanced HCC by focusing on the important function of KLF2. METHODS: The Cancer Genome Atlas (TCGA), Cancer Genome Consortium database (ICGC), and the Gene Expression Comprehensive Database (GEO) provided the raw data of this study research. The cBioPortal platform, CeDR Atlas platform, and the Human Protein Atlas (HPA) website were applied to analyze the mutational landscape and single-cell sequencing data of KLF2. Basing on the results of single-cell sequencing analyses, we further explored the molecular mechanism of KLF2 regulation in the fibrosis and immune infiltration of HCC. RESULTS: Decreased KLF2 expression was discovered to be mainly regulated by hypermethylation, and indicated a poor prognosis of HCC. Single-cell level expression analyses revealed KLF2 was highly expressed in immune cells and fibroblasts. The function enrichment analysis of KLF2 targets indicated the crucial association between KLF2 and tumor matrix. 33-genes related with cancer associated fibroblasts (CAFs) were collected to identify the significant association of KLF2 with fibrosis. And SPP1 was validated as a promising prognostic and diagnostic marker for advanced HCC patients. CXCR6 CD8+ T cells were noted as a predominant proportion in the immune microenvironment, and T cell receptor CD3D was discovered to be a potential therapeutic biomarker for HCC immunotherapy. CONCLUSION: This study identified that KLF2 is an important factor promoting HCC progression by affecting the fibrosis and immune infiltration, highlighting its great potential as a novel prognostic biomarker for advanced HCC.

Pan-cancer analysis of the oncogenic role of HNRNPR in human tumors.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) are potential cancer biomarkers. Little is known about the role of HNRNPR, an essential member of the hnRNP family, in human tumours. This study aims to explore the potential value of HNRNPR across cancers, based on The Cancer Genome Atlas (TCGA). The expression level, mutation, DNA methylation, phosphorylation status, survival status, pathological stage, tumor mutation burden (TMB), microsatellite instability (MSI), immune cell infiltration, and immune signature related to HNRNPR were analyzed. HNRNPR expression level was increased in several types of cancer and was associated with poor prognosis, especially in liver hepatocellular carcinoma (LIHC). HNRNPR was also correlated with antitumour immunity, and associated with TMB, MSI, and immune cell activation status across cancers. Furthermore, nomograms were established to predict the prognosis of LIHC, based on HNRNPR and other clinical characteristics. Functional enrichment analysis showed the mechanisms of HNRNPR-mediated LIHC progression. Loss-of-function experiments demonstrated that inhibition of HNRNPR could remarkably suppress hepatocellular carcinoma (HCC) cell proliferation, migration, invasion, and Epithelial-Mesenchymal Transition abilities. Our study offers a comprehensive understanding of the oncogenic roles of HNRNPR across different tumours, and demonstrates that HNRNPR might foster the proliferation, migration, and invasion abilities of HCC cells.

Survival nomograms for colorectal carcinoma patients with lung metastasis and lung-only metastasis, based on the SEER database and a single-center external validation cohort.

BACKGROUND: We analysed the survival of colorectal cancer (CRC) patients with lung metastasis and lung-only metastasis and determined the risk factors for lung metastasis in CRC patients. METHODS: Data from colorectal cancer patients with lung metastasis diagnosed from 2010 to 2015 were obtained from the SEER database. Survival was analysed using the Kaplan-Meier method and log-rank test, the Cox proportional hazards regression model, and a competing risk model. The predictive ability of the nomgram was assessed by the concordance index (C-index) and calibration curves. The data from the SEER database for the period 2016-2019 was used as an external validation set. The characteristics of 70 CRC patients treated at Shanghai East Hospital between 2016 and 2019 were retrospectively analysed and data from China was chosen as an external validation set. RESULTS: The median survival time for colorectal cancer patients with lung metastasis was 12 months, while this value was 24 months in patients with lung-only metastasis. Among all CRC patients with lung metastasis, age, grade, T stage, N stage, presence of liver, brain or bone metastasis, anatomic site and surgery were related to overall survival (OS). In CRC patients with lung-only metastasis, age, T stage, marital status, chemotherapy and surgery were independent prognostic factors affecting OS. Two nomograms predicting OS were established, with great discrimination (C-index between 0.67 and 0.81) and excellent calibration. Factors including age, race, sex, tumour grade, T stage, N stage, presence of liver, brain or bone metastasis, marital status, insurance status and anatomic location were related to the occurrence of lung metastasis in CRC patients. CONCLUSION: We developed two reliable clinical prediction models among CRC patients to predict the OS rates in patients with lung metastasis and lung metastasis only.

Serum lnc34a is a potential prediction biomarker for bone metastasis in hepatocellular carcinoma patients.

BACKGROUND: Early screening and intervention therapies are crucial to improve the prognosis of hepatocellular carcinoma (HCC) patients with bone metastasis. We aimed to identify serum lncRNA as a prediction biomarker in HCC bone metastasis. METHODS: The expression levels of lnc34a in serum samples from 157 HCC patients were detected by quantitative real-time polymerase chain reaction (PCR). Univariate analysis and multivariate analysis were performed to determine statistically significant variables. RESULTS: Expression levels of lnc34a in serum from HCC patients with bone metastasis were significantly higher than those without bone metastasis. The high expressions of lnc34a, vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage were associated with bone metastasis by analysis. Moreover, lnc34a expression was specifically associated with bone metastasis rather than lung or lymph node metastasis in HCC. CONCLUSIONS: High serum lnc34a expression was a independent risk factor for developing bone metastasis in HCC.

The molecular mechanism of LncRNA34a-mediated regulation of bone metastasis in hepatocellular carcinoma.

BACKGROUND: Bone metastasis (BM) has long been recognized as a major threat to the quality of life of hepatocellular cancer (HCC) patients. While LncRNA34a (Lnc34a) has been shown to regulate colon cancer stem cell asymmetric division, its effect on HCC BM remains unknown. METHODS: In situ hybridization and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression of Lnc34a in HCC tissues and cell lines. Ventricle injection model was constructed to explore the effect of Lnc34a on BM in vivo. The methylation of miR-34a promoter and histones deacetylation were examined by using bisulfate-sequencing PCR and chromatin immunoprecipitation assays. RNA pull down and RNA immunoprecipitation were performed to investigated the interaction between Lnc34a and epigenetic regulators. Dual-luciferase reporter assay was conducted to find miR-34a target. The involvement of TGF-ß pathway in the BM from HCC was determined by qRT-PCR, western, and elisa assays. RESULTS: We found that Lnc34a was significantly overexpressed in HCC tissues and associated with BM. Both in vitro and in vivo experiments indicate that the restoration or knockdown of Lnc34a expression in HCC cells had a marked effect on cellular migration, invasion, and metastasis. Mechanistic analyses suggested that Lnc34a epigenetically suppresses miR-34a expression through recruiting DNMT3a via PHB2 to methylate miR-34a promoter and HDAC1 to promote histones deacetylation. On the other hand, miR-34a targets Smad4 via the TGF-ß pathway, followed by altering the transcription of the downstream genes (i.e., CTGF and IL-11) that are associated with BM. CONCLUSIONS: Our study is the first to document the pro-bone metastatic role of Lnc34a in BM of HCC and reveal a novel mechanism for the activation of the TGF-ß signaling pathway in HCC BM, providing evidence of a potential therapeutic strategy in HCC BM.

HMGB2 drives tumor progression and shapes the immunosuppressive microenvironment in hepatocellular carcinoma: insights from multi-omics analysis.

Background: Hepatocellular carcinoma (HCC) poses a significant health burden globally, with high mortality rates despite various treatment options. Immunotherapy, particularly immune-checkpoint inhibitors (ICIs), has shown promise, but resistance and metastasis remain major challenges. Understanding the intricacies of the tumor microenvironment (TME) is imperative for optimizing HCC management strategies and enhancing patient prognosis. Methods: This study employed a comprehensive approach integrating multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (Bulk RNA-seq), and validation in clinical samples using spatial transcriptomics (ST) and multiplex immunohistochemistry (mIHC). The analysis aimed to identify key factors influencing the immunosuppressive microenvironment associated with HCC metastasis and immunotherapy resistance. Results: HMGB2 is significantly upregulated in HCCTrans, a transitional subgroup associated with aggressive metastasis. Furthermore, HMGB2 expression positively correlates with an immunosuppressive microenvironment, particularly evident in exhausted T cells. Notably, HMGB2 expression correlated positively with immunosuppressive markers and poor prognosis in HCC patients across multiple cohorts. ST combined with mIHC validated the spatial expression patterns of HMGB2 within the TME, providing additional evidence of its role in HCC progression and immune evasion. Conclusion: HMGB2 emerges as a critical player of HCC progression, metastasis, and immunosuppression. Its elevated expression correlates with aggressive tumor behavior and poor patient outcomes, suggesting its potential as both a therapeutic target and a prognostic indicator in HCC management.

Circ-0044539 promotes lymph node metastasis of hepatocellular carcinoma through exosomal-miR-29a-3p.

Lymph node metastasis (LNM) is a common invasive feature of hepatocellular carcinoma (HCC) associated with poor clinical outcomes. Through microarray profiling and bioinformatic analyses, we identified the circ-0044539-miR-29a-3p-VEGFA axis as a potential key factor in the progression of HCC LNM. In HCC cells and nude mice, circ-0044539 downregulation or miR-29a-3p upregulation was associated with small tumor size, PI3K-AKT-mTOR pathway inactivation, and downregulation of the key LNM factors (HIF-1α and CXCR4). Furthermore, circ-0044539 was also responsible for exosomal miR-29a-3p secretion. Exosomal miR-29a-3p was then observed to migrate to the LNs and downregulate High-mobility group box transcription factor 1 (Hbp1) in Polymorphonuclear Myeloid-derived suppressor cells (PMN-MDSCs), inducing the formation of a microenvironment suitable for tumor colonization. Overall, circ-0044539 promotes HCC cell LNM abilities and induces an immune-suppressive environment in LNs through exosomes, highlighting its potential as a target for HCC LNM and HCC immunotherapy.

Corrigendum: Establishment and validation of prognostic nomograms for patients with parotid gland adenocarcinoma not otherwise specified: a SEER analysis from 2004 to 2016.

[This corrects the article DOI: 10.3389/fsurg.2021.799452.].

Variability of radiotherapy volume delineation: PSMA PET/MRI and MRI based clinical target volume and lymph node target volume for high-risk prostate cancer.

PURPOSE: A comparative retrospective study to assess the impact of PSMA Ligand PET/MRI ([68 Ga]-Ga-PSMA-11 and [18F]-F-PSMA-1007 PET/MRI) as a new method of target delineation compared to conventional imaging on whole-pelvis radiotherapy for high-risk prostate cancer (PCa). PATIENTS AND METHODS: Forty-nine patients with primary high-risk PCa completed the whole-pelvis radiotherapy plan based on PSMA PET/MRI and MRI. The primary endpoint compared the size and overlap of clinical target volume (CTV) and nodal gross tumour volume (GTVn) based on PSMA PET/MRI and MRI. The diagnostic performance of two methods for pelvic lymph node metastasis (PLNM) was evaluated. RESULTS: In the radiotherapy planning for high-risk PCa patients, there was a significant correlation between MRI-CTV and PET/MRI-CTV (P = 0.005), as well as between MRI-GTVn and PET/MRI-GTVn (P < 0.001). There are non-significant differences in the CTV and GTVn based on MRI and PET/MRI images (P = 0.660, P = 0.650, respectively). The conformity index (CI), lesion coverage factor (LCF) and Dice similarity coefficient (DSC) of CTVs were 0.999, 0.953 and 0.954. The CI, LCF and DSC of GTVns were 0.927, 0.284, and 0.32. Based on pathological lymph node analysis of 463 lymph nodes from 37 patients, the sensitivity, specificity of PET/MRI in the diagnosis of PLNM were 77.78% and 99.76%, respectively, which were higher than those of MRI (P = 0.011). Eight high-risk PCa patients who finished PSMA PET/MRI changed their N or M stage. CONCLUSION: The CTV delineated based on PET/MRI and MRI differ little. The GTVn delineated based on PET/MRI encompasses metastatic pelvic lymph nodes more accurately than MRI and avoids covering pelvic lymph nodes without metastasis. We emphasize the utility of PET/MRI fusion images in GTVn delineation in whole pelvic radiotherapy for PCa. The use of PSMA PET/MRI aids in the realization of more individual and precise radiotherapy for PCa.

Expression of connective tissue growth factor and interleukin-11 in intratumoral tissue is associated with poor survival after curative resection of hepatocellular carcinoma.

In the present study, we evaluated the prognostic value of intratumoral and peritumoral expression of connective tissue growth factor (CTGF), transforming growth factor-beta 1 (TGF-ß1), and interleukin-11 (IL-11) in patients with hepatocellular carcinoma (HCC) after curative resection. Expression of CTGF, TGF-ß1, and IL-11 was assessed by immunohistochemical staining of tissue microarrays containing paired tumor and peritumoral liver tissue from 290 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of these and other clinicopathologic factors were evaluated. The median follow-up time was 54.3 months (range, 4.3-118.3 months). High intratumoral CTGF expression was associated with vascular invasion (P = 0.015), intratumoral IL-11 expression correlated with higher tumor node metastasis (TNM) stage (P = 0.009), and peritumoral CTGF overexpression correlated with lack of tumor encapsulation (P = 0.031). Correlation analysis of these proteins revealed that intratumoral CTGF and IL-11 correlated with high intratumoral TGF-ß1 expression (r = 0.325, P < 0.001; and r = 0.273, P < 0.001, respectively). TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.010), and intratumoral IL-11 expression (P = 0.015) were independent prognostic factors for progression-free survival (PFS). Vascular invasion (P = 0.032), TNM stage (P < 0.001), high intratumoral CTGF levels (P = 0.036), and intratumoral IL-11 expression (P = 0.013) were independent prognostic factors for overall survival (OS). High intratumoral CTGF and intratumoral IL-11 expression were associated with PFS and OS after hepatectomy, and the combination of intratumoral CTGF with IL-11 may be predictive of survival.

The expression of HIF-1α in primary hepatocellular carcinoma and its correlation with radiotherapy response and clinical outcome.

The purpose of this study was to evaluate the relationship between hypoxia-inducible factor-1α (HIF-1α) protein expression in hepatocellular carcinoma (HCC), and responses of abdominal metastatic lymph nodes (LNs) from HCC patients treated with external beam radiotherapy (EBRT). HIF-1α immunohistochemical staining was performed on tissue microarrays (TMAs) of primary HCC specimens from 69 HCC patients with abdominal LN metastases. All patients received abdominal metastatic LN EBRT at the Department of Radiation Oncology at Zhongshan Hospital. A receiver-operating characteristic (ROC)-based approach and logistical regression analysis were used to determine the predictive value of HIF-1α expression in primary tumors with HCC metastatic LN EBRT response. Kaplan-Meier curves and log-rank tests were used to analyze patient survival. Cox proportional hazards regression model was used to analyze independent prognostic factors. HIF-1α expression was correlated with blood hemoglobin (Hb: r = -0.280, P = 0.020), response of abdominal metastatic LNs to EBRT (r = 0.286, P = 0.017), locoregional recurrence (r = 0.278, P = 0.021), and cancer-specific deaths (r = 0.298, P = 0.013). HIF-1α expression was predictive of EBRT response of metastatic LNs [area under the curve (AUC): 0.646; 95% confidence interval (CI): 0.499-0.793; P = 0.047], locoregional recurrence (AUC: 0.657; 95% CI: 0.509-0.805; P = 0.049) and cancer-specific deaths (AUC: 0.671; 95% CI: 0.531-0.812; P = 0.035). Patients with tumors exhibiting high HIF-1α expression had significantly poorer overall survival (OS) than those with low tumor expression of HIF-1α (P = 0.016). Multivariate analysis showed that Hb (P = 0.035), vascular invasion (P = 0.026), Child-Pugh score (P < 0.001), intrahepatic tumor control (P < 0.001), and HIF-1α (P = 0.020) were independent prognosis factors for OS of HCC patients after receiving abdominal metastatic LN EBRT. HIF-1α expression in primary HCCs was associated with EBRT response of abdominal metastatic LNs and poor prognosis.

Identification of a Prognostic Transcriptome Signature for Hepatocellular Carcinoma with Lymph Node Metastasis.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, and the prognosis of HCC patients with lymph node metastasis (LNM) is poor. However, robust biomarkers for predicting the prognosis of HCC LNM are still lacking. This study used weighted gene coexpression network analysis of GSE28248 (N = 80) microarray data to identify gene modules associated with HCC LNM and validated in GSE40367 dataset (N = 18). The prognosis-related genes in the HCC LNM module were further screened based on the prognostic curves of 371 HCC samples from TCGA. We finally developed a prognostic signature, PSG-30, as a prognostic-related biomarker in HCC LNM. The HCC subtypes identified by PSG-30-based consensus clustering analysis showed significant differences in prognosis, clinicopathological stage, m6A modification, ferroptosis activation, and immune characteristics. In addition, RAD54B was selected by regression model as an independent risk factor affecting the prognosis of HCC patients with LNM, and its expression was significantly positively correlated with tumor mutational burden and microsatellite instability in high-risk subtypes. Patients with high RAD54B expression had a better prognosis in the immune checkpoint inhibitor-treated cohorts but had a poor prognosis in the HCC sorafenib-treated group. The association of high RAD54B expression with LNM in breast cancer (BRCA) and cholangiocarcinoma and its prognostic effect in BRCA LNM cases suggest the value of RAD54B at the pancancer level. In conclusion, PSG-30 can effectively identify HCC LNM population with poor prognosis, and high-risk patients with high RAD54B expression may be more suitable for immunotherapy.

Adjuvant chemotherapy improves survival in high-risk stage II colon cancer: a retrospective cohort study.

Background: The survival advantage of postoperative chemotherapy for high-risk stage II colon cancer (CC) patients remains unclear. Objectives: The purpose was to evaluate the survival of high-risk stage II CC cases treated with chemotherapy and to construct survival prediction models to predict the survival benefit from chemotherapy. Design: The study is a retrospective observational cohort study. Methods: Data on patients with stage II CC diagnosed from 2005 to 2019 who underwent radical surgery were obtained from the Surveillance, Epidemiology and End Results (SEER) database. A 1:1 propensity score matching (PSM) was applied to obtain two cohorts, chemotherapy versus no chemotherapy. A chi-square analysis was used to assess the differences before and after PSM in the above two groups. Kaplan-Meier survival analysis and Cox proportional hazards regression were applied to investigate the 5- and 10-year overall survival (OS) and cancer cause-specific survival (CSS). The predictive power of the constructed models was assessed by the concordance index (C-index) and calibration curves. Results: Of the 37,050 cases, 14,744 (39.8%) stage II CC were at high-risk and 29.2% of them received chemotherapy. Age, T stage, marital status, histologic grade, gender, and site independently influenced the reception of chemotherapy. The survival advantage of chemotherapy in the high-risk patients remained positive before and after PSM. The estimated 3, 5, and 10 years OS rates of chemotherapy group were 9.3, 10.7, and 15.6% higher than the nonchemotherapy group, respectively. Four nomograms predicting OS and CSS were established, with great discrimination (C-index between 0.627 and 0.691) and excellent calibration. Conclusion: Postoperative chemotherapy is beneficial for high-risk stage II CC patients, including the elderly patients (over 65 years of age). Our study developed nomograms to quantify the survival benefit of chemotherapy among high-risk stage II CC patients to develop personalized treatment recommendations and guide management decisions.

Gross tumor volume delineation in primary prostate cancer on 18F-PSMA-1007 PET/MRI and 68Ga-PSMA-11 PET/MRI.

BACKGROUND: We aimed to assess the clinical value of 18F-PSMA-1007 and 68Ga-PSMA-11 PET/MRI in the gross tumor volume (GTV) delineation of radiotherapy for prostate cancer (PCa). METHODS: Sixty-nine patients were retrospectively enrolled (57 in the 18F subgroup and 12 in the 68Ga subgroup). Three physicians delineated the GTV and tumor length by the visual method and threshold method with thresholds of 30%, 40%, 50%, and 60% SUVmax. The volume correlation and differences in GTVs were assessed. The dice similarity coefficient (DSC) was applied to estimate the spatial overlap between GTVs. For 51 patients undergoing radical prostatectomy, the tumor length (Lpath) of the maximum area was measured, and compared with the longest tumor length obtained based on the images (LMRI, LPET/MRI, LPET, LPET30%, LPET40%, LPET50%, LPET60%) to determine the best delineation method. RESULTS: In the 18F subgroup, (1) GTV-PET/MRI (p < 0.001) was significantly different from the reference GTV-MRI. DSC between them was > 0.7. (2) GTV-MRI (R2 = 0.462, p < 0.05) was the influencing factor of DSC. In the 68Ga subgroup, (1) GTV-PET/MRI (p < 0.05) was significantly different from the reference GTV-MRI. DSC between them was > 0.7. (2) There was a significant correlation between GTV-MRI (r = 0.580, p < 0.05) and DSC. The longest tumor length measured by PET/MRI was in good agreement with that measured by histopathological analysis in both subgroups. CONCLUSION: It is feasible to visually delineate GTV on PSMA PET/MRI in PCa radiotherapy, and we emphasize the utility of PET/MRI fusion images in GTV delineation. In addition, the overlap degree was the highest between GTV-MRI and GTV-PET/MRI, and it increased with increasing volume.

Potential prognostic biomarkers for bone metastasis from hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) most commonly develops in patients who have a viral infection, especially in the case of hepatitis B virus (HBV), and in patients with a chronic liver disease. HCC patients with bone metastasis (BM) suffer from pain and other symptoms that significantly reduce their quality of life. Identification of patients who are at high risk for BM after undergoing potentially curative treatment for HCC remains challenging. Here, we aimed to identify HCC BM-related genes and proteins to establish prediction biomarkers. METHODS: RNA was extracted from 48 pairs of intratumoral and peritumoral formalin-fixed, paraffin-embedded tissue from HCC patients with and without BM. A cDNA-mediated annealing, selection, extension and ligation assay containing 502 cancer-related genes was used to identify novel BM-associated genes. An additional independent study with 350 HCC patients who had undergone hepatectomy was conducted to evaluate the expression of candidate genes at the protein level using immunohistochemistry on tissue microarrays (TMAs). Of the 350 patients, 273 (78.0%) were infected with HBV. RESULTS: Seven intratumoral genes and 17 peritumoral genes were overexpressed in patients with BM, whereas 15 intratumoral genes and 28 peritumoral genes were underexpressed in patients with BM. We selected the following four genes for further analysis because they were differentially expressed in the cancer gene-specific microarray and were previously reported to be associated with BM: connective tissue growth factor (CTGF), matrix metalloproteinase-1 (MMP-1), transforming growth factor ß1 (TGF-ß1), and interleukin-11 (IL-11). We assessed the protein expression of these selected genes using immunohistochemistry on TMAs including 350 HCC patient specimens. We determined that expression of intratumoral CTGF, intratumoral IL-11, and peritumoral MMP-1 were independent prognostic factors for developing BM in HCC patients. Combining intratumoral CTGF and IL-11 expression was also an independent risk factor for BM development. CONCLUSIONS: Sixty-seven genes were differentially expressed in HCC patients with and without BM. High intratumoral CTGF, positive IL-11, and high peritumoral MMP-1 expression were associated with BM after hepatectomy. Intratumoral CTGF expression combined with IL-11 expression may serve as a useful predictive biomarker for HCC BM.

Expression of cytokeratin 19 and matrix metalloproteinase 2 predicts lymph node metastasis in hepatocellular carcinoma.

The purpose of this study was to assess the value of cytokeratin 19 (CK19) and matrix metalloproteinase 2 (MMP-2) in predicting lymph node metastasis (LNM) and survival after curative resection in hepatocellular carcinoma (HCC) patients. Expression of CK19 and MMP-2 in tumor tissue was assessed through immunohistochemical staining of tissue microarrays (TMAs), which were constructed using samples from HCC patients with (n = 123) and without (n = 145) LNM. Positive CK19 expression was correlated with LNM (P < 0.001), satellite lesions (P = 0.016), and lymph node location (P = 0.039). High MMP-2 expression correlated with LNM (P < 0.001), UICC T stage (P = 0.023), and Edmondson grade (P = 0.022). Moreover, CK19 expression correlated with MMP-2 expression (P = 0.033). CK19 and MMP-2 expression were predictive of HCC LNM (AUC: 0.640; 95% CI: 0.572-0.707; P < 0.001 and AUC: 0.611; 95% CI: 0.544-0.679; P = 0.002, respectively). CK19 and MMP-2 expression were independent prognostic factors for disease-free survival (P = 0.031 and P = 0.012, respectively) and overall survival (P = 0.013 and P = 0.018, respectively) in HCC patients with LNM. CK19 expression (P < 0.001), MMP-2 expression (P = 0.006), and UICC T stage (P < 0.001) were independent risk factors for developing LNM in HCC. These findings show that CK19 and MMP-2 expression may be beneficial in predicting HCC LNM and survival.

Establishment and Validation of Prognostic Nomograms for Patients With Parotid Gland Adenocarcinoma Not Otherwise Specified: A SEER Analysis From 2004 to 2016.

Background: Parotid gland adenocarcinoma not otherwise specified (PANOS) is a rare malignant tumor with limited data on its characteristics and prognosis. This research is aimed at characterizing PANOS and developing prognostic prediction models for patients with PANOS. Methods: Cases from 2004-2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) Program database. Univariate and multivariate Cox regression were applied to ascertain the factors associated with survival. Competing risk analysis and Gray's tests were employed to analyze cancer-specific death. Propensity score matching (1:1) was conducted to reduce the influence of confounding variables. Results: A total of 446 patients with a median age of 66 years were selected, of which 307 were diagnosed with stage III/IV PANOS. The 5-year overall survival (OS) rate of all patients was 51.8%, and the median survival time was 66 months. Surgical treatment clearly improved survival time (p < 0.001). In the subgroup analysis, radiotherapy showed survival benefits in patients with stage III/IV disease (p < 0.001). Multivariate Cox regression analyses showed that age, T classification, N classification, M classification and surgery were independent prognostic indicators for OS; T classification, N classification, M classification and surgery were independent risk factors for cancer-specific survival (CSS). In addition, age was independently associated with other cause-specific death. Based on the results of multivariate analysis, two nomograms were developed and verified by the concordance index (C-index) (0.747 and 0.780 for OS and CSS) and the area under the time-dependent receiver operating characteristic (ROC) curve (0.756, 0.764, and 0.819 regarding for nomograms predicting 3-, 5-, and 10- year OS, respectively and 0.794, 0.789, and 0.806 for CSS, respectively). Conclusions: Our study clearly presents the clinicopathological features and survival analysis of patients with PANOS. In addition, our constructed nomogram prediction models may assist physicians in evaluating the individualized prognosis and deciding on treatment for patients.

A nomogram to predict the prognosis of patients with unresected rectal adenocarcinoma undergoing chemoradiotherapy: a population-based study.

Background: Chemotherapy combined with radiotherapy is the main treatment strategy for unresectable rectal cancer. However, the prognostic factors of patients with unresectable rectal cancer treated with radiotherapy and chemotherapy have not been systematically studied. Therefore, this study investigated the prognostic factors and prognosis based on surveillance, epidemiology and final results of the SEER medical insurance database. Methods: Primary rectum patients were selected from the SEER database. The independent prognostic factors associated with overall survival (OS), cancer-specific survival (CSS) and noncancer-related death were evaluated using the Kaplan-Meier method and log-rank test, a competing risk model, and the Cox proportional hazards regression model. Two nomograms were established for predicting the 1- and 3-year OS and CSS of patients. Results: A total of 3,998 rectal adenocarcinoma cancer patients who received chemoradiotherapy but had not undergone surgery were included in this study and divided into training (n = 3559) and validation cohorts (n = 439). Patients in the training cohort had a 1-year OS rate of 65.7±0.8%, a 3-year OS rate of 26.6±0.8%, a 5-year OS rate of 1.6±0.8%, and a median survival rate of 20.0 months (range, 19.22-20.8 months). The following factors were significant prognostic factors of OS: age (p< 0.001); tumour grade (p< 0.001); T stage (p< 0.001); M stage (p< 0.001); bone metastasis (p<0.001); brain metastases (p<0.001); liver metastases (p<0.001); lung metastases (p<0.001); marital status (p<0.001) and insurance status (p=0.005). Age (p< 0.001), tumour grade (p< 0.001), T stage (p< 0.001), M stage (p< 0.001), bone metastasis (p<0.001), brain metastases (p<0.001), liver metastases (p<0.001), lung metastases (p<0.001) and race (p=0.034) were independent prognostic factors of CSS. Age (p< 0.001), T stage (p< 0.001), N stage (p=0.007), M stage (p<0.001), liver metastases (p<0.001), lung metastases (p<0.001), marital status (p<0.001) and insurance status (p=0.019) were independently associated with noncancer-related death. Conclusion: Age, tumour grade, T and M stage, bone, brain, liver and lung metastases, marital status and insurance status are independent risk factors for the OS of rectal adenocarcinoma patients who have undergone chemoradiotherapy but have not undergone surgery. Age, tumour grade, T stage, M stage, bone, brain, liver, lung metastases and race were independent prognostic factors of CSS. Age, T, N and M stage, liver and lung metastases, marital status and insurance status, were independently associated with noncancer-related death. Interestingly, the earlier the T stage was, the higher the rate of noncancer-related death. Two nomograms were developed to predict OS and CSS, and the C-indexes were 0.6776 and 0.6744, respectively. Rectal cancer screening is strongly recommended for patients under the age of 50.

Evaluation of Hybrid PET/MRI for Gross Tumor Volume (GTV) Delineation in Colorectal Cancer Liver Metastases Radiotherapy.

PURPOSE: Hybrid PET/MRI has been increasingly incorporated into the practice of radiation oncologists since it contains both anatomical and biological data and may bring about personalized radiation plans for each patient. The objective of this study was to evaluate the feasibility of GTV delineation from hybrid PET/MRI compared with that from current-practice MRI during radiotherapy planning in patients with colorectal liver metastases. PATIENTS AND METHODS: Twenty-four patients (thirty lesions) with colorectal liver metastases were prospectively enrolled in this study. Three physicians delineated the target volume with the most popular delineating methods-the visual method. First of all, differences among the three observers were assessed. The difference and correlation of GTV values obtained by MRI, PET, and hybrid PET/MRI were subjected to statistical analysis afterwards. Finally, the dice similarity coefficient (DSC) was calculated to assess the spatial overlap. Based on the value of DSC, we also evaluate the correlation between DSC and tumor size. GTV-MRI was set as a reference. RESULTS: There was no significant difference among observers in GTV-MRI (F=0.118, p=0.889), GTV-PET (F=0.070, p=0.933) and GTV-PET/MRI (F=0.40, p=0.961). 83.33% of GTV-PET/MRI and 63.33% of GTV-PET were larger than the reference GTV-MRI. Statistical analysis revealed that GTV-PET/MRI (p<0.001) and GTV-PET (p<0.05) diverged statistically significantly from GTV-MRI. GTV-PET (r=0.992, p<0.001) and GTV-PET/MRI (r=0.997, p<0.001) were significantly related to GTV-MRI. The average DSC value between GTV-MRI and GTV-PET was 0.51 (range 0-0.90) and that between GTV-MRI and GTV-PET/MRI was 0.72 (range 0.42-0.90). There was a positive correlation between the DSC and GTV-MRI (r=0.851, p<0.05). CONCLUSION: With the database used, there is good agreement among observers. Hybrid PET/MRI in colorectal liver metastases radiotherapy may affect the GTV delineation. Moreover, the overlap degree between GTV-MRI and GTV-PET/MRI is higher and increases with volume.