The Prognostic Value of Alpha-Fetoprotein Ratio in Patients With Resectable Alpha-Fetoprotein-Negative Hepatocellular Carcinoma.

PURPOSE: This study aimed to investigate the prognostic value of alpha-fetoprotein (AFP) ratio in patients with AFP-negative hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We retrospectively analyzed 600 AFP-negative HCC patients who underwent hepatectomy. The AFP ratio was calculated as the ratio of AFP level 1 week before surgery to the level 20-40 days after hepatectomy. Immunohistochemistry assay was used to assess protein expression in HCC tissue. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). RESULTS: The study found that a cutoff value of 1.6 ng/ml for AFP ratio, determined using X-tile software, was optimal for predicting prognosis. Patients with a high AFP ratio had a worse prognosis compare to those with a low AFP ratio (DFS, P = .026; OS, P = .034). Patients with a high AFP ratio had a worse prognosis compared to those with a low AFP ratio. Multivariate analysis revealed that AFP ratio >1.6, negative HepPar-1 expression, and vascular invasion were independent predictors of both DFS and OS. Vascular invasion had a higher area under the curve (AUC) than AFP ratio and HepPar-1 expression in predicting recurrence and death. The combination of AFP ratio, HepPar-1 expression, and vascular invasion provided better predictive accuracy for DFS and OS. CONCLUSION: The AFP ratio is a potential prognostic marker for AFP-negative HCC patients after hepatectomy. Combining the analysis of AFP ratio with HepPar-1 expression and vascular invasion can enhance the accuracy of predicting prognosis in these patients.

Comprehensive analysis reveals potential therapeutic targets and an integrated risk stratification model for solitary fibrous tumors.

Solitary fibrous tumors (SFTs) are rare mesenchymal tumors with unpredictable evolution and with a recurrence or metastasis rate of 10-40%. Current medical treatments for relapsed SFTs remain ineffective. Here, we identify potential therapeutic targets and risk factors, including IDH1 p.R132S, high PD-L1 expression, and predominant macrophage infiltration, suggesting the potential benefits of combinational immune therapy and targeted therapy for SFTs. An integrated risk model incorporating mitotic count, density of Ki-67+ cells and CD163+ cells, MTOR mutation is developed, applying a discovery cohort of 101 primary non-CNS patients with negative tumor margins (NTM) and validated in three independent cohorts of 210 SFTs with the same criteria, and in 36 primary CNS SFTs with NTM. Compared with the existing models, our model shows significantly improved efficacy in identifying high-risk primary non-CNS and CNS SFTs with NTM for tumor progression.Our findings hold promise for advancing therapeutic strategies and refining risk prediction in SFTs.

A Model Based on Artificial Intelligence Algorithm for Monitoring Recurrence of HCC after Hepatectomy.

BACKGROUND: There is no satisfactory indicator for monitoring recurrence after resection of hepatocellular carcinoma (HCC). This retrospective study aimed to design and validate an HCC monitor recurrence (HMR) model for patients without metastasis after hepatectomy. METHODS: A training cohort was recruited from 1179 patients with HCC without metastasis after hepatectomy between February 2012 and December 2015. An HMR model was developed using an AdaBoost classifier algorithm. The factors included patient age, TNM staging, tumor size, and pre/postoperative dynamic variations of alpha-fetoprotein (AFP). The diagnostic efficacy of the model was evaluated based on the area under the receiver operating characteristic curves (AUCs). The model was validated using a cohort of 695 patients. RESULTS: In preoperative patients with positive or negative AFP, the AUC of the validation cohort in the HMR model was .8877, which indicated better diagnostic efficacy than that of serum AFP (AUC, .7348). The HMR model predicted recurrence earlier than computed tomography/magnetic resonance imaging did by 191.58 ± 165 days. In addition, the HMR model can predict the prognosis of patients with HCC after resection. CONCLUSIONS: The HMR model established in this study is more accurate than serum AFP for monitoring recurrence after hepatectomy for HCC and can be used for real-time monitoring of the postoperative status in patients with HCC without metastasis.

Alpha-Fetoprotein Ratio Predicts Alpha-Fetoprotein Positive Hepatocellular Cancer Patient Prognosis after Hepatectomy.

BACKGROUND: This study was conducted to investigate the effect of alpha-fetoprotein (AFP) ratio on the prognosis of AFP-positive hepatocellular carcinoma (HCC) patients after hepatectomy. METHODS: We retrospectively included 879 HCC patients with AFP-positive who underwent hepatectomy from February 2012 to October 2017 and randomly divided into training cohort and validation cohort. AFP ratio was equal to the AFP level within one week before hepatectomy to AFP level within 20-40 days after surgery. The end point of follow-up was disease-free survival (DFS) and overall survival (OS). RESULTS: AFP ratio was not associated with clinical characteristics in training cohort and validation cohort. According to the X-tile software, the optimum cut-off point was 17.8 for AFP ratio. Significant differences between AFP ratio high and AFP ratio low were observed in DFS and OS in both cohort (p < 0.05). Kaplan-Meier curves and receiver-operating curves were showed that AFP ratio was better than AFP level preoperation in predicting the prognosis of AFP-positive HCC patients after hepatectomy. The multivariate analysis demonstrated that AFP ratio was a significant independent risk factor for both OS and DFS in HCC patients with AFP-positive. CONCLUSIONS: AFP ratio might be a prognosis predictor for HCC patients with AFP-positive after hepatectomy.

Sleep quality, anxiety and depression in advanced lung cancer: patients and caregivers.

OBJECTIVE: To investigate the clinical implications of sleep quality, anxiety and depression in patients with advanced lung cancer (LC) and their family caregivers (FCs). METHODS: A total of 98 patients with advanced LC and their FCs (n=98) were recruited from the Oncology Department in Nanfang Hospital. The Pittsburgh Sleep Quality Index (PSQI), consisting of seven components that evaluate subjective sleep quality, sleep latency, duration of sleep, sleep efficiency, sleep disturbances, sleep medication usage and daytime dysfunction, was used to assess sleep quality. Using the tool of Zung Self-rating Anxiety Scale (SAS) and Zung Self-rating Depression Scale (SDS), we tested the patients' status of anxiety and depression, respectively. RESULTS: The prevalences of poor sleep quality, anxiety and depression in patients were 56.1%, 48.9% and 56.1%, respectively, while those in FCs were 16.3%, 32.6% and 25.5%, respectively. Patients had higher PSQI, SAS and SDS scores than did FCs (p<0.05). Significant correlations were found between the patients' and FCs' scores of PSQI/SAS/SDS (p<0.05). Multivariate Cox regression analyses indicated that sleep disturbances in patients (HR 0.413, 95% CI 0.21 to 0.80, p=0.01) and the global PSQI score of FCs (HR 0.31, 95% CI 0.14 to 0.71, p=0.00) were independent risk factors for patients' first-line progression-free survival (PFS). Moreover, patients' sleep latency (HR 2.329, 95% CI 1.36 to 3.96, p=0.00) and epidermal growth factor receptor mutations (HR 1.953, 95% CI 1.12 to 3.38, p=0.01) were significant prognostic factors for their overall survival (OS). CONCLUSIONS: We demonstrated that presence of sleep disturbances in patients with advanced LC and the global PSQI Score of their FCs may be risk predictors for patients' poor first-line PFS. Patients' sleep latency was a potential risk factor for their OS.

Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer.

BACKGROUND: This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy. METHODS: We conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. RESULTS: We enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05). CONCLUSIONS: The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.

Diagnostic and Prognostic Characteristics of Circulating Free DNA Methylation Detected by the Electrochemical Method in Malignant Tumors.

Prior research has established an electrochemical method based on the differential adsorption capacity of gold surfaces with different methylated DNA degrees and found that this method might be valuable for cancer diagnosis by detecting circulating free DNA methylation. However, further investigation on the underlying mechanism and validation of its diagnostic and prognostic values in a large cohort of malignant tumors was limited. We found that DNA with different methylation levels formed particles of diverse sizes on the gold surface. Hydrophobic bonds played a significant role in the binding process of methylated DNA to the gold surface. The detection condition of an adsorption time of 10 min and temperature of 20 °C was optimal. In a large cohort of plasma samples from the patients with different malignant tumors, as well as normal individuals, we found that the electrochemical detection method based on the differential adsorption capacity of methylated DNA degree on a gold surface could be used as a noninvasive tool for malignant tumor diagnosis and prognostic evaluation. The diagnostic efficiency of this method in malignant tumors was even slightly better than that of the current tumor biomarkers widely used in routine clinical practice (circulating free DNA (cfDNA) vs. carcinoembryonic antigen (CEA), 0.8131 vs. 0.7191 and cfDNA vs. CA19-9, 0.7687 vs. 0.6693).

Plasma SGIP1 methylation in diagnosis and prognosis prediction in hepatocellular carcinoma.

Aberrant methylation of some genes can serve as promising biomarkers in hepatocellular carcinoma (HCC). This study aimed to investigate the diagnostic and prognostic value of plasma SGIP1 methylation in HCC. The study included a total of 269 subjects, of which 129 were with HCC, 45 with liver cirrhosis (LC), 45 with chronic hepatitis B (CHB), and 50 were healthy controls (HCs). The aberrant methylation was detected by quantitative methylation-specific polymerase chain reaction (qMSP). The area under the curve (AUC) was 0.872 in distinguishing HCC from HCs, with a sensitivity of 85.3% and a specificity of 88%. The AUC was 0.728, when it distinguished HCC from CHB, with a sensitivity of 43.4% and a specificity of 97.8%. The AUC was 0.728 in distinguishing HCC from LC, with a sensitivity of 43.4% and a specificity of 97.8%. Elevated levels of SGIP1 methylation in HCC patients showed poorer overall survival (OS), progression-free survival (PFS), and metastasis-free survival (MFS) than those with low levels (Kaplan-Meier method and the log-rank test, p<0.05). SGIP1 methylation in different study groups demonstrated different sensitivities. SGIP1 methylation detection in the plasma may serve as a non-invasive diagnostic and prognostic biomarker for HCC.

Lymphocyte-to-C-reactive protein ratio is a potential new prognostic biomarker for patients with lung cancer.

Aim: To compare and evaluate the prognostic value of various pretreatment combinations of inflammatory factors in patients with lung cancer (LC). Materials & methods: This study enrolled 1005 patients with LC and categorized into a discovery cohort and a validation cohort. Results: A combination of Lymphocyte-to-C-reactive protein levels (LCR) demonstrated the highest correlation with poor first-line progression-free survival (PFS) and overall survival (OS) (p < 0.05), but not disease-free survival (p > 0.05) compared with other parameters in LC patients. Decreased preoperative LCR was an independent prognostic factor for first-line PFS and OS (p < 0.05), but not disease-free survival (p > 0.05) in patients. Conclusion: Pretreatment LCR is a promising biomarker for first-line PFS and OS in patients with LC.

Risk stratification for nasopharyngeal carcinoma: a real-world study based on locoregional extension patterns and Epstein-Barr virus DNA load.

AIM: The present study aimed to evaluate the combined value of locoregional extension patterns (LEPs) and circulating cell-free Epstein-Barr virus (cf EBV) DNA for risk stratification of locoregionally advanced nasopharyngeal carcinoma (LA-NPC) to better guide therapeutic strategies. METHODS: A total of 7227 cases of LA-NPC were reviewed retrospectively and classified into six groups according to their LEP (ascending, descending, or mixed type) and pre-treatment cf EBV-DNA load (⩾ versus <4000 copy/ml). Using a supervised statistical clustering approach, patients in the six groups were clustered into low, intermediate, and high-risk clusters. Progression-free survival (PFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS) were calculated using the Kaplan-Meier method and differences were compared using the log-rank test. RESULTS: Survival curves for the low, intermediate, and high-risk clusters were significantly different for all endpoints. The 5-year survival rate for the low, intermediate, and high-risk clusters, respectively, were: PFS (83.5%, 73.2%, 62.6%, p < 0.001), OS (91.0%, 82.7%, 73.2%, p < 0.001), DMFS (92.3%, 83.0%, 73.4%, p < 0.001), and LRRFS (91.0%, 88.0%, 83.3%, p < 0.001). The risk clusters acted as independent prognostic factors for all endpoints. Among the patients in the high-risk cluster, neoadjuvant chemotherapy combined with concurrent chemoradiotherapy (CCRT) significantly improved the patients 5-year PFS (66.4% versus 57.9%, p = 0.014), OS (77.6% versus 68.6%; p < 0.002), and DMFS (76.6% versus 70.6%; p = 0.028) compared with those treated with CCRT. CONCLUSION: Our results could facilitate the development of risk-stratification and risk-adapted therapeutic strategies for patients with LA-NPC.

Effect of delta α-fetoprotein on the detection of liver cancer recurrence.

BACKGROUND: We explored the ability of delta α-fetoprotein (ΔAFP) to detect recurrence in patients with liver cancer treated with hepatectomy. METHODS: A total of 1,846 patients diagnosed with local liver cancer who underwent hepatectomy at Sun Yat-sen University Cancer Center were enrolled in the present study. Receiver operating characteristic curve analysis was used to determine the cutoff value of ΔAFP at the last follow-up or recurrence. RESULTS: Recurrence occurred in 51.5% (950/1,846) of liver cancer patients. The cutoff value of ΔAFP was 1.295 ng/mL in our model. Sensitivity in our model was higher than the normal range for AFP level for detecting recurrence (59.8% vs. 43.8%), but specificity was similar (98.4% vs. 99.8%). ΔAFP in preoperative AFP-positive patients (77.16% vs. 63.28%) and AFP-negative patients (31.20% vs. 11.70%) was more sensitive than normal AFP. ΔAFP was superior to AFP in the early (78.13% vs. 63.75%) or late recurrence (56.08% vs. 39.75%) of liver cancer. Moreover, in 18.3% of patients with recurrence (174/950), ΔAFP detected recurrence earlier than computed tomography/magnetic resonance imaging by 158.33 days. ΔAFP during follow-up indicated a worse prognosis after hepatectomy. CONCLUSIONS: The cutoff value of ΔAFP is more sensitive for monitoring recurrence than a normal AFP level in liver cancer patients.

The prevalence of EML4-ALK variants in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

To investigate the prevalence of EML4-ALK variants in non-small-cell lung cancer (NSCLC) patients. Materials & methods: Database of Pubmed, Embase, Medline and Cochrane Library were searched systematically to April 2018. Results: A total of 39 articles including 1903 NSCLC patients with ALK positive were recruited. The overall pooled prevalence for EML4-ALK variant 1 to 3 was 81.84% (95% CI: 76.68-86.99%), ranging from 86.64% tested by RT-PCR to 70.85% tested by other methods (p = 0.00). Subgroup analysis showed that the pooled prevalences of variant 1, 2 and 3 were 40.38% (95% CI: 34.83-45.93%), 6.59% (95% CI: 4.27-8.91%) and 26.54% (95% CI: 20.89-32.2%), respectively. Conclusion: This present study provides the exact prevalence of EML4-ALK rearrangement in different variants for NSCLC patients with ALK positive.

The Percentage of Anaplastic Lymphoma Kinase-Positive Tumor Cells Has Clinical Implications for Patients with Non-Small Cell Lung Cancer.

Objectives: Anaplastic lymphoma kinase (ALK) is one of the leading therapeutic targets in patients with non-small cell lung cancer (NSCLC). However, the clinical importance that the percentage of ALK-positive tumor cells has on NSCLC remains unclear. Methods: A total of 344 ALK-positive patients were enrolled in this study. The percentage of ALK-positive tumor cells was identified by fluorescence in situ hybridization. The discrimination and calibration analyses of the nomogram were estimated with Harrell's C-index. Results: Higher percentages (≥50%) of ALK-positive tumor cells were significantly correlated with male gender, poor differentiation, and normal levels of carbohydrate antigen 153 (CA153) and blood platelets (p < 0.05). A shorter first-line progression-free survival (PFS) was correlated with a lower percentage (15-49%) of ALK-positive tumor cells, chemotherapy, a poor performance state, non-adenocarcinoma, as well as abnormal CA153 and Cyfra21-1 levels; and an abnormal thrombin time (p < 0.05). A low percentage of ALK-positive tumor cells, crizotinib treatment, CA153 levels, and neutrophil count were independent risk factors for poor PFS in the multivariate analysis (p < 0.05). The nomogram showed a C-index of 0.76 for first-line PFS. Conclusion: A nomogram including the percentage of ALK-positive tumor cells may act as a crucial indicator for first-line PFS in ALK-positive NSCLC patients.

Prognostic Implications of Tripartite Motif Containing 24 Expression Levels in Patients with Solid Tumors: A Systematic Review and Meta-Analysis.

Objective: To systematically investigate the prognostic implications of tripartite motif containing 24 (Trim 24) expression levels in Patients with solid tumors. Materials and Methods: Pubmed, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched through December 2017 to identify studies examining the relationship between Trim 24 expression levels and outcomes in solid tumor patients. The hazard ratios (HRs) with corresponding 95% confidence intervals were used to evaluate the association between Trim 24 and overall survival (OS). Results: Ten studies with 1370 patients were included. The overall pooled prevalence for Trim 24 overexpression was 59.0% (p < 0.01). Moreover, the pooled HR of Trim 24 for OS was 0.43 (p = 0.04) by univariate analysis in 10 articles (1370) and 0.62 (p = 0.08) by multivariate analysis in 5 studies (845). Trim 24 over-expression was associated with tumor invasiveness (odds ratio [OR] = 2.05, p < 0.01) and tumor-node-metastasis stage (OR = 2.42, p = 0.03). Conclusions: This study demonstrated that Trim 24 expression levels may be a useful prognostic biomarker in patients with solid tumors.

Mutation spectrum of germline cancer susceptibility genes among unselected Chinese colorectal cancer patients.

Background: Genetic factors play an important role in colorectal cancer (CRC) risk, yet the prevalence and spectrum of germline cancer susceptibility gene mutations among unselected Chinese CRC patients is largely undetermined. Methods: We performed next-generation sequencing with a 73-genes panel and analyzed the prevalence and spectrum of germline mutations in 618 unselected Chinese CRC patients. We classified all identified germline alterations for pathogenicity and calculated the frequencies of pathogenic mutations. Clinical characteristics were assessed by age and mutation status. Protein expressions and interactions of MLH1 missense variants were evaluated by western blot and co- immunoprecipitation. Results: Overall, 112 (18.1%) of 618 unselected Chinese CRC patients were found to carry at least one pathogenic or likely pathogenic variant (totaling 97 variants), including 70 (11.3%) Lynch syndrome (LS) mutation carriers and 42 (6.8%) non-LS mutation carriers. LS mutation carriers were significantly younger at CRC diagnosis and were more likely to have right-sided, poorly differentiated, early stage, high-frequency microsatellite instability (MSI-H) or dMMR CRC and a family history of cancer compared with noncarriers. Non-LS mutation carriers were more likely to be proficient mismatch repair (pMMR) than noncarriers (p=0.039). We found four clinical variables (gender, tumor histological stage, cancer stage and mutation status) that showed significant differences between patients younger and older than 50 years old. Higher mutation rates were found in patients under 50 years old (p=0.017). Thirty-three novel variants were discovered and evaluated as pathogenic mutations by our study. Conclusion: Given the high frequency and wide spectrum of mutations, genetic testing with a multigene panel should be considered for all Chinese CRC patients under 50 years old and is also needed to determine whether a gene is associated with CRC susceptibility and to promote clinical translation.

Hypermethylation of APC2 Is a Predictive Epigenetic Biomarker for Chinese Colorectal Cancer.

OBJECTIVE: To investigate methylation of the adenomatosis polyposis coli homologue (APC2) promoter and its correlation with prognostic implications in Chinese colorectal cancer (CRC). METHODS: The mRNA expression of APC2 in colorectal tissues was evaluated using the database of The Cancer Genome Atlas (TCGA). Methylation analysis of APC2 in tumor (n = 66) and corresponding adjacent formalin-fixed and paraffin-embedded (FFPE) tissues (n = 44) was performed by Sequenom EpiTYPER® and verified by cloning-based bisulfite sequencing analysis. Demethylation and retrieval of APC2 expression in cell lines HT29, HCT116, and SW480 were treated with 5-aza-2'-deoxycytidine (5-AZC). RESULTS: Analysis of TCGA showed that APC2 mRNA was significantly downregulated in primary tumors when compared to normal tissues (p < 0.05). APC2 methylation was upregulated (43.93% vs 7.31%, p < 0.05) in tumors compared to adjacent FFPE tissues. In vitro experiments demonstrated that 5-AZC downregulated the methylation of APC2 and retrieved its expression of mRNA and protein levels (p < 0.05). Multivariate Cox regression indicated that APC2_CPG_14 was an independent risk factor for overall survival (HR = 6.38, 95% CI: 1.59-25.64, p < 0.05). CONCLUSION: This study indicates that APC2 is hypermethylated and may be a tumorigenesis biomarker for Chinese CRC patients.

Light-Emitting Diode Irradiation (640 nm) Regulates Keratinocyte Migration and Cytoskeletal Reorganization Via Hypoxia-Inducible Factor-1α.

OBJECTIVE: The objective of this study was to determine the effect of light-emitting diode (LED) irradiation on the migration and proliferation of keratinocytes. BACKGROUND DATA: Keratinocytes play a key role in re-epithelialization during wound healing; it is speculated that low-level LED therapy might improve keratinocyte migration and proliferation. MATERIALS AND METHODS: Human keratinocyte cells (HKCs) were isolated from child or adult foreskins and irradiated with LED light with a wavelength of 640 nm and a dosage of 12 or 24 J/cm(2). Cell motility, migration, and proliferation were examined using live cell imaging, scratch assay, and a colorimetric cell counting assay, respectively. Hypoxia-inducible factor-1α (HIF-1α) protein levels were analyzed by using Western blotting. Filamentous actin (F-actin) was stained by phalloidin. YC-1 [3-(5-hydroxymethyl-2-furyl)-1-benzylindazole] was used as an HIF-1 inhibitor, and CoCl2 (cobalt chloride) and DMOG (dimethyloxaloyl glycine) are HIF-1α activators. RESULTS: LED irradiation significantly promoted cell motility and migration, but did not significantly influence cell proliferation in HKCs. Furthermore, LED irradiation resulted in a reorganization of cellular F-actin and a dramatic upregulation of HIF-1α expression. Suppression of HIF-1α using the compound YC-1 prevented reorganization of the actin cytoskeleton following LED irradiation, suggesting that the effect of LED irradiation on the cytoskeleton is mediated through HIF-1α. Conversely, chemical activation of HIF-1α via DMOG or CoCl2 resulted in a reorganization of F-actin. CONCLUSIONS: LED irradiation may increase keratinocyte migration via HIF-1α-dependent cytoskeletal reorganization.