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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, The tumor mutational burden (TMB) value correlated with smoking status in lung adenocarcinoma patients, but not in lung squamous cell carcinoma patients in both NGS panels. The TMB value combined with smoking status might be used as a potential prognostic indicator for advanced non‐small cell lung cancer patients receiving immune checkpoint inhibitor combination therapy.

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.

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.

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.

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 A...

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, Emba...

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.

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) compared with other parameters in LC patients. Decreased preoperative LCR was an independent prognostic factor for first-line PFS and OS (p 0.05) in patients. Conclusion: Pretreatment LCR is a promising biomarker for first-line PFS and OS in patients with LC.

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.

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.

To investigate the prevalence of

Objective: There is no satisfactory indicator for monitoring recurrence after resection in hepatocellular carcinoma (HCC). For patients without metastasis after hepatectomy, an HCC monitor recurrence (HMR) model was designed and validated by a multicenter retrospective study. Methods: A training cohort was recruited of 1179 patients with HCC without metastasis after hepatectomy from February 2012 to December 2015. An HMR model was proposed with an AdaBoost classifier algorithm; 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 relative to that of the traditional AFP monitoring recurrence model based on the areas under the respective receiver operating characteristic curves (AUCs). Prediction of recurrence was evaluated relative to computed tomography/magnetic resonance imaging (CT/MRI). The model was validated via an internal cohort comprising 695 patients, and two external cohorts of 30 and 33 patients, respectively. Results: In preoperative patients with positive or negative AFP, the AUCs of the HMR model (0.8708-0.9609) indicated better diagnostic efficacy compared with serum AFP (0.7348-0.8196). The HMR model predicted recurrence earlier than did CT/MRI, by 77.64 to 191.58 days. Conclusion: The HMR model was more accurate than serum AFP for monitoring recurrence after hepatectomy of HCC, and can be used for real-time monitoring of the postoperative status of patients with HCC without metastasis. The HMR model should help individualize strategies for reexaminations, and guide adjuvant treatment schemes for patients with HCC. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant no. 81602468 & 81800556). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The Ethics Committee of Sun Yat-Sen University Cancer Center (SYSUCC) approved this study. Every participant provided signed informed consent.

Simple Summary Previous studies have established an electrochemical detection method for the rapid detection of cfDNA (circulating free DNA) methylation and found that this technology might be a potential method for cancer diagnosis. However, the underlying mechanism and its role in the diagnosis and prognosis of malignant tumors are not well-characterized. In present study, we utilized the electrochemical detection method to detect the DNA methylation status by using electron microscopies and infrared spectroscopy and found that DNA with different methylated levels adsorbed to the gold surface differently, which was likely mediated by hydrophobic bonds. In addition, after detection of the cfDNA methylation status from 505 normal individuals, 725 cancer patients before treatment, and 549 patients after treatment, we found that the cfDNA adsorption rate could be used as an indicator for the diagnosis and prognosis prediction of pan-cancer. Our research provides a novel method for the liquid biopsy of cancer for diagnosis and prognosis predictions. Abstract 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).

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.

The objective of this study was to determine the effect of light-emitting diode (LED) irradiation on the migration and proliferation of keratinocytes.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.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.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.LED irradiation may increase keratinocyte migration via HIF-1α-dependent cytoskeletal reorganization.