Distribution characteristics of immune infiltration and lymphovascular invasion in patients with breast cancer skin recurrence.

BACKGROUND: To assess the distribution characteristics of immune infiltration and lymphovascular invasion in breast cancer skin recurrence patients. METHODS: We retrospectively analyzed the clinicopathological data of patients who underwent radical surgery for primary breast cancer and experienced skin recurrence between January 2001 and April 2019. Immune and lymphovascular biomarkers were quantified in primary breast cancers, skin lesions and visceral metastatic lesions. Differences in biomarkers distribution between matched tissues were statistically analyzed using the Wilcoxon signed-rank test and Kruskal-Wallis one-way ANOVA. RESULTS: A total of 71 female breast cancer patients were reviewed in this study. Our study found that the expression levels of various lymphocyte immune markers in primary tumor specimens were higher than those in skin recurrences. The expression of CD8, CD57 and CD31 in primary breast cancer was higher than those in the skin. Compared to visceral metastatic lesions, D2-40 was highly expressed in the skin, while CD8 tended to decrease. In the skin specimens, the expression of CD8 (P < 0.001), FOXP3 (P = 0.006) and CD68 (P < 0.001) in the intratumoral area was higher, while the expression of CD57 (P < 0.001) was higher in the peritumoral area. Analyzing specimens from the same patient at different time points of skin progression, it was found that the expression of peritumoral CD4 decreased (P = 0.044) as the disease progressed. The low expression of D2-40 and CD163 in the skin lesions suggested a decrease in DFS. CONCLUSION: The immune microenvironment of breast cancer skin recurrence may be in a state of suppression, and this suppression may intensify with disease progression. The pattern of skin recurrence may be more inclined toward lymphatic invasion. Our study provides new insights into the biological behaviors of this disease and its response to immunotherapy.

Synergy of a CuO/C3N4 interface and CuO nanoparticles in the ethynylation of formaldehyde for 1,4-butynediol synthesis.

Catalysts made of CuO/Bi2O3 nanoparticles supported on g-C3N4 were synthesized using a MOF-derived strategy. The activation of CuO to CuCCCu species and stabilization of the catalyst were facilitated by the synergistic effect of the CuO/C3N4 interface and CuO nanoparticles, resulting in enhanced catalytic efficacy in the ethynylation of formaldehyde.

Redox homeostasis dysregulation in noise-induced hearing loss: oxidative stress and antioxidant treatment.

Noise exposure is an important cause of acquired hearing loss. Studies have found that noise exposure causes dysregulated redox homeostasis in cochlear tissue, which has been recognized as a signature feature of hearing loss. Oxidative stress plays a pivotal role in many diseases via very complex and diverse mechanisms and targets. Reactive oxygen species are products of oxidative stress that exert toxic effects on a variety of physiological activities and are considered significant in noise-induced hearing loss (NIHL). Endogenous cellular antioxidants can directly or indirectly counteract oxidative stress and regulate intracellular redox homeostasis, and exogenous antioxidants can complement and enhance this effect. Therefore, antioxidant therapy is considered a promising direction for NIHL treatment. However, drug experiments have been limited to animal models of NIHL, and these experiments and related observations are difficult to translate in humans; therefore, the mechanisms and true effects of these drugs need to be further analyzed. This review outlines the effects of oxidative stress in NIHL and discusses the main mechanisms and strategies of antioxidant treatment for NIHL.

Genetic analysis of oligo-recurrence breast cancer: correlation with clinical outcomes.

BACKGROUND: We aimed to identify the relationship between the genomic characteristics and clinical outcomes of oligo-metastatic breast cancer. METHODS: Oligo-metastatic breast cancer diagnosed by pathology from January 2001 and August 2019 were reviewed and we matched the poly-metastatic patients based on the clinicopathological features of patients included. Clinicopathological values and data of genomic alterations were collected. Oligo-recurrence (oligo-R) was defined as a situation where disease progression occurred in less than 5 anatomical sites and other anatomic areas still suppressed by the ongoing therapy. RESULTS: A total of 26 breast cancer patients were enrolled in our study, including 14 patients with strict oligo-metastatic disease (oligo-R > 6 months) and 12 with simultaneous poly-metastatic disease. PIK3CA, TP53 and ERBB2 were the most common shared alterations identified in patients included. Based on the median time of oligo-R, we divided the patients with oligo-metastasis into longer oligo-R group (oligo-R > 31.04 months) and shorter oligo-R group (oligo-R ≤ 31.04 months). The analysis of PIK3CA mutation sites showed that H1047R mutation was closely associated with oligo-metastasis, rather than poly-metastasis. H1047R mutation also predicted a better prognosis (oligo-R > 31.04 months) in oligo-metastatic breast cancer. In addition, HER2 positive was more likely to be related to a good outcome in patients with oligo-metastasis. CONCLUSIONS: Through the genetic analysis of samples from oligo-metastasis, we found the prognostic values of PIK3CA H1047R and HER2 in oligo- and poly-metastasis. We improved the stratification of prognosis and provided new insights for biological behaviors of oligo-metastatic breast cancer.

The prognostic significance of skin involvement in breast cancer patients with chest wall recurrence.

PURPOSE: To assess the prognostic significance of skin involvement in breast cancer patients with chest wall recurrence (CWR). METHODS: We retrospectively analyzed the clinicopathological data of breast cancer patients with CWR who were diagnosed pathologically between January 2000 and April 2020. Disease-free survival (DFS) was the time from radical resection for CWR to disease recurrence. Progression-free survival (PFS) was defined as the time from the diagnosis of locally unresectable CWR to the first sign of disease progression. Persistent chest wall progression was defined as three consecutive chest wall progressions with no distant organ involvement. RESULTS: A total of 476 patients with CWR were included in this study. Skin involvement was confirmed in 345 patients. Skin involvement was significantly correlated with a high T stage (p = 0.003), more positive nodes at initial examination (p < 0.001) and lymphovascular invasion (p < 0.001). Kaplan-Meier analysis showed that skin involvement was a predictor of shorter DFS (p < 0.001), including both local disease progression (p < 0.001) and distant disease progression (p = 0.022). Multivariate analysis showed that skin involvement was an independent biomarker for DFS (p = 0.043). Patients with skin involvement were more likely to experience persistent chest wall progression (p = 0.040). After eliminating the potential deviation caused by an insufficient follow-up time, persistent chest wall progression was more likely to be associated with a high N stage (p = 0.002), negative progesterone receptor (PR; p = 0.001) and positive human epidermal growth factor receptor 2 (HER2; p = 0.046) of the primary site, and negative oestrogen receptor (ER; p = 0.027) and PR (p = 0.013) of the chest wall lesion and skin involvement (p = 0.020). CONCLUSION: Skin involvement was a predictor of poor disease control in patients with CWR and was closely related to persistent chest wall progression. We stratified the prognosis of individualized treatment for breast cancer patients with CWR to provide new insights into the biological behaviours of the disease.

Skin involvement is a predictor of poor local disease control in breast cancer patients with CWR and a factor contributing to persistent chest wall progression after CWR. We stratified the prognosis of individualized treatment for breast cancer patients with CWR.

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy.

Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.

The prognostic value and immune microenvironment association of AR in HER2+ nonmetastatic breast cancer.

This study aimed to investigate the prognostic value of AR in HER2+ nonmetastatic breast invasive ductal carcinoma (IDC) and its relationship with the immune microenvironment. HER2+ nonmetastatic breast IDC patients diagnosed by pathology who underwent surgery at Sun Yat-sen University Cancer Center from 2016 to 2017 were included. AR+ and AR- breast IDC samples were matched 1:1 in age, T stage, and N stage for immune infiltration analysis. A total of 554 patients with HER2+ nonmetastatic breast cancer were included in this retrospective study, regardless of HR status. The cut-off value for AR was set at 10%. ER+ (p < 0.001) and PR+ (p < 0.001) were associated with positive AR expression. Kaplan-Meier survival curve analysis suggested that AR was closely correlated with overall survival (OS) (p = 0.001) but not disease-free survival (DFS) (p = 0.051). After eliminating the potential impact caused by HR, AR also predicted longer OS (p = 0.014) and was an independent predictive factor for OS of HER2+HR- nonmetastatic breast IDC patients, as revealed by multivariate analysis (p = 0.036). For AR+ and AR- matched HER2+HR- patients, TILs (p = 0.043) and PD-L1 (p = 0.027) levels were significantly lower in AR+ patients. The strongest negative correlation was observed between AR and PD-L1 (Pearson's r = -0.299, p = 0.001). AR+ status was markedly related to better OS in HER2+HR- nonmetastatic breast cancer patients, while a negative correlation was observed between AR and PD-L1/TILs. We provide new insights into the prognostic value of AR and its association with the immune microenvironment to optimize treatment strategies in HER2+ nonmetastatic breast IDCs.

MAPKAPK5-AS1/miR-515-5p/CAB39 Axis Contributes to Non-small Cell Lung Cancer Cell Proliferation and Migration.

Several studies have elucidated the pivotal function that long noncoding RNAs (lncRNAs) exerted on the initiation and development of various human carcinomas, encompassing non-small cell lung cancer (NSCLC). In spite of the fact that lncRNA MAPKAPK5 antisense RNA 1 (MAPKAPK5-AS1) has already been investigated by researchers and confirmed to play oncogenic roles in colorectal cancer, the underlying regulatory function of MAPKAPK5-AS1 in NSCLC cells still remain unclear. In our research, we found that MAPKAPK5-AS1 was expressed at high levels in NSCLC cells. Biological functional assays unclosed that downregulation of MAPKAPK5-AS1 repressed proliferative and migratory capacities whereas promoted apoptotic level in NSCLC cells. Molecular mechanism experiments confirmed that, in NSCLC cells, MAPKAPK5-AS1 combined with miR-515-5p and negatively modulated miR-515-5p expression level. Besides, calcium-binding protein 39 (CAB39) expression level was verified to be negatively modulated by miR-515-5p whereas positively modulated by MAPKAPK5-AS1 in NSCLC cells. Furthermore, rescued-function assays disclosed that inhibited miR-515-5p expression or overexpressed CAB39 could restore the suppressive influence of MAPKAPK5-AS1 silence on NSCLC progression. In summary, MAPKAPK5-AS1 upregulates CAB39 expression level to facilitate NSCLC progression by sequestering miR-515-5p, providing promising biomarkers for NSCLC treatment.

Current Situation of Diagnosis and Treatment of HER2-Positive Metastatic Breast Cancer Patients in China: A Nationwide Cross-Sectional Survey of Doctors.

BACKGROUND: The Advanced Breast Cancer Alliance conducted a nationwide investigation to understand the current situation of the diagnosis and treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients. METHODS: In 2019, electronic questionnaires including basic information about respondents, characteristics of patients, and the present status of diagnosis and treatment were sent to 495 doctors from 203 medical centers covering 28 provinces. RESULTS: The factors that influenced treatment plans included the disease process, the performance status, and the economic status of patients. Regimens and response to neoadjuvant/adjuvant chemotherapy were important factors in the decision of the first-line treatment. Overall, 54% of doctors retained trastuzumab and replaced chemotherapy drugs in second-line treatment regimens for patients with progression-free survival (PFS) ≥ 6 months in the first-line setting, while 52% of participants chose pyrotinib plus capecitabine for patients with PFS < 6 months. Economic factors played an important role in doctors' decision-making and the varying treatment options for respondents in first-tier, second-tier, and other cities. CONCLUSIONS: This large-scale survey regarding the diagnosis and treatment of HER2-positive MBC patients revealed that clinical decisions made by Chinese doctors followed the guidelines, but their choices were constrained by economic factors.

Ferroptosis in glioma treatment: Current situation, prospects and drug applications.

Ferroptosis is a regulatory form of iron-dependent cell death caused by the accumulation of lipid-based reactive oxygen species (ROS) and differs from apoptosis, pyroptosis, and necrosis. Especially in neoplastic diseases, the susceptibility of tumor cells to ferroptosis affects prognosis and is associated with complex effects. Gliomas are the most common primary intracranial tumors, accounting for disease in 81% of patients with malignant brain tumors. An increasing number of studies have revealed the particular characteristics of iron metabolism in glioma cells. Therefore, agents that target a wide range of molecules involved in ferroptosis may regulate this process and enhance glioma treatment. Here, we review the underlying mechanisms of ferroptosis and summarize the potential therapeutic options for targeting ferroptosis in glioma.

Cryoablation reshapes the immune microenvironment in the distal tumor and enhances the anti-tumor immunity.

As one of the local treatments, cryoablation plays an increasingly important role in the comprehensive treatment of malignant tumors with its advantages of less trauma, high reproducibility, and minimally invasive. Activation of anti-tumor immunity, another characteristic of cryoablation, has attracted more and more attention with the extensive application of immunotherapy. Unfortunately, the mechanism by which cryoablation enhances anti-tumor immunity is still unclear. In this study, we applied a multi-omics approach to investigate the effects of local cryoablation in the distal tumor microenvironment. The results revealed that large amounts of tumor antigens were released post-cryoablation, leading to a sterile inflammatory response in distant tumors. During this period, activated lysosome-related pathways result in over-expression of SNAP23 (Synaptosome associated protein 23) and STXBP2 (Syntaxin binding protein 2), activation of immune effector cells, suppression of the release of immunosuppressive factors, and finally enhancement of anti-tumor immunity, which shows a broad prospect in combined immunotherapy.

SIX5-activated LINC01468 promotes lung adenocarcinoma progression by recruiting SERBP1 to regulate SERPINE1 mRNA stability and recruiting USP5 to facilitate PAI1 protein deubiquitylation.

Increasing research has uncovered the involvement of long noncoding RNAs (lncRNAs) in the progression of multiple cancers including lung adenocarcinoma (LUAD). RT-qPCR and western blot were done to measure RNAs and proteins. Functional assays assessed LUAD cell biological behaviors under knockdown or overexpression of LINC01468, SIX5, SERBP1 or SERPINE1, and the specific function of those genes in regulating LUAD progression was evaluated via animal experiments. Supported by bioinformatics analysis, the interaction among genes was verified via mechanism assays. Upregulation of LINC01468 in LUAD tissues and cells as well as its association with poor clinical outcome was predicted. LINC01468, transcriptionally activated by SIX5, could strengthen proliferative, migratory and invasive abilities of LUAD cells. The oncogenic role of LINC01468 was further validated via animal experiments. SIX5 was a positive transcription regulator of LINC01468 and could exacerbate LUAD cell malignant behaviors. LINC01468 could recruit SERBP1 to enhance SERPINE1 mRNA stability and interact with USP5 to affect PAI1 protein ubiquitination. The oncogenic role of SERBP1 and SERPINE1 was also confirmed. Rescue experiments finally verified LINC01468 modulated proliferation, migration and invasion of LUAD cells via upregulation of SERPINE1. Our observations could contribute to deeper understanding of LUAD.

The prognostic value of baseline hematological parameters of peripheral blood in metastatic gastric cancer treated with apatinib.

Background: There is strong evidence that apatinib is effective in the treatment of third- or later-line advanced metastatic gastric cancer (mGC). Hematology prediction index is a convenient and cheap method to predict the prognosis of disease. However, the prognosis of baseline hematological parameters of peripheral blood, such as neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen 125 (CA125) and albumin (ALB) on mGC treated with apatinib have not been identified. Methods: We retrospectively analyzed mGC received apatinib between 1 January 2014 and 30 June 2021. Survival analyses were performed using the Kaplan-Meier method and Cox-proportional hazards model. Results: A total of 117 patients were included in this study. The cutoff value of NLR, CA125 and ALB was 2.25, 19.24 U/ml and 37.60 g/L, respectively. The disease control rates (DCR) in the high and low NLR groups were 52.94% and 73.47% (P=0.024); 48.28% and 74.58% (P=0.003) in high and low CA125 groups; 72.97% and 41.86% (P=0.001) in high and low ALB groups. By survival analysis, increasing NLR (P=0.003), CA125 (P<0.001) and decreasing ALB (P<0.001) predicted a shorter PFS after apatinib. NLR (P=0.015), CA125 (P=0.004) and ALB (P=0.005) were significantly predictors for PFS in mGC treated with aptinib. Conclusion: Increasing NLR, CA125 and decreasing ALB were associated with poorer clinical efficiency and prognosis after apatinib treatment.

Distribution Characteristics and Prognostic Value of Immune Infiltration in Oligometastatic Breast Cancer.

BACKGROUND: To assess the distribution characteristics and the prognostic value of immune infiltration in female oligometastatic breast cancer patients. METHODS: We retrospectively analyzed the clinicopathological data of oligometastatic breast cancer (OMBC) patients diagnosed between June 2000 and January 2020. Immune markers were quantified by immunohistochemistry on FFPE tissues in paired normal breast tissues, primary breast cancers and oligometastatic lesions. Survival analyses were performed using the Kaplan-Meier curves and Cox-proportional hazards model. RESULTS: A total of 95 female OMBC patients visited Sun Yat-sen University Cancer Center between June 2000 and January 2020, and 33 of them had matched normal breast tissues, primary cancers and oligometastatic lesions and were reviewed in immune infiltration analysis. CD8 of primary tumors had a higher expression than that in matched normal tissues. The expressions of CD8 and FOXP3 were higher in the primary sites than that in the oligometastatic lesions. CD3, CD4 and CD8 were significantly lower in the intratumoral regions than that in the peritumoral regions both in primary and oligometastatic lesions. Notably, the high percentage of CD3 in the intratumoral oligometastatic lesions predicted the longer PFS and OS, and higher CD4 in the same lesions also predicted a better OS. There was obviously positive correlation between CD4/CD3 and Ki-67 in primary cancers and negative correlation between CD4/CD3 and ER in oligometastatic sites. CONCLUSION: We explored immune distribution and evolution in time and space in OMBC to provide new understandings for biological behaviors of this disease and further divided patients in different prognosis.

Identification of a risk prediction model for clinical prognosis in HER2 positive breast cancer patients.

Background New biomarkers are needed to identify different clinical outcomes for HER2+ breast cancer (BC). Methods Differential genes of HER2+ BC were screened based on TCGA database. We used WGCNA to identify the genes related to the survival. Genetic Algorithm was used to structure risk prediction model. The prognostic model was validated in GSE data. Results We constructed a risk prediction model of 6 genes to identify prognosis of HER2+ BC, including CLEC9A, PLD4, PIM1, PTK2B, AKNAD1 and C15orf27. Kaplan-Meier curve showed that the model effectively distinguished the survival of HER2+ BC patients. The multivariate Cox regression suggested that the risk model was an independent predictor for HER2+ BC. Analysis related to immune showed that significant differences in immune infiltration between high- and low-risk groups classified by the prognostic model. Conclusions Our study identified a risk prediction model of 6 genes that could distinguish the prognosis of HER2+ BC.

Miller-Payne Grading and 70-Gene Signature Are Associated With Prognosis of Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Early-Stage Breast Cancer After Neoadjuvant Chemotherapy.

INTRODUCTION: HR+/HER2- breast cancer (BC) has a much lower pathological complete response (pCR) rate to neoadjuvant chemotherapy (NAC). Therefore, to better stratify the relapse risk for HR+/HER2- non-pCR populations, it is essential to accurate identification new prognostic markers. MATERIALS AND METHODS: The study retrospectively analyzed 105 stage II-III patients who were diagnosed with HR+/HER2- BC and received NAC followed by breast and axilla surgery between 2013 and 2019 in Sun Yat-Sen University Cancer Center. The Miller-Payne (MP) grading system was used to evaluate pathological responses to NAC. The 70-gene signature was used to classify the prognosis signatures. RESULTS: Among the 105 patients, the study demonstrated that larger tumor size and lower progesterone receptor level at baseline and larger tumor size postoperative were statistically significantly associated with worse disease-free survival (DFS) (p = 0.004, p = 0.021, and p = 0.001, respectively). Among 54 patients who underwent the 70-gene assays, 26 (48.1%) had a low-risk signature; 28 (51.9%) patients had a high-risk signature. Patients with poor response (MP grades 1-2) were more likely to with a high-risk 70-gene signature than those with good response (MP grades 4-5). The final analysis showed that DFS was longer in the low-risk group than in the high-risk group [52.4 vs. 36.1 months of the median DFS, hazard ratio (HR) for recurrence, 0.29; 95% confidence interval (CI), 0.10-0.80; p = 0.018]. DFS was longer in the good response (MP grades 3-4) group than in the poor response (MP grades 1-2) group (94.7% vs. 60% of the patients free from recurrence; HR, 0.16; 95% CI, 0.05-0.47; p = 0.037). When stratified by MP grades combined with the 70-gene signature, subgroup analyses showed the good-response low-risk group with the best DFS, whereas the poor-response high-risk group showed the worst DFS (p = 0.048). Due to the short median follow-up time of 34.5 months (5.9-75.1 months), MP grades and the 70-gene signature did not show significant prognostic value for overall survival. CONCLUSION: The study showed that analysis of MP grades combined with the 70-gene signature with residual NAC-resistant breast samples has a significant correlation with DFS.

Safety, tolerability, and pharmacokinetics of BAT8001 in patients with HER2-positive breast cancer: An open-label, dose-escalation, phase I study.

BACKGROUND: The introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer. METHODS: This trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3 + 3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective. RESULTS: Between March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, γ-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients. CONCLUSIONS: BAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

Surveillance Strategy for Patients With BCLC Stage B Hepatocellular Carcinoma After Achieving Complete Remission: Data From the Real World.

Purpose: There is a lack of consensus on the surveillance strategy for Barcelona Clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC) patients with complete remission (CR). We performed a real-world, retrospective analysis of the surveillance strategy for BCLC stage B HCC patients after radical therapy with CR to support clinical decision-making. Materials and Methods: We analyzed 546 BCLC stage B HCC patients with CR after radical treatments (surgery/ablation) at Sun Yat-sen University Cancer Center, from January 2007 to December 2019. The intensity of surveillance interval was defined as the mean of surveillance interval within 2 years. The primary endpoint of the study was overall survival (OS) and extra-Milan criteria relapse. Results: During a median follow-up time of 23.9 months (range = 3.1-148.3 months), there were 11.9% of patients died, 56.6% of patients developed recurrence, the vast majority of patients experienced recurrence within 2 years, and 27.8% patients developed extra-Milan criteria recurrence. The median disease-free survival and OS were 33.6 and 60.0 months, respectively. Patients were divided into regular surveillance group (RS) (≤4.3 months) and irregular surveillance (IRS) group (>4.3 months) based on the optimal cutoff value of the intensity of surveillance interval. The RS group owned a lower incident of extra-Milan criteria relapse and smaller and fewer tumors at recurrence than IRS group, which contributed to the prolonged OS. Besides, the cutoff values of surveillance interval that could lead to significant differences in the incidence of extra-Milan criteria relapse during 0-6, 6-12, and 12-18 months after CR were 2.6, 2.9, and 3 months, respectively. Conclusions: The average surveillance interval for patients with BCLC stage B HCC achieved CR should not exceed 4.3 months during the first 2 years' follow-up. During three different phases of the initial 18 months after CR, individualized surveillance showed intervals no more than 3 months were required to reduce the incidence of extra-Milan criteria relapse.

TACE-Sorafenib With Thermal Ablation Has Survival Benefits in Patients With Huge Unresectable Hepatocellular Carcinoma.

PURPOSE: To investigate the effectiveness and safety of transarterial chemoembolization (TACE) combined with sorafenib and thermal ablation in patients with huge hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This retrospective study examined 50 patients with huge unresectable HCC treated from January 2009 to December 2015. Among them, 28 cases received TACE-sorafenib treatment (TACE-sorafenib group), and 22 cases received TACE-sorafenib plus thermal ablation treatment (TACE-sorafenib-thermal ablation group). The Overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared. RESULTS: The median follow-up was 13.5 months (ranges 4.2 to 96.7 months). The median OS was significantly longer in the TACE-sorafenib-thermal ablation group than that in the TACE-sorafenib group (20.8 vs. 10.4 months, P=0.003). The median PFS of the ablation and no ablation groups were 4.3 vs. 7.1 months (P=0.546). The treatment modality was an independent predictor of OS (P=0.004). There were no notable drug-related high grade adverse events or permanent adverse sequelae. CONCLUSION: TACE-sorafenib-thermal ablation provided extended OS to patients with huge unresectable HCC and could be a better choice than TACE-sorafenib.

In silico prediction and validation of potential therapeutic genes in pancreatic ß-cells associated with type 2 diabetes.

Diabetes mellitus is becoming a major health burden worldwide. Pancreatic ß-cell death is a characteristic of type 2 diabetes (T2D), but the underlying mechanisms of pancreatic ß-cell death remain unknown. Therefore, the aim of the present study was to identify potential targets in the pancreatic islet of T2D. The GSE20966 dataset was obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes (DEGs) were identified by using the GEO2R tool. The Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analysis of DEGs were further assessed using the Database for Annotation, Visualization and Integrated Discovery. Furthermore, protein-protein interaction (PPI) networks were constructed for the up- and downregulated genes using STRING databases and were then visualized with Cytoscape. The body weight, fasting blood glucose (FBG), pancreatic index and biochemistry parameters were measured in db/db mice. Moreover, the morphology of the pancreas was detected by hematoxylin and eosin staining, and hub genes were assessed using reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. In total, 570 DEGs were screened, including 376 upregulated and 194 downregulated genes, which were associated with 'complement activation, classical pathway', 'proteolysis', 'complement activation' and 'pancreatic secretion pathway'. It was found that the body weight, FBG, alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, blood urea nitrogen, creatinine, fasting serum insulin, glucagon and low-density lipoprotein cholesterol levels were significantly higher in db/db mice, while high-density lipoprotein cholesterol levels and the pancreatic index were significantly decreased. Furthermore, albumin, interleukin-8, CD44, C-C motif chemokine ligand 2, hepatocyte growth factor, cystic fibrosis transmembrane conductance regulator, histone cluster 1 H2B family member n, mitogen-activated protein kinase 11 and neurotrophic receptor tyrosine kinase 2 were identified as hub genes in PPI network. RT-qPCR and western blotting results demonstrated the same expression trend in hub genes as found by the bioinformatics analysis. Therefore, the present study identified a series of hub genes involved in the progression of pancreatic ß-cell, which may help to develop effective therapeutic strategy for T2D.