Tumor-infiltrating lymphocytes-based subtypes and genomic characteristics of EBV-associated lymphoepithelioma-like carcinoma.

Tumor-infiltrating lymphocytes (TILs) offer a key for morphological diagnosis of lymphoepithelioma-like carcinoma (LELC) and are the foundation of oncoimmunology. To date, no reports have found a specific risk stratification value of TILs and related it to genomic variation in LELC. Based on the stromal TILs (str-TILs) ratio, we classified 105 Epstein-Barr virus (EBV)-associated LELC cases into two subtypes: patients with ≥60% str-TILs area ratio in tumor were classified as subtype I, and otherwise as subtype II. Subtype I patients had significantly better progression-free survival (PFS) and overall survival (OS). We also explored the genomic characteristics of EBV-associated LELC within different involved organs. We performed whole-exome sequencing for 51 patients with enough tissue and analyzed the genomic characteristics of EBV-associated LELC. Overall, EBV-associated LELCs were characterized by a low somatic mutation rate and copy number variations; the enriched genetic lesions affected RTK-RAS, PI3K, and cell cycle pathways. Moreover, EBV-associated LELCs from different organs were more similar to each other genetically as compared with other traditional carcinomas of the same sites-as evidenced by unsupervised clustering based on the quantitative data from both mutation signature and chromosomal aneuploidies. Notably, EBV-associated LELC patients with oncogenic driver alterations showed a worse prognosis compared with patients without such alterations. © 2022 The Pathological Society of Great Britain and Ireland.

Circular RNA hsa_circ_0084054 promotes the progression of periodontitis with diabetes via the miR-508-3p/PTEN axis.

BACKGROUND AND OBJECTIVE: Diabetes is an important risk factor for periodontitis, and circular RNA (circRNA) may play an important role in aggravating inflammation and accelerating disease progression by regulating miRNA/mRNA. This study aimed to investigate the role and mechanism of the hsa_circ_0084054/miR-508-3p/PTEN axis in the progression of periodontitis with diabetes. METHODS: First, circRNA sequencing was used to screen the differentially expressed circRNAs of periodontal ligament cells (PDLCs) treated with high glucose and/or Porphyromonas gingivalis lipopolysaccharide (LPS) in vitro, and the overtly differentially expressed hsa_circ_0084054 was selected and was also verified in periodontal ligament (PDL) tissue from periodontitis patients with diabetes. Then, its ring structure was tested by Sanger sequencing, RNase R, and actinomycin D assays. The bioinformatics analysis, dual luciferase reporter assay, and RIP assay were used to explore the interaction of hsa_circ_0084054/miR-508-3p/PTEN axis, whose effects on inflammation, oxidative stress, and apoptosis of PDLCs were evaluated through the measurement of inflammatory factors, reactive oxygen species (ROS), total superoxide dismutase (SOD), malondialdehyde (MDA), and Annexin V/PI assay. RESULTS: By high-throughput sequencing, it was found that hsa_circ_0084054 was significantly increased in HG + LPS group compared with control group and LPS group, which was also verified in periodontal ligament (PDL) tissue from periodontitis patients with diabetes. Silencing hsa_circ_0084054 in PDLCs decreased the expression of inflammatory factors (IL-1ß, IL-6, TNF-α), the levels of ROS and MDA, and the proportion of apoptotic cells; conversely, SOD activity was enhanced. In addition, we found that hsa_circ_0084054 could up-regulate the expression of PTEN through sponge miR-508-3p to inhibit AKT phosphorylation, finally trigger the aggravation of oxidative stress and inflammation in periodontitis patients with diabetes. CONCLUSION: hsa_circ_0084054 can aggravate inflammation and promote the progression of periodontitis with diabetes by regulating miR-508-3p/PTEN signaling axis, which may serve as a new target for the intervention of periodontitis with diabetes.

Differential expression profile of microRNAs in the lung tissues of coal workers with pneumoconiosis and patients with silicosis.

The purpose of this study was to characterize the microRNA (miRNA) profile of the lung tissues from coal workers' pneumoconiosis (CWP) and silicosis and to analyze the changes in downstream genes, biological processes, and signaling pathways based on the differently expressed miRNAs. Lung tissues from three CWP patients, eight silicosis patients, and four healthy controls were collected and analyzed for their miRNA profiles using Affymetrix® GeneChip® miRNA Arrays. Differentially expressed miRNAs (DEMs) were identified between the different groups. The miRanda and TargetScan databases were used to predict the putative target genes, and volcano and heat maps were drawn. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were then performed to screen the DEMs-associated biological process and signaling pathways, respectively. Further identification with a comprehensive literature research involving particle exposure, fibrosis, inflammation and lung cancer were used to further screen DEMs of CWP and silicosis. Microarray data showed that 375 and 88 miRNAs were differentially expressed in CWP and silicosis lung tissues compared with healthy lung tissues, while 34 miRNAs were differentially expressed in CWP compared with silicosis lung tissues. The GO and KEGG pathway analyses showed that, the target genes were mainly enriched in the TGF-ß, MAPK, p53 and other signal pathways. These results provided insight into the miRNA-related underlying mechanisms of CWP and silicosis, and they provided new clues for miRNAs as biomarkers for the diagnosis and differential diagnosis of these two diseases.

The Novel Tumor Microenvironment-Related Prognostic Gene AIF1 May Influence Immune Infiltrates and is Correlated with TIGIT in Esophageal Cancer.

BACKGROUND: Esophageal carcinoma (EC) is the sixth most common cause of cancer-related mortality worldwide. Studying the associations of the tumor microenvironment (TME) with pathology and prognosis would illustrate the underlying mechanism of prognostic prediction and provide novel targets for immunotherapy in the treatment of EC. METHODS: Transcriptomic profiles of 159 EC patients were obtained from The Cancer Genome Atlas (TCGA) database. Stromal and immune scores were calculated using the ESTIMATE algorithm. Differentially expressed genes (DEGs) were identified by the optimal score cutoff. Functional enrichments were analyzed by DAVID, while prognostic genes were explored using the Kaplan-Meier method. Validation analysis was performed using immunohistochemistry in tissue microarrays containing samples from 145 EC patients. Multiplex immunofluorescence staining was performed to detect a panel of 6 immune markers, including T-cell immunoreceptor with Ig and ITIM domains (TIGIT), in 90 EC patients. RESULTS: Immune scores significantly increased with increasing age, while stromal scores were dramatically elevated with increasing tumor stage. Fifteen TME-related DEGs including allograft inflammatory factor 1 (AIF1) were identified as prognostic factors of EC. Furthermore, the validation cohort indicated that AIF1 was negatively associated with the prognosis of esophageal squamous cell carcinoma patients. Subsequent analyses suggested that AIF1 may affect immune infiltrates, including T cells and natural-killer cells. Moreover, a correlation between AIF1 and TIGIT was identified. CONCLUSIONS: These results indicate that the TME-related gene AIF1 is a promising predictor of prognosis and is related to immune infiltrates and TIGIT expression in EC. However, further mechanistic studies are needed.

The re-evaluation of optimal lymph node yield in stage II right-sided colon cancer: is a minimum of 12 lymph nodes adequate?

PURPOSE: Adequate lymphadenectomy is critical for accurate nodal staging and planning adjuvant therapy in colon cancer. However, the optimal lymph node (LN) yield for stage II right-sided colon cancer (RSCC) is still unclear. This population-based study aimed to determine the optimal LN yield associated with survival and LN positivity in patients with stage II RSCC. METHODS: All patients with stage II-III RSCC were identified from the Surveillance, Epidemiology, and End Results database over a 10-year interval (2006-2015). The optimal threshold for LN yield was explored using an outcome-oriented approach based on survival and LN positivity. RESULTS: The median number of LNs examined for all 17,385 patients with stage II RSCC was 17 (IQR 12-23). Nineteen LNs were determined as the optimal cut-off point to maximize survival benefit from lymphadenectomy. Increased LN yield was associated with a gradual increase in the risk of node positivity, with no change after 19 nodes. Compared with patients with 19 or more LNs examined, the group with fewer LNs had a significantly poor cancer-specific survival (< 12 nodes: hazard ratio (HR) 2.26, P < 0.001; 12-18 nodes: HR 1.58, P < 0.001) and overall survival (< 12 nodes: HR 1.80, P < 0.001; 12-18 nodes: HR 1.31, P < 0.001). Similar survival results were found in the validation cohort. Patients with older age, small tumor size, and appendix and transverse colon cancer were more likely to receive inadequate LN harvest. CONCLUSION: A minimum of 19 LNs is needed to be examined for optimal survival and adequate node staging in lymph node-negative RSCC.

PD-1 high expression predicts lower local disease control in stage IV M0 nasopharyngeal carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) play a critical role in tumor immune surveillance and immune suppression. Understanding tumor infiltrating T cell subset density, location and PD-1/PD-L1 expression might provide insight for the prediction of tumor therapeutic response and clinical outcome. The purpose of this study was to evaluate the expression and localization of CD8, FoxP3, PD-1, and PD-L1 in primary tumor tissues and their effects on prognosis of stage IV M0 locally advanced nasopharyngeal carcinoma (NPC) patients. METHODS: Sixty NPC patients with stage IV M0 locally advanced disease were treated with definitive chemoradiation. Tumor biopsies from primary lesion were analyzed for the expression and localization of CD8, FoxP3, PD-1, and PD-L1 by immunohistochemistry. Their associations with local disease control and survival of NPC were analyzed. RESULTS: The average follow-up time was 43 months (range from 14 to 61 months). High expression of CD8+, FoxP3+, PD-1+ and PD-L1+ was observed in 60, 86.7, 56.7, and 91.7% of patients, respectively. There was no correlation between clinicopathological features and the expression of these immune markers. High PD-1 expression was found to be associated with lower local disease control (5-year LRFS 23.2% vs 96.8%, p < 0.001) and unfavorable clinical outcome (5-year OS 47.4% vs 73.3%, p = 0.014). In multivariate analysis, PD-1 expression was also an adverse prognostic factor for 5-year OS (HR: 3.68, P = 0.023) and LRFS (HR: 16.89, 1.27-11.84, P = 0.007). Those with PD-1 distribution in both stroma and tumor region had the poorest prognosis. However, PD-1 expression has no significant correlation with 5-year RRFS (p = 0.980) and DMFS (p = 0.865). Patients with both PD-1 and PD-L1 high expression had significant poor local disease control (5-year LRFS 96.0% vs 43.0%, p < 0.001) and overall survival (5-year OS 80.8% vs 45.1%, p < 0.001) compared with the others. Other immune markers were not found having corrections with disease control and survival. CONCLUSIONS: PD-1 high expression, especially with PD-L1 co-expression, is associated with high local recurrence and unfavorable clinical outcome for stage IV M0 NPC patients, and might be a potential target for immunotherapy.

Tumor-Infiltrating CD4+ Lymphocytes Predict a Favorable Survival in Patients with Operable Esophageal Squamous Cell Carcinoma.

BACKGROUND The immune status within the tumor microenvironment has not been well determined in esophageal squamous cell carcinoma (ESCC). The aim of this study was to investigate the distributions of tumor-infiltrating T lymphocytes (TILs), and analyze their associations with clinical characteristics and prognosis; as well as investigate the expression of programmed death-ligand 1 (PD-L1) which has been identified as a favorable indicator of prognosis in our previous study on ESCC. MATERIAL AND METHODS Five hundred and thirty-six patients who underwent radical surgery for ESCC between January 2008 and April 2012 in Department of Thoracic Surgery at Zhejiang Cancer Hospital were included in the study. Immunohistochemistry was used to investigate the infiltration of various TILs (CD3+, CD4+, CD8+ T lymphocytes) in ESCC tissues. Chi-square test and Cox proportional hazards regression were used to explore the correlations between TILs abundance and clinicopathological variables and survival. RESULTS The infiltration of intraepithelial CD4+ (iCD4+) lymphocytes was markedly higher than it in the stromal region (44.2% for intraepithelial versus 28.9% for stromal, p<0.001). Moreover, increased iCD4+ lymphocytes were significantly associated with longer overall survival (OS, p=0.001) in univariate analysis and were identified as an independent predictor for improved OS in multivariate analysis (hazard ratio [HR]=0.67, 95% confidence interval [CI]: 0.51-0.88, p=0.040). Neither the infiltration of CD3+ nor CD8+ lymphocytes showed the prognostic value in ESCC (p>0.05). Unexpectedly, combined with our previous study results, the TILs infiltration in ESCC showed an inverse association with the expression of PD-L1 (p=0.027). CONCLUSIONS Our results suggested that iCD4+ lymphocytes infiltration could be a favorable indicator for prognosis in ESCC.

A Rarely Seen Phenolato and Azido-Bridged Polymeric Cadmium(II) Complex Derived from 2-Bromo-6-[(2-isopropylaminoethylimino)methyl]phenol.

A rarely seen phenolato and azido-bridged polymeric cadmium(II) complex derived from the Schiff base ligand 2-bromo-6-[(2-isopropylaminoethylimino)methyl]phenol (HL) has been prepared and characterized by elemental analysis, IR spectroscopy, and single crystal X-ray diffraction. The Schiff base ligand coordinates to the Cd atom through the NNO donor set. The Cd atom is hexa-coordinated in an octahedral geometry. Adjacent two Cd atoms are bridged by two phenolato groups generating a dimer with Cd···Cd distance of 3.475(1) Å. The dimers are further linked via azido bridges forming 2D sheets parallel to the bc plane.

Programmed death-ligand 1 expression associated with molecular characteristics in surgically resected lung adenocarcinoma.

BACKGROUND: Several clinical trials have shown that immune treatment focus on programmed death-1 and programmed death-ligand 1 (PD-L1) yields a good clinical efficacy in advanced non-small cell lung cancer (NSCLC). We investigated whether the PD-L1 expression was related to clinicopathologic and molecular characteristics in patients with surgically resected NSCLC. METHODS: Between December 2008 and 2013, formalin-fixed, paraffin-embedded samples were obtained from patients with lung adenocarcinoma at Zhejiang Cancer Hospital. RT-PCR was used to analyze EGFR, KRAS, NRAS, PIK3CA, BRAF, HER2 mutations and ALK, ROS1, RET fusion genes. The PD-L1 expression was evaluated by immunohistochemistry and staining of 5 % or more was scored as positive expression. Survival analysis was evaluated using the Kaplan-Meier method. Multivariate regression was performed using the Cox proportional hazards model. RESULTS: Mutations were detected in 76.6 % of the 385 patients tested: EGFR mutation (n = 205, 53.2 %), followed by EML4-ALK rearrangement (n = 18, 4.7 %), KRAS (n = 16, 4.2 %), HER2 (n = 9, 2.3 %), ROS1 rearrangement (n = 8, 2.1 %), PIK3CA (n = 6, 1.6 %), RET rearrangement (n = 6,1.6 %), BRAF (n = 2, 0.5 %), and NRAS mutations (n = 1, 0.2 %). Twenty-four (6.2 %) patients carried coexisting mutations. PD-L1 expression was detected in 48.3 % (186/385) of all the patients. PD-L1 positive patients more frequently carried coexisting mutations (18/24, 75 %), followed by single-gene (145/271, 53.5 %) and pan-negative mutations (23/90, 25.6 %). PD-L1 expression decreased disease-free survival (DFS) in univariate analysis (P = 0.014). Multivariate analysis revealed that PD-L1 expression was not an independent risk factor for poor DFS and overall survival (OS) (P = 0.22 and 0.37, respectively). CONCLUSIONS: PD-L1 overexpression is more frequently observed in oncogene-mediated lung adenocarcinoma, especially with coexisting mutation subtypes. PD-L1 expression is not a prognostic factor in surgically resected lung adenocarcinoma patients.

Hydroxyapatite-Coated Small Intestinal Submucosa Membranes Enhanced Periodontal Tissue Regeneration through Immunomodulation and Osteogenesis via BMP-2/Smad Signaling Pathway.

Periodontitis, a chronic infection causing periodontal tissue loss, may be effectively addressed with in situ tissue engineering. Small intestinal submucosa (SIS) offers exceptional biocompatibility and biodegradability but lacks sufficient osteoconductive and osteoinductive properties. This study develops and characterizes SIS coated with hydroxyapatite (SIS-HA) and gelatin methacrylate hydroxyapatite (SIS-Gel-HA) using biomineralization and chemical crosslinking. The impact on periodontal tissue regeneration is assessed by evaluating macrophage immune response and osteogenic differentiation potential of periodontal ligament stem cells (PDLSCs) in vitro and rat periodontal defects in vivo. The jejunum segment, with the highest collagen type I content, is optimal for SIS preparation. SIS retains collagen fiber structure and bioactive factors. Calcium content is 2.21% in SIS-HA and 2.45% in SIS-Gel-HA, with no significant differences in hydrophilicity, physicochemical properties, protein composition, or biocompatibility among SIS, SIS-HA, SIS-Gel, and SIS-Gel-HA. SIS is found to upregulate M2 marker expression, both SIS-HA and SIS-Gel-HA enhance the osteogenic differentiation of PDLSCs through the BMP-2/Smad signaling pathway, and SIS-HA demonstrates superior in vitro osteogenic activity. In vivo, SIS-HA and SIS-Gel-HA yield denser, more mature bones with the highest BMP-2 and Smad expression. SIS-HA and SIS-Gel-HA demonstrate enhanced immunity-osteogenesis coupling, representing a promising periodontal tissue regeneration approach.

Impact of the immune molecular profile of the tumor microenvironment on the prognosis of NSCLC.

The present study aimed to clarify the association between macrophages, tumor neo-vessels and programmed cell death-ligand 1 (PD-L1) in the tumor microenvironment and the clinicopathological features of patients with non-small cell lung cancer (NSCLC), and to explore the prognostic factors of stromal features in NSCLC. To determine this, tissue microarrays containing samples of 92 patients with NSCLC were studied using immunohistochemistry and immunofluorescence. The quantitative data demonstrated that in tumor islets, the number of CD68+ and CD206+ tumor-associated macrophages (TAMs) was 8-348 (median, 131) and 2-220 (median, 52), respectively (P<0.001). In tumor stroma, the number of CD68+ and CD206+ TAMs was 23-412 (median, 169) and 7-358 (median, 81), respectively (P<0.001). The number of CD68+ TAMs in each location of the tumor islets and tumor stroma was significantly higher than that of CD206+ TAMs, and they were significantly correlated (P<0.0001). The quantitative density of CD105 and PD-L1 in tumor tissues was 19-368 (median, 156) and 9-493 (median, 103), respectively. Survival analysis revealed that a high density of CD68+ TAMs in tumor stroma and islets and a high density of CD206+ TAMs and PD-L1 in tumor stroma were associated with worse prognosis (both P<0.05). Collectively, the survival analysis demonstrated that the high-density group was related to a worse prognosis regardless of combined neo-vessels and PD-L1 expression with the CD68+ TAMs in tumor islets and stroma, or CD206+ TAMs in tumor islets and stroma. To the best of our knowledge, the present study was the first to provide a multi-component combined prognostic survival analysis of different types of macrophages in different regions with tumor neo-vessels and PD-L1, which demonstrated the importance of macrophages in tumor stroma.

Heterogeneous distribution pattern of CD3+ tumor-infiltrated lymphocytes (TILs) and high combined positive score (CPS) favored the prognosis of resected early stage small-cell lung cancer.

PURPOSE: This study aimed to illustrate the heterogeneity of immune features in small cell lung cancer (SCLC). METHODS: Immunohistochemistry (IHC) staining of CD3, CD4, CD8 and PD-L1 were performed with 55 SCLC FFPE samples from radical resections. Quantitative assessment of CD3+ tumor-infiltrated lymphocytes (TILs) to present the heterogeneity in the tumor and the stroma areas. Hotspots of TILs were evaluated to illustrate the potential relationship between TIL-density and its immune competence. Programmed death ligand-1 (PD-L1) expressed on both tumor TILs (t-TILs) and stroma TILs (s-TILs) was evaluated and quantitatively described as values of tumor positive score (TPS) and combined positive score (CPS). The clinical value of TPS and CPS were further identified according to their relationship with disease-free survival (DFS). RESULTS: More abundant CD3+ TILs were observed in the tumor stroma than that within the parenchyma (15.02±2.25% vs. 1.58±0.35%) . The amount of CD3+ s-TILs were positively correlated with DFS. The CD3+/CD4+ subset of the TILs was found more favorable to DFS compared to the CD3+/CD8+ subset. Hotspots of CD3+ TILs were observed in tumor regions and patients with more Hotspots of CD3+ TILs have better outcomes. CPS were more reliable than TPS to describe PD-L1 expression in SCLC and it was found positively correlated with tumor size and DFS. CONCLUSIONS: The immune microenvironment of SCLC was heterogeneous. Hotspots, the amount of CD3/CD4+ TILs and the CPS value were found valuable in determine the anti-tumor immunity and predicting the clinical outcome of SCLC patients.

Collagen Membrane Derived from Fish Scales for Application in Bone Tissue Engineering.

Guided tissue/bone regeneration (GTR/GBR) is currently the main treatment for alveolar bone regeneration. The commonly used barrier membranes in GTR/GBR are collagen membranes from mammals such as porcine or cattle. Fish collagen is being explored as a potential substitute for mammalian collagen due to its low cost, no zoonotic risk, and lack of religious constraints. Fish scale is a multi-layer natural collagen composite with high mechanical strength, but its biomedical application is limited due to the low denaturation temperature of fish collagen. In this study, a fish scale collagen membrane with a high denaturation temperature of 79.5 °C was prepared using an improved method based on preserving the basic shape of fish scales. The fish scale collagen membrane was mainly composed of type I collagen and hydroxyapatite, in which the weight ratios of water, organic matter, and inorganic matter were 20.7%, 56.9%, and 22.4%, respectively. Compared to the Bio-Gide® membrane (BG) commonly used in the GTR/GBR, fish scale collagen membrane showed good cytocompatibility and could promote late osteogenic differentiation of cells. In conclusion, the collagen membrane prepared from fish scales had good thermal stability, cytocompatibility, and osteogenic activity, which showed potential for bone tissue engineering applications.

Programmed death-ligand 1 and mammalian target of rapamycin signaling pathway in locally advanced rectal cancer.

PURPOSE: To evaluate the role of programmed death-ligand 1 (PD-L1) and mammalian target of rapamycin (mTOR) signaling pathway in locally advanced rectal cancer (LARC). METHODS: Between February 2012 and February 2018, 103 patients with LARC treated by neoadjuvant chemoradiotherapy (neoCRT) and total mesorectal excision (TME) were included. PD-L1, mTOR and p-mTOR of pair-matched pre-neoCRT biopsies and post-neoCRT surgical tissue were evaluated by immunohistochemistry. RESULTS: The mean combined positive score (CPS), tumor proportion score (TPS) and immune cell score (IC) of pre-neoCRT were 2.24 (0-70), 1.87 (0-70) and 0.67 (0-10), respectively. The mean CPS, TPS and IC of post-neoCRT were 2.19 (0-80), 1.38 (0-80) and 1.60 (0-20), respectively. Significant difference was observed in terms of IC between pre-neoCRT and post-neoCRT (p = 0.010). The 5-year disease-free survival (DFS) rate of the whole group was 62.4%. Multivariate analysis by Cox model indicated that pre-neoCRT TPS [hazard ratio (HR) 1.052, 95% confidence interval (CI) 1.020-1.086, p = 0.001] and post-neoCRT CPS (HR 0.733, 95% CI 0.555-0.967, p = 0.028) were associated with DFS. In the 89 patients without pathological complete response, p-mTOR and IC were upregulated after neoCRT. CONCLUSIONS: For patients with LARC treated by neoCRT and TME, p-mTOR and IC were upregulated after neoCRT. Pre-neoCRT TPS and post-neoCRT CPS were independent prognostic predictors of DFS.

Glasgow prognostic score and combined positive score for locally advanced rectal cancer.

Purpose: This study was performed to investigate the association of Glasgow prognostic score (GPS), combined positive score (CPS), and clinicopathological characteristics of locally advanced rectal cancer. Methods: Between February 2012 and February 2018, 103 patients with locally advanced rectal cancer treated by neoadjuvant chemoradiotherapy and total mesorectal excision (TME) were retrospectively evaluated. Results: According to the classification of the GPS, 85 (82.5%), 13 (12.6%), and 5 patients (4.9%) were classified as a score of 0, 1, and 2, respectively. Patients were classified into the GPS-low group (GPS of 0, n = 85) and GPS-high group (GPS of 1 or 2, n = 18) with an area under the curve of 0.582 for overall survival (OS). The mean programmed death-ligand 1 (PD-L1) CPS of the whole group was 2.24 (range, 0-70). The PD-L1 CPS of the GPS-high group was higher than the GPS-low group (P < 0.001). Multivariate analysis by Cox proportional hazards model indicated that GPS was associated with OS and disease-free survival (DFS). Furthermore, PD-L1 CPS was associated with DFS (hazard ratio, 1.050; 95% confidence interval, 1.017-1.083; P = 0.003). Conclusion: Elevated GPS was related to the PD-L1 CPS. GPS and PD-L1 CPS were associated with the prognosis of locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by TME.

Advances of Hydrogel Therapy in Periodontal Regeneration-A Materials Perspective Review.

Hydrogel, a functional polymer material, has emerged as a promising technology for therapies for periodontal diseases. It has the potential to mimic the extracellular matrix and provide suitable attachment sites and growth environments for periodontal cells, with high biocompatibility, water retention, and slow release. In this paper, we have summarized the main components of hydrogel in periodontal tissue regeneration and have discussed the primary construction strategies of hydrogels as a reference for future work. Hydrogels provide an ideal microenvironment for cells and play a significant role in periodontal tissue engineering. The development of intelligent and multifunctional hydrogels for periodontal tissue regeneration is essential for future research.

Clinical features and prognosis of resectable pulmonary primary invasive mucinous adenocarcinoma.

Background: According to the latest the World Health Organization (WHO) classification in 2015, invasive mucinous adenocarcinoma (IMA) is defined as a new pathological subtype of lung adenocarcinoma (LUAD). However, whether this rare subtype of lung pathology has any difference in prognosis than conventional LUAD is debatable. Our study attempted to compare clinical characteristics and prognosis of IMA vs. noninvasive mucinous adenocarcinomas (NMA). Methods: A total of 1,857 patients with LUAD who underwent radical resection were screened from 2010 to 2015 at Zhejiang Cancer Hospital. Patients with pulmonary IMA were matched 1:1 by using propensity scores with LUAD adjusted for clinicopathological characteristics. After follow-up, overall survival (OS) and disease-free survival (DFS) were explored by Kaplan-Meier and Cox regression analyses. Forest plots were used for subgroup analyses. Results: Following screening, 499 patients with LUAD were enrolled, with 97 IMA and 402 NMA. Compared to NMA of the lung, IMA was proportionately lower in women (50.5% vs. 63.4%; P=0.026) and nonsmokers (P<0.001). IMA was also associated with earlier tumor stage I (68.0% vs. 55.5%; P=0.033) and lower frequency of upper lobe tumors compared to NMA (P=0.007). Following propensity score matching, 97 pairs were selected, among which we found that patients with pulmonary IMA had a longer OS than those with NMA (P=0.014). According to the subgroup analysis, improved OS in the IMA cohort versus the NMA cohort was observed across various factors, including the absence of lymphovascular invasion or perineural invasion. Conclusions: In this study, we found that resectable IMA patients had a better OS than NMA patients. This study contributes to the understanding of IMA in depth, but it needs to be validated through additional multicenter studies.

Tumor immune microenvironment and immunotherapy efficacy in BRAF mutation non-small-cell lung cancer.

Previous small-size studies reported BRAF-mutated NSCLC patients have comparable sensitivity to immune checkpoint inhibitors (ICIs). However, how BRAF mutation affects the tumor immune microenvironment (TIME) is unknown. We performed Nanostring-panel RNA sequencing to evaluate TIME in 57 BRAF mutated and wild-type (WT) NSCLC specimens (cohort A). The efficacy of ICI monotherapy or combined therapies was determined in 417 patients with WT and BRAF mutated NSCLC (cohort B). We found that BRAF-mutant tumors had similar ratios of CD8+ T cells to Tregs, the balance of cytotoxicity gene expression signatures and immune suppressive features, and similar ICI-response-related biomarkers to WT NSCLC. A similar TIME pattern was observed between the BRAF V600E and Non-V600E subgroups of NSCLC. The further retrospective study confirmed that treatment with ICI monotherapy or combined therapies resulted in similar overall survival (OS) (HR: 0.85; 95% CI, 0.56 to 1.30; p = 0.47) and progress-free survival (PFS) (HR: 1.02; 95% CI, 0.72 to 1.44; p = 0.91) of patients with WT (n = 358) and BRAF mutant (n = 59) NSCLC. Similarly, both patients with BRAF V600E or Non-V600E NSCLC had similar responses to immunotherapy. Our findings support that BRAF mutation did not modulate TIME in NSCLC and therapeutic responses to ICIs. Patients with NSCLC harboring BRAF mutation should not be denied treatment with ICIs.

Artificial Intelligence-Assisted Score Analysis for Predicting the Expression of the Immunotherapy Biomarker PD-L1 in Lung Cancer.

Programmed cell death ligand 1 (PD-L1) is a critical biomarker for predicting the response to immunotherapy. However, traditional quantitative evaluation of PD-L1 expression using immunohistochemistry staining remains challenging for pathologists. Here we developed a deep learning (DL)-based artificial intelligence (AI) model to automatically analyze the immunohistochemical expression of PD-L1 in lung cancer patients. A total of 1,288 patients with lung cancer were included in the study. The diagnostic ability of three different AI models (M1, M2, and M3) was assessed in both PD-L1 (22C3) and PD-L1 (SP263) assays. M2 and M3 showed improved performance in the evaluation of PD-L1 expression in the PD-L1 (22C3) assay, especially at 1% cutoff. Highly accurate performance in the PD-L1 (SP263) was also achieved, with accuracy and specificity of 96.4 and 96.8% in both M2 and M3, respectively. Moreover, the diagnostic results of these three AI-assisted models were highly consistent with those from the pathologist. Similar performances of M1, M2, and M3 in the 22C3 dataset were also obtained in lung adenocarcinoma and lung squamous cell carcinoma in both sampling methods. In conclusion, these results suggest that AI-assisted diagnostic models in PD-L1 expression are a promising tool for improving the efficiency of clinical pathologists.