Salicylaldehyde-derived piperazine-functionalized hydrazone ligand-based Pt(II) complexes: inhibition of EZH2-dependent tumorigenesis in pancreatic ductal adenocarcinoma, synergism with PARP inhibitors and enhanced apoptosis.

Piperazine is an important functional unit of many clinically approved drugs, including chemotherapeutic agents. In the current study, methyl piperazine was incorporated and eight salicylaldehyde-derived piperazine-functionalized hydrazone ONN-donor ligands (L) and their Pt(II) complexes (L-PtCl) were prepared. The structures of all these ligands (L1-L8) and Pt(II) complexes (C1-C8) were determined using 1H and 13C NMR, UV-vis, FT-IR and HR-ESI MS analyses, whereas the structures of C1, C5, C6, C7 and C8 were determined in the solid state using single crystal X-ray diffraction analysis. Solution state stabilities of C3, C4, C5 and C6 were determined via time-dependent UV-vis spectroscopy. All these complexes (C1-C8) were studied for their anticancer effect in pancreatic ductal adenocarcinoma cells, including BxPC3, MIAPaCa-2 and PANC1 cells. C1-C8 displayed a potential cytotoxic effect in all these cancer cells, among which C5, C6 and C8 showed the strongest inhibitory effect in comparison with standard chemotherapeutic agents, including 5-fluorouracil (5-FU), cisplatin (CP), oxaliplatin and doxorubicin (DOX). C5, C6 and C8 suppressed the growth of pancreatic cancer cells in a dose-dependent manner. Moreover, C5, C6 and C8 inhibited clonogenic potential and invasion ability and induced apoptosis in PANC1 cells. Importantly, C5, C6 and C8 synergized the anticancer effect with PARP inhibitors, including olaparib, veliparib and niraparib, in pancreatic cancer cells, thus suggesting an important role of C5, C6 and C8 in induction of apoptosis in combination with PARP inhibitors. C5 combined with PARP inhibitors induced caspase3/7 activity and suppressed ATP production. Mechanistically, C5, C6 and C8 inhibited EZH2 protein expression to suppress EZH2-dependent tumorigenesis. Overall, these results highlighted the importance of these piperazine-functionalized Pt(II) complexes as potential anticancer agents to suppress pancreatic ductal adenocarcinoma tumorigenesis by targeting the EZH2-dependent pathway.

Recent progress in aqueous aluminum-ion batteries.

Aqueous aluminum-ion batteries have many advantages such as their safety, environmental friendliness, low cost, high reserves and the high theoretical specific capacity of aluminum. So aqueous aluminum-ion batteries are potential substitute for lithium-ion batteries. In this paper, the current research status and development trends of cathode and anode materials and electrolytes for aqueous aluminum-ion batteries are described. Aiming at the problem of passivation, corrosion and hydrogen evolution reaction of aluminum anode and dissolution and irreversible change of cathode after cycling in aqueous aluminum-ion batteries. Solutions of different research routes such as ASEI (artificial solid electrolyte interphase), alloying, amorphization, elemental doping, electrolyte regulation, etc and different transformation mechanisms of anode and cathode materials during cycling have been summarized. Moreover, it looks forward to the possible research directions of aqueous aluminum-ion batteries in the future. We hope that this review can provide some insights and support for the design of more suitable electrode materials and electrolytes for aqueous aluminum-ion batteries.

Intertumoral Heterogeneity Based on MRI Radiomic Features Estimates Recurrence in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) heterogeneity impacts prognosis, and imaging is a potential indicator. PURPOSE: To characterize HCC image subtypes in MRI and correlate subtypes with recurrence. STUDY TYPE: Retrospective. POPULATION: A total of 440 patients (training cohort = 213, internal test cohort = 140, external test cohort = 87) from three centers. FIELD STRENGTH/SEQUENCE: 1.5-T/3.0-T, fast/turbo spin-echo T2-weighted, spin-echo echo-planar diffusion-weighted, contrast-enhanced three-dimensional gradient-recalled-echo T1-weighted with extracellular agents (Gd-DTPA, Gd-DTPA-BMA, and Gd-BOPTA). ASSESSMENT: Three-dimensional volume-of-interest of HCC was contoured on portal venous phase, then coregistered with precontrast and late arterial phases. Subtypes were identified using non-negative matrix factorization by analyzing radiomics features from volume-of-interests, and correlated with recurrence. Clinical (demographic and laboratory data), pathological, and radiologic features were compared across subtypes. Among clinical, radiologic features and subtypes, variables with variance inflation factor above 10 were excluded. Variables (P < 0.10) in univariate Cox regression were included in stepwise multivariate analysis. Three recurrence estimation models were built: clinical-radiologic model, subtype model, hybrid model integrating clinical-radiologic characteristics, and subtypes. STATISTICAL TESTS: Mann-Whitney U test, Kruskal-Wallis H test, chi-square test, Fisher's exact test, Kaplan-Meier curves, log-rank test, concordance index (C-index). Significance level: P < 0.05. RESULTS: Two subtypes were identified across three cohorts (subtype 1:subtype 2 of 86:127, 60:80, and 36:51, respectively). Subtype 1 showed higher microvascular invasion (MVI)-positive rates (53%-57% vs. 26%-31%), and worse recurrence-free survival. Hazard ratio (HR) for the subtype is 6.10 in subtype model. Clinical-radiologic model included alpha-fetoprotein (HR: 3.01), macrovascular invasion (HR: 2.32), nonsmooth tumor margin (HR: 1.81), rim enhancement (HR: 3.13), and intratumoral artery (HR: 2.21). Hybrid model included alpha-fetoprotein (HR: 2.70), nonsmooth tumor margin (HR: 1.51), rim enhancement (HR: 3.25), and subtypes (HR: 5.34). Subtype model was comparable to clinical-radiologic model (C-index: 0.71-0.73 vs. 0.71-0.73), but hybrid model outperformed both (C-index: 0.77-0.79). CONCLUSION: MRI radiomics-based clustering identified two HCC subtypes with distinct MVI status and recurrence-free survival. Hybrid model showed superior capability to estimate recurrence. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Pathological response and tumor stroma immunogenic features predict long-term survival in non-small cell lung cancer after neoadjuvant chemotherapy.

PURPOSE: Major pathological response (MPR) has become a surrogate endpoint for overall survival (OS) in non-small cell lung cancer (NSCLC) after neoadjuvant therapy, however, the prognostic histologic features and optimal N descriptor after neoadjuvant therapy are poorly defined. METHODS: We retrospectively analyzed data from 368 NSCLC patients who underwent surgery after neoadjuvant chemotherapy (NAC) from January 2010 to December 2020. The percentage of residual viable tumors in the primary tumor, lymph nodes (LN), and inflammation components within the tumor stroma were comprehensively reviewed. The primary endpoint was OS. RESULTS: Of the 368 enrolled patients, 12.0% (44/368) achieved MPR in the primary tumor, which was associated with significantly better OS (HR, 0.36 0.17-0.77, p = 0.008) and DFS (HR = 0.59, 0.36-0.92, p = 0.038). In patients who did not have an MPR, we identified an immune-activated phenotype in primary tumors, characterized by intense tumor-infiltrating lymphocyte or multinucleated giant cell infiltration, that was associated with similar OS and DFS as patients who had MPR. Neoadjuvant pathologic grade (NPG), consisting of MPR and immune-activated phenotype, identified 30.7% (113/368) patients that derived significant OS (HR 0.28, 0.17-0.46, p < 0.001) and DFS (HR 0.44, 0.31-0.61, p < 0.001) benefit from NAC. Moreover, the combination of NPG and the number of positive LN stations (nS) in the multivariate analysis had a higher C-index (0.711 vs. 0.663, p < 0.001) than the ypTNM Stage when examining OS. CONCLUSION: NPG integrated with nS can provide a simple, practical, and robust approach that may allow for better stratification of patients when evaluating neoadjuvant chemotherapy in clinical practice.

Tumor stroma ratio, tumor stroma maturity, tumor-infiltrating immune cells in relation to prognosis, and neoadjuvant therapy response in esophagogastric junction adenocarcinoma.

Accurate predictions on prognosis and neoadjuvant therapy response are crucial for esophagogastric junction adenocarcinoma (EGJA) patients. Therefore, we aimed to investigate the predictive abilities of several indicators, including tumor stroma ratio (TSR), tumor stroma maturity (TSM), and the density and spatial distribution of tumor-infiltrating immune cells (TIICs), such as T cells, B cells, and tumor-associated macrophages (TAMs). Resection and biopsy specimens of a total of 695 patients were included, obtained from the National Cancer Center (NCC) and The Cancer Genome Atlas (TCGA) cohorts. TSR and TSM were evaluated based on histological assessment. TIICs were quantified by QuPath following immunohistochemical (IHC) staining in resection specimens, while the Klintrup-Mäkinen (KM) grade was employed for evaluating TIIC in biopsy specimens. Patients with high stromal levels or immature stroma had relatively worse prognoses. Furthermore, high CD8+T cell count in the tumor periphery, as well as low CD68+ TAM count either in the tumor center or in the tumor periphery, was an independent favorable prognostic factor. Significantly, the combination model incorporating TSM and CD163+TAMs emerged as an independent prognostic factor in both two independent cohorts (HR 3.644, 95% CI 1.341-9.900, p = 0.011 and HR 1.891, 95% CI 1.195-2.99, p = 0.006, respectively). Additionally, high stromal levels in preoperative biopsies correlated with poor neoadjuvant therapy response (p < 0.05). In conclusion, our findings suggest that TSR, TSM, CD8+T cell, CD68+TAMs, and CD163+TAMs predict the prognosis to some extent in patients with EGJA. Notably, the combined model incorporating TSM and CD163+TAM can contribute significantly to prognostic stratification. Additionally, high stromal levels evaluated in preoperative biopsy specimens correlated with poor neoadjuvant therapy response.

dbCRAF: a curated knowledgebase for regulation of radiation response in human cancer.

Radiation therapy (RT) is one of the primary treatment modalities of cancer, with 40-60% of cancer patients benefiting from RT during their treatment course. The intrinsic radiosensitivity or acquired radioresistance of tumor cells would affect the response to RT and clinical outcomes in patients. Thus, mining the regulatory mechanisms in tumor radiosensitivity or radioresistance that have been verified by biological experiments and computational analysis methods will enhance the overall understanding of RT. Here, we describe a comprehensive database dbCRAF (http://dbCRAF.xialab.info/) to document and annotate the factors (1,677 genes, 49 proteins and 612 radiosensitizers) linked with radiation response, including radiosensitivity, radioresistance in cancer cells and prognosis in cancer patients receiving RT. On the one hand, dbCRAF enables researchers to directly access knowledge for regulation of radiation response in human cancer buried in the vast literature. On the other hand, dbCRAF provides four flexible modules to analyze and visualize the functional relationship between these factors and clinical outcome, KEGG pathway and target genes. In conclusion, dbCRAF serves as a valuable resource for elucidating the regulatory mechanisms of radiation response in human cancers as well as for the improvement of RT options.

Analysis of intestinal flora in elderly Uygur patients with sarcopenia.

OBJECTIVE: This study was designed to analyze the structural characteristics of the intestinal flora of elderly Uygur patients with sarcopenia, thereby providing new ideas for clinical treatment. METHODS: Firstly, fecal samples were collected from 40 elderly Uygur patients with sarcopenia (Sarcopenia group) and 40 healthy people (Control group). Next, significant differences in the intestinal flora between the two groups were analyzed based on 16S rDNA high-throughput sequencing. The linear discriminant analysis effect size (LEfSe) was used to estimate the magnitude of the effect of each component (species) abundance on the differential effect. Additionally, an analysis was also performed on the relationship between the intestinal flora and the cytokines in the peripheral blood of patients with sarcopenia. RESULTS: The results of ß diversity showed that there were differences in the structure of the intestinal flora between the two groups. Besides, the phylum level of intestinal flora between the two groups was not significantly different. However, the difference was significant in the intestinal flora at the order, family, and genus levels between the two groups. Among them, Lachnoclostridium, Photobacterium, Anaerobic Bacillus, Hydrogenophilus, and Eubacterium were enriched in the Sarcopenia group; Prevotella 9, Firmicutes FCS020 group, Streptobacillus, Aggregatibacter, Corynebacterium, Clostridium Difficile, and Haloanaerobium were enriched in the Control group. The LEfSe outcomes further showed that Lachnoclostridium was highly enriched in the Sarcopenia group; Prevotella 9 and Firmicutes FCS020 group were significantly enriched in the Control group. Furthermore, the relative abundance of Lachnoclostridium and Streptobacillus were significantly different in patients with high and low IL-6 levels. CONCLUSION: In conclusion, Lachnoclostridium is significantly enriched in the intestines of elderly Uygur patients with sarcopenia; the increase in Lachnoclostridium abundance and the decrease in Streptobacillus abundance are associated with high levels of IL-6. Therefore, abnormal intestinal flora is related to inflammatory reflexes in patients with sarcopenia.

Effect Predictor of Driver Synonymous Mutations Based on Multi-Feature Fusion and Iterative Feature Representation Learning.

Accurate identification of driver mutations is crucial in genetic studies of human cancers. While numerous cancer driver missense mutations have been identified, research into potential cancer drivers for synonymous mutations has shown limited success to date. Here, we developed a novel machine learning framework, epSMic, for predicting cancer driver synonymous mutations. epSMic employs an iterative feature representation scheme that facilitates the learning of discriminative features from various sequential models in a supervised iterative mode. We constructed the benchmark datasets and encoded the embedding sequence, physicochemical property, and basic information such as conservation and splicing feature. The evaluation results on benchmark test datasets demonstrate that epSMic outperforms existing methods, making it a valuable tool for researchers in identifying functional synonymous mutations in cancer. We hope epSMic can enable researchers to concentrate on synonymous mutations that have a functional impact on cancer.

Gastric tubular adenocarcinoma with diffuse neutrophils infiltrating: characteristics and probable treatment strategy.

BACKGROUND: Gastric adenocarcinoma is a highly heterogeneous malignancy with varying prognoses. In clinicopathological practice, we noticed a special tubular adenocarcinoma with diffuse neutrophils infiltrating (TADNI). However, the proportion and characteristics of TADNI remain unclear. This study aimed to evaluate the features of TADNI and explore probable treatments. METHODS: We divided 289 tubular adenocarcinoma cases into the TADNI and non-TADNI (nTADNI) groups by histological neutrophil quantity and performed immunohistochemistry of treatment-associated markers (CXCR1, CXCR2, PD-L1, CD8, HER2 and VEGFR2). Then we evaluated the clinical and morphological features in these cases. We also compared the value of histological features and peripheral blood neutrophil test. In addition, multiomics bioinformatic analyses were performed using the public datasets. RESULTS: In our cohort, TADNI accounted for 10.4% of all tubular adenocarcinoma cases. These cases had worse prognoses (especially the neutrophils mainly outside the tubes) than nTADNI cases. The histological identification of TADNI had more prognostic value than peripheral blood neutrophils. CXCR1/CXCR2 expression was significantly high in TADNI group which indicated that CXCR1/CXCR2 inhibitors might be beneficial for TADNI patients. There were no significant differences in the expression of PD-L1, CD8, HER2 and VEGFR2. The analyses of TCGA data confirmed that TADNI cases had poorer prognoses and higher CXCR1/CXCR2 expression. Bioinformatic results also revealed molecular features (more hsa-mir-223 expression, fewer CD8-positive T cells and regulatory T cells, tighter communication between tumor cells' CXCR1/CXCR2 and neutrophils' CXCL5/CXCL8) of this type. CONCLUSIONS: TADNI is a special morphological subtype with poorer prognoses and unique molecular characteristics, which might benefit from CXCR1/CXCR2 inhibitors.

ABCB4 gene mutation-associated cirrhosis with systemic amyloidosis: A case report.

BACKGROUND: Gene mutations in ATP-binding cassette, subfamily B (ABCB4) lead to autosomal recessive disorders. Primary light amyloidosis is a rare and incurable disease. Here, we report a rare case of liver cirrhosis caused by ABCB4 gene mutation combined with primary light amyloidosis. CASE SUMMARY: We report a case of a 25-year-old female who was hospitalized due to recurrent abdominal pain caused by calculous cholecystitis and underwent cholecystectomy. Pathological examination of the liver tissue suggested liver cirrhosis with bile duct injury. Exon analyses of the whole genome from the patient's peripheral blood revealed the presence of a heterozygous mutation in the ABCB4 gene. Bone marrow biopsy tissues, renal puncture examination, and liver mass spectrometry confirmed the diagnosis of a rare progressive familial intrahepatic cholestasis type 3 with systemic light chain type κ amyloidosis, which resulted in cirrhosis. Ursodeoxycholic acid and the cluster of differentiation 38 monoclonal antibody daretozumab were administered for treatment. Following treatment, the patient demonstrated significant improvement. Urinary protein became negative, peripheral blood-free light chain and urine-free light chain levels returned to normal, and the electrocardiogram showed no abnormalities. Additionally, the patient's lower limb numbness resolved, and her condition remained stable. CONCLUSION: This report presents the diagnosis and treatment of liver cirrhosis, a rare disease that is easily misdiagnosed or missed.

Important oncogenic and immunogenic roles of SPP1 and CSF1 in hepatocellular carcinoma.

The treatment and prognosis of liver cancer remain the focus of medical research. Studies have shown that SPP1 and CSF1 play important roles in cell proliferation, invasion, and metastasis. Therefore, this study analyzed the oncogenic and immunologic roles of SPP1 and CSF1 in hepatocellular carcinoma (HCC). We found that the expression levels of SPP1 and CSF1 in HCC were markedly increased and positively correlated. High SPP1 expression was significantly associated with poor OS, DSS, PFS, and RFS. It was not affected by gender, alcohol use, HBV, or race, whereas CSF1 was affected by these factors. Higher expression levels of SPP1 and CSF1 indicated higher levels of immune cell infiltration and a higher immune score with the R software package ESTIMATE. Further analysis revealed that many genes work co-expressed between SPP1 and CSF1 with the LinkedOmics database, which were mainly involved in signal transduction, the integral components of the membrane, protein binding, and osteoclast differentiation. In addition, we screened ten hub genes using cytoHubba, among which the expression of four genes was significantly associated with the prognosis of HCC patients. Finally, we demonstrated the oncogenic and immunologic roles of SPP1 and CSF1 using the vitro experiments. Reducing the expression of either SPP1 or CSF1 could significantly reduce the proliferation of HCC cells and the expression of CSF1, SPP1, and the other four hub genes. This study suggested that SPP1 and CSF1 interact with each other and have the potential to be therapeutic and prognostic targets for HCC.

The efficacy of additional surgical resection after endoscopic resection in pT1b esophageal squamous cell carcinoma: A multi-institutional retrospective study in China.

BACKGROUND: pT1b esophageal squamous cell carcinoma (ESCC) patients treated by endoscopic resection (ER) required additional treatment with surgical resection (SR) or chemoradiotherapy (CRT) according to 2020 Japan Gastroenterological Endoscopy Society (JGES) guideline. Given the evidences for this recommendation were largely based on small-size studies, our study collected 166 cases of ER-treated pT1b patients in order to investigate the efficacy of additional SR as compared to ER-alone treatment. METHODS: A multi-institutional retrospective study in China was conducted. The pT1b ESCC treated by ER + SR (n = 42) and ER-alone (n = 124) from 2007 to 2018 were recruited. Meanwhile, patients with positive lymphovascular invasion (LVI(+)) and/or with positive vertical margin (VM(+)) were put into high-risk group, and those with both VM(-) and LVI(-) were selected into low-risk group. The clinicopathological parameters, lymph node metastasis (LNM), and survival between ER + SR and ER-alone groups were analyzed. RESULTS: In high-risk group, concurrent LNM revealed in surgically resected specimens accounted for 52.6% cases in ER + SR group. After surgical removal, the incidence of post-resection LNM dropped down to 5.6%. However, in low-risk group, patients with ER + SR treatment did not exhibit any concurrent LNM in surgically resected specimens, and the incidence of their overall LNM was similar to that in ER-alone group (0% vs. 2.8%, p = 1.000). More importantly, these cases demonstrated significantly shorter overall survival (OS) than that in ER-alone group (81.8% and 100.0%, respectively, at 3 years; log-Rank: P = 0.010). CONCLUSIONS: For ER-treated pT1b patients in high-risk group, additional SR is strongly recommended. However, for those in low-risk group, additional SR does not generate much benefit for clearance of LNM, but brings harm to shorten their OS. Therefore, additional SR is not recommended for ER-treated pT1b patient in low-risk group.

Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations.

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies. © 2022 The Pathological Society of Great Britain and Ireland.

Hepatic artery intervention combined with immune-targeted therapy is superior to sequential therapy in BCLC-C hepatocellular carcinoma.

BACKGROUND: Hepatic artery intervention combined with immunotarget therapy exerts excellent disease control and prolongs survival. However, the arrangement of hepatic artery intervention and systemic therapy confuses clinical decisions. METHODS: A two-center, retrospective clinical study was approved by the Institutional Ethics Committee. From December 2018 to February 2022, patients with Barcelona Clinic Liver Cancer stage C (BCLC-C) hepatocellular carcinoma (HCC) who received targeted therapy plus PD-1 inhibitors with or without hepatic artery intervention were included. According to the treatment mode, the patients were assigned to three groups: initial hepatic artery intervention combined with immunotarget therapy, immunotarget therapy sequential hepatic artery interventional therapy, and immunotarget therapy only. The survival, response, and adverse events were compared among the three groups. Subgroup analysis and univariate and multivariate prognostic analyses were also evaluated. RESULTS: The median follow-up time was 18.3 months (95% CI 16.7 to 20.0 months). A total of 163 patients with BCLC-C stage HCC were assigned to three groups: initial hepatic artery intervention plus PD-1 inhibitors plus targeted therapy (HPT, n = 66), PD-1 inhibitors plus targeted therapy followed by hepatic artery intervention (PTH, n = 56) and PD-1 inhibitors plus targeted therapy (PT, n = 41). The median progression-free survival was 8.37 months (95% CI 6.35-10.39) with HPT versus 5.3 months (95% CI 3.48-7.12) with PTH versus 6.33 months (95% CI 3.75-8.92) with PT. The progression-free survival of the HPT group was better than that of the PTH group (HR 0.66, 95% CI 0.45-0.97, p = 0.027) and PT group (HR 0.60, 95% CI 0.39-0.92, p = 0.01). The median overall survival was 14.6 months (95% CI 10.6-18.7) with HPT, 10.0 months (95% CI 8.2-11.8) with PTH and 11.3 months (95% CI 8.3-14.3) with PT. The 1-year overall survival (OS) rates in the HPT, PTH and PT groups were 50%, 33.9%, and 34.1%, respectively. Overall survival was significantly longer in the HTP group than in the PT group (HR 0.60, 95% CI 0.361-0.996, p = 0.032). Compared with the PTH group, the overall survival of the HTP group had a prolonged survival trend (HR 0.66, 95% CI 0.416-1.032, p = 0.059). All treatment modalities were deemed equally safe. Multivariate analysis suggested that the mode of treatment, albumin level, Child‒Pugh grade and hepatectomy history were independent prognostic factors for BCLC-C HCC patients. CONCLUSIONS: Initial hepatic artery intervention combined with immunotarget therapy gained survival benefits with tolerable side effects compared with immunotarget sequential hepatic artery intervention and immunotarget therapy alone. Multivariate analysis suggested that liver reserve function was closely correlated with prognosis.

Research progress on polysaccharide components of Cistanche deserticola as potential pharmaceutical agents.

Cistanche deserticola is a traditional and precious Chinese herbal medicine, known as "desert ginseng", with anti-inflammatory, anti-oxidant, improving immunity, nourishing the kidneys and other pharmacological effects. Its chemical components mainly include phenylethanol glycosides, iridoids, polysaccharides and volatile components, among which polysaccharides have received extensive attention due to their biological activities such as regulating immune activity, anti-aging, anti-spleen deficiency and antitumor. In recent years, a large number of research have been carried out on the extraction and isolation, chemical structure analysis and biological activity of Cistanche deserticola polysaccharides. The methods of polysaccharide extraction mainly include traditional extraction method, ultrasonic assisted method, microwave assisted method and enzyme assisted method, etc. The extracted polysaccharides were analyzed by chemical methods including methylation, acid hydrolysis and Smith degradation and spectroscopy methods such as NMR and IR. A variety of polysaccharides with new structures were obtained, and some polysaccharides with known structures were also investigated for their biological activities and their structure-activity relationships. However, the relationship between polysaccharides structure and their biological activities is still unclear due to the large number of polysaccharide components, their complex structures and the lack of systematic research and analysis on them. It is expected that the subsequent study of polysaccharide structure and active conformational relationship will be highly valuable for the application of Cistanche deserticola in pharmaceutical sciences and health food.

Comparison of the Clinicopathological Characteristics and Prognosis of Esophageal Squamous Cell Carcinoma with Intramural Metastases and Multiple Primary Carcinomas.

BACKGROUND: It is difficult to distinguish esophageal squamous cell carcinoma with intramural metastases (IM) from multiple primary oesophageal carcinoma (MPEC). Nevertheless, there are significant differences in their prognoses and treatments. Therefore, our study aims to clarify the clinicopathological and prognostic characteristics of these two entities and to provide clues for differential diagnosis. METHODS: We retrospectively analyzed 6304 patients who underwent esophagectomy without neoadjuvant therapy. The clinicopathological and prognostic features of patients with IM and MPEC were evaluated. P53 and Rb1 were detected by immunohistochemical (IHC) staining using a tissue microarray. RESULTS: Among the 6304 patients, 127 (2.0%) had IM, and 138 (2.2%) had MPEC. Patients with IM were more likely to have an advanced pT (p < 0.001), pN (p < 0.001), more lymphovascular invasion (p < 0.001) and neural invasion (p < 0.001). Additionally, patients with IM had an extremely poor prognosis compared to those with MPEC, with 5-year overall survival (OS) rates of 18.9% and 56.9%, respectively. Meanwhile, IM was found to be an independent poor prognostic indicator for OS and DFS. In the IM group, all patients showed consistent p53 expression in both primary and IM foci. Of note, Rb1 loss was found in 3 pairs of primary foci and metastases, along with p53 nonsense mutation. CONCLUSIONS: Patients with IM had more risk factors and extremely worse prognosis than those with MPEC. It is essential to discriminate IM from MPEC when managing multifocal carcinomas. IHC staining of p53 and Rb1 may aid in differential diagnosis.

Primary immature teratoma in the liver with growing teratoma syndrome and gliomatosis peritonei: a rare case report.

BACKGROUND: Primary liver immature teratoma is extremely rare and only 4 cases have been reported, let alone with growing teratoma syndrome (GTS) and/or gliomatosis peritonei (GP). CASE PRESENTATION: Here, we report a case of a 44-year-old female presenting with progressive abdominal distension and elevated serum alpha fetal protein (AFP) level. CT/MRI scans revealed a large cystic-solid mass in the right lobe of the liver, accompanied with implant or metastasis in the abdominal cavity. Pathologic examination at biopsy suggested immature teratoma. After 4 cycles of chemotherapy, an MRI showed a slight increase in tumor size. Therefore, surgical resection of the right lobe of the liver was performed. The final histological diagnosis was a mature teratoma (tumor size 28 cm × 14 cm × 13 cm), with no residual immature component, and the diagnosis of GTS was considered. The patient continued to receive 2 courses of postoperative chemotherapy. An abdominal CT scan revealed innumerable miliary nodules in bilateral adnexal areas 2 months after surgery. Histologically, large numbers of mature glia were observed, supporting the diagnosis of GP. CONCLUSIONS: We report for the first time a case of primary liver immature teratoma with GTS and GP in an adult. Longer follow-up is needed to assess definitive efficacy.

Molecular characteristics of multifocal esophageal squamous cell carcinomas to discriminate multicentric origin from intramural metastasis.

Multifocal esophageal squamous cell carcinomas (ESCCs) can be diagnosed as of multicentric origin (MO) or intramural metastasis (IMM). We aimed here to accurately discriminate MO from IMM and explore the tumor immune microenvironment of multifocal ESCCs. Multifocal ESCCs were identified in 333 ESCC patients, and in 145 patients discrimination between MO and IMM was not possible by histopathological examination. Of the 145 patients, tissues of 14 were analyzed by whole-exome sequencing (WES) of 71 different tumor regions, and MO, IMM, and MO/IMM mixed groups were identified in three, ten, and one cases, respectively, based on the similarity of genomic architecture between or among different tumors from one patient. Further phylogenetic analyses revealed complex clonal evolution patterns in IMM cases, and tumor cells disseminated from the primary tumors to IMM tumors were independent of lymph node metastasis. The NanoString-based assay showed that immune cell infiltrates were significantly enriched, and that the immune and proliferation pathways were more activated, in large tumors than in small ones in MO but not IMM cases. Similarly, PD-L1 expression and the density of paratumoral CD8+ T cells were higher in large tumors than in small tumors in MO. Taken together, through analysis of the genomic and immune landscapes, our study has comprehensively characterized the heterogeneity and clonal relationship of multifocal ESCCs, which may be helpful in distinguishing MO from IMM, and for interpreting the immunotherapy responses for multifocal ESCC patients. © 2022 The Pathological Society of Great Britain and Ireland.

Thermal stress involved in TRPV2 promotes tumorigenesis through the pathways of HSP70/27 and PI3K/Akt/mTOR in esophageal squamous cell carcinoma.

BACKGROUND: The transient receptor potential vanilloid receptor 2 (TRPV2) has been found to participate in the pathogenesis of various types of cancers, however, its role(s) in the tumorigenesis of ESCC remain poorly understood. METHODS: Western blotting and immunohistochemistry were performed to determine the expression profiles of TRPV2 in the ESCC patient tissues. A series of in vitro and in vivo experiments were conducted to reveal the role of TRPV2 in the tumorigenesis of ESCC. RESULTS: Our study first uncovered that the activation of TRPV2 by recurrent acute thermal stress (54 °C) or O1821 (20 µM) promoted cancerous behaviours in ESCC cells. The pro-angiogenic capacity of the ESCC cells was found to be enhanced profoundly and both tumour formation and metastasis that originated from the cells were substantially promoted in nude mouse models upon the activation of TRPV2. These effects were inhibited significantly by tranilast (120 µM) and abolished by TRPV2 knockout. Conversely, overexpression of TRPV2 could switch the cells to tumorigenesis upon activation of TRPV2. Mechanistically, the driving role of TRPV2 in the progression of ESCC is mainly regulated by the HSP70/27 and PI3K/Akt/mTOR signalling pathways. CONCLUSIONS: We revealed that TRPV2-PI3K/Akt/mTOR is a novel and promising target for the prevention and treatment of ESCC.