Favorable response to PD-1 inhibitor plus chemotherapy as first-line treatment for metastatic gastric mixed neuroendocrine-non-neuroendocrine tumor: a case report.

Gastric mixed neuroendocrine-non-neuroendocrine tumor (MiNEN), a rare malignancy, currently has no standard treatment. Here, we report a patient with pathologically confirmed gastric MiNEN following radical surgery with rapid postoperative distant tumor recurrence. Immunofluorescence results suggested intensive lymphocyte infiltration in the tumor. The programmed death receptor ligand 1 (PD-L1) immunohistochemistry 22C3 pharmDx assay showed tumor proportion score was 5% and combined positive score was 10. After 6 cycles of treatment with etoposide and cisplatin in combination with toripalimab, efficacy was assessed as a complete response. Our report shows that for gastric MiNEN patients with high expression of PD-L1, chemotherapy combined with immune checkpoint inhibitors may achieve more significant efficacy.

Huaier improves the efficacy of anti-PD-L1 Ab in the treatment of hepatocellular carcinoma by regulating tumor immune microenvironment.

BACKGROUND: Combination therapy is an effective method for augmenting the efficacy of immune checkpoint inhibitors (ICIs). Huaier is a commonly used Chinese patent medicine with substantial antitumor effects. The combination of Huaier and ICIs may increase the efficacy of ICIs against hepatocellular carcinoma (HCC). METHODS: The major components of Huaier were detected by high-performance liquid chromatography-mass spectrometry. The optimal antitumor dose of Huaier was investigated in H22-bearing mice. Next, Huaier was combined with anti-CD8α antibody (Ab) or anti-PD-L1 Ab to observe the antitumor effect. The safety of these combination drugs was evaluated through blood biochemical tests and hematoxylin and eosin staining of histological sections. RT-qPCR, immunohistochemistry, flow cytometry, and transcriptome sequencing were performed to investigate the potential action mechanism of anti-PD-L1 Ab combined with Huaier against HCC. RESULTS: HPLC-MS/MS identified 333 components of Huaier, including carboxylic acids and derivatives, thienothiophenes, phenols, flavonoids and so on. Huaier exhibited significant antitumor effects, with the strongest effect noted at a dose of 4 g/kg. Huaier boosted CD8+ T cells infiltration into the tumor. Next, CD8+ T cells were depleted by with anti-CD8α Ab, and the antitumor effect of Huaier was suppressed. Flow cytometry results revealed that CD8+ T cells were reduced in the Huaier+anti-CD8α Ab group, with the antitumor effect of this group being inhibited. This indicated that CD8+ T cells were key players in the antitumor activity of Huaier. Meanwhile, Huaier inhibited microvessel density (MVD), downregulated vascular endothelial growth factor A (VEGFA), and upregulated PD-L1 in tumor tissues. Finally, Huaier combined with anti-PD-L1 Ab exhibited a greater antitumor effect in the H22-bearing mice. And the results of liver and kidney function tests and histological section analysis unveiled that the safety of these drugs was excellent. According to the transcriptome sequencing results, Huaier combined with anti-PD-L1 Ab possibly exerted anti-HCC effects through immunomodulation, immune response, and so on. CONCLUSIONS: Huaier exhibited a significant antitumor effect. It promoted CD8+ T cells infiltration, upregulated PD-L1 expression, downregulated VEGFA expression, and inhibited MVD, thereby playing a significant antitumor immunoregulatory effect. The combination of Huaier and anti-PD-L1 Ab has significant antitumor effects, and this regimen has good safety. Therefore, Huaier combined with anti-PD-L1 Ab is a promising therapeutic approach against HCC.

Clinicopathological features of a rare cancer: Intrahepatic lymphoepithelioma-like cholangiocarcinoma with Epstein-Barr virus infection.

PURPOSE: Epstein-Barr virus-related lymphoepithelioma-like cholangiocarcinoma (EBV-LELCC), a subtype of intrahepatic cholangiocarcinoma (IHCC), is an extremely rare cancer. To date, only few cases have been reported. Therefore, more studies are needed to provide new insights into its clinicopathological characteristics and treatment. METHODS: We retrospectively collected data from 16 EBV-LELCC patients admitted to our hospital between January 2013 and February 2022. We summarized their clinical characteristics and analyzed the genomic features of 5 patients by whole-exon sequencing. In addition, the Kaplan-Meier method was used to assess the prognostic differences between EBV-LELCC and EBV-negative IHCC. RESULTS: A total of 16 EBV-LELCC patients aged between 35 and 70 were included in this study and were characterized by female predominance. Eight genetic mutations including KMT2C, ARID1B, BAZ1A, NPM1, POLE, PER3, TOPBP1, USP1 were identified from 5 patients. There were 11 stage I, 2 stage III and 3 stage IV patients in this study. The overall survival of stage I and stage III EBV-LELCC patients after radical surgery was significantly better than that of EBV-negative IHCC patients with matched stage (p = 0.0119). Notably, a stage IV patient treated with a variety of antitumor modalities including surgery, interventional therapy, radiotherapy, chemotherapy, targeted therapy and immunotherapy achieved long-term survival of more than seven years. CONCLUSION: Altogether, EBV-LELCC presents a more favorable prognosis than IHCC. This study suggests that patients with early EBV-LELCC have a good prognosis after radical surgery, and even patients with advanced EBV-LELCC are expected to have a longer survival under appropriate and timely treatment. For such a rare cancer with unique clinicopathological features and molecular patterns, more research is needed to facilitate its diagnosis and treatment.

Identification of Immune Subtypes and Candidate mRNA Vaccine Antigens in Small Cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have demonstrated promising outcomes in small cell lung cancer (SCLC), but not all patients benefit from it. Thus, developing precise treatments for SCLC is a particularly urgent need. In our study, we constructed a novel phenotype for SCLC based on immune signatures. METHODS: We clustered patients with SCLC hierarchically in 3 publicly available datasets according to the immune signatures. ESTIMATE and CIBERSORT algorithm were used to evaluate the components of the tumor microenvironment. Moreover, we identified potential mRNA vaccine antigens for patients with SCLC, and qRT-PCR were performed to detect the gene expression. RESULTS: We identified 2 SCLC subtypes and named Immunity High (Immunity_H) and Immunity Low (Immunity_L). Meanwhile, we obtained generally consistent results by analyzing different datasets, suggesting that this classification was reliable. Immunity_H contained the higher number of immune cells and a better prognosis compared to Immunity_L. Gene-set enrichment analysis revealed that several immune-related pathways such as cytokine-cytokine receptor interaction, programmed cell death-Ligand 1 expression and programmed cell death-1 checkpoint pathway in cancer were hyperactivated in the Immunity_H. However, most of the pathways enriched in the Immunity_L were not associated with immunity. Furthermore, we identified 5 potential mRNA vaccine antigens of SCLC (NEK2, NOL4, RALYL, SH3GL2, and ZIC2), and they were expressed higher in Immunity_L, it indicated that Immunity_L maybe more suitable for tumor vaccine development. CONCLUSIONS: SCLC can be divided into Immunity_H and Immunity_L subtypes. Immunity_H may be more suitable for treatment with ICIs. NEK2, NOL4, RALYL, SH3GL2, and ZIC2 may be act as potential antigens for SCLC.

A Local Strategy Toward Concurrent Chemoradiotherapy Based on Fibrin Gel for Postsurgical Cancer Treatment.

PURPOSE: Postoperative cancer recurrence and metastasis have always been huge challenges in cancer therapy. The concurrent cisplatin (CDDP)-based chemoradiotherapy regimen is a standard therapeutic strategy in some cancer treatments after surgical resection. However, severe side effects and unsatisfactory local tumor concentrations of CDDP have hampered the application of this concurrent chemoradiotherapy. Therefore, a superior option that can enhance CDDP-based chemoradiotherapy efficacy with milder concurrent therapy-related toxicity is highly desirable. METHODS AND MATERIALS: We developed a platform based on fibrin gel (Fgel) loaded with CDDP to be implanted into the tumor bed after surgery combined with concurrent radiation therapy for the prevention of postoperative local cancer recurrence and distant metastasis. The postoperative subcutaneous tumor mouse models established by incomplete resection of primary tumors were used to evaluate the therapeutic advantages of this chemoradiotherapy regimen for postsurgical treatment. RESULTS: The local and sustained release of CDDP from Fgel could enhance the antitumor efficacy of radiation therapy in the residual tumor with lower systemic toxicity. The therapeutic benefits of this approach are demonstrated in breast cancer, anaplastic thyroid carcinoma, and osteosarcoma mouse models. CONCLUSIONS: Our work offers a general platform for concurrent chemoradiotherapy to prevent postoperative cancer recurrence and metastasis.

Polyethyleneimine-based immunoadjuvants for designing cancer vaccines.

Despite extensive efforts to improve the effectiveness of cancer vaccines, the lack of immunogenicity remains an issue. Adjuvants are required to enhance the immunogenicity of antigens and activate the immune response. However, only a few adjuvants with acceptable toxicity have sufficient potency for use in cancer vaccines, necessitating the discovery of potent adjuvants. The most well-known cationic polymer polyethyleneimine (PEI) acts as a carrier for delivering antigens, and as an immunoadjuvant for enhancing the innate and adaptive immunity. In this review, we have summarized PEI-based adjuvants and discussed how to improve and boost the immune response to vaccines. We further focused on PEI-based adjuvants in cancer vaccines. Finally, we have proposed the potential challenges and future issues of PEI-based adjuvants to elicit the effectiveness of cancer vaccines.

Glycyrrhetinic acid: A potential drug for the treatment of COVID-19 cytokine storm.

BACKGROUND: The cytokine storm (CS) triggered by coronavirus disease 2019 (COVID-19) has caused serious harm to health of humanity and huge economic burden to the world, and there is a lack of effective methods to treat this complication. PURPOSE: In this research, we used network pharmacology and molecular docking to reveal the interaction mechanism in the glycyrrhetinic acid (GA) for the treatment of CS, and validated the effect of GA intervention CS by experiments. STUDY DESIGN: First, we screened corresponding target of GA and CS from online databases, and obtained the action target genes through the Venn diagram. Then, protein-protein interaction (PPI) network, Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment of the action target genes were acquired by R language to predict its mechanism. Next, molecular docking was performed on core targets. Finally, experiments in which GA intervened in lipopolysaccharide (LPS)-induced CS were implemented. RESULTS: 84 action target genes were obtained from online database. The PPI network of target genes showed that TNF, IL6, MAPK3, PTGS2, ESR1 and PPARG were considered as the core genes. The results of GO and KEGG showed that action target genes were closely related to inflammatory and immune related signaling pathways, such as TNF signaling pathway, IL-17 signaling pathway, Human cytomegalovirus infection, PPAR signaling pathway and so on. Molecule docking results prompted that GA had fine affinity with IL6 and TNF proteins. Finally, in vivo and in vitro experimental results showed that GA could significantly inhibit LPS-induced CS. CONCLUSION: GA has a potential inhibitory effect on CS, which is worthy of further exploration.

Inspiration for COVID-19 Treatment: Network Analysis and Experimental Validation of Baicalin for Cytokine Storm.

Background: Cytokine storm (CS) is a systemic inflammatory syndrome and a major cause of multi-organ failure and even death in COVID-19 patients. With the increasing number of COVID-19 patients, there is an urgent need to develop effective therapeutic strategies for CS. Baicalin is an anti-inflammatory and antiviral traditional Chinese medicine. In the present study, we aimed to evaluate the therapeutic mechanism of baicalin against CS through network analysis and experimental validation, and to detect key targets of CS that may bind closely to baicalin through molecular docking. Method: Access to potential targets of baicalin and CS in public databases. We constructed the protein-protein interaction (PPI) network of baicalin and CS by Cytoscape 9.0 software and performed network topology analysis of the potential targets. Then, the hub target was identified by molecular docking technique and validated in the CS model. Finally, GO and KEGG pathway functional enrichment analysis of common targets were confirmed using R language, and the location of overlapping targets in key pathways was queried via KEGG Mapper. Result: A total of 86 overlapping targets of baicalin and CS were identified, among which MAPK14, IL2, FGF2, CASP3, PTGS2, PIK3CA, EGFR, and TNF were the core targets. Moreover, it was found that baicalin bound most closely to TNF through molecular docking, and demonstrated that baicalin can effectively inhibit the elevation of TNF-α in vitro and in vivo. Furthermore, bioenrichment analysis revealed that the TNF signaling pathway and IL-17 signaling pathway may be potential key pathways for baicalin to treat CS. Conclusion: Based on this study, baicalin was identified as a potential drug for the alleviation of CS, and the possible key targets and pathways of baicalin for the treatment of CS were elucidated to reveal the main pharmacological mechanisms.

An in situ spontaneously forming micelle-hydrogel system with programmable release for the sequential therapy of anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is a lethal malignancy with a 1 year survival rate of less than 20%. Combination chemotherapy with cisplatin and paclitaxel is recommended as a critical therapeutic approach toward ATC. However, harsh side-effects on patients and unsatisfactory intratumoral concentrations hamper the effectiveness of systemic chemotherapy. In this work, an in situ spontaneously forming micelle-hydrogel system (iMHS) with programmable-release characteristics was developed for sequential chemotherapy. Taking advantage of the diffusion rate of the hydrophobic drug in the micellar network and the degradation of the hydrogel matrix, iMHS supported sequential chemotherapy via programmatic release. Moreover, in vitro and in vivo studies demonstrated the superiority of sequential release from iMHS over other approaches, regardless of the genetic profile (e.g., different BRAF, TP53, and TERT promoter mutations, etc.). Additionally, iMHS presented the significant ability to prevent local tumor recurrence in a post-surgical model. Overall, iMHS may serve as a promising strategy for the enhanced localized treatment of ATC via the programmable release of chemotherapy drugs with implied translational value.

Identification of potential immune-related circRNA-miRNA-mRNA regulatory network in cutaneous squamous cell carcinoma.

Circulating RNAs (circRNAs) are involved in tumor development and progression by participating in immune regulation. Nevertheless, the circRNAs expression profiles and their roles on the immunomodulatory effects in cutaneous squamous cell carcinoma (cSCC) have rarely been studied. In our study, we identified the differentially expressed circRNAs (DEcircRNAs), miRNAs (DEmiRNAs), mRNAs (DEmRNAs) in cSCC and established the circRNA competing endogenous RNAs (ceRNAs) network. Subsequently, the hub differentially expressed immune-related genes were identified and validated by immunochemistry as well as the GO and KEGG pathway analysis were performed. 54 differentially expressed circRNAs were identified and hub differentially expressed immune-related genes were identified and they were mostly associated with immune response in the progression of cSCC. Our results indicated that the potential immune-related circRNA-miRNA-mRNA network may assist in understanding the molecular mechanisms underlying the carcinogenesis and progression in cSCC. Moreover, the immune-related genes may provide an insight into the pathogenesis, molecular biomarkers, and potential therapeutic targets for cSCC patients.

Prognostic value of pretreatment circulating basophils in patients with glioblastoma.

Accumulating evidence demonstrated that atopic diseases were inversely related to glioma susceptibility and associated with improved prognosis of patients with glioma. This study aimed to elucidate the impacts of basophils, one of the important effector cells in the pathobiology of atopic disease, on prognosis of patients with glioblastoma (GBM). A total of 268 patients were newly diagnosed with GBM and treated with operation at our institution from January 2010 to December 2017. The association between pre-operation circulating eosinophil, basophil, neutrophil, lymphocyte, monocyte count and GBM progression free survival (PFS) was investigated. Moreover, based on the results of multivariate analysis, a prognostic nomogram was established and evaluated. Kaplan-Meier method showed that basophils ≥0.015 × 109/L (p = 0.015) and lymphocytes ≥1.555 × 109/L (p = 0.005) were correlated with better PFS. Cox regression model showed that basophils ≥0.015 × 109/L were an independent prognostic factor for PFS. Prognostic nomogram was established and the concordance index (C-index) for PFS prediction was 0.629. The calibration plots for the probability of 0.5-, 1- and 3-year PFS showed optimal consistency between the prediction by nomogram and actual observation. Increased pre-operation circulating basophils portend better PFS, which might be a useful and novel marker for the prognosis of GBM patients.

Epidermal growth factor receptor-mutant pulmonary adenocarcinoma coexisting with tuberculosis: A case report.

RATIONALE: Lung cancer and pulmonary infections can have similar clinical and radiographic manifestations. Treatment for the coexistence of epidermal growth factor receptor (EGFR)-mutant pulmonary adenocarcinoma and tuberculosis remains unclear. PATIENT CONCERNS: We reported a case of EGFR-mutant lung adenocarcinoma (mimicking pulmonary infections) that coexisted with pulmonary tuberculosis during the course of the disease. DIAGNOSES: The patient was initially diagnosed with pneumonia-like pulmonary adenocarcinoma with EGFR exon 19 deletions based on computed tomography scan, fiberoptic bronchoscopy, pathology, and genetic analysis, and then coexistence with active tuberculosis (TB) was confirmed via laboratory examinations and TB-DNA polymerase chain reaction. INTERVENTIONS: Antibiotics and gefitinib were administered initially. A combination of gefitinib and anti-TB treatment was then administered when active TB was confirmed, and osimertinib was then prescribed because the disease was progressive and EGFR T790 M mutation was detected. OUTCOMES: The patient has survived with a stable disease status to date. LESSONS: Exploring and ruling out differential diagnoses between pulmonary malignancies and infectious diseases is vital for treatment decisions and outcomes. The combined gefitinib-anti-TB regimen was safe, though it needed modification.

Prognostic significance of malignant ascites in gastric cancer patients with peritoneal metastasis: A systemic review and meta-analysis.

BACKGROUND: Recent evidence indicates that malignant ascites may be associated with the high malignancy and poor prognosis of gastric cancer (GC) with peritoneal metastasis (PM), but no robust consensus has been reached until now. AIM: To evaluate the prognostic significance of malignant ascites in GC patients with PM. METHODS: Two independent authors conducted database searches. The searches were performed in the EMBASE, PubMed, and Cochrane Library databases, and the terms used to search included stomach neoplasms, GC, ascites, peritoneal effusion, survival, and survival analysis. Outcomes included overall survival and hazard ratios with 95% confidence intervals (CIs). Three pairs of comparisons for measuring survival were made: (1) Patients with ascites vs those without ascites; (2) Patients with massive ascites vs those with mild to moderate ascites; and (3) Patients with massive ascites vs those with no to moderate ascites. RESULTS: Fourteen articles including fifteen studies were considered in the final analysis. Among them, nine studies assessed the difference in prognosis between patients with and without malignant ascites. A pooled HR of 1.63 (95%CI: 1.47-1.82, P < 0.00001) indicated that GC patients with malignant ascites had a relatively poor prognosis compared to patients without ascites. We also found that the prognosis of GC patients with malignant ascites was related to the volume of ascites in the six other studies. CONCLUSION: GC patients with malignant ascites tend to have a worse prognosis, and the volume of ascites has an impact on GC outcomes.

Systemic Chemotherapy in Metastasis-Induced Acute Pancreatitis Patients With Small Cell Lung Cancer.

OBJECTIVES: Small cell lung carcinoma (SCLC) is a highly malignant tumor characterized by early metastasis even at the time of diagnosis. Although pancreatic metastasis occurring in SCLC is a common observation in the literatures, there is currently very limited experience with the metastasis-induced acute pancreatitis in SCLC patients. METHODS: Here we retrospectively analyzed patients with metastasis-induced acute pancreatitis and SCLC in West China Hospital between 2009 and 2017. The patients were diagnosed as having SCLC by bronchoscopic biopsy or computed tomography-guided percutaneous biopsy. Metastasis-induced pancreatitis was established by clinical symptoms, radiologic surveillance, serum amylase, and lipase level. The series included 14 patients, 4 women and 10 men, with a mean age of 54 years (range, 29-76 years). The patients underwent chemotherapy plus palliative treatment (n = 8) or palliative care alone (n = 6). RESULTS: Compared with patients receiving palliative treatment alone, a trend toward improved survival was observed in patients who underwent chemotherapy. CONCLUSION: Our personal experience indicated that chemotherapy might provide a survival benefit in SCLC patients with metastasis-induced pancreatitis, especially those with good performance status.