Synchronous Double Primary Tumors of Liver (Small Cell Neuroendocrine Carcinoma and Hepatocellular carcinoma): A Case Report.

This study presents a case of dual primary liver cancer involving small cell neuroendocrine carcinoma and hepatocellular carcinoma. The 58-year-old Chinese male patient, who has a medical history of viral hepatitis B, presented with right upper abdominal pain persisting for one month. Imaging studies indicated the presence of multiple liver masses in segments V and VII-VIII, as well as a mass in the left lung. Subsequent hepatic biopsy performed on both segments confirmed the presence of hepatocellular carcinoma in segment V and small cell neuroendocrine carcinoma in segment VII-VIII. After undergoing one cycle of chemotherapy, the lung mass exhibited a reduction in size, while the liver masses showed an inadequate response. Subsequently, the patient underwent Transcatheter Arterial Chemoembolization (TACE) and Hepatic Artery Infusion Chemotherapy (HIAC), resulting in partial remission (PR). However, the patient was diagnosed with brain metastasis and subsequently treated with Sorafenib and Tirelizumab, a Programmed Death 1 (PD-1) immune checkpoint inhibitor. The efficacy evaluation indicated stability, and no severe adverse effects were observed at the time of writing. The patient's survival time was 16 months.

Indocyanine Green Imaging in Laparoscopic Cholecystectomy Plus Laparoscopic Common Bile Duct Exploration: A Suitable Option for Patients With Difficult Exploration (With Videos).

BACKGROUND: The clinical application of indocyanine green (ICG) fluorescence imaging technology in biliary surgery has gradually highlighted its role, and its role in laparoscopic cholecystectomy plus laparoscopic common bile duct exploration (LC+LCBDE) still needs to be further explored. Therefore, we evaluated the clinical value of ICG fluorescence imaging in LC+LCBDE. MATERIALS AND METHODS: Data from 131 patients who underwent LC+LCBDE in our department between January 2019 and June 2021 were retrospectively collected and analyzed. Overall, 59 and 72 patients underwent ICG+LC+LCBDE and LC+LCBDE, respectively, and were assigned to the ICG (ICG+LC+LCBDE) and non-ICG (LC+LCBDE) groups based on their medical records. The clinical data of all patients were obtained, and the differences between the ICG and non-ICG groups were compared. RESULTS: A total of 131 patients successfully underwent surgery. There were no differences in baseline characteristics between the 2 groups. In terms of perioperative results, no significant between-group differences in biliary tract exposure before Calot's triangle dissection were noted; however, patients in the ICG group had better biliary tract observations after Calot's triangle dissection, shorter operative time, fewer complications, earlier postoperative exhaust, and lower hospital costs. CONCLUSIONS: ICG imaging can assist surgeons in determining biliary tract structures and injuries during surgery and in preventing operation-related bile leakage. ICG imaging is a technique worthy of promotion in difficult surgery.

Efficacy of transcatheter arterial chemoembolization using pirarubicin-loaded microspheres combined with lobaplatin for primary liver cancer.

BACKGROUND: Drug-eluting beads show good safety and promising efficacy when used as part of a transarterial chemoembolization regimen for primary liver cancer. However, data on the clinical efficacy and safety of pirarubicin-loaded beads combined with lobaplatin are lacking in China. AIM: To evaluate the efficacy and safety of transcatheter arterial chemoembolization using pirarubicin-loaded beads combined with lobaplatin for primary liver cancer. METHODS: Between January 2019 and March 2020, 60 patients with primary liver cancer were selected at Hebei North University Affiliated First Hospital. According to different treatment methods, the participants were categorized into two groups with 30 patients treated with pirarubicin-loaded microspheres combined with lobaplatin included in an observation group and 30 patients treated with pirarubicin emulsion with lipiodol combined with lobaplatin were included in a control group. The progression-free survival, overall survival, clinical response rate, disease control rate, liver and kidney function and adverse reactions were compared between the two groups. RESULTS: The progression-free survival was 14 mo in the observation group, which was significantly higher than 9 mo of the control group (P < 0.05). The 6-mo, 12-mo and 18-mo survival rates were 93.33% (28/30), 66.67% (20/30) and 23.33% (7/30), respectively in the observation group, which were significantly higher than 83.33% (25/30), 50.00% (15/30) and 13.33% (4/30), respectively, of the control group (all P < 0.05). The clinical efficacy rate and disease control rate were 73.33% and 93.33%, respectively, in the observation group, which were significantly higher than those of the control group (53.55% and 80.00%, respectively, all P < 0.05). There was no significant difference in alpha-fetoprotein between the two groups before the treatment (P > 0.05). After the treatment, alpha-fetoprotein was 289.06 ± 76.21 ng/mL in the observation group and 365.01 ± 73.11 ng/mL in the control group, which were low in both groups compared with those before the treatment (all P < 0.05). The incidence of nausea and vomiting was significantly lower in the observation group than in the control group (P < 0.05). There was no significant difference for the adverse reactions of pain and fever between the two groups (P < 0.05). CONCLUSION: The combination of pirarubicin-loaded beads and lobaplatin can improve treatment efficacy resulting in mild liver function damage and postoperative complications in patients with primary liver cancer. It can be used in clinical practice.

Anti-HER2 scFv-CCL19-IL7 recombinant protein inhibited gastric tumor growth in vivo.

HER-2 targeted therapies, such as monoclonal antibodies (mAbs) and CAR-T cell therapy have been applied in the treatment of various of cancers. However, the anti-HER2 CAR-T cell therapy are limited by its expensive production procedure and fatal side effects such as cytokine storm or "On target, off tumor". The application of anti-HER2 mAbs to the soild tumor are also plagued by the patients resistant with different mechanisms. Thus, the recombinant protein technology can be presented as an attractive methods in advantage its less toxic and lower cost. In this study, we produced a HER-2-targeting recombinant protein, which is the fusion of the anti-HER-2 single chain fragment variable domain, CCL19 and IL7 (HCI fusion protein). Our results showed that the recombinant protein can induce the specific lysis effects of immune cells on HER-2-positive gastric tumor cells and can suppress gastric tumor growth in a xenograft model by chemotactic autoimmune cell infiltration into tumor tissues and activated T cells. Taken together, our results revealed that the HCI fusion protein can be applied as a subsequent clinical drug in treating HER-2 positive gastric tumors.

Folate Receptor-Alpha Targeted 7x19 CAR-γδT Suppressed Triple-Negative Breast Cancer Xenograft Model in Mice.

Background: Triple-negative breast cancer (TNBC) is the worst prognosis subtype of breast cancer due to lack of specific targets. Recent studies have shown that immunotherapy may solve that problem by targeting folate receptor-alpha (FRα). Methods: Gene modified γδ T cells were manufactured to express FRa specific chimeric antigen receptor (FRa CAR) and secrete interleukin-7 (IL-7) and chemokine C-C motif ligand 19 (CCL19). CAR-γδT cells that secrete IL-7 and CCL19 (7 × 19 CAR-γδT) were evaluated for their antitumor activity both in vitro and in vivo. Results: 7 × 19 CAR-γδT showed remarkable antitumor activity in vitro. Combined with PBMC, 7 × 19 CAR-γδT inhibited TNBC xenograft model growth superiorly compared with single-application or conventional CAR-γδT cells. Histopathological analyses showed increased DC or T cells infiltration to tumor tissues. Conclusion: Taken together, our results showed that 7 × 19 CAR-γδT have remarkable anti-TNBC tumor activity and showed a broad application prospect in the treatment of incurable TNBC patients.

Efficacy and safety of short duration radiotherapy combined with chemotherapy for advanced rectal cancer.

BACKGROUND: Radiotherapy or chemoradiotherapy is widely used for the treatment of rectal cancer preoperatively. Although the combination of radiotherapy and chemotherapy as an established preoperative neoadjuvant therapy shows high efficacy in the treatment of rectal cancer, some patients experience a response of poor tolerance and outcomes due to the long duration radiotherapy. The study compared short duration radiotherapy plus chemotherapy vs long duration radiotherapy plus chemotherapy for rectal cancer to determine whether short duration radiation treatment should be considered to diminish complications, reduce risk of recurrence and improve survival in patients with rectal cancer. AIM: To evaluate the efficacy and safety of short duration radiotherapy combined with chemotherapy for the treatment of advanced rectal cancer. METHODS: One hundred patients with stage IIIB or higher severe rectal cancer were selected as the study subjects at The First Affiliated Hospital of Hebei North University between December 2018 and December 2019. The patients were assigned to different groups based on the treatment regimens. Fifty patients who received preoperative short durations of radiotherapy plus chemotherapy were enrolled in an observation group and fifty patients who received conventional radiotherapy and chemotherapy were enrolled in a control group. Colonoscopic biopsy was performed for all patients with pathological diagnosis of rectal cancer. The expression of tumor-related factors such as RUNX3 and Ki-67 was quantitatively analyzed using immunohistochemistry in the tissues of the patients before and after treatment. Moreover, the duration of procedure, the amount of bleeding during the operation, the anus-conserving rate, the incidence of postoperative complications (wound infection, anastomotic leakage, postoperative intestinal obstruction, etc.) and postoperative pathology were compared between the two groups. The overall survival rate, recurrence rate and distant metastasis rate were also compared through postoperative reexamination and regular follow-up. RESULTS: There was no significant difference in the positive expression rate of RUNX3 and Ki-67 between the two groups before the treatment (P > 0.05). Compared with the pretreatment value, the positive rate of RUNX3 was increased and the positive rate of Ki-67 was decreased in both groups after the treatment (all P < 0.05). The incidence of leukopenia, thrombocytopenia, neutropenia and diarrhea were higher in the observation group than in the control group (all P < 0.05). There was no significant difference in the incidence of anemia, fatigue, neurotoxicity and nausea and vomiting between the two groups (all P > 0.05). No significant difference was observed in the duration of procedure, intraoperative bleeding, the anus-conserving rate and the incidence of postoperative complications between the two groups (P > 0.05). After 1 year of follow-up, the 1-yr survival rate was 80.0% in the observation group and 68.0% in the control group, the recurrence rate was 8.0% in the observation group and 10.0% in the control group, the distant metastasis rate was 6.0% in the observation group and 8.0% in the control group difference (all P < 0.05). CONCLUSION: Short duration radiotherapy combined with chemotherapy can improve the cure rate, prolong the survival time and reduce the incidence of complications in patients with advanced rectal cancer.

Role of chemokines in hepatocellular carcinoma (Review).

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide, with an unsatisfactory prognosis, although treatments are improving. One of the main challenges for the treatment of HCC is the prevention or management of recurrence and metastasis of HCC. It has been found that chemokines and their receptors serve a pivotal role in HCC progression. In the present review, the literature on the multifactorial roles of exosomes in HCC from PubMed, Cochrane library and Embase were obtained, with a specific focus on the functions and mechanisms of chemokines in HCC. To date, >50 chemokines have been found, which can be divided into four families: CXC, CX3C, CC and XC, according to the different positions of the conserved N­terminal cysteine residues. Chemokines are involved in the inflammatory response, tumor immune response, proliferation, invasion and metastasis via modulation of various signaling pathways. Thus, chemokines and their receptors directly or indirectly shape the tumor cell microenvironment, and regulate the biological behavior of the tumor. In addition, the potential application of chemokines in chemotaxis of exosomes as drug vehicles is discussed. Exosomes containing chemokines or expressing receptors for chemokines may improve chemotaxis to HCC and may thus be exploited for targeted drug delivery.

Identification and Validation of DEPDC1B as an Independent Early Diagnostic and Prognostic Biomarker in Liver Hepatocellular Carcinoma.

Liver hepatocellular carcinoma (LIHC) is one of the most lethal tumors worldwide, and while its detailed mechanism of occurrence remains unclear, an early diagnosis of LIHC could significantly improve the 5-years survival of LIHC patients. It is therefore imperative to explore novel molecular markers for the early diagnosis and to develop efficient therapies for LIHC patients. Currently, DEPDC1B has been reported to participate in the regulation of cell mitosis, transcription, and tumorigenesis. To explore the valuable diagnostic and prognostic markers for LIHC and further elucidate the mechanisms underlying DEPDC1B-related LIHC, numerous databases, such as Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan-Meier plotter, and The Cancer Genome Atlas (TCGA) were employed to determine the association between the expression of DEPDC1B and prognosis in LIHC patients. Generally, the DEPDC1B mRNA level was highly expressed in LIHC tissues, compared with that in normal tissues (p < 0.01). High DEPDC1B expression was associated with poor overall survival (OS) in LIHC patients, especially in stage II, IV, and grade I, II, III patients (all p < 0.05). The univariate and multivariate Cox regression analysis showed that DEPDC1B was an independent risk factor for OS among LIHC patients (HR = 1.3, 95% CI: 1.08-1.6, p = 0.007). In addition, the protein expression of DEPDC1B was validated using Human Protein Atlas database. Furthermore, the expression of DEPDC1B was confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) assay using five pairs of matched LIHC tissues and their adjacent noncancerous tissues. The KEGG pathway analysis indicated that high expression of DEPDC1B may be associated with several signaling pathways, such as MAPK signaling, the regulation of actin cytoskeleton, p53 signaling, and the Wnt signaling pathways. Furthermore, high DEPDC1B expression may be significantly associated with various cancers. Conclusively, DEPDC1B may be an independent risk factor for OS among LIHC cancer patients and may be used as an early diagnostic marker in patients with LIHC.

Bioinformatics analysis reveals TSPAN1 as a candidate biomarker of progression and prognosis in pancreatic cancer.

Pancreatic cancer (PCC) is a common malignant tumor of the digestive system that is resistant to traditional treatments and has an overall 5-year survival rate of <7%. Transcriptomics research provides reliable biomarkers for diagnosis, prognosis, and clinical precision treatment, as well as the identification of molecular targets for the development of drugs to improve patient survival. We sought to identify new biomarkers for PCC by combining transcriptomics and clinical data with current knowledge regarding molecular mechanisms. Consequently, we employed weighted gene co-expression network analysis and differentially expressed gene analysis to evaluate genes co-expressed in tumor versus normal tissues using pancreatic adenocarcinoma data from The Cancer Genome Atlas and dataset GSE16515 from the Gene Expression Omnibus. Twenty-one overlapping genes were identified, with enrichment of key Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways, including epidermal growth factor receptor signaling, cadherin, cell adhesion, ubiquinone, and glycosphingolipid biosynthesis pathways, and retinol metabolism. Protein-protein interaction analysis highlighted 10 hub genes, according to Maximal Clique Centrality. Univariate and multivariate COX analyses indicated that TSPAN1 serves as an independent prognostic factor for PCC patients. Survival analysis distinguished TSPAN1 as an independent prognostic factor among hub genes in PCC. Finally, immunohistochemical staining results suggested that the TSPAN1 protein levels in the Human Protein Atlas were significantly higher in tumor tissue than in normal tissue. Therefore, TSPAN1 may be involved in PCC development and act as a critical biomarker for diagnosing and predicting PCC patient survival.

Effector cells derived from naive T cells used in tumor immunotherapy of mice bearing B16 melanoma.

BACKGROUND: Adoptive cell transfer (ACT) immunotherapy has been used clinically for years to treat malignancies. Improving the killing efficiency of effector cells, such as tumor-specific cytotoxic T lymphocytes (CTLs), is an important component for enhancing the clinical response of cancer immunotherapy. Hence, we explored a novel method for preparing cancer-specific CTLs using naive T lymphocytes. METHODS: C57BL/6 mice bearing B16 melanoma tumors were pretreated with cyclophosphamide (CTX) by peritoneal injection. The immunosuppressive influence of CTX on tumor regression and the tumor microenvironment was assessed. Naive T cells and T cell pools were isolated via negative selection using immunomagnetic beads. The proliferative potential and cytokine production of different T cell subpopulations were evaluated in vitro. Tumor-specific CTLs derived from naive T cells (naive CD4+ T cells: naive CD8+ T cells = 2:1) and pooled T cells were generated in vitro, respectively. B16 melanoma-bearing C57BL/6 mice were pretreated with CTX, followed by ACT immunotherapy using dendritic cell-induced CTLs. The homing abilities of the effector cells and interleukin-2 (IL-2), interferon-γ, granzyme B, and perforin mRNA levels in tumor tissues were evaluated, and the change in tumor volume was measured. RESULTS: Mice receiving CTX peritoneal pretreatment injections did not display tumor regression compared with control mice. However, a significant downregulation of splenic Tregs and tumor growth factor-ß1 (TGF-ß1) and interleukin-10 (IL-10) serum levels was observed (P < 0.05). Naive T cells showed a stronger proliferative capacity and elevated cytokine production than did pooled T cells (P < 0.05). In addition, effector cells generated from naive T cells displayed more potent antitumor activity in vivo than those derived from pooled T cells (P < 0.05). CONCLUSION: Effector cells derived from the naive T cells possess a stronger proliferative potential, homing capacity, and enhanced cytokine production, which leads to a superior antitumor response.

Tracking in vivo migration and distribution of antigen-specific cytotoxic T lymphocytes by 5,6-carboxyfluorescein diacetate succinimidyl ester staining during cancer immunotherapy.

BACKGROUND: Killing of targeted tumors during adoptive cell transfer therapy is associated with cytotoxic T lymphocyte (CTL) numbers, immunophenotype, tumor-specificity, and in vivo residence time, migration, and distribution. Therefore, tracing in vivo persistence, migration, and distribution of CTLs is important for cancer immunotherapy. METHODS: Optimal staining concentration for CTL proliferation was determined by cell counting kit-8 (CCK-8) assay and killing efficiencies of CTLs or carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled melanoma antigen-specific cytotoxic T lymphocytes (CFSE-CTLs) for malignant melanoma cells in vitro were compared. Additionally, CFSE-CTLs were intravenously transfused to mice receiving B16 melanoma, and their residence time, migration, and distribution in vivo were observed by measuring fluorescence intensities of CFSE-CTLs per gram of tissue (%FI/g) in various tissues and analyzing tumor/non-tumor (T/NT) values. Anti-tumor effects of transferred CTLs and correlation between %FI/g and D-value of tumor size were analyzed. RESULTS: Five-micromolar CFSE was optimal for labeling CTLs with minimal cytotoxicity. No significant difference occurred between CTLs and CFSE-CTLs for tumor cell killing (P = 0.849) or interleukin-2 (P = 0.318) and interferon-γ (P = 0.201) levels. Distribution of CTLs in vivo varied with time. A negative correlation between %FI/g in tumors and D-value of tumor sizes by Spearman correlation analysis was observed. CTLs were recruited to and killed tumors from 6 hours to 3 days after cell infusion. CTLs were observed up to three weeks later in the tumor, liver, kidneys, and spleen; this was related to the abundant blood supply or the nature of immune organs. CONCLUSIONS: CCK-8 assay is a novel method to select optimal CFSE staining concentrations. Fluorescence intensity of transferred CTLs reflects their killing efficiency of tumors. CFSE fluorescent markers can trace in vivo CTL persistence, migration, and distribution because of its stability, long half-life, and low toxicity.