Development and Optimization of A Human Hepatocellular Carcinoma Patient-Derived Organoid Model for Potential Target Identification and Drug Discovery.

Hepatocellular carcinoma (HCC) is a highly prevalent and lethal tumor worldwide and its late discovery and lack of effective specific therapeutic agents necessitate further research into its pathogenesis and treatment. Organoids, a novel model that closely resembles native tumor tissue and can be cultured in vitro, have garnered significant interest in recent years, with numerous reports on the development of organoid models for liver cancer. In this study, we have successfully optimized the procedure and established a culture protocol that enables the formation of larger-sized HCC organoids with stable passaging and culture conditions. We have comprehensively outlined each step of the procedure, covering the entire process of HCC tissue dissociation, organoid plating, culture, passaging, cryopreservation, and resuscitation, and provided detailed precautions in this paper. These organoids exhibit genetic similarity to the original HCC tissues and can be utilized for diverse applications, including the identification of potential therapeutic targets for tumors and subsequent drug development.

Growth differentiation factor 1-induced tumour plasticity provides a therapeutic window for immunotherapy in hepatocellular carcinoma.

Tumour lineage plasticity is an emerging hallmark of aggressive tumours. Tumour cells usually hijack developmental signalling pathways to gain cellular plasticity and evade therapeutic targeting. In the present study, the secreted protein growth and differentiation factor 1 (GDF1) is found to be closely associated with poor tumour differentiation. Overexpression of GDF1 suppresses cell proliferation but strongly enhances tumour dissemination and metastasis. Ectopic expression of GDF1 can induce the dedifferentiation of hepatocellular carcinoma (HCC) cells into their ancestral lineages and reactivate a broad panel of cancer testis antigens (CTAs), which further stimulate the immunogenicity of HCC cells to immune-based therapies. Mechanistic studies reveal that GDF1 functions through the Activin receptor-like kinase 7 (ALK7)-Mothers against decapentaplegic homolog 2/3 (SMAD2/3) signalling cascade and suppresses the epigenetic regulator Lysine specific demethylase 1 (LSD1) to boost CTA expression. GDF1-induced tumour lineage plasticity might be an Achilles heel for HCC immunotherapy. Inhibition of LSD1 based on GDF1 biomarker prescreening might widen the therapeutic window for immune checkpoint inhibitors in the clinic.

Targeting tumor lineage plasticity in hepatocellular carcinoma using an anti-CLDN6 antibody-drug conjugate.

Tumor lineage plasticity is emerging as a critical mechanism of therapeutic resistance and tumor relapse. Highly plastic tumor cells can undergo phenotypic switching to a drug-tolerant state to avoid drug toxicity. Here, we investigate the transmembrane tight junction protein Claudin6 (CLDN6) as a therapeutic target related to lineage plasticity for hepatocellular carcinoma (HCC). CLDN6 was highly expressed in embryonic stem cells but markedly decreased in normal tissues. Reactivation of CLDN6 was frequently observed in HCC tumor tissues as well as in premalignant lesions. Functional assays indicated that CLDN6 is not only a tumor-associated antigen but also conferred strong oncogenic effects in HCC. Overexpression of CLDN6 induced phenotypic shift of HCC cells from hepatic lineage to biliary lineage, which was more refractory to sorafenib treatment. The enhanced tumor lineage plasticity and cellular identity change were potentially induced by the CLDN6/TJP2 (tight junction protein 2)/YAP1 (Yes-associated protein 1) interacting axis and further activation of the Hippo signaling pathway. A de novo anti-CLDN6 monoclonal antibody conjugated with cytotoxic agent (Mertansine) DM1 (CLDN6-DM1) was developed. Preclinical data on both HCC cell lines and primary tumors showed the potent antitumor efficiency of CLDN6-DM1 as a single agent or in combination with sorafenib in HCC treatment.

The tumor immune microenvironment transcriptomic subtypes of colorectal cancer for prognosis and development of precise immunotherapy.

BACKGROUND: Biomarkers based on immune context may guide prognosis prediction. T-cell inactivation, exclusion, or dysfunction could cause unfavorable tumor microenvironments, which affect immunotherapy and prognosis. However, none of the immuno-biomarkers reported to date can differentiate colorectal-cancer (CRC) patients. Thus, we aimed to classify CRC patients according to the levels of T-cell activation, exclusion, and dysfunction in the tumor microenvironment. METHODS: RNAseq data of 618 CRC patients from The Cancer Genome Atlas and microarray data of 316 CRC patients from Gene Expression Omnibus were analysed using the Tumor Immune Dysfunction and Exclusion algorithm. Unsupervised clustering was used to classify patients. RESULTS: Based on the expression signatures of myeloid-derived suppressor cells, cancer-associated fibroblasts, M2-like tumor-associated macrophages, cytotoxic T-lymphocytes, and PD-L1, all patients were clustered into four subtypes: cluster 1 had a high level of immune dysfunction, cluster 2 had a low level of immune activation, cluster 3 had intense immune exclusion, and cluster 4 had a high level of immune activation and a moderate level of both dysfunction and exclusion signatures. Compared with cluster 1, the hazard ratios and 95% confidential intervals for overall survival were 0.63 (0.35-1.13) for cluster 2, 0.55 (0.29-1.03) for cluster 3, and 0.30 (0.14-0.64) for cluster 4 in multivariate Cox regression. Similar immune clustering and prognosis patterns were obtained upon validation in the GSE39582 cohort. In subgroup analysis, immune clustering was significantly associated with overall survival among stage I/II patients, microsatellite stable/instability-low patients, and patients not treated with adjuvant therapy. CONCLUSIONS: Our findings demonstrated that classifying CRC patients into different immune subtypes serves as a reliable prognosis predictor and may help to refine patient selection for personalized cancer immunotherapy.

Pancreatic neuroendocrine tumors: A review of serum biomarkers, staging, and management.

Pancreatic neuroendocrine tumors (pNETs) are a heterogeneous group of tumors with complicated treatment options that depend on pathological grading, clinical staging, and presence of symptoms related to hormonal secretion. With regard to diagnosis, remarkable advances have been made: Chromogranin A is recommended as a general marker for pNETs. But other new biomarker modalities, like circulating tumor cells, multiple transcript analysis, microRNA profile, and cytokines, should be clarified in future investigations before clinical application. Therefore, the currently available serum biomarkers are insufficient for diagnosis, but reasonably acceptable in evaluating the prognosis of and response to treatments during follow-up of pNETs. Surgical resection is still the only curative therapeutic option for localized pNETs. However, a debulking operation has also been proven to be effective for controlling the disease. As for drug therapy, steroids and somatostatin analogues are the first-line therapy for those with positive expression of somatostatin receptor, while everolimus and sunitinib represent important progress for the treatment of patients with advanced pNETs. Great progress has been achieved in the combination of systematic therapy with local control treatments. The optimal timing of local control intervention, planning of sequential therapies, and implementation of multidisciplinary care remain pending.

Identification of prognostic claudins signature in hepatocellular carcinoma from a hepatocyte differentiation model.

BACKGROUND: Loss of terminal differentiation markers and gain of stem cell-like properties are a major hallmark of cancer malignant progression. Identification of novel biomarkers representing tumor developmental progeny and predictive of patients' prognosis would greatly benefit clinical cancer management. METHODS: Human embryonic stem cells were induced to differentiate into hepatocytes along hepatic lineages. Transcriptomic data from different liver developmental stages were analyzed combining with the RNA-seq data from The Cancer Genome Atlas (TCGA) project. Kaplan-Meier survival analysis and Cox regression analyses were used to analyze the clinical significance in HCC patients. RESULTS: A shifted expression pattern of claudin (CLDN) family genes were identified to be closely associated with liver development and tumor progression. Claudins with hepatic features were found to be significantly down-regulated and predicted better prognosis in HCC patients. Conversely, another set of claudins with embryonic stem cell features were found to be significantly up-regulated and predicted worse prognosis in HCC patients. A claudin signature score system was further established by combining the two sets of claudin genes. The newly established claudins signature could robustly predict HCC patients' prognosis in the training, testing, and independent validation cohorts. CONCLUSIONS: In the present study, we developed a novel embryonic developmental claudins signature to monitor the extent of tumor dedifferentiation in HCC from an in vitro hepatocyte differentiation model. The claudins signature might present a great potential in predicting prognostic significance in HCC as cell surface biomarkers, and provide novel therapeutic targets for precision oncology further in the clinic.

A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets.

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients With Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of 3 chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into 3 groups and treated by laparoscopic HIPPC with 1 of the 3 following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin (L-OHP), Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the 3 groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months and the median survival was 7.5 months for all patients. Patients in the Ra/L-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/L-OHP group and Ra/MMC group is significantly longer than Ra/DDP group (P<0.05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky performance scale, and incidence rate of port-site metastases among the 3 groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provide modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutical combination of Ra/L-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

Development of an oncogenic dedifferentiation SOX signature with prognostic significance in hepatocellular carcinoma.

BACKGROUND: Gradual loss of terminal differentiation markers and gain of stem cell-like properties is a major hall mark of cancer malignant progression. The stem cell pluripotent transcriptional factor SOX family play critical roles in governing tumor plasticity and lineage specification. This study aims to establish a novel SOX signature to monitor the extent of tumor dedifferentiation and predict prognostic significance in hepatocellular carcinoma (HCC). METHODS: The RNA-seq data from The Cancer Genome Atlas (TCGA) LIHC project were chronologically divided into the training (n = 188) and testing cohort (n = 189). LIRI-JP project from International Cancer Genome Consortium (ICGC) data portal was used as an independent validation cohort (n = 232). Kaplan-Meier and multivariable Cox analyses were used to examine the clinical significance and prognostic value of the signature genes. RESULTS: The SOX gene family members were found to be aberrantly expressed in clinical HCC patients. A five-gene SOX signature with prognostic value was established in the training cohort. The SOX signature genes were found to be closely associated with tumor grade and tumor stage. Liver cancer dedifferentiation markers (AFP, CD133, EPCAM, and KRT19) were found to be progressively increased while hepatocyte terminal differentiation markers (ALB, G6PC, CYP3A4, and HNF4A) were progressively decreased from HCC patients with low SOX signature scores to patients with high SOX signature scores. Kaplan-Meier survival analysis further indicated that the newly established SOX signature could robustly predict patient overall survival in both training, testing, and independent validation cohort. CONCLUSIONS: An oncogenic dedifferentiation SOX signature presents a great potential in predicting prognostic significance in HCC, and might provide novel biomarkers for precision oncology further in the clinic.

Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Predictor of Sorafenib Benefit in Patients with Hepatocellular Carcinoma.

Sorafenib is the most recommended first-line systemic therapy for advanced hepatocellular carcinoma (HCC). Yet there is no clinically applied biomarker for predicting sorafenib response. We have demonstrated that a vascular pattern, named VETC (Vessels that Encapsulate Tumor Clusters), facilitates the release of whole tumor clusters into the bloodstream; VETC-mediated metastasis relies on vascular pattern, but not on migration and invasion of cancer cells. In this study, we aimed to explore whether vascular pattern could predict sorafenib benefit. Two cohorts of patients were recruited from four academic hospitals. The survival benefit of sorafenib treatment for patients with or without the VETC pattern (VETC+ /VETC- ) was investigated. Kaplan-Meier analyses revealed that sorafenib treatment significantly reduced death risk and prolonged overall survival (OS; in cohort 1/2, P = 0.004/0.005; hazard ratio [HR] = 0.567/0.408) and postrecurrence survival (PRS; in cohort 1/2, P = 0.001/0.002; HR = 0.506/0.384) in VETC+ patients. However, sorafenib therapy was not beneficial for VETC- patients (OS in cohort 1/2, P = 0.204/0.549; HR = 0.761/1.221; PRS in cohort 1/2, P = 0.121/0.644; HR = 0.728/1.161). Univariate and multivariate analyses confirmed that sorafenib treatment significantly improved OS/PRS in VETC+ , but not VETC- , patients. Further mechanistic investigations showed that VETC+ and VETC- HCCs displayed similar levels of light chain 3 (LC3) and phosphorylated extracellular signal-regulated kinase (ERK) in tumor tissues (pERK) or endothelial cells (EC-pERK), and greater sorafenib benefit was consistently observed in VETC+ HCC patients than VETC- irrespective of levels of pERK/EC-pERK/LC3, suggesting that the different sorafenib benefit between VETC+ and VETC- HCCs may not result from activation of Raf/mitogen-activated protein kinase kinase (MEK)/ERK and vascular endothelial growth factor (VEGF)A/VEGF receptor 2 (VEGFR2)/ERK signaling or induction of autophagy. Conclusion: Sorafenib is effective in prolonging the survival of VETC+ , but not VETC- , patients. VETC pattern may act as a predictor of sorafenib benefit for HCC.

Aberrant MCT4 and GLUT1 expression is correlated with early recurrence and poor prognosis of hepatocellular carcinoma after hepatectomy.

The tumor microenvironment is a key determinant of cancer cell biology. The microenvironment is a complex mixture of tumor cells, stromal cells, and proteins, extracellular matrix, oxygen tension, and pH levels surrounding the cells that regulate the tumor progress. This study identified the prognostic factors associated with hepatocellular carcinoma (HCC) and MCT4 and GLUT1 expression levels in HCC specimens. In this study, we analyzed MCT4 and GLUT1 expression levels in tissue samples from 213 patients with HCC by immunohistochemical analyses and in HCC tumor tissues and matched adjacent nonneoplastic tissues by quantitative real-time PCR. We conducted a prognostic analysis of the overall survival (OS) and time to recurrence (TTR) using immunoreactivity and other common clinical and pathological parameters. All variables with prognostic impact were further analyzed by multivariate analysis. We found that MCT4 and GLUT1 expression levels were significantly higher in tumor tissues than in adjacent nontumor tissues, and they were positively correlated with tumor size. Survival analysis showed that patients with high expression levels of MCT4 or GLUT1 had a poor OS and TTR. In patients with HCC, MCT4 expression was an independent negative prognostic factor for OS (hazard ratio [HR] = 1.617; 95% confidence interval [CI] = 1.102-2.374; P = 0.014), and metabolic indicators were independent prognostic factors for OS (HR = 1.617, 95% CI = 1.102-2.374, P = 0.006) and TTR (HR = 1.348, 95% CI = 1.079-1.685, P = 0.009). Interestingly, patients with positive metabolic indicator expression in tumor cells had a significantly shorter OS and earlier TTR than those with negative metabolic indicator expression in tumor cells in the ≤5 cm and >5 cm subgroups. In summary, using the expression of MCT4 and GLUT1 and their metabolic parameters to determine the metabolic status of tumors is promising for predicting the prognosis of patients with HCC.

Optimized construction of MUC1-VNTRn DNA vaccine and its anti-pancreatic cancer efficacy.

Considering mucin 1-variable number tandem repeat (MUC1-VNTRn) as a novel target for pancreatic cancer immunotherapy, the present study aimed to screen and identify the pVAX1-MUC1-VNTRn DNA vaccine with the strongest immunogenicity. Following construction of a pVAX1-MUC1-VNTRn plasmid, immature dendritic cells (DCs) were subjected to transfection, and mature DCs were then co-cultured with autologous T-cells. The numbers of cytotoxic T lymphocytes (CTLs) secreting interferon (IFN)-γ were determined using an enzyme-linked immunospot assay, and CytoTox® was also used to examine the MUC1-VNTRn-specific Lethal effect of CTLs on Capan2 cells. Additional in vivo experiments in mice were performed to confirm the antitumor effect of the DNA vaccine candidate. The present study successfully constructed the pVAX1-MUC1-VNTRn plasmid, which expresses the target protein in eukaryotic cells. Additionally, upon uptake of the pVAX1-MUC1-VNTRn plasmid, the immature DCs differentiated into mature DCs. The levels of the DC surface molecules cluster of differentiation (CD) 80, CD86, human leukocyte antigen-antigen D related, interleukin (IL)-12, IL-17 and IFN-γ were significantly higher, while the levels of IL-10 and IL-14 were lower, in mature DCs of the stimulated groups compared with the immature DCs of the non-stimulated groups (all P<0.01). In addition, the MUC1-VNTR6 and MUC1-VNTR9 groups, in which DCs were capable of activating autologous T-cells, showed increased IFN-γ-producing T-cells compared with the other groups (strong MUC1-VNTR1, weak VNTR1, VNTR3, VNTR4 and MUC1-cDNA groups; all P<0.001). In addition, the Lethal effect of CTLs on Capan2 cells in these two groups was stronger compared with the other groups (all P<0.001). Furthermore, the induced protective and therapeutic immune responses in mouse experiments showed that the pVAX1-MUC1-VNTR6DNA vaccine likely possessed the strongest immunogenicity, and its ability to inhibit panc02-MUC1 tumor growth was superior to other DNA vaccines (P<0.01). The present study provides compelling evidence that pVAX1-MUC1-VNTRn has the potential to express the target protein in eukaryotic cells, and thatpVAX1-MUC1-VNTR6 was characterized by the strongest Lethal effect in both in vivo and in vitro experiments.

Port-Site Metastases and Chimney Effect of B-Ultrasound-Guided and Laparoscopically-Assisted Hyperthermic Intraperitoneal Perfusion Chemotherapy.

PURPOSE: CO2 leakage along the trocar (chimney effect) has been proposed to be an important factor underlying port-site metastasis after laparoscopic surgery. This study aimed to test this hypothesis by comparing the incidence of port-site metastasis between B-ultrasound-guided and laparoscopically-assisted hyperthermic intraperitoneal perfusion chemotherapy (HIPPC). MATERIALS AND METHODS: Sixty-two patients with malignant ascites induced by gastrointestinal or ovarian cancer were divided into two groups to receive either B-ultrasound-guided or laparoscopically-assisted HIPPC. Clinical efficacy was assessed from the objective remission rate (ORR), the Karnofsky Performance Status (KPS) score, and overall survival. The incidence of port-site metastasis was compared between the two groups. RESULTS: Patients in the B-ultrasound (n=32) and laparoscopy (n=30) groups were comparable in terms of age, sex, primary disease type, volume of ascites, and free cancer cell (FCC)-positive ascites. After HIPPC, there were no significant differences between the B-ultrasound and laparoscopy groups in the KPS score change, ORR, and median survival time. The incidence of port-site metastasis after HIPPC was not significantly different between the B-ultrasound (3 of 32, 9.36%) and laparoscopy (3 of 30, 10%) groups, but significantly different among pancreatic, gastric, ovarian, and colorectal cancer (33.33, 15.79, 10.00, and 0.00%, p<0.001). CONCLUSION: The chimney effect may not be the key reason for port-site metastasis after laparoscopy. Other factors may play a role, including the local microenvironment at the trocar site and the delivery of viable FCCs (from the tumor or malignant ascites) to the trauma site during laparoscopic surgery.

Laparoscopic Hyperthermic Intraperitoneal Perfusion Chemotherapy for Patients with Malignant Ascites Secondary to Unresectable Gastric Cancer.

BACKGROUND: To compare the efficacy of three chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into three groups and treated by laparoscopic HIPPC with one of the three following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin [trans-(±)-diaminocyclohexane oxalatoplatinum (l-OHP)], Ra with cisplatin (DDP), and Ra with mitomycin C (MMC). Perioperative complications, patients' quality of life, and survival were recorded and compared among the three groups. RESULTS: The intraoperative course was successful in all patients, and no perioperative death or complication related to laparoscopic HIPPC was documented. The median follow-up period was 9 months, and the median survival was 7.5 months for all patients. Patients in the Ra/l-OHP group had a median survival of 8.7 months, the Ra/DDP group had a median survival of 5.6 months, and the Ra/MMC group had a median survival of 7.5 months. Patients' median survival in the Ra/l-OHP group and Ra/MMC group was significantly longer than in the Ra/DDP group (P < .05). No significant difference was found in total remission rate of ascites, increase in the Karnofsky Performance Scale, and incidence rate of port-site metastases among the three groups. CONCLUSIONS: Laparoscopy-assisted HIPPC provides modest yet encouraging efficacy for malignant ascites secondary to disseminated GC. Our preliminary data indicate that the chemotherapeutic combination of Ra/l-OHP and Ra/MMC might be more beneficial compared with Ra/DDP in terms of patients' survival.

The complete mitochondrial genome of Japanese macaque, Macaca fuscata fuscata (Macaca, Cercopithecinae).

In this study, the complete mitochondrial genome sequence of Japanese macaque, Macaca fuscata fuscata, with the total length of 16,565 bp, is determined for the first time. This mitogenome harbors 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes, and 1 control region (D-loop). The overall base composition is A (31.7%), C (30.5%), G (12.9%), and T (24.9%), so the slight A-T bias (56.6%) was detected. Most of the genes are distributed on H-strand, except for the ND6 subunit gene and eight tRNA genes. The complete mitochondrial genome sequence reported here will provide new genetic resource to uncover the monkey's evolution.

Multivariate comparison of B-ultrasound guided and laparoscopic continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy for malignant ascites.

OBJECTIVE: Clinical efficacy of B-ultrasound-guided and laparoscopy-assisted continuous hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) for treatment of malignant ascites was investigated. METHODS: Sixty-two patients with malignant ascites induced by ovarian or gastrointestinal cancers were randomly treated with B-ultrasound-guided CHIPC (therapeutic group) or laparoscopy-assisted CHIPC (control group) performed at the same center. Hospitalization costs and surgical duration were evaluated. Follow-up was conducted for 21 months with B-ultrasound or computed tomography at least once per month for assessment of ascites amount and tumor progression. Clinical efficacy was assessed by modified World Health Organization criteria. Survival time, Karnofsky performance score (KPS) of quality of life (QOL), and complications were recorded for all patients. RESULTS: Overall condition, primary disease type, and ascites amounts were comparable between groups. Significantly shorter mean duration of perfusion catheter placement (35 vs. 85 min) and mean hospitalization cost (36,000 vs. 55,000 ¥/patient) were observed in the therapeutic group than the control group (P < 0.01). Significantly different KPS scores were not observed before or after CHIPC (23.13 vs. 22.64 %) in both groups (P > 0.05). No significant differences in objective remission rates of malignant ascites (93.75 vs. 93.34 %), median survival times (9 vs. 8 months), or stamp hole metastasis rates (18.75 vs. 18.15 %) were observed between groups (P > 0.05). CONCLUSIONS: B-ultrasound-guided and laparoscopy-assisted CHIPC have similar clinical efficacy for improving QOL and prolonging patient survival. B-ultrasound-guided CHIPC may, however, shorten operation times and reduce hospitalization costs, making the treatment available to a broader patient population, although port hole metastasis remains an issue.

[Predicting value of serum CEA and CA19-9 in neoadjuvant chemotherapy for advanced gastric carcinoma].

OBJECTIVE: To investigate the predictive value of CEA and CA19-9 in tumor progression, prognosis and neoadjuvant chemotherapy of advanced gastric cancer. METHODS: Clinical data of 322 patients with advanced gastric cancer(54 cases undergoing neoadjuvant chemotherapy) from the Affiliated Oncologic Hospital of Guangzhou Medical College were reviewed. Serum CEA and CA19-9 levels were detected by electrochemiluminescence immunoassay, while the expression of CEA and CA19-9 protein in 54 pairs of tumor tissues and matched biopsies neoadjuvant chemotherapy were determined by immunohistochemistry. RESULTS: The expression levels of serum CEA and CA19-9 were closely related to tumor invasion, lymph node metastasis and TNM stage(all P<0.05). The 5-year cumulative survival rates of patients with serum CEA-positive and CA19-9-positive were 17.0% and 11.9%, compared with 34.6% and 34.8% of the patients with serum CEA-negative and CA19-9-negative respectively (both P<0.05). Neoadjuvant chemotherapy could down-regulate CEA and CA19-9 expressions in tumor tissues(P<0.05), while there was no significantly difference in serum level(P>0.05). CONCLUSIONS: The expressions of serum CEA and CA19-9 are closely associated with tumor progression and prognosis in advanced gastric cancer. However, further study should be done to evaluate their value in selecting patients to receive neoadjuvant chemotherapy.

GP73 expression and its significance in the diagnosis of hepatocellular carcinoma: a review.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, and its incidence has been increasing worldwide. Serum alpha-fetoprotein (AFP) levels and abdominal ultrasound have been widely used for diagnosis as well as surveillance of HCC. However, the sensitivity and specificity of both AFP levels and ultrasound for HCC surveillance have some shortcomings, particularly in the early stages of the disease. Golgi protein-73 (GP73) is a type II Golgi-localized integral membrane protein that is normally expressed in epithelial cells of many human tissues. It is essential for human survival, and might have multiple roles for GP73 in epithelial cell function such as in the kidney and liver. However, details of its biochemical function and regulation of GP73 expression are unknown at present. GP73 expression is upregulated in serum samples from patients with liver disease, with expression being highest in HCC. Therefore, it may be useful as a new serum marker for detection of HCC in at high-risk population. But, this hypothesis needs to be proven in large cohorts.

[Literature review of the efficacy and safety of hyperthermic intraperitoneal perfusion chemotherapy after cytoreductive surgery in the treatment of pseudomyxoma peritonei].

OBJECTIVE: To evaluated the safety and efficacy of hyperthermic intraperitoneal perfusion chemotherapy(HIPC) in the prevention and treatment of pseudomyxoma peritonei (PMP) recurrence after cytoreductive surgery(CRS). METHODS: Studies published in English before 2010 on HIPC after CRS for PMP were searched in PubMed database. Each study was carefully evaluated based on pre-determined criteria. Study results were comprehensively displayed in a form. A descriptive systematic review was performed. RESULTS: A total of 11 studies were included. The median survival time of patients in these studies ranged from 25.6 months to 156 months. The ranges of 1-year, 2-year, 3-year, 5-year, and 10-year survival rates were 72%-100%, 55%-96%, 59%-96%, 52%-96%, and 55%-96%, respectively. The overall complication rate ranged from 2%-15%, and the total perioperative mortality were from 0 to 7%. CONCLUSION: HIPC after CRS is effective and safe for patients with PMP.

Chemotherapy with laparoscope-assisted continuous circulatory hyperthermic intraperitoneal perfusion for malignant ascites.

AIM: To investigate the procedure, feasibility and effects of laparoscope-assisted continuous circulatory hyperthermic intraperitoneal perfusion chemotherapy (CHIPC) in treatment of malignant ascites induced by peritoneal carcinomatosis from gastric cancers. METHODS: From August 2006 to March 2008, the laparoscopic approach was used to perform CHIPC on 16 patients with malignant ascites induced by gastric cancer or postoperative intraperitoneal seeding. Each patient underwent CHIPC three times after laparoscope-assisted perfusion catheters placing. The first session was completed in operative room under general anesthesia, 5% glucose solution was selected as perfusion liquid, and 1500 mg 5-fluorouracil (5-FU) and 200 mg oxaliplatin were added in the perfusion solution. The second and third sessions were performed in intensive care unit, 0.9% sodium chloride solution was selected as perfusion liquid, and 1500 mg 5-FU was added in the perfusion solution alone. CHIPC was performed for 90 min at a velocity of 450-600 mL/min and an inflow temperature of 43 +/- 0.2 degrees C. RESULTS: The intraoperative course was uneventful in all cases, and the mean operative period for laparoscope-assisted perfusion catheters placing was 80 min for each case. No postoperative deaths or complications related to laparoscope-assisted CHIPC occurred in this study. Clinically complete remission of ascites and related symptoms were achieved in 14 patients, and partial remission was achieved in 2 patients. During the follow-up, 13 patients died 2-9 mo after CHIPC, with a median survival time of 5 mo. Two patients with partial remission suffered from port site seeding and tumor metastasis,and died 2 and 3 mo after treatment. Three patients who are still alive today survived 4, 6 and 7 mo, respectively. The Karnofsky marks of patients (50-90) increased significantly (P < 0.01) and the general status improved after CHIPC. Thus satisfactory clinical efficacy has been achieved in these patients treated by laparoscopic CHIPC. CONCLUSION: Laparoscope-assisted CHIPC is a safe, feasible and effective procedure in the treatment of debilitating malignant ascites induced by unresectable gastric cancers.