[Drug research and development and unmet needs for advanced-stage hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide and is a global health challenge. Radical surgical resection is the most effective method to achieve long-term survival for HCC. Regrettably, the vast majority of HCC patients lose the opportunity for radical resection at the time of diagnosis due to advanced tumors or poor liver reserve capacity. HCC is resistant to conventional chemotherapy, and in the past, there have been no definite and effective systemic therapeutic drugs. Fortunately, over the last decade, the research and development of molecular targeted therapy and immunotherapy drugs for HCC have made rapid progress, and a variety of drugs and combination therapy regimens have been successively approved for clinical use. However, the overall therapeutic effect is still not ideal and needs further improvement.

[Mediating effects of obesity and metabolic factors in hyperuricemia and prehypertension].

Objective: To assess the mediating effects of obesity and metabolic factors in the relationship between hyperuricemia (HUA) and prehypertension. Methods: A total of 9 399 individuals were selected using a multistage stratified whole-group random sampling method from 90 villages (neighborhood committees) in 30 towns (streets) of 5 districts (counties) in Fuzhou. A total of 4 754 study subjects were included. A linear regression model was used to analyze the association of HUA with obesity and metabolic factors. Single-factor and multi-factor logistic regression models were used to analyze the association of HUA, obesity, and metabolic factors with prehypertension. Mediating effects models were used to analyze the mediating effects of obesity and metabolic factors on the association between HUA and prehypertension. Results: After adjusting for confounders, the association between HUA and cholesterol, triglycerides, HDL-C, LDL-C, BMI, waist circumference, creatinine, and urea nitrogen were significantly correlated (P<0.001). HUA, waist circumference, BMI, and triglycerides were significantly associated with prehypertension (P<0.001). Waist circumference, BMI, and triglycerides mediated the relationship between HUA and prehypertension, with OR (95%CI) of 1.018 (1.007-1.027), 1.010 (1.002-1.018), and 1.010 (1.003-1.017) (P<0.001), with mediating proportions of 7.76%, 4.31%, and 4.31% respectively. No mediating effect of cholesterol, HDL-C, LDL-C, creatinine, and urea nitrogen was found on the relationship (P>0.05). Conclusions: Waist circumference, BMI, and triglycerides all had mediating effects in the association between HUA and prehypertension. For the general population, weight control, waist circumference, and a high-fat diet should be used to reduce the occurrence of prehypertension.

[The influence of HBsAg expression in liver tissue on the postoperative recurrence of HCC patients].

Objective: To investigate the influence of HBsAg expression in peritumoral tissue of hepatocellular carcinoma (HCC) patients on their postoperative recurrence. Methods: The HCC patients treated in Shanghai Eastern Hepatobiliary Surgery Hospital from October 2009 to August 2010 were selected. The clinicopathological data and adjacent tissues of 718 patients were collected, and dextran polymer immunohistochemical staining was used to detect the expression of HBsAg in adjacent tissues. According to the expression of HBsAg in adjacent tissues, the tissues were divided into HBsAg positive group and HBsAg negative group. Kaplan-Meier method and Log rank test were used for survival analysis, and Cox regression model was used for multivariate analysis. Results: Among the 718 patients in the whole group, 153 were HBsAg negative and 565 were HBsAg positive. There was a statistically significant difference in serum HBV DNA level between HBsAg-positive and HBsAg-negative patients (P<0.001). The number of patients with serum DNA≥2 000 IU/ml and<2 000 IU/ml in HBsAg negative group were 52 and 93, while the patients in HBsAg positive group were 325 and 205. The cumulative recurrence rates of all patients at 1, 3, and 5 years after surgery were 30.2%, 54.3%, and 62.7%, respectively. The expression of HBsAg was related to the recurrence (P=0.038). Multivariate analysis showed that γ-GT, PT, multiple tumors, tumor length, and portal vein invasion were independent risk factors for recurrence of HCC (P<0.05). In HBeAg-negative patients with low viral load (HBV DNA <2 000 IU/ml) and without cirrhosis, the recurrence rates of HBsAg-positive patients were 14.3% and 31.0% at 3 and 5 years, respectively, compared with HBsAg negative patients (all 0), the difference was statistically significant (P=0.021). Conclusion: The positive expression of HBsAg in peritumoral tissue increases the postoperative recurrence risk of HCC patients.

[Advances in the study of programmed cell death protein 1 and its ligand inhibitors in the treatment of late stage HCC].

The treatment of late stage hepatocellular carcinoma (HCC) presently remains a great challenge. A very few drugs have been recently approved for clinical use except sorafenib and lenvatinib. After decades of failure and experience with molecular targeted and immunosuppressive therapy, immune checkpoint inhibitors are becoming one of the potentially effective therapies for patients with HCC, whose tumor is in the middle and late stages. Moreover, immune checkpoint is one of the main mechanisms of tumor immune evasion; of which programmed cell death protein 1 and its ligand (PD1/PD-L1) are important immune checkpoint targets, and its related pathway has shown to have an antitumor effect in a variety of solid or hematologic tumors and its inhibitors can effectively exert antitumor immunosuppressive effects. This review summarizes the current role of PD1/PD-L1 inhibitors in the treatment of late stage HCC, and explores the forecasting value of combined therapy strategy for HCC.

[A comparative study of intrahepatic cholangiocarcinoma and hepatocellular carcinoma with reference to clinical features and prognosis].

Objective: To comparatively study intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) with reference to clinical features and prognosis in Chinese Han population. Methods: 699 cases of HCC and 170 cases of ICC confirmed by surgical pathological files from 2009 to 2010 were included and followed-up. The differences in demographic characteristics, hepatitis B virus infection, clinical characteristics, biochemical indexes, tumor markers and prognosis of HCC and ICC were analyzed retrospectively by means of paired t-test, analysis of variance, chi-square test and Pearson's correlation coefficient. Results: Among 869 cases of primary liver cancer, HCC and ICC accounted for 80.43% and 19.57%. The old aged (P < 0.001) male incidence of HCC was higher than that of ICC (P < 0.001). The infection rates of hepatitis B virus were 89.84% and 35.88% in HCC and ICC, respectively, and the infection rates of hepatitis B, serum HBsAg postive rate and DNA account in HCC were higher than ICC (P < 0.001). The incidence of liver cirrhosis and hepatic schistosomiasis in HCC was also significantly different from that in ICC (both P < 0.01). Pearson's correlation analysis showed that there was a significant negative correlation between HCC or ICC tumor type and hepatic schistosomiasis (r = -0.018, P < 0.001), and there was a significant positive correlation between HCC and hepatic cirrhosis (r = 0.179, P < 0.001, and r = 0.528, P < 0.001, respectively). However, the proportion of cirrhosis and schistosomiasis in hepatitis B positive ICC cases was not significantly different from that in HCC cases (P > 0.05). Among the biochemical indicators, there were significant differences between HCC and ICC in the abnormal rate of ALT(P < 0.01), AST(P < 0.05), ALP (P < 0.01), GGT (P < 0.01) and TBIL (P < 0.01) while there was no significant difference between ALB and pre-ALB (P > 0.05) in HCC and ICC groups. The content and abnormal rate of alpha-fetoprotein were higher in HCC (P < 0.01), while the content and abnormal rate of carcinoembryonic antigen and carbohydrate antigen 19-9 were higher in ICC (P < 0.01). The 10-year survival rate and median survival time (46.92% and 80.3 months) of HCC were higher than those of ICC (12.57% and 12.4 months) (P < 0.01). Conclusion: In the study population, compared with ICC cases, the old aged male HCC cases are more common and has higher infection rate of hepatitis B virus and cirrhosis, but liver schistosomiasis is less common. The inflammatory damage, secretion and metabolic function of HCC were different from that of ICC cases, while the synthetic reserve function was similar to that of ICC and the prognosis of HCC cases was significantly better. The incidence of cirrhosis and schistosomiasis in ICC cases with positive hepatitis B virus infection was not significantly different from that of HCC cases.

Influences of remifentanil on myocardial ischemia-reperfusion injury and the expressions of Bax and Bcl-2 in rats.

OBJECTIVE: To investigate the influences of remifentanil on myocardial ischemia-reperfusion injury in rats and the expressions of b-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax) and other apoptosis-related proteins. MATERIALS AND METHODS: A total of 60 Sprague-Dawley (SD) rats were randomly divided into sham operation (S) group, model (M) group, low-dose remifentanil (L) group and high-dose remifentanil (H) group, with 15 rats in each group. The rat model of myocardial ischemia-reperfusion injury was established by the ligation of the left anterior descending branch (LAD). After ischemia for 30 min and reperfusion for 24 h, the cardiac function of rats in each group was measured by an ultrasonic instrument. Triphenyl tetrazolium chloride (TTC) staining was used to detect the myocardial infarction area of rats in each group. The activity of myocardial enzymes in the serum of rats in each group was detected. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was adopted to examine the apoptosis level of rat cardiomyocytes in each group. Quantitative polymerase chain reaction (qPCR) and Western blotting were applied to detect the expression levels of apoptosis-related proteins and messenger ribonucleic acids (mRNAs) in rat cardiomyocytes in each group. RESULTS: Compared with those in S group, left ventricular internal dimension in systole (LVIDs) and left ventricular internal dimension in diastole (LVIDd) were markedly increased (p<0.01), while left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were notably decreased in M group (p<0.01). LVIDs and LVIDd in L group and H group were lower than those in M group (p<0.05, p<0.01), whereas LVEF and LVFS were higher than those in M group (p<0.05, p<0.01). The myocardial infarction area in M group was significantly larger than that in S group (p<0.01), and those in L group and H group were remarkably smaller than that in M group (p<0.05, p<0.01). The activities of aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and creatine kinase-muscle/brain (CK-MB) in the serum of rats in M group were evidently higher than those in S group (p<0.01), and compared with those in M group, those in L group and H group were significantly decreased (p<0.05, p<0.01). The apoptosis level of myocardial cells in M group was significantly higher than that in S group (p<0.01), while those in L group and H group were markedly lower than that in M group (p<0.05, p<0.01). Compared with those in S group, the expression levels of cleaved caspase-3 and its mRNAs in myocardial cells in M group were remarkably increased (p<0.01), while those of Bcl-2/Bax and it mRNAs were significantly decreased (p<0.01). The expression levels of cleaved caspase-3 and its mRNAs in myocardial cells in L group and H group were significantly lower than those in M group (p<0.05, p<0.01), but those of Bcl-2/Bax and its mRNAs were significantly higher than those in M group (p<0.05, p<0.01). CONCLUSIONS: Remifentanil can effectively reduce myocardial cell injury caused by myocardial ischemia-reperfusion in rats, improve cardiac function, reduce the myocardial infarction area, decrease cleaved caspase-3 in myocardial cells, and increase Bcl-2/Bax.

[Advances in the application of artificial intelligence in cancer diagnosis and treatment].

The application of artificial intelligence is developing rapidly in various fields with the improvement of computing power, big data processing, and diversity of algorithms. It has a great potential value in the field of medical and healthcare, especially in the field of cancer diagnosis and treatment. In addition, it can analyze a large amount of data, information, and knowledge instantaneously. Therefore, it serves as a powerful tool for doctors to make the best treatment decisions. Notably, the development of science and technology truly transform into the actual interests of patients. This paper introduces advances in the application of artificial intelligence in diagnosis and treatment of cancer through digital pathology, medical imaging, and genomic medicine.

[Modern knowledge and development trend of intrahepatic cholangiocellular carcinoma].

Although intrahepatic cholangiocellular carcinoma (ICC) has a relatively low incidence rate, it ranks the second in the most common primary malignant liver tumors, with hepatocellular carcinoma ranking the first. Meanwhile, its incidence and mortality rates tend to increase significantly in the past decades. On the one hand, due to a lack of characteristic clinical symptoms, specific tumor markers, and imaging findings, early diagnosis of ICC is extremely difficult; on the other hand, ICC has highly malignant biological behaviors and early extrahepatic metastasis, so patients often experience early recurrence even if surgical resection is performed, which leads to the poor prognosis of such patients. Unfortunately, since ICC has a low incidence rate and relatively few patients, it is not taken seriously in clinical practice. Since there is a lack of clinical data, specimens, and in-depth studies on ICC, its pathogenesis remains unclear. This article discusses recent advances in ICC, including risk factors, molecular mechanism, new diagnostic markers, and therapies (including molecular targeted drugs).

Classification of colon cancer based on the expression of randomly selected genes.

In order to ascertain the relationship between gene expression and colon cancer localization, a classification method based on random gene selection and a self-organizing map network is proposed. Different numbers of genes were selected randomly from 54,675 genes of 53 colon cancer patients in stage union for international cancer control II. These patients were then divided into two sets: a training set of 36 and a validation set of 17 patients. In this study, we randomly selected 1000, 100, 50, 30, 10, 5, and 3 genes, 1000 times, respectively. The minimum misclassification ratio of each gene group was 3/17 to 4/17, and the percentage of gene groups that were less than 0.25 was approximately 1-7%. Moreover, the misclassification ratio of most gene groups (about 82-89%) was lower than 0.4. Through the analysis of these low misclassification ratio gene groups, we found that there were few common genes between them. This revealed that colon cancer localization is not associated with a single gene group but with many gene groups. Furthermore, K-fold cross validation was used to test the reliability of the possible informative genes, and the results indicated that using gene expression to classify colon tumor localization was not feasible.

Cancer classification based on gene expression using neural networks.

Based on gene expression, we have classified 53 colon cancer patients with UICC II into two groups: relapse and no relapse. Samples were taken from each patient, and gene information was extracted. Of the 53 samples examined, 500 genes were considered proper through analyses by S-Kohonen, BP, and SVM neural networks. Classification accuracy obtained by S-Kohonen neural network reaches 91%, which was more accurate than classification by BP and SVM neural networks. The results show that S-Kohonen neural network is more plausible for classification and has a certain feasibility and validity as compared with BP and SVM neural networks.

Plain articaine or prilocaine for spinal anaesthesia in day-case knee arthroscopy: a double-blind randomized trial.

BACKGROUND: Both prilocaine and articaine are short-acting local anaesthetics suited for spinal anaesthesia for day-case knee arthroscopy. Articaine is thought to have a faster onset and shorter duration of action than prilocaine, although no comparative study has been published in the anaesthetic literature. METHODS: In this prospective randomized double-blind study, spinal anaesthesia was performed in 72 ASA I-II patients undergoing knee arthroscopy with 50 mg of either plain prilocaine or plain articaine. The primary outcome variable was duration of motor block. Secondary outcomes were onset of sensory and motor blocks, maximum spread of the sensory block, time to spontaneous voiding, and side-effects. RESULTS: Time to full motor function recovery was shorter after articaine than prilocaine [mean (SD) 140 (33) vs 184 (46) min, respectively, P<0.001]. Time to spontaneous voiding was shorter after articaine than prilocaine [mean (SD) 184 (39) vs 227 (45) min, respectively, P<0.001]. One patient in the articaine group reported mild transient neurological symptoms (TNS) limited to the first postoperative day, but there were no significant differences in adverse effects between the groups. CONCLUSIONS: Spinal anaesthesia with plain articaine 50 mg resulted in a faster recovery of motor function and earlier spontaneous voiding compared with plain prilocaine 50 mg. Surgical anaesthesia was not different. The incidence of TNS was low.

Mechanism of anesthetic action: oxygen pathway perturbation hypothesis.

Although more than 150 years have passed since the discovery of general anesthetics, precisely how they work remains a mystery. We propose a novel unitary mechanism of general anesthesia verifiable by experiments. In the proposed mechanism, general anesthetics perturb oxygen pathways in both membranes and oxygen-utilizing proteins, such that the availability of oxygen to its sites of utilization is reduced, which in turn triggers cascading cellular responses through oxygen-sensing mechanisms, resulting in general anesthesia. Despite the general assumption that cell membranes are readily permeable to oxygen, existing publications indicate that these membranes are plausible oxygen-transport barriers. The present hypothesis provides a unified framework for explaining phenomena associated with general anesthesia and experimental results on the actions of general anesthetics. If verified by experiments, the proposed mechanism also has other significant medical and biological implications.

No effective prophylaxis of heterotopic ossification with short-term ibuprofen.

Ninety-five patients underwent primary total hip arthroplasty and routinely received ibuprofen for 5 days as prophylaxis for heterotopic ossification. This group was compared with a group of 99 patients who received indomethacin for 7 days as prophylaxis. After a follow-up of 1 year, the incidence of heterotopic ossification in the ibuprofen group was significantly higher than in the indomethacin group. The widespread ossification, Brooker grades III and IV, was prevented better by indomethacin than by ibuprofen. We conclude that ibuprofen for 5 days is not effective as prophylaxis for heterotopic ossification after primary total hip arthroplasty.

The Geomedic knee prosthesis. A long-term follow-up study.

A retrospective long-term follow-up study of 189 Geomedic total knee arthroplasties in 143 patients was performed. One hundred and eighteen knees were replaced in patients with rheumatoid arthritis and seventy-one knees were replaced in patients with osteoarthritis. Fifty-seven knees were examined clinically with an average follow-up of 11 years. Seventy percent of these knees were painless. Lucent lines at the tibial bone-cement interface were observed in 62% of the follow-up radiographs (81 knees, mean follow-up: 10.5 years). Thirty-four prostheses (18%) were removed, with loosening of the tibial component as the main cause. Retropatellar pain was not a significant problem. The 13-year survival rate was 78%, with implant removal as an endpoint. Radiographically loosened components included, the 13-year survival rate was 58%.

Signal intensity correlation of MRI with pathological findings in spinal neurinomas.

MR signal intensities at 0.282 T were correlated with the pathological findings in 23 cases of spinal neurinoma. With T2-weighted images (SE-T2WI or RARE-T2WI), all the tumors displayed high signal intensities similar to that of cerebrospinal fluid, indicating long T2 values. It is shown that the long T2 values of neurinomas are caused not only by intratumoral cystic formation, as reported by other authors, but also by intratumoral Antoni B structure, intratumoral micronecrosis and intratumoral vascular malformation. On SE-T1WI, the majority of neurinomas (73.9%) were isointense to spinal cord while the minority (26.1%) were hypointense. The similarity of the T1 values of neurinomas to that of the spinal cord may be related to the abundance of Schwann cells within the tumors, but tumors hypointense to cord and tumors isointense to cord on T1WI showed no significant difference in their gross and microscopic pathology.

Contrast agents for magnetic resonance spectroscopy: a method to obtain increased information in in vivo and in vitro spectroscopy.

The concept of contrast, which now is an integral part of many magnetic resonance imaging studies, can be extended successfully to magnetic resonance spectroscopy. It involves the use of paramagnetic molecules whose distribution is restricted in some manner, thereby causing differential effects on the NMR spectra. As an illustrative example, the effects of lipophilic nitroxide stable free radicals on the NMR spectra of serum and lipoproteins are shown. These nitroxides differentially broaden away components of the spectra due to the nuclei of methylene and methyl groups, which enables the usually obscured peaks of lactate to be observed fully. The concept can be applied to differential distribution of the contrast agent on the basis of solubility, charge, and/or compartmentalization. It can be used with any type of NMR spectroscopy and any type of paramagnetic contrast (broadening) agent.

The effect of biphosphonate on induced heterotopic bone.

HEBP (1-hydroxy, ethylidene-1, 1-biphosphonate) inhibited mineralization and was observed in matrix-induced heterotopic bone in rabbits. In one group of rabbits, HEBP was administered continuously until sacrifice 20 weeks after the operation. Another group of animals received HEBP for the first four weeks only. The effect of HEBP on de novo bone formation was determined by histologic and biochemical analyses. Implant alkaline and acid phosphatase levels and implant calcium and phosphate contents were measured. The implants of HEBP-treated animals showed diminished implant resorption and, at the same time, formation of atypical osteoid tissue. Quantitative measurements revealed a decrease of acid phosphatase activity, whereas implant alkaline phosphatase activity was unaffected. The mineralization, as depicted by the implant calcium and phosphate content, was almost completely inhibited during HEBP-administration. These effects were completely reversible after the withdrawal of the drug. Remineralization began directly after discontinuation, and recovered only 12 weeks later. The results of this study confirm reports that HEBP cannot prevent the formation of heterotopic ossification. The only effect would be a delay of mineralization during its administration.

Heterotopic ossification following total hip arthroplasty: a review.

Heterotopic ossification is the most frequent complication of total hip arthroplasty. When formed in the para-articular tissues, it may cause pain and restriction of hip motion. The present article extensively reviews the current literature on heterotopic ossification following total hip arthroplasty with regard to epidemiologic factors, clinical presentation and possible pathogenesis. Preventive measures are emphasized. Postoperative treatment with radiation and nonsteroidal antiinflammatory drugs have yielded good results in the prevention of heterotopic ossification. On the other hand, biophosphonates were ineffective. In comparison with radiation therapy, prophylaxis with nonsteroidal antiinflammatory drugs gave better results. Further research is still needed to define the most effective and safe medication regimen.

Development of nitroxides for selective localization inside cells.

The use of nitroxides to measure intracellular phenomena, especially oxygen concentrations, is a new and potentially important approach to a number of physiological and pathophysiological studies. This study provides data indicating the feasibility of developing nitroxides that localize selectively in the intracellular compartment; it is based on the use of readily hydrolysed ester linkages, such that the nitroxides become converted intracellularly to ionic derivatives that do not cross cell membranes readily. Up to 120-fold increased concentrations of intracellular nitroxides (and their one electron reduction product, the hydroxylamines) were obtained. The ESR spectra of the intracellular nitroxides were consistent with their conversion to the ionic species. Preliminary studies indicate that these nitroxides have the properties needed for their use as probes of intracellular concentrations of oxygen and that it should be feasible to synthesize nitroxides that will be even more effective for this purpose.

Metabolism of aqueous soluble nitroxides in hepatocytes: effects of cell integrity, oxygen, and structure of nitroxides.

The optimum use of nitroxides in viable biological systems, including live animals, requires knowledge of the metabolism of nitroxides by major organ systems, especially the liver. We report here details of the metabolism of several prototypic aqueous soluble nitroxides in suspensions of freshly isolated hepatocytes. The general patterns of metabolism were similar to those observed in other types of cells (previous studies have been done principally in cells from tissue culture, such as CHO cells) including the primary initial reaction being reduction to the hydroxylamine, an increased rate of metabolism of some nitroxides in hypoxic cells, faster rates of reduction of nitroxides on six-membered piperidine rings compared to five-membered pyrrolidine rings, and most metabolism being intracellular. Metabolism in hepatocytes differed from other cell lines in having (1) significant reduction in the extracellular medium due to ascorbate that was released from damaged hepatocytes; (2) decreased rates of metabolism in freeze-thawed cells due to damage to subcellular organelles. These results provide much of the data needed to understand the role of the liver in the metabolism of nitroxides by intact animals and explain some previously puzzling results which indicated an apparent unusually high rate of metabolism of a charged nitroxide (Cat1) by hepatocytes. Our results also indicate that the use of freshly isolated cells or tissue homogenates may introduce experimental artifacts in the study of the metabolism of nitroxides.