Weihua Qiu

Pharmacokinetics of mycophenolic acid and determination of area under the curve by abbreviated sampling strategy in Chinese liver transplant recipients.

ObjectivesThis study aimed to: (i) define the clinical pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients; and (ii) develop a regression model best fitted for the prediction of MPA area under the plasma concentration-time curve from 0 to 12 hours (AUC12) by abbreviated sampling strategy.MethodsForty liver transplant patients received mycophenolate mofetil 1g as a single dose twice daily in combination with tacrolimus. MPA concentrations were determined by high-performance liquid chromatography before dose (C0) and at 0.5 (C0.5), 1 (C1), 1.5 (C1.5), 2 (C2), 4 (C4), 6 (C6), 8 (C8), 10 (C10) and 12 (C12) hours after administration on days 7 and 14. A total of 72 pharmacokinetic profiles were obtained. MPA AUC12 was calculated with 3P97 software. The trough concentrations (C0) of tacrolimus and hepatic function were also measured simultaneously. Multiple linear regression analysis was used to establish the models for estimated MPA AUC12. The agreement between predicted MPA AUC12 and observed MPA AUC12 was investigated by Bland-Altman analysis.ResultsThe pattern of MPA concentrations during the 12-hour interval on day 7 was very similar to that on day 14. In the total of 72 profiles, the mean maximum plasma concentration (Cmax) and time to reach Cmax (tmax) were 9.79 ± 5.26 mg/L and 1.43 ± 0.78 hours, respectively. The mean MPA AUC12 was 46.50 ± 17.42 mg · h/L (range 17.99–98.73 mg · h/L). Correlation between MPA C0 and MPA AUC12 was poor (r2 = 0.300, p = 0.0001). The best model for prediction of MPA AUC12 was by using 1, 2, 6 and 8 hour timepoint MPA concentrations (r2 = 0.921, p = 0.0001). The regression equation for estimated MPA AUC12 was 5.503 + 0.919 · C1 + 1.871 · C2 + 3.176 · C6 + 3.664 · C8. This model had minimal mean prediction error (1.24 ± 11.19%) and minimal mean absolute prediction error (8.24 ± 7.61%). Sixty-three of 72 (88%) estimated MPA AUC12 were within 15% of MPA AUC12. Bland-Altman analysis also revealed the best agreement of this model compared with the others and a mean error of ±9.89 mg · h/mL.ConclusionThis study showed the wide variability in MPA AUC12 in Chinese liver transplant recipients. Single timepoint MPA concentration during the 12-hour dosing interval cannot reflect MPA AUC12. MPA AUC12 could be predicted accurately using 1, 2, 6 and 8 hour timepoint MPA concentrations by abbreviated sampling strategy.

A Newly Identified Variation at the Entry of the Recurrent Laryngeal Nerve into the Larynx

ABSTRACT Objectives: We aimed to highlight a new anatomical variation of the recurrent laryngeal nerve (RLN), and to emphasize its implications for thyroid surgery. Methods: A prospective study was carried out in a group of 3,078 consecutive thyroidectomies from 1998 to 2008. Total, near-total, subtotal, and partial thyroidectomy were performed for various thyroid diseases. The RLN was routinely identified and exposed in its entire course until the entry into the larynx. The postoperative complications of patients with different variations were compared. Results: 4,241 RLNs were successfully identified in all patients unilaterally or bilaterally. In addition to extralaryngeal branching and nonrecurrent laryngeal nerves, an unreported variation was identified in 44 RLNs (1.04%) at their entries into the larynx. The variation happened at the trunk or the branches of the RLN entering the larynx far from the posterior of cricothyroid joint, and the entry was higher than the superior cornu of the thyroid cartilage and the arch of the cricoid. The median distance from the entry to the posterior of cricothyroid joint was more than 5 mm. As the trunk or the branches had to travel along the lateral edge of the upper 1/3 of the thyroid before entering the larynx, the incidence of RLN palsy was higher than that in extralaryngeal branching variations (p < .05). Conclusion: This newly discovered variation of the RLN is more vulnerable to injury and should be brought to the attention of surgeons.

The feasibility of total or near-total bilateral thyroidectomy for the treatment of bilateral multinodular goiter.

Objective: To evaluate the feasibility and safety of total and near-total bilateral thyroidectomy for the treatment of bilateral multinodular goiter. Methods: 346 patients with a diagnosis of bilateral multinodular goiter were randomly divided into two groups. 165 patients underwent total thyroidectomy or near-total thyroidectomy (group A), while 181 patients were exposed to a partial or subtotal thyroid gland removal treatment (group B). The incidences of postoperative complications and recurrence rate were monitored during the average follow-up period of 36 and 39 months, respectively. Results: Six and two patients from groups A and B, respectively, were diagnosed with papillary carcinoma and excluded from the study. Transient recurrent laryngeal nerve paralysis occurred in three patients each from group A (1.89%, 3/159) and group B (1.68%, 3/179) postoperatively. Injury to superior laryngeal nerve was confirmed in three patients (two in group A and one in group B). Eleven (6.92%, 11/159) and nine (5.03%, 9/179) cases in groups A and B, respectively, suffered from transient hypocalcemia symptoms. There was no statistical difference in complications between two groups. Permanent hypoparathyroidism was not observed in either group. No recurrence was observed in group A, while 12 cases (6.70%, 12/179) were observed in group B. The recurrence rate was significantly different between the two groups (p <.05). Conclusion: It is safe and feasible to perform either total or near-total thyroidectomy in patients with bilateral multinodular goiter. These treatments provide decisive advantages over partial and subtotal thyroidectomies in terms of the recurrence and reoperation rate with comparable postoperative complications.

Emerging role of autophagy during ischemia-hypoxia and reperfusion in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary malignancy found in the liver. Autophagy is the intracellular bulk degradation process for long-lived proteins and dysfunctional organelles. In this study, we report that autophagy plays a role in HCC cell proliferation in response to ischemia-hypoxia (I/H) and reperfusion and discuss its potential therapeutic implications. By establishing a simulated model in cultured HepG2 (p53 wild-type) and Hep3B (p53 null) hepatoma cells in vitro, we found that exposure to I/H induced a significant increase in microtubule-associated protein 1 light chain 3 (LC3) lipidation and subsequent LC3 puncta formation. While the proliferation of HCC cells was stimulated upon acute I/H exposure compared to that of control, inhibition of autophagy by autophagy-related protein 7 interference abolished it. In addition, the steady-state levels of sequestosome 1 (p62) in both HepG2 and Hep3B cells were reduced following I/H exposure, supporting the notion that acute I/H induces autophagy. Intriguingly, the p62 level further decreased during reperfusion following I/H, accompanied by increased LC3 lipidation. The intracellular reactive oxygen species (ROS) accumulated during acute I/H exposure and persisted through reperfusion in both HepG2 and Hep3B cells and the ROS levels increased at a much faster rate during reperfusion than during I/H periods in both cells. Autophagy functions as a promoter for HCC cell survival during acute I/H and reperfusion and this also points to potential therapy for hepatoma by perturbing the acute I/H-reperfusion-autophagy axis.

Pseudomonas aeruginosa -mannose-sensitive hemagglutinin inhibits pancreatic cancer cell proliferation and induces apoptosis via the EGFR pathway and caspase signaling

Pseudomonas aeruginosa-mannose-sensitive hemagglutinin (PA-MSHA) has demonstrated efficacy against several solid tumors. In this study, we found that PA-MSHA inhibited the proliferation of PANC-1 and SW1990 pancreatic cancer cells, but had no obvious effects on HPDE6-C7 normal human pancreatic duct epithelial cells. Electron microscopy revealed the presence of apoptotic bodies and intracellular vacuole formation in PA-MSHA-treated pancreatic cancer cells. Flow cytometric analysis indicated the rate of apoptosis correlated with the PA-MSHA concentration. We observed a decrease in cell fractions in G0/G1 and G2/M phases, and an increase in the fraction in S phase (p < 0.01). PA-MSHA thus caused cell cycle arrest. Increasing concentrations of PA-MSHA did not alter total levels of EGFR, AKT or ERK, but levels of the corresponding phosphoproteins decreased. PA-MSHA also reduced tumor volume in a xenograft mouse model of pancreatic cancer (p < 0.01). Furthermore, caspase-3 levels decreased while the levels of cleaved caspase-3 increased (p < 0.01). These data suggest that by blocking cell cycle progression, PA-MSHA induces apoptosis and inhibits tumor growth. PA-MSHA-mediated inhibition of EGFR signaling and activation of the caspase pathway may play an important role in the induction of apoptosis in pancreatic cancer cells.

Modified protocol for enhanced recovery after surgery is beneficial for Chinese cancer patients undergoing pancreaticoduodenectomy

Radical surgical resection remains the only effective treatment for advanced pancreatic cancer. Effective protocols for recovery from post-operative complications that result in high rates of morbidity and mortality are therefore essential. The enhanced recovery after surgery (ERAS) protocol is an interdisciplinary multimodal concept based on modern anesthesia and analgesia combined with other fast rehabilitation parameters. It was first applied in the field of elective colorectal surgery, and eventually extended to several surgical diseases. In this study, we investigated the feasibility and safety of implementing the ERAS protocol in patients undergoing pancreaticoduodenectomy (PD). We randomly divided 159 patients who underwent PD into two groups who were managed using either ERAS or the conventional protocol. We observed that in those treated with the ERAS protocol several post-operative recovery factors were greatly improved, and there were no complications requiring readmission. We therefore propose that ERAS can improve post-operative recovery of PD patients and shorten the waiting time to chemotherapy, which may improve the overall survival of surgically treated pancreatic cancer patients.

Phenotypic and Signaling Consequences of a Novel Aberrantly Spliced Transcript FGF Receptor-3 in Hepatocellular Carcinoma.

Fibroblast growth factor receptor 3 (FGFR3) plays important roles in cell proliferation, differentiation, and angiogenesis. FGFR3 is abnormally upregulated in hepatocellular carcinoma (HCC), where it correlates positively with clinicopathologic index, HCC differentiation, and advanced nuclear grade. In this study, we describe an aberrantly spliced transcript of FGFR3, termed FGFR3Δ7-9, was identified as a high frequency even in HCC. FGFR3Δ7-9 lacks exons encoding the immunoglobulin-like III domain and promoted the proliferation, migration, and metastasis of HCC cells both in vitro and in vivo Coimmunoprecipation and surface plasmon resonance assays demonstrated that the binding affinity of the aberrant FGFR3Δ7-9 receptor to FGFs was significantly higher than wild-type FGFR3IIIc Furthermore, FGFR3Δ7-9 could be self-activated by homodimerization and autophosphorylation even in the absence of ligand. Finally, FGFR3Δ7-9 more potently induced phosphorylation of the ERK and AKT kinases, leading to abnormal downstream signaling through the ERK and PI3K/AKT/mTOR pathways. FGFR3Δ7-9 also upregulated the metastasis-associated molecules Snail, MMP-9, and downregulated E-cadherin, which associated directly with FGFR3Δ7-9 Thus, as a ligand-dependent or -independent receptor, FGFR3Δ7-9 exerted multiple potent oncogenic functions in HCC cells, including proliferation, migration, and lung metastatic capacity. Overall, FGFR3 mRNA missplicing in HCC contributes significantly to its malignant character, with implications for therapeutic targeting. Cancer Res; 76(14); 4205-15. ©2016 AACR.

The Different Induction Mechanisms of Growth Arrest DNA Damage Inducible Gene 45 β in Human Hepatoma Cell Lines

Aims: Downregulation of the growth arrest and DNA damage-inducible gene 45 β (GADD45β) has been verified to be specific to HCC and consistent with the degree of malignancy. The differences in induction mechanisms of GADD45β were investigated based on transcriptional regulation. Methods: Following our published data from S-adenosylmethionine (SAMe), oxaliplatin and sorafenib were further used to stimulate GADD45β expression in cultured HepG2 (p53 wild type) and Hep3B (p53 null) hepatoma cells in vitro. The different effects on cell viability, DNA synthesis and caspase activities were also measured. Results: Oxaliplatin and sorafenib could induce GADD45β in both HepG2 and Hep3B in a dose-dependent manner with rapid and direct cytotoxic effect. Transcriptional activity of NF-ĸB and E2F-1 were both enhanced by oxaliplatin and sorafenib. However, SAMe could only induce GADD45β in HepG2 through the NF-ĸB pathway, resulting in a slow and indirect cytotoxic effect. Although all three inducers could lead to a pronounced rise in caspase activities, only high concentration of SAMe could inhibit DNA synthesis as significantly as the chemo drugs. No apparent changes in GADD45β induction, promoter activity or cytotoxic effects were observed in Hep3B+p53 when treated with oxaliplatin and sorafenib, while relatively significant changes occurred with SAMe. Conclusion: GADD45β induction is a novel mechanism of SAMe-mediated hepatoprotection with p53 involvement.

Up-regulation of chemokine receptor CCR4 is associated with Human Hepatocellular Carcinoma malignant behavior

Studies indicate that the chemokine receptor is responsible for poor prognosis of hepatocellular carcinoma (HCC) patients. In this study, we initially demonstrated that CCR4 is overexpressed in HCC specimens, and its elevation in HCC tissues positively correlates with tumor capsule breakthrough and vascular invasion. Although overexpression of CCR4 failed to influent proliferation of HCC cells in vitro apparently, the prominent acceleration on HCC tumor growth in vivo was remarkable. The underlying mechanism may be involved in neovascularization. Interestingly, different from effect on proliferation, CCR4 overexpression could trigger HCC metastasis both in vitro and in vivo also induced HCC cell epithelial-mesenchymal transition (EMT) as well. Then we identified matrix metalloproteinase 2 (MMP2) as a direct target of CCR4 which plays an important role in CCR4-mediated HCC cell invasion, which was up-regulated by ERK/AKT signaling. Positive correlation between CCR4 and MMP2 expression was also observed in HCC tissues. In conclusion, our study suggested that chemokine receptor CCR4 promotes HCC malignancy and facilitated HCC cell metastases via ERK/AKT/MMP2 pathway. These findings suggest that CCR4 may be a potential new diagnostic and prognostic marker in HCC, and targeting CCR4 may be a potential therapeutic option for blocking HCC metastasis.

The plication and splinting procedure for idiopathic sclerosing encapsulating peritonitis.

Idiopathic sclerosing encapsulating peritonitis (ISEP) is a rare cause of small intestinal obstruction. Histologically, ISEP is characterized by a thick fibrotic membrane encasing the small bowel without any apparent pathophysiological factors. While ISEP is predominantly present congenitally in female adolescents from subtropical region, it has been identified throughout the world. Evidence-based effective diagnostics and treatments are pitifully thin. We experienced six cases, four males and two females, which exhibited symptoms in their later thirties and forties. Five patients presented with acute and subacute intestinal obstruction, and one patient with cryptorchidism and seminoma was referred. Due to the limitation in distention and motility of bowel loops of ISEP, imaging exams may not be very reliable for accurate diagnosis and estimation of obstruction progress. They were successfully treated with the mesenteric plication and intraluminal splinting procedures. Two cases had an uneventful postoperative period, and the returns of normal bowel function were delayed in the other four patients. Two recurrences of small bowel obstructions were noted over a mean follow-up period of 33 months with mild symptoms. This article reviews the patterns of clinical presentations, diagnostic clues, and theories of potential risk factors of ISEP as well as its controversial surgical managements.