Cheng-Maw Ho

Survival in patients with recurrent hepatocellular carcinoma after primary hepatectomy: Comparative effectiveness of treatment modalities

BACKGROUND Insufficient data are available on the survival of recurrent hepatocellular carcinoma after primary hepatectomy in patients receiving different treatments. We evaluated retrospectively the effects of treatment modalities on long-term survival. METHODS Between 2001 and 2007, 435 posthepatectomy hepatocellular carcinoma patients who developed recurrence were grouped by treatment modality into re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups. Treatment strategies for both primary hepatocellular carcinoma and its recurrence were selected using the same criteria. Postrecurrence survival was estimated using the Kaplan-Meier method and compared using the Cox proportional hazard model with adjusted independent prognostic factors. Survival rates after primary resection without recurrence were also compared. RESULTS In re-resection, radiofrequency ablation, transarterial chemoembolization, and supportive treatment groups, the 2-year postrecurrence survival rates were 90%, 96%, 75%, and 20%, respectively, and the 5-year survival rates were 72%, 83%, 56%, and 0%, respectively. The adjusted hazard of death was less for the re-resection and radiofrequency ablation groups than for the transarterial chemoembolization group, and the adjusted hazard ratios for the re-resection and radiofrequency ablation groups were 0.45 (95% confidence interval, 0.20-0.98) and 0.25 (0.08-0.81), respectively. The adjusted hazard ratio (95% confidence interval) of death for the radiofrequency ablation group compared to the re-resection group was 0.64 (0.19-2.19). Survival in the single resection group did not differ from that in the re-resection and radiofrequency ablation groups. CONCLUSION Postrecurrence survival in the re-resection and radiofrequency ablation groups was significantly better than that in the transarterial chemoembolization group and similar to that of patients in the primary resection without recurrence group.

Up-regulation of microRNA-190b plays a role for decreased IGF-1 that induces insulin resistance in human hepatocellular carcinoma.

Background & Aims Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally. Methods The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells. Results Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients. Conclusions Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC.

Downregulation of alpha-fetoprotein expression by LHX4: A critical role in hepatocarcinogenesis

LHX4 is a member of the LIM-homeobox family and plays a critical role in pituitary development and differentiation. Several lines of evidences have reported their aberrant expression in cancers. However, the exact roles of LHX4 in carcinogenesis remain unclear. In this study, LHX4 expression was analyzed in tumor and paired non-tumor tissues obtained from patients with hepatocellular carcinoma (HCC) using western blotting and immunohistochemistry. LHX4 was found to be downregulated in tumor tissues and negatively correlated with differentiation grade and alpha-fetoprotein (AFP) levels in 66 HCC patients. To clarify the biological functions of LHX4, transient or stable transfectants overexpressing LHX4 were generated in human hepatoma cells (Huh7 and HepG2). LHX4 overexpression in Huh7 and HepG2 cells induced a more differentiated phenotype by reducing AFP expression. Using in silico analysis, the evolutionary conserved region within the AFP promoter containing LHX4-binding site was identified, implying that AFP is a putative target for LHX4. Moreover, ectopic LHX4 overexpression attenuated Huh7 and HepG2 proliferation. Importantly, the growth-inhibitory effect of LHX4 was reversed by replenishing AFP to the LHX4-overexpressing cells, providing a functional relevance between LHX4 and AFP. Finally, we analyzed expressions of LHX4 and AFP during normal liver development. Hepatic LHX4 expression increased in adult liver in a manner that parallel AFP repression. In conclusion, these data indicate that LHX4 may act as a potential tumor suppressor in hepatocarcinogenesis, suggesting that targeting LHX4 to downregulate AFP might have therapeutic implications.

Robotic liver donor right hepatectomy: A pure, minimally invasive approach.

Right hepatectomy for a living liver donor via a pure minimally invasive approach is a challenging procedure and only a few cases have been reported. Between May 2013 and August 2015, 13 patients underwent robotic living donor right hepatectomy in our institute, and 54 patients received open surgery. In this series, no conversion was conducted for robotic donor right hepatectomy. The 2 groups shared similar blood loss (169 versus 146 mL), complication rates (7.7% versus 9.3%), and recovery of donor liver function (peak alanine aminotransferase, 269 versus 252 IU/mL). The robotic group needed longer operation time (596 versus 383 minutes) but less postoperative patient‐controlled analgesia (0.58 versus 0.84 ng/kg) and a shorter period before returning to work/school (52.9 versus 100.0 days) and sex (100.0 versus 156.0 days). For recipient outcomes regarding the donor procedure, the robotic group shared similar experiences in early allograft dysfunction, complications, and 1‐year recipient liver function with the open group. With respect to documented benefits of minimally invasive left‐sided liver donor procedure, the development of right donor hepatectomy is slow. In conclusion, with substantial improvements in patient recovery after the minimally invasive approach, the robotic platform would be a big step toward completing pure minimally invasive liver donor surgery. Liver Transplantation 22 1509–1518 2016 AASLD.

Lysophosphatidic acid alters the expression profiles of angiogenic factors, cytokines, and chemokines in mouse liver sinusoidal endothelial cells

Background and Aims Lysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs. Methods Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR’s and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor. Results LPAR1 and LPAR3 mRNA’s were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism. Conclusion LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration.

Simulation of Portal Hemodynamic Changes in a Donor After Right Hepatectomy

Remnant livers will be regenerated in live donors after a large volume resection for transplantation. How the structures and hemodynamics of portal vein will evolve with liver regeneration remains unknown. This prompts the present hemodynamic simulation for a 25 year-old man who received a right donor lobectomy. According to the magnetic resonance imaging/computed tomography images taken prior to the operation and one month after the operation, three sequential models of portal veins (pre-op, immediately after the operation, and one-month post-op) were constructed by AMIRA and HYPERMESH, while the immediately after the operation model was generated by removing the right branch in the pre-op model. Hemodynamic equations were solved subject to the sonographically measured inlet velocity. The simulated branch velocities were compared with the measured ones. The predicted overall pressure in the portal vein after resection was found to increase to a magnitude that has not reached to an extent possibly leading to portal hypertension. As expected, blood pressure has a large change only in the vicinity of the resection region. The branches grew considerably different from the original one as the liver is regenerated. Results provide useful evidence to justify the current computer simulation.

Post-transplant malignancy in liver transplantation: a single center experience.

AbstractWe aim to determine the incidence of malignancy after liver transplantation (LT) compared to general population.The records of patients who received LTs at our center from October 1989 and November 2012 were retrospectively reviewed. The standardized incidence ratio (SIR) of cancer in the patients was compared to general population using the data from the Taiwan Cancer Registry. Survival was estimated using the Kaplan–Meier method.A total of 444 patients were included. Malignancy was found in 46 (28 de novo and 19 recurrent malignancies) patients (10.4%) with the median follow up of 4.2 ± 4.2 years. The median time of cancer occurrence after transplant was 1.2 ± 1.9 years (range, 0.2–9.1 years). Post-transplant lymphoproliferative disorder was the most frequent de novo malignancy (57.1% [16/28]). The cumulative incidence rates of all malignancies were 5.1%, 10.4%, 12.8%, 15.8%, and 15.8% at 1, 3, 5, 10, and 15 years, respectively. The cumulative incidence rates of de novo malignancies were 3.4%, 5.97%, 7.7%, 10.9%, and 10.9 % at 1, 3, 5, 10, and 15 years. Compared to general population, transplant recipients had significantly higher incidence of all de novo cancers (SIR: 3.26, 95% confidence interval [CI]: 2.17–4.72), hematologic (SIR: 58.4; 95% CI, 33.3–94.8), and bladder (SIR: 10.2, 95% CI: 1.1–36.7) cancers. The estimated mean survivals after transplantation in cancer-free, de novo cancer, and recurrent cancer patients were 17.7 ± 0.5, 11.3 ± 1.2, and 3.6 ± 0.6 years, respectively.There is a significantly increased risk of malignancies after LT in the Taiwanese population.

Sirolimus‐induced signaling modifications in Kaposi’s sarcoma with resolution in a liver transplant recipient

Ho C‐M, Huang S‐F, Hu R‐H, Ho M‐C, Wu Y‐M, Lee P‐H. Sirolimus‐induced signaling modifications in Kaposi’s sarcoma with resolution in a liver transplant recipient.
Clin Transplant 2010: 24: 127–132.

Comparison of Critical Conservative Treatment Versus Emergency Operation in Children With Ruptured Appendicitis With Tumor Formation

BACKGROUND AND PURPOSE Management of ruptured appendicitis with tumor formation in children includes emergency appendectomy or initial conservative treatment, the choice of which remains controversial. This study compared the clinical courses of children with ruptured appendicitis with tumor formation (RATF) who received emergency appendectomy or initial conservative management. METHODS A retrospective study was conducted of 59 pediatric patients with RATF treated from January 1996 to September 2002. Twenty seven patients received emergency appendectomy and 32 patients received initial conservative treatment. Patients who received initial conservative treatment were further divided into those who recovered from the initial conservative treatment (n = 23) and those 9 patients who failed initial conservative treatment and received appendectomy at the same admission. Clinical factors including age, gender, body weight, duration of symptoms, duration of ileus after initial treatment, duration of fever and the usage of antibiotics, hospital stays, and major and minor complications were compared between groups. RESULTS The emergency appendectomy group and initial conservative treatment group had similar distributions of age, gender, body weight, and duration of symptoms. Patients who received emergency appendectomy had a shorter duration of fever (2.7 +/- 1.9 vs 8.0 +/- 7.0 days; p = 0.003) but were fed later (4.4 +/- 3.9 vs 1.8 +/- 2.9 days; p = 0.005) compared with those who received conservative treatment initially. Patients who received emergency appendectomy also had a higher complication rate (33.3% vs 17.4%; p = 0.038). Patients who recovered from initial conservative treatment were fed earlier after operation (0.7 +/- 0.6 vs 4.2 +/- 4.1 days; p = 0.002), had a lower complication rate (33.3% vs 4.3%; p = 0.02) and a shorter hospital stay (16.6 +/- 10.9 vs 29.3 +/- 33.6 days; p = 0.03) than those who failed initial conservative treatment. Histopathological study of the appendix in the 17 patients who received interval appendectomy showed fecal materials (58.8%) and fecoliths (29.4%) in lumen, microscopically suppurative inflammation (31.3%), and focal mild inflammation (31.3%). CONCLUSIONS In this study, conservative treatment of RATF in children was associated with a lower complication rate. Pathological analysis of the appendix suggests that interval appendectomy should be advocated in patients with successful initial conservative treatment.

Antifibrotic Activity of Human Placental Amnion Membrane‐Derived CD34+ Mesenchymal Stem/Progenitor Cell Transplantation in Mice With Thioacetamide‐Induced Liver Injury

Liver fibrosis represents the end stage of chronic liver inflammatory diseases and is defined by the abnormal accumulation of extracellular matrix in the liver. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension. Liver transplantation has been the most effective treatment for these diseases, but the procedure is limited by the shortage of suitable donors. Mesenchymal stromal cells (MSCs) have shown great potential in the treatment of chronic inflammatory diseases associated with fibrosis. This study aimed to evaluate the therapeutic effect of MSC‐based cell transplantation as an alternative treatment for liver fibrosis. A CD34‐positive subpopulation of human placental amnion membrane‐derived stem/progenitor cells (CD34+ AMSPCs) was isolated through the depletion of CD34‐negative stromal fibroblasts (CD34− AMSFCs) facilitated by CD34 fluorescence‐activated cell sorting, enriched and expanded ex vivo. These cells express pluripotency markers and demonstrate multidirectional differentiation potentials. Comparative analysis was made between CD34+ AMSPCs and CD34− AMSFCs in terms of the expressions of stemness surface markers, embryonic surface antigens, and multilineage differentiation potentials. A mouse model of liver fibrosis was established by thioacetamide (TAA) administration. When injected into the spleen of TAA‐injured mice, human placental amnion membrane‐derived MSCs (hAM‐MSCs) can engraft into the injury site, ameliorate liver fibrosis, and restore liver function, as shown by pathological and blood biochemical analysis and downregulated gene expressions associated with liver damage. CD34+ AMSPCs represent a more primitive subset of hAM‐MSCs and could be a suitable candidate with a potentially better safety profile for cell‐based therapy in treatment of liver diseases associated with fibrosis.