Yuji Morine

Expression of hypoxia-inducible factor-1 alpha, histone deacetylase 1, and metastasis-associated protein 1 in pancreatic carcinoma : correlation with poor prognosis with possible regulation

Objectives: Hypoxia-inducible factor 1&agr; (HIF-1&agr;) is a transcription factor that plays an important role in tumor growth and metastasis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1&agr; expression; however, the association between HIF-1&agr; and histone deacetylase 1 (HDAC1), metastasis-associated protein 1 (MTA1) is not fully understood. Methods: Hypoxia-inducible factor 1&agr;, HDAC1, and MTA1 expressions were detected by immunohistochemistry in 39 pancreatic carcinoma patients. The correlations between the expression of HIF-1&agr;, HDAC1, or MTA1 and clinical features and the prognosis were analyzed. Results: Hypoxia-inducible factor 1&agr;, HDAC1, and MTA1 positive stainings were found in 41%, 56%, and 31%, respectively. There was no correlation between HIF-1&agr;, HDAC1, or MTA1 expression levels and any clinical parameters. The survival rate for patients with HIF-1&agr; and HDAC1-positive stainings were significantly lower than for patients with HIF-1&agr; and HDAC1-negative stainings. The MTA1 overexpression group did not have a significantly lower prognosis than the MTA1 underexpression group. The survival rate for the HDAC1(+)/MTA1(2-3) group was significantly lower than for the other groups. Conclusions: These results suggest that HIF-1&agr; expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis for pancreatic carcinoma and indicates that HIF-1&agr; and HDAC1/MTA1 are a promising therapeutic target in pancreatic carcinoma treatment.

Japanese clinical practice guidelines for pancreaticobiliary maljunction

There have been no clinical guidelines for the management of pancreaticobiliary maljunction (PBM). The Japanese Study Group on Pancreaticobiliary Maljunction (JSPBM) has proposed to establish clinical practice guidelines on how to deal with PBM, with the support of the Japan Biliary Association (JBA). Because the body of evidence-based literature is relatively small, we decided to create guidelines based on the consensus of experts, using the medical literature for reference. A total of 46 clinical questions (CQs) were considered by the members of the editorial committee responsible for the guidelines. The CQs covered distinct aspects of PBM: (1) Concepts and Pathophysiology (10 CQs); (2) Diagnosis (10 CQs); (3) Pancreatobiliary complications (9 CQs); and (4) Treatments and prognosis (17 CQs). Statements and comments for each CQ were prepared by the guidelines committee members and collaborating partners. The CQs were completed after review by members of the editorial committee, meetings of this committee, public comments on the homepages of the JSPBM and the JBA, public hearings, and assessment and approval by the guidelines evaluation board. PBM includes cases where the bile duct is dilated (PBM with biliary dilatation) and those in which it is not (PBM without biliary dilatation). In these guidelines, PBM with biliary dilatation is defined as being identical to congenital biliary dilatation of Todani type I (except for type Ib) and type IV-A, both of which are accompanied by PBM in almost all cases. These guidelines are created to provide assistance in the clinical practice of PBM management; their contents focus on clinical utility, and they include general information on PBM to make this disease more widely recognized.

Clinical roles of increased populations of Foxp3+CD4+ T cells in peripheral blood from advanced pancreatic cancer patients.

Objectives: Further metastasis should be avoided in pancreatic cancer (PC) patients for effective surgical treatment. Regulatory T cells (Foxp3+CD4+ T cells including CD4+CD25+ T cells and CD4+CD25− T cells) play important roles in tumor immunity. This study aimed to investigate whether regulatory T cells participate in metastasis. Methods: Peripheral blood was withdrawn from PC patients, as well as healthy volunteer donors as controls. The peripheral blood mononuclear cells (PBMCs) were subjected to FACScan analysis after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Tumor markers, including DUPAN2 and CA19-9, surface markers, such as the CD4/CD8 ratio, and the CD57+ cell population were assessed. Clinical stages were classified according to the TNM classification. Results: The Foxp3+CD4+ T-cell population among the PBMCs was significantly increased in PC patients (8.10% ± 4.65%) compared with healthy donors (2.47 ± 0.78%) (P < 0.001). No significant relationships existed for the tumor markers, CD4/CD8 ratio, and CD57+ cells. However, a significant correlation was found between Foxp3+CD4+ T cells among the PBMCs and the TNM stage (P < 0.05). Conclusions: Foxp3+CD4+ T cells are good markers for metastasis detection in PC patients and more accurate than other conventional tumor markers, especially at advanced stages of the disease.

Current Concept of Small-for-Size Grafts in Living Donor Liver Transplantation

The extended application of living donor liver transplantation (LDLT) has revealed the problem of graft size mismatching called “small-for-size (SFS) graft syndrome.” The initial trials to resolve this problem involved increasing the procured graft size, from left to right, and even extension to include a right lobe graft. Clinical cases of living right lobe donations have been reported since then, drawing attention to the risks of increasing the liver volume procured from a living donor. However, not only other modes of increasing graft volume such as auxiliary or dual liver transplantation, but also control of the increased portal pressure caused by an SFS graft, such as a portosystemic shunt or splenectomy, have been trialed with some positive results. To establish an effective strategy for transplanting SFS grafts and preventing SFS graft syndrome, it is essential to have precise knowledge and tactics to evaluate graft quality and graft volume, when performing these LDLTs with portal pressure control. We reviewed the updated literature on the pathogenesis of and strategies for using SFS grafts.

Molecular signatures of noncancerous liver tissue can predict the risk for late recurrence of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to tumor metastases or recurrence even after undergoing potentially curative treatment. There are two types of HCC recurrence. The early and late tumor recurrences appear in distinct biological contexts, and their clinical courses are quite different. Therefore, it is important to precisely and distinctly discriminate the risk of each type of HCC recurrence. Many researchers have used DNA microarray technology to reclassify HCC with respect to its malignant potential. Some of these studies successfully identified specific gene-expression signatures derived from the cancerous tissues of HCC for predicting the early recurrence due to intrahepatic metastasis. However, there are no well-defined predictors for late recurrence. Recently, a few studies have focused on the nontumorous portion of liver tissues to predict late recurrence, possibly due to de novo hepatocarcinogenesis based on the idea of “field cancerization.” This study reviewed the possible value of a gene-expression analysis of noncancerous liver tissue to clarify the risk for multicentric late recurrence of HCC. These findings may have important implications for chemopreventive strategies and tailored surveillance programs. Furthermore, this approach may also be applicable to other multifocal tumors, such as head and neck carcinoma.

Evaluation and management of hepatic injury induced by oxaliplatin-based chemotherapy in patients with hepatic resection for colorectal liver metastasis.

Patients with colorectal liver metastasis (CRLM) can be cured with surgical resection. Recent advances in systemic chemotherapy, including molecular target agents, can be used to introduce “conversion surgery” and achieve R0 resection even in patients with initially unresectable CRLM. Furthermore, neoadjuvant chemotherapy also tries to be applied in patients with resectable CRLM to maximize the remnant liver and reduce the residual micrometastasis before surgery. The development of chemotherapy‐induced hepatic injuries is increasingly being recognized, including sinusoidal obstructive syndrome (SOS), steatosis, steatohepatitis and biliary sclerosis. Especially, oxaliplatin (L‐OHP)‐based chemotherapy in clinical settings appears to be primarily associated with SOS. Various reports have tried to demonstrate the rationale of the correlation between L‐OHP‐based chemotherapy and SOS for the following hepatic surgery. While we can recognize that this pathophysiological disadvantage leads to hepatic dysfunction and the increasing postoperative morbidity, the essential part of this problem including clinical disadvantage, onset mechanism, evaluation systems, and targeted agents for prevention and treatment of SOS continue to be unclear. In this review, we summarize the current experience with hepatic injury induced by L‐OHP‐based chemotherapy, focusing on SOS‐based on clinical and experimental data, in order to assist in the resolution of these identified factors. Finally, the need for reliable methods to identify the risk of SOS, to evaluate SOS status and to predict the safety of surgical treatment in patients with chemotherapy prior to surgery will be emphasized.

Real time elastography for noninvasive diagnosis of liver fibrosis

BACKGROUND/PURPOSE The accurate preoperative evaluation of liver fibrosis stage is important in determining surgical procedures. Although percutaneous liver biopsy is the gold standard, it may cause undesirable complications, such as bleeding. This study aimed to evaluate the usefulness of real-time tissue elastography for the preoperative assessment of liver fibrosis stage. METHODS We focused on a new mode of sonogram, real-time elastography, which can show tissue elasticity on images, and express the elasticity numerically. The elastic ratio of the liver for the intercostal muscle for each patient was calculated preoperatively, using the sonography device. The liver fibrosis stages were finally determined in the operative specimens from 41 patients. We examined the correlation between the elastic ratio and the histological fibrosis stage. RESULTS The lower the elastic ratio, the more advanced was the liver fibrosis stage. There was a significant correlation between the elastic ratio and the histological fibrosis stage. The area under the receiver-operating characteristics curve for the diagnosis of significant liver fibrosis using this device was superior to those conventionally determined by blood parameters. CONCLUSIONS Real-time elastography is a promising sonography-based noninvasive method for the preoperative assessment of liver fibrosis.

Biliary reconstruction in right lobe living donor liver transplantation

We read with interest the article by Yan et al., which presented the decreased incidence of biliary complications in their right lobe living donor liver transplantation (LDLT) series. They reported that their technical refinements decreased the post-LDLT biliary complication rate down to less than 5%. Those included intraoperative cholangiogram, careful bile duct dissection, high hilar dissection technique in recipients, continuous sutures for the posterior wall and interrupted for the anterior wall, and a specialized single surgeon with the application of microsurgery. Although their refinements are appraised positively, we have several questions and comments. One of the points of concern in their report might be the short observation period. The mean follow-up period in their article was around a year, and this may still be too short for discussing bile duct complications. Over half of bile duct stenosis occurs after 1-year period from LDLT according to the majority of previous reports. Another concern is the uniform patient background; most of their cases were hepatitis B associated. Recently, it has been well known that the incidence of bile duct stenosis following LDLD for hepatitis C was more frequent than that for other indications, and visa versa; bile duct complication is among the significant determinant factor for aggressive recurrent hepatitis C. For microsurgical biliary reconstruction, they performed this in only four cases, and another 20 cases probably underwent reconstruction under surgical telescope. Therefore, it might be difficult to conclude that their methods had the advantages in bile duct reconstruction in LDLT at this moment with insufficient observation periods, extremely small patient numbers, and uniform patient backgrounds. Nevertheless, the new application of microsurgery in biliary reconstruction is appreciated. Most of their techniques might have been practiced widely in most LDLT centers, resulting in post-LDLT bile duct stenosis rates around 20–30% in the previously reported major series. This means that bile duct stenosis in LDLT might occur at such a rate, because of the tiny ducts, immunological, virological and/or preservation insults. Bile duct stenosis is a kind of different complication from other surgical or technical complications. The superiority of duct–duct reconstruction is its easy endoscopic access in the event of actual complications. It is a surprise that Yan et al. applied continuous sutures for tiny bile duct anastomosis. They were the techniques previously applied but abandoned because of the increased incidence of bile duct stenosis with incorporation of continuous sutures and T-tube use. The tight continuous sutures might have not only squeezed up the anastomoses, but also jeopardized the peri-biliary vascular plexus, as Kasahara et al. reported. In order to clarify the usefulness of their technique, we ask several questions. How much would be the complication rate at the present time with the current follow-up periods? How could we confirm the superiority of their techniques, including microsurgical reconstruction and the use of continuous sutures?

Human adipose-derived stem cells: Potential clinical applications in surgery

Regenerative medicine is emerging as a rapidly evolving field of research and therapeutics. Stem cells hold great promise for future translational research and clinical applications in many fields. Much research has focused on mesenchymal stem cells isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells. By contrast, adipose tissue represents an abundant and easily accessible source of adult stem cells, termed adipose-derived stem cells (ADSCs), with the ability to equally differentiate along multiple lineage pathways. These stem cells have angiogenic properties, possibly because of their secretion of cytokines. They may also play a role in healing acute and chronic tissue damage. Subsequently, they have a wide range of potential clinical implications. This article reviews the potential preclinical and clinical applications of mesenchymal stem cells, especially ADSCs, in surgery.

Strategies for improving the outcomes of small-for-size grafts in adult-to-adult living-donor liver transplantation

Living-donor liver transplantation (LDLT) has been refined and accepted as a valuable treatment for patients with end-stage liver disease in order to overcome the shortage of organs and mortality on the waiting list. However, graft size problems, especially small-for-size (SFS) grafts, remain the greatest limiting factor for the expansion of LDLT, especially in adult-to-adult transplantation. Various attempts have been made to overcome the problems regarding SFS grafts, such as increasing the graft liver volume and/or controlling excessive portal inflow to a small graft, with considerable positive outcomes. Recent innovations in basic studies have also contributed to the treatment of SFS syndrome. Herein, we review the literature and assess our current knowledge of the pathogenesis and treatment strategies for the use of SFS grafts in adult-to-adult LDLT.