Liver Targeting of Interferon Through Pullulan Conjugation

Purpose. The purpose of this study was to actively target interferon (IFN) to the liver through its chemical conjugation with pullulan, a water-soluble polysaccharide with a high affinity for the liver. Methods. Chemical conjugation of IFN with pullulan was achieved by a cyanuric chloride method. Following intravenous injection of the conjugates to mice, their body distribution and the activity of an IFN-induced enzyme, 2,5-oligoadenylate (2-5A) synthetase in the liver and other organs, were evaluated. Results. The cyanuric chloride method enabled us to prepare an IFN-pullulan conjugate that retained approximately 7–9 % of the biological activity of IFN. Pullulan conjugation enhanced the liver accumulation of IFN and the retention period with the results being reproducible. When injected intravenously to mice, the IFN-pullulan conjugate enhanced the activity of 2-5A synthetase in the liver. The activity could be induced at IFN doses much lower than those of free IFN injection. In addition, the liver 2-5A synthetase induced by conjugate injection was retained for 3 days, whereas it was lost within the first day for the free IFN-injected mice. Conclusions. IFN-pullulan conjugation was promising for IFN targeting to the liver with efficient exertion of its antiviral activity therein.     

Metabolism-based inactivation of neuronal nitric-oxide synthase by components of cigarette and cigarette smoke.

It has been shown that administration of cigarette smoke to rats leads to loss of neuronal nitric-oxide synthase (nNOS) activity and nNOS protein in penile tissue. The exact mechanism for this loss of activity and protein is not known. In the current study, we investigated whether extracts prepared from cigarette smoke or from the cigarette itself could directly inhibit nNOS activity. We discovered that the cigarette smoke extract and the cigarette extract cause a time-, concentration-, and calmodulin-dependent inactivation of nNOS in an in vitro system containing the purified enzyme. L-Arginine, but not D-arginine, protects nNOS from this time-dependent inactivation, suggesting an active site directed event. The kinetics of inactivation are consistent with the metabolism-based or suicide inactivation of nNOS. Based on studies with other metabolism-based inactivators, this cigarette-mediated inactivation may render nNOS more susceptible to proteasomal degradation and thereby may explain the loss of nNOS protein in vivo. The component(s) responsible for nNOS inactivation is not volatile, is not retained by a 3,000 molecular weight cut-off membrane, binds to activated charcoal, and is highly water-soluble under both acidic and basic conditions. The discovery of a direct inactivation of nNOS by an organic, cationic compound(s) present in tobacco and tobacco smoke provides a basis for further study of not only the mechanisms responsible for the biological effects of tobacco but also a search for a potentially novel inactivator of nNOS.     

Predictive factors for surgical complications of laparoscopy-assisted distal gastrectomy for gastric cancer

Background  Some studies have found high incidences of intraoperative and postoperative complications for patients with gastric cancer. To determine the predictive factors for the surgical complications of laparoscopic gastric surgery, surgical outcomes were evaluated. Methods  Between April 2002 and December 2007, 152 patients with preoperatively diagnosed early gastric cancer who underwent laparoscopy-assisted distal gastrectomy (LADG) were enrolled. Visceral (VFA) and subcutaneous fat areas (SFA) were assessed by Fat Scan software. The predictive factors for surgical complications of LADG were evaluated by univariate and logistic regression analyses. Results  Of 152 patients, conversion to open surgery due to uncontrollable bleeding was observed in nine male patients, and postoperative complications were detected in seven male and one female patient (four anastomotic leakage, two intraabdominal abscess, one pancreatic fistula, and one lymphorrhea). High body mass index (BMI) and high VFA independently predicted conversion to open surgery and postoperative complications. VFA was significantly higher, operation time was longer, blood loss was greater, and SFA was lower in male than in female patients, whereas no significant difference was observed in BMI between male and female patients. Conclusions  High BMI and high VFA can predict technical difficulties during laparoscopic gastric surgery and postoperative complications. Particularly, LADG should be performed cautiously to prevent surgical complications for male patients with high VFA. Predictive impact of VFA should be further determined in a larger set of patients.     

Right liver graft without middle hepatic vein reconstruction from a living donor

A case of adult-to-adult, living-donor liver transplantation using a right liver graft is described. In the donor operation, when the middle hepatic vein (MHV) was clamped after hepatic transection, reversed flow was detected in MHV tributaries by intraoperative color Doppler ultrasonography. Regurgitated flow in the clamped inferior right hepatic vein was also demonstrated. Portal flow remained hepatopetal during the procedure. Based on these ultrasonographic findings, neither the MHV tributaries nor the inferior right hepatic vein was reconstructed.     

Peripheral small-sized (2 cm or less) non-small cell lung cancer with mediastinal lymph node metastasis; clinicopathologic features and patterns of nodal spread

Objective: The diagnosis of small-sized (2 cm or less) non-small cell lung cancer (NSCLC) has increased with the development of computed tomography (CT), whereas unexpected extensive multiple-level mediastinal involvement has been occasionally detected in this small-sized lung cancer. To establish the optimal surgical strategy, we retrospectively analyzed the clinicopathologic features, efficacy of preoperative investigations and lobe specific patterns of nodal spread in small-sized NSCLC with mediastinal involvement. Methods: Among 1550 resected lung cancer cases between 1981 and 2000, 267 (17.2%) had peripheral small-sized NSCLC. Of these, 29 patients (10.8%) with mediastinal lymph node involvement who underwent pulmonary resection and systematic nodal dissection were reviewed. Results: Among 29 patients, 27 patients (93.1%) were adenocarcinoma, and 51.7% (15/29) showed no lymph node enlargement on CT (cN0). Surgical pathology revealed multiple-level mediastinal involvement in 65.5% (19/29) of all patients and 60.0% (9/15) of cN0 patients. All of right upper lobe tumors (n=11) showed multiple-level involvement. Thallium-201 single photon emission computed tomography (201Tl-SPECT) was positive for increased focal uptake in the mediastinum in 72.7% (8/11) of patients. Conclusions: The vast majority of cases were adenocarcinoma, and two thirds of them showed multiple-level mediastinal involvement, even in cN0 patients. We thus recommend to perform systematic nodal dissection or meticulous sampling for accurate intrathoracic staging, especially for right upper lobe tumor. 201Tl-SPECT appears to be more sensitive preoperative investigation for mediastinal metastasis compared with CT scan.     

Primary hepatic leiomyosarcoma in a woman after renal transplantation: report of a case

In contrast to malignant lymphomas or skin cancer, smooth muscle tumors including leiomyosarcoma are rarely associated with transplant recipients. We herein present a 33-year-old woman with end-stage renal disease who received a transplant at 27 years of age. Four years after the transplantation, at age 31, she underwent a mastectomy because of primary right breast cancer, which was found to be a 5-mm-sized mucinous carcinoma with no regional lymph node metastasis. Six years after the transplantation, a liver tumor was unexpectedly discovered. An explorative laparotomy revealed a well-encapsulated tumor occupying the posterior portion of the right lobe of the liver. The patient underwent a posterior segmentectomy. Histologically, the tumor possessed intermingling fascicles of spindle cells with eosinophilic cytoplasm and elongated nuclei. Based on an immunohistochemical examination, the tumor cells were positive for the muscle-associated antibody. In addition, RNA probes for Epstein-Barr virus were negative based on in situ hybridization. The histologic, immunohistochemical findings were considered to be diagnostic for leiomyosarcoma, which is a low-grade malignancy. Two years after surgery, the patient is doing well with no recurrence of liver tumors or breast cancer. Received: April 16, 2001 / Accepted: September 11, 2001     

Laparoscopy-assisted distal gastrectomy with laparoscopic sentinel lymph node biopsy after endoscopic mucosal resection for early gastric cancer

Background There has been a trend toward minimally invasive treatment of early gastric cancer. We report the preliminary results of laparoscopy-assisted distal gastrectomy with laparoscopic sentinel lymph node biopsy after endoscopic mucosal resection. Methods Six patients underwent laparoscopy-assisted distal gastrectomy after endoscopic mucosal resection between February 2002 and October 2005 at Mie University Hospital. These patients first underwent laparoscopic sentinel lymph node biopsy and then laparoscopy-assisted distal gastrectomy with lymphadenectomy. Results No patient underwent conversion to open surgery during the operation. None of the patients had any postoperative complications. The mean length of postoperative hospital stay was 11.3 days. Sentinel lymph nodes were identified laparoscopically in five patients. There were 20 sentinel and 85 nonsentinel lymph nodes in the six patients. Postoperatively, tissue sections showed that none of the lymph nodes were metastasized. Immunohistochemistry with D2-40 antibody showed that there were normal lymphatics in the submucosal layer with mucosal defects at the endoscopic mucosal resection site. No patients had any tumor recurrence during followup. Conclusions Laparoscopy-assisted distal gastrectomy after endoscopic mucosal resection was a safe and curative procedure. Endoscopic mucosal resection before sentinel lymph node biopsy was acceptable for early gastric cancer.     

Predictive factors for the effect of the α1-D/A adrenoceptor antagonist naftopidil on subjective and objective criteria in patients with neurogenic lower urinary tract dysfunction

Study Type – Therapy (RCT)
Level of Evidence 1b What's known on the subject? and What does the study add? α‐blockers may have little effect in the facilitation of storage and emptying in patients with neurogenic lower urinary tract dysfunction (NLUTD). Naftopidil is a novel α‐blocker, which is selective for the α1‐D/A adrenoceptor. This study showed the first objective evidence for the effect of naftopidil in treatment of NLUTD patients by pressure‐flow study.

OBJECTIVES

? To assess the effect of α1‐D/A adrenoceptor antagonist naftopidil on patients with neurogenic lower urinary tract dysfunction (NLUTD) and voiding difficulty. ? To explore the effectiveness of naftopidil in these patients by using urodynamic variables, including pressure flow study (PFS), and to find good and simple parameters (International Prostate Symptom Score (IPSS), Post‐void residual urine (PVR), and uroflowmetry (UFM) parameters) as substitution of PFS for predicting the effect of naftopidil.

PATIENTS AND METHODS

? The main inclusion and exclusion criteria were, IPSS ≥8, voiding symptoms with IPSS ≥5, IPSS‐quality of life (QOL) ≥2, PVR ≥50 mL, and without prostatic enlargement ≥20 mL. ? After initial assessment, patients were stepwisely administered for 12 weeks with the following: placebo for 2 weeks, naftopidil 25 mg/day for 2 weeks, naftopidil 50 mg/day for 2 weeks, and naftopidil 75 mg/day for 6 weeks. At the end of both placebo and 6 weeks’ naftopidil 75 mg/day, their IPSS, UFM, PVR, and PFS were assessed. ? A total of 82 Japanese patients (men 40, women 42) with lower urinary tract symptoms complicated by NLUTD, with a mean age of 63.9 years, were included from private or institutional clinics. ? The lesions were spinal cord 42, and peripheral nervous system 40. The spinal cord lesions were all lumbar spine (injury or lumbar canal stenosis).

RESULTS

? In all patients, pressure at maximum urinary flow rate (P_detQ_max) in PFS significantly decreased (P < 0.05), and maximum urinary flow rate in UFM significantly increased (P < 0.01). Analysis of data for men and for women also showed a significant decrease in PVR, %PVR, and total IPSS score. ? The degree of improvement of voided volume, PVR (%), and IPSS in patients with PVR <300 mL was significantly greater than those in patients with PVR ≥300 mL. ? The degree of improvement of P_detQ_max in PFS, and IPSS in patients with bladder contractility was significantly greater than that in patients without bladder contractility.

CONCLUSIONS

? α1‐D/A adrenoceptor antagonist naftopidil has a significant effect on both symptoms and urodynamic variables of patients of both genders with NLUTD in Japan. ? PVR <300 mL and bladder contractility are predictive factors for the efficacy of naftopidil on patients with NLUTD.     

Donor evaluation and hepatectomy for living-donor liver transplantation

In the past decade, considerable technical advances have been accomplished in living-donor liver transplantation (LDLT). The procedure has become accepted globally as a standard modality for the treatment of end-stage liver disease and hepatocellular carcinoma in both pediatric and adult populations. During the period of this procedure’s development, however, tragedy has occurred. Serious morbidity and even mortality have been experienced and reported in live donors. The transplant community has been very much aware of its responsibilities toward live donor care, and much effort has been made to improve and secure the overall outcomes of donors. Unlike in deceased-donor liver transplantation (DDLT), opportunity or chance plays a lesser role in the availability of an organ for LDLT. Judgment calls are often made by individuals; therefore, the evaluation process includes social and ethical aspects not encountered among the usual indications for hepatobiliary surgical disease. Thus, the selection of live donors should be made from a wider perspective compared with that for conventional patient care. The approach to selecting live donors may vary slightly between the West, where a large number of DDLTs are performed daily, and the Far East, where they are much less frequent. However, the recognition that the transplant community has a responsibility to provide care to living donors is common. This review provides an overview of the current donor evaluation and surgical procedures involved in LDLT, with the recognition that an open and educated debate is key to ensuring public confidence and maintaining ethical standards in the field.