Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels, as prognostic indicators in NSCLC.

OBJECTIVES: Non-small cell lung cancer (NSCLC) tissue produces numerous growth factors, which are multifunctional and considered predictive of patient survival. This study sought to evaluate the relationship between concentrations of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) in NSCLC tissue and clinicopathological factors, and determine whether these factors correlate with long-term survival. METHODS: We retrospectively investigated 71 patients with histologically confirmed adenocarcinoma or squamous cell carcinoma of the lung, for whom the primary curative approach was surgery, and who received no chemotherapy or radiotherapy prior to surgery. bFGF, VEGF, HGF were measured in extracts prepared from these 71 frozen tissue samples by ELISA. Five- and 10-year survival was obtained to determine the most important predictors of long-term survival. RESULTS: Among clinicopathological parameters, the mean concentration of bFGF was significantly higher in tissue extracts from cases involving metastatic nodal involvement (87.5+/-69.3 ng/100 mg protein) than in those without nodal involvement (57.6+/-42.5 ng; P<0.05). Levels of VEGF in adenocarcinoma (26.8+/-34.0 ng) were higher than for squamous cell carcinoma (12.2+/-13.8 ng; P<0.05). HGF levels also demonstrated histological differences (14.7+/-7.7 vs. 10.6+/-9.7 ng, P<0.05). bFGF protein levels were basically the same, but showed no statistically significant differences with respect to histological type (72.5+/-55.2 vs. 63.6+/-51.5 ng). Patients with high levels of bFGF or VEGF showed significantly worse survival rates than patients with low levels (P=0.0059; P=0.0134). In particular, high concentrations of both bFGF and VEGF correlated with markedly poor prognosis (P<0.0001). Multivariate analysis indicated that lymph node involvement and levels of bFGF and VEGF were independent prognostic factors in cases of NSCLC (adenocarcinoma or squamous cell carcinoma) involving patients who had undergone curative resection. CONCLUSIONS: Adenocarcinoma associated with lung cancer is regarded to have biological characteristics that distinguish it from squamous cell carcinoma. Node invasion may be associated with bFGF. bFGF and VEGF augment each other and are associated with leading to poor prognosis. The results of this study suggests that effective therapy to block angiogenesis may need to address at least both of these factors in cases of NSCLC.     

Clinical trial of risedronate in Japanese volunteers: single and multiple oral dose studies

The tolerability and pharmacokinetics of risedronate after a single oral administration and during multiple oral administrations were examined in healthy adult male volunteers. In the single dose study, the dose was increased gradually from 1mg to 2.5, 5, 10, or 20mg. Subsequently, risedronate was given by multiple administration, 5mg per dosing, once daily, for 7 days. The observed adverse events, whose causality was possibly related or unknown, included headache, diarrhea, increased body temperature, increased CK-BB, and increased urinary ₂-microglobulin excretion rate. However, none of these adverse events was clinically significant. The results thus showed that risedronate was well tolerated when delivered as a single administration of up to 20mg or as a multiple administration of up to 5mg/day. In the multiple dose study, changes in urinary deoxypyridinoline suggested the bone antiresorptive activity of risedronate. In the single dose study, AUC and C_max, after the administration of risedronate at 1, 2.5, 5, 10, and 20mg, increased dose dependently, and the T_max, t_1/2, and urinary excretion rates were nearly constant. Therefore, the pharmacokinetic profile of risedronate was considered to show linearity in a dosage range of up to 20mg. Furthermore, the results obtained in the multiple administration study indicated that the plasma concentrations of risedronate reached a steady state on day 4 of administration. The plasma concentrations of risedronate after the administration of 2.5mg risedronate to the Japanese population were nearly comparable to the serum concentrations after the administration of 5mg risedronate to the United Kingdom study population.     

Oxygen supply to the liver in patients with alcoholic liver disease assessed by organ-reflectance spectrophotometry

In the present study we have investigated hepatic hemodynamics in patients with alcoholic liver disease using reflectance spectrophotometry and the hydrogen clearance method. Analysis of 38 cases has shown that estimated regional hepatic-tissue hemoglobin concentration, expressed as a difference in absorbance between 569 and 650 nm (delta Er569-650), decreased significantly with progress of fibrosis or fat accumulation in the liver. This suggests that the relative compression of the vascular compartment is due to the progress of alcoholic liver disease. Estimated hepatic hemoglobin concentration also correlated positively with prothrombin time, and negatively with serum gamma-globulin level and 15-min retention rate of indocyanine green. The difference in absorbance between 569 and 650 nm obtained by reflectance spectrophotometry was positively correlated with the regional hepatic blood flow as measured by the hydrogen clearance method. Thus, it is concluded that the estimated regional hepatic-tissue hemoglobin concentration decreases with progress of fibrosis and fat accumulation in the liver, and that this decreased oxygen supply to the liver may have an important role in the progress of alcoholic liver disease.     

Laparoscopic resection for gastrointestinal stromal tumors in the stomach

Purpose

Gastrointestinal stromal tumors (GISTs) should be surgically resected, even those smaller than 5?cm in size, which is the threshold of clinical malignancy for submucosal tumors (SMTs) in the gastrointestinal tract. This study reviewed the use of laparoscopic surgery for gastric partial resection of GISTs or SMTs that were suspected to be GISTs.

Methods

Eighteen patients underwent laparoscopic partial resection of the stomach for GISTs or SMTs. The tumor location was confirmed by intraluminal endoscopy. One-half of the circumference around the tumor was dissected, and the tumor was turned toward the abdominal cavity. The nonresected part of the tumor and the edge of the incision line was lifted up using forceps, and the incision line was closed using laparoscopic stapling devices.

Results

Two cases were diagnosed as GIST by endoscopic biopsy. Six patients underwent endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) examinations, which diagnosed five GISTs. There were 18 tumors smaller than 5?cm, including 10 GISTs, 4 leiomyomas, 3 schwannomas, and one heterotopic pancreas.

Conclusions

Endoscopic ultrasound-guided FNAB is recommended for definite preoperative diagnosis of histopathologically unknown SMTs to determine the indications for surgery. The laparoscopic approach with the assistance of endoscopy is useful for improving the curability, with minimal invasiveness for the partial resection of GISTs.     

Intermittent oral hormonal chemotherapy using estramustine phosphate and etoposide for the treatment of hormone-refractory prostate cancer

Seventeen patients were given lower dose and intermittent oral administration of estramustine phosphate (6 mg/kg/day) and etoposide (30 mg/m2/day) for 7 days. Then administration was discontinued for 7 days. This administration cycle was repeated. Therapy was continued until evidence of disease progression or unacceptable toxicity occurred. Fifteen of the 17 patients were finally evaluated for PSA response. Overall, the pretreatment PSA levels were lowered at least 50% from baseline in 7 (47%) of the 15 patients. The median survival was 65 weeks. Five of the 17 patients complained of anorexia or nausea during the treatment, but none of them showed over grade 2 anorexia, none requiring transfusion or hospitalization. None of the patients showed edema, deep venous thrombosis, thrombocytopenia, anemia or myocardial infarction. Because of its rare and mild adverse effects, this intermittent administration of oral estramustine and oral etoposide may be a useful and secure regimen for hormone refractory prostate cancer.     

Living-related liver transplantation for Alagille syndrome

Alagille syndrome (AGS) is an autosomal dominant genetic disorder characterized by chronic cholestasis, congenital heart disease, peculiar facies, butterfly-like vertebrae, and posterior embryotoxon. Liver dysfunction is the common presentation of AGS, and liver transplantation may be indicated. This study examines the outcome of living-related liver transplantation (LRLT) for AGS. Twenty patients with AGS (median age 5.0 years, range 0.6-12.9) underwent LRLT at Kyoto University Hospital between June 1990 and February 2002. Five potential donors were excluded because of paucity of intrahepatic bile ducts diagnosed by preoperative liver biopsy and one because of a hepatic vascular anomaly. The overall 5-year patient survival was 80.4%. Three patients died as the result of the following: complications related to surgery, heart failure caused by progressive pulmonary artery stenosis, and a graft with unsuspected bile duct paucity. Liver dysfunction was improved in all successful cases, and catch-up growth occurred in 90% of patients. LRLT is an efficacious treatment modality for AGS if donors are selected by cautious evaluation to rule out unsuspected bile duct paucity.     

Less invasive needle thoracoscopic laser ablation of small bullae for primary spontaneous pneumothorax.

OBJECTIVE: The purpose of this study was to establish a new surgical technique of thoracoscopic laser ablation for the patients of primary spontaneous pneumothorax (PSP) with small bullae, by using endoscopic equipment with a 2-mm diameter. METHOD: According to the size of a bulla identified by high-resolution computed tomography (HRCT), we have a protocol to determine an indication; the conventional video-assisted thoracic surgery (VATS) procedure by both stapler bullectomy and laser ablation to visceral pleura surrounding the bulla (bullae size: greater than 2 cm), or a new VATS procedure using needle shaped thoracoscopy and endoscopic equipment with a 2-mm diameter (needle VATS) by laser bulla ablation alone (bullae size: less than 2 cm). RESULTS: The conventional VATS was performed in 54 patients and needle VATS in 60 patients. In the needle VATS group, operation time was shorter than that of the VATS group (39+/-17 min vs. 56+/-22 min). Use of non-steroidal anti-inflammatory drugs for postoperative wound pain could be reduced in the needle VATS group (3% vs. 56%). There were no complications in the needle VATS group, but three complications (5.6%) in the VATS group, including prolonged air leakage (>4 days) in two and refractory intercostal pain in one. The rate of recurrence after the operation was similar in both groups (3.7% vs. 3.3%). The needle VATS allowed wound healing without a scar and reduced the patient's cosmetic problems. CONCLUSION: The needle VATS procedure for patients with a bulla size less than 2-cm diameter was as useful as the conventional VATS procedure.     

Dietary calcium and phosphorus ratio regulates bone mineralization and turnover in vitamin D receptor knockout mice by affecting intestinal calcium and phosphorus absorption.

The effects of the dietary Ca and P ratio, independent of any vitamin D effects, on bone mineralization and turnover was examined in 60 VDRKO mice fed different Ca/P ratio diets. High dietary Ca/P ratio promoted bone mineralization and turnover with adequate intestinal Ca and P transports in VDRKO mice. INTRODUCTION: To clarify the effects of the dietary calcium (Ca) and phosphorus (P) ratio (Ca/P ratio) on bone mineralization and turnover in null-vitamin D signal condition, vitamin D receptor knockout (VDRKO) mice were given diets containing different Ca/P ratios. MATERIALS AND METHODS: Five groups of 4-week-old VDRKO mice, 10 animals each, were fed diets for 4 weeks. Group 1 was wild-type littermate mice, fed the diet containing 0.5% Ca and P (Ca/P = 1). Group 2 was the control and was fed a similar diet (Ca/P = 1). Groups 3, 4, 5, and 6 were fed the following diets: 0.5% Ca and 1.0% P (Ca/P = 0.5), 1.0% Ca and 1.0% P (Ca/P = 1), 1.0% Ca and 0.5% P (Ca/P = 2), and 0.5% Ca and 0.25% P (Ca/P = 2). RESULTS AND CONCLUSIONS: Compared with group 2, serum calcium and phosphorus levels in groups 4-6 significantly increased. Serum parathyroid hormone levels increased in group 3 and decreased in group 5. The amounts of intestinal calcium absorption decreased in groups 3 and 4. Phosphorus absorption increased in group 3 and decreased in groups 4-6. Bone mineral content (BMC) and bone mineral density (BMD) of the femur in group 3 significantly decreased and increased in group 5. In the primary spongiosa of the proximal tibia, the trabecular bone volume (BV/TV) and osteoid thickness (O.Th) in group 3 significantly increased, and decreased in group 6. In groups 5 and 6, the numbers of the trabecular osteoclasts increased. In groups 2 and 4, and the secondary spongiosa was identified in 5 of 10 mice. In group 3, there was no secondary spongiosa in either mouse. Osteoid maturation time (OMT) significantly decreased, and bone formation rate (BFR/BS) increased in groups 4-6. These data indicate that the dietary Ca/P ratio regulates bone mineralization and turnover by affecting the intestinal calcium and phosphorus transports in VDRKO mice. They may suggest the existence of Ca/P ratio-dependent, vitamin D-independent calcium and phosphorus transport system in the intestine.     

Estimation of collimator scatter factor, S(c), of rectangular fields by a saturation model

We estimated collimator scatter factor, S(c), of symmetric rectangular fields of any size by applying a two-component scatter model to measured in-air output data in width and length directions of measured rectangles. The in-air output was measured for symmetric rectangles with combined width and length sizes of 7 x 7 and 6 x 6 using 10 MV and 4 MV X-rays of Varian's Clinac 2100 C/D, respectively. The model consists of scatter components from the primary collimator and flattening filter and from the collimator jaws: the former shows a saturation curve and the latter increases linearly with enlarging field size. This model was fitted to the measured dataset firstly in the width and secondly in the length directions of rectangles; then, by compiling interpolated matrix data, the S(c) table of symmetric rectangles was constructed. In addition, using this S(c) table, values of S(c) were calculated for a few asymmetric rectangles by Day's method, and were in good agreement with measured values. Therefore, we think that our method is practical and precise for constructing the S(c) table of symmetric rectangles from measured data, and that using this table, the S(c) of any asymmetric rectangles may be calculated.     

Clinical outcomes of living donor liver transplantation for hepatitis C virus (HCV)-positive patients

BACKGROUND: Whether hepatitis C virus recurrence occurs earlier and with greater severity for living donor liver transplantation (LDLT) than for deceased donor liver transplantation (DDLT) has recently become a subject of debate. METHODS: We retrospectively evaluated clinical outcomes for a cohort of 91 HCV-positive patients who underwent LDLT at Kyoto University with a median follow-up period of 25 months. RESULTS: Overall 5-year patient survival for HCV patients was similar to that for non-HCV patients (n=209) who underwent right-lobe LDLT at our institute (69% vs. 71%). Survival rate of patients without HCC (n=34) tended to be better than that of patients with HCC (n=57) (82% vs. 60%, P=0.069). According to annual liver biopsy, rate of fibrosis progression to stage 2 or more (representing significant fibrosis) was 39% at 2 years after LDLT. Univariate analysis showed that female recipient and male donor represented significant risk factors for significant fibrosis. Progression to severe recurrence (defined as the presence of liver cirrhosis (F4) in a liver biopsy and/or the development of clinical decompensation) was observed in five patients. CONCLUSIONS: Postoperative patient survival was similar for HCV-positive and -negative recipients in our adult LDLT series. Rates of progression to severe disease due to HCV recurrence seemed comparable between our LDLT recipients and DDLT recipients described in the literature. Although longer-term follow-up is required, our results suggest that LDLT can produce acceptable outcomes also for patients suffering from HCV-related cirrhosis.