Cyclosporin A Enhances Susceptibility of Multi-drug Resistant Human Cancer Cells to Anti-P-glycoprotein Antibody-dependent Cytotoxicity of Monocytes, but Not of Lymphocytes

Cyclosporin A (CsA) was previously found to bind to P-glycoprotein expressed on multidrug-resistant (MDR) cancer cells. In the present study, the effect of CsA on anti-P-glycoprotein monoclonal antibody (mAb)-dependent cell-mediated cytotoxicity (ADCC) against human MDR cells was examined. The ADCC reaction was assessed by 4-h ⁵¹Cr-release assay. Highly purified lymphocytes (> 99%) and monocytes (>99%) obtained from blood mononuclear cells (MNC) of healthy donors were used as effector cells. CsA decreased the cytotoxic activity of MNC against MDR cells, but enhanced their ADCC activity in the presence of anti-P-glycoprotein mAb MRK16. Lymphocyte-mediated ADCC and natural killer activity against MDR cells were also suppressed by addition of CsA. CsA induced a significant dose-dependent increase in monocyte-mediated ADCC activity. Interestingly, pretreatment of MDR cancer cells, but not of monocytes, with CsA significantly enhanced ADCC activity mediated by monocytes, but not by lymphocytes. A CsA analog (PSC833) and FK-506, but not verapamil also increased the sensitivity of MDR cells to ADCC by monocytes. CsA did not affect the binding of monocytes to MDR cells in the presence of MRK16 mAb. These results indicate that CsA may directly enhance the susceptibility of MDR cancer cells to the monocyte-mediated ADCC reaction.     

Influence of Systemic Chemotherapy on Anti-P-glycoprotein Antibody-dependent Cell-mediated Cytotoxicity in Patients with Small Cell Lung Cancer

Anti-P-glycoprotein antibody (MRK-16)-dependent cell-mediatedcytotoxicity (ADCC by blood mononuclear cells (MNC was examinedin patients with small cell lung cancer (SCLC) before and aftersystemic chemotherapy. The effect of in vitro treatment of MNCwith interleukin (IL)-2 and macrophage-colony-stimulating factor(M-CSF) was also examined. The ADCC reaction was assessed bya 6 h ⁵¹ Cr-release assay using a multidrug-resistant (MDR)SCLC cell line (H69/VP cells). The MRK-16 monoclonal antibodywas able to augment spontaneous cytotoxicity by MNC, even inSCLC patients. Pretreatment of MNC with IL-2 significantly augmentedtheir ADCC ability in SCLC patients, while M-CSF had no effecton ADCC activity. After the first cycle of systemic chemotherapy,the ADCC activity tended to decline, but ADCC of MNC pretreatedwith IL-2 was not affected. The results suggest that anti-P-glycoproteinantibody, in combination with a cytokine such as IL-2, may betherapeutically useful against human SCLC resistant to chemotherapeuticdrugs.     

Increased Prevalence of HTLV-I Infection in Patients with Hepatocellular Carcinoma Associated with Hepatitis C Virus

The progression from chronic hepatitis C virus (HCV) infection to hepatocellular carcinoma (HCC) has been reported. We evaluated whether co-infection with the human T-lymphotropic virus type I (HTLV-I) might be associated with this transition in a cross-sectional analysis of 127 patients with HCV-chronic hepatitis (mean age=51.7) and 43 patients with HCV-associated HCC (mean age=62.4); the seroprevalence of anti-HTLV-I was 9.5% and 30.2%, respectively. For subjects 50 years or older, the seroprevalence of anti-HTLV-I in HCC patients was 13/41 (31.7%) which was significantly higher than that in chronic hepatitis patients (6/82, 7.3%) ( P =0.001). The relative risk (RR) of association was 12.8 ( P =0.0004) among the males, however, no association was evident among the females, RR=1.3 ( P =0.80). The increased prevalence of HTLV-I positivity among the HCC cases could not be attributed to a higher rate of prior transfusion. These data suggest that co-infection with HTLV-I may contribute to the development of HCC among patients with HCV-induced chronic liver diseases in a highly HTLV-I-endemic area.     

Refractive changes in diabetic patients during intensive glycaemic control

AIMS: To evaluate the clinical course and the characteristics of transient refractive error occurring during intensive glycaemic control of severe hyperglycaemia. METHODS: 28 eyes of patients with persistent diabetes were included in this prospective study. During the observation period, patients underwent general ophthalmological examination and A-mode scan ultrasonography was performed at each examination-at days 1, 3, and 7, and then once every week or every other week until recovery of hyperopia. RESULTS: A transient hyperopic change occurred in all patients receiving improved control after hyperglycaemia. Hyperopic change developed a mean of 3.4 (SD 2. 0) days after the onset of treatment, and reached a peak at 10.3 (6. 1) days, where the maximum hyperopic change in an eye was 1.47 (0. 87) D (range 0.50-3.75 D). Recovery of the previous refraction occurred between 14 and 84 days after the initial assessment. There was a positive correlation between the magnitude of the maximum hyperopic change and (1) the plasma glucose concentration on admission (p<0.01), (2) the HbA(1c) level on admission (p<0.005), (3) the daily rate of plasma glucose reduction over the first 7 days of treatment (p<0.001), (4) the number of days required for hyperopia to reach its peak (p<0.001), and (5) the number of days required for the development and resolution of hyperopic changes (p<0.0001). There was a negative correlation between the maximum hyperopic change of an eye and baseline value of refraction (p<0.01). During transient hyperopia, no significant changes were observed in the radius of the anterior corneal curvature, axial length, lens thickness, or depth of anterior chamber. CONCLUSIONS: The degree of transient hyperopia associated with rapid correction of hyperglycaemia is highly dependent on the rate of reduction of the plasma glucose level. A reduction of refractive index in intraocular tissues, especially in lens, appears to be responsible for this hyperopic change.     

Assessment of fracture and bone mineral density measurement

In this paper, the assessment of radiographic vertebral fracture (prevalent fracture and incident fracture) in the diagnosis of osteoporosis and the therapeutical assessment by bone mineral density measurements are reviewed.     

Three-dimensional reconstruction of biliary tract using spiral computed tomography for laparoscopic cholecystectomy

To increase the safety of laparoscopic cholecystectomy, we have analyzed the biliary tract in a three-dimensional fashion. The union of the biliary ducts was studied in 50 patients using spiral computed tomography (CT) after intravenous infusion cholangiography. Depending on the union and course of the cystic duct to the common bile duct, cystic duct anatomy was classified into six categories: ipsilateral gallbladder side (type I) and contralateral side with anterior course (type II); contralateral side with posterior course (type III); intrahepatic side (type IV); intrapancreatic side (type V); and unclassified (type VI). The length of the cystic duct was also determined. The cystic duct was identified in 42 cases (84%); 30 cases (60%) were type I, 9 cases (18%) type III, and a single case (2%) of types II, IV and V, respectively. The length of the cystic duct was < or =2 cm in 30 cases that had a shorter operating time compared to 12 cases with a cystic duct <2 cm (p <0.01). In conclusion, three-dimensional reconstruction of the cystic duct anatomy using spiral CT provides simple classification of bile duct anatomy, and this preoperative information may increase the safety of laparoscopic cholecystectomy.     

A gastric duplication cyst with an aberrant pancreatic ductal system: report of a case

We report an extremely rare case of a gastric duplication cyst together with an aberrant pancreatic ductal system, which communicated with the stomach rather than the pancreatic ductal system with no evidence of pancreatitis. A 46-year-old woman developed severe abdominal pain after a 10-year history of occasional mild abdominal pain. Upper gastrointestinal barium radiography showed a rigidity of the stomach wall, and gastroscopy revealed a fistula orifice at a greater curvature of the gastric body. Subsequent endoscopic suction of mucous secretion from within the fistula provided immediate pain relief. Abdominal computed tomography and ultrasonography showed a cystic mass contiguous with the stomach wall. Surgical exploration revealed an uncommon anomaly of a gastric duplication cyst with the aberrant pancreatic lobe. The patient made an uneventful recovery and remains well 4 years after surgery. We also herein review ten other similar cases of this uncommon congenital anomaly reported in the literature. Received: August 20, 2001 / Accepted: January 8, 2002     

Management of adrenal metastasis from hepatocellular carcinoma

Purpose: Although the adrenal gland is a common site of extrahepatic metastasis from hepatocellular carcinoma (HCC), there are no definitive guidelines for the treatment of adrenal metastasis. This study examines the effectiveness of various treatments for this disease. Methods: We retrospectively analyzed 20 patients treated for adrenal metastasis of HCC by adrenalectomy (n = 13), transarterial chemoembolization (TACE), or percutaneous ethanol injection therapy (PEIT) (n = 7). Results: There were no significant differences in cumulative survival rates between patients given adrenalectomy and those given TACE or PEIT, either after completing treatment for primary HCC or after the first treatment for adrenal metastasis. Six of seven patients with tumor thrombi in the inferior vena cava (IVC) from adrenal metastasis underwent adrenalectomy combined with intracaval thrombectomy, five of whom survived for more than 1 year after surgery, and two of whom are still alive without any recurrence more than 3 years after surgery. PEIT showed good results for small adrenal metastasis. Conclusion: These findings suggest that therapeutic modalities should be chosen according to the clinical features of each individual, including the size of the metastatic tumor, whether there is invasion into the IVC, the function of the remaining liver, and the existence of intra- and/or nonadrenal extrahepatic lesions. Furthermore, intracaval tumor thrombectomy could be indicated for patients with IVC thrombus if they are suitable candidates for surgery. Received: July 9, 2001 / Accepted: July 2, 2002 Reprint requests to: Y. Shimahara     

Effects of local administration of interferon-beta on proliferation of retinal pigment epithelium in rabbit after laser photocoagulation

PURPOSE: To investigate whether local administration of interferon (IFN)-beta promotes proliferation of the retinal pigment epithelium (RPE) in vivo. METHODS: Following local injection of IFN-beta into the sub-Tenon space of rabbit eyes, the penetration of IFN-beta into various intraocular areas was determined by means of enzyme-linked immuno-adsorbent assay. Retinal lesions were produced by laser photocoagulation (PC), and IFN-beta (1 x 10(6) IU, 1 x 10(5) IU, or 1 x 10(4) IU) was administered into the sub-Tenon space. Physiological saline was substituted for IFN-beta in controls. The proliferation of RPE cells was inspected histopathologically. RESULTS: After IFN-beta administration, IFN-beta was found in all intraocular areas examined, with the highest concentration detected in the choroid. After PC, profuse proliferation of RPE cells began earlier in the rabbits that received the highest dose of IFN-beta than in the control rabbits; repair of the central part of the coagulated lesion in those rabbits was complete within 7 days after PC. In control rabbits, the histopathologic wound repair process proceeded more slowly and to a limited extent. Proliferation of RPE cells in the low and medium dose IFN-beta-treated rabbits was similar to that in the control rabbits. CONCLUSION: The present study demonstrates that repair of the PC-induced retinal lesions, particularly the proliferation of RPE cells, is promoted in vivo by local administration of IFN-beta.     

Prognostic significance of high-resolution CT findings in small peripheral adenocarcinoma of the lung: a retrospective study on 64 patients

OBJECTIVE: We studied the prognostic importance of high-resolution CT (HRCT) findings in lung adenocarcinomas. PATIENTS AND METHODS: HRCT findings (lesion size, percentage of ground-glass opacity (GGO) areas of lesion, and presence or absence of lobulation, coarse spiculation, air space, pleural tag, and multiplicity of lesion), clinical data (age and surgical method), and pathologic findings (tumor subtypes and presence or absence of nodal metastasis) in 64 consecutive patients with 64 peripheral adenocarcinomas of 20 mm or less (mean, 13 mm), including 36 women and 28 men with a mean age of 64 years were analyzed and correlated with survival of the patients using Kaplan-Meier method and stepwise Cox proportional hazards modeling. Follow-up periods of the patients ranged from 6 to 45 months (mean, 22 months). Tumors were classified into six subtypes (types A-F) according to tumor growth patterns defined by Noguchi et al. RESULTS: Six (9%) of the 64 patients died of lung cancer. In univariate analyses, a significant difference was noted for lesion size (P=0.043), the percentage of GGO areas (P=0.005), and tumor subtypes (P=0.006). Lesion size of <15 mm (n=35), a lesion with GGO areas of >57% (n=36), and type A (n=16) or type B adenocarcinomas (n=16) indicated a significantly better survival. In multivariate analyses using these three parameters as independent variables, the percentage of GGO areas was the only significant independent factor for survival (P=0.044, relative risk=0.95). CONCLUSION: GGO areas measured on HRCT may have an independent prognostic significance of small adenocarcinomas of the lung.