Production, Binding and Cytotoxicity of Human/Mouse Chimeric Monoclonal Antibody-Neocarzinostatin Conjugate

A human/mouse chimeric Fab monoclonal antibody A7 (chFabA7) was covalently coupled to neocarzinostatin (NCS) by the SPDP method at various chFabA7:NCS substitution ratios. The antigen-binding activity of the conjugate, examined by ELISA using fixed antigen-positive colon cancer cells, was identical to that of the parent chFabA7 when one mole of NCS was conjugated, but was reduced with 2 or 3 moles of conjugated NCS. By means of a colony-forming assay, the cytocidal effect of the conjugate on antigen-positive cancer cells was found to be stronger than that of free NCS, whereas in antigen-negative cancer cells it was similar to that of free NCS. This effect was attenuated by adding an excess amount of monoclonal antibody A7. These findings indicate that the conjugate has an antigen-specific cytocidal action, and thus chFabA7-NCS is a promising tool for targeting cancer chemotherapy.     

Enhancement of Antitumor Activity of Cisplatin on Human Gastric Cancer Cells in vitro and in vivo by Buthionine Sulfoximine

An attempt was made to evaluate the enhancement of the antitumor activity of cisplatin (DDP) by buthionine sulfoximine (BSO) in vitro and in vivo. In the in vitro study, pre-treatment with BSO (5, 10 and 25 mM ) increased the antitumor activity of DDP against the gastric cancer cell lines MKN-28 and MKN-45, whereas BSO alone exhibited only slight antitumor activity (inhibition rate, 20–30%). In the in vivo study, the antitumor effects of DDP against human gastric cancer xenografts St-15 and SC-l-NU in BALB/c nu/nu mice were enhanced pretreatment with BSO, which was administered intraperitoneally at a dose of 500 mg/kg according to a schedule of qd × 3. BSO alone showed no antitumor effects against these tumors in nude mice. The side effects (assessed in terms of death rate and body weight loss) associated with the maximum tolerated dose of DDP (9 mg/kg) were not increased by BSO pretreatment. As BSO increased the antitumor activity of DDP without a corresponding increment of its toxicity, BSO appears to be a promising agent for further study.     

Enhanced Tumor Localization of Radiolabeled Fab Fragments of Monoclonal Antibody A7 in Nude Mice Bearing Human Pancreatic Carcinoma Xenografts

Much recent research has been directed toward the use of monoclonal antibodies (MAb) for the inimunodetection of solid tumors. In pancreatic cancer, the results of conventional immunoscintigraphy using intact MAb remain disappointing. Clear immunoseintigrapliy with radiolabeled MAb requires a high tumor tissue/blood ratio of radioactivity and a low normal tissue/blood ratio of radioactivity. In this study, ¹²⁵I-labeled Fab fragments produced by papain digestion of MAb A7 were injected intravenously into nude mice bearing a human pancreatic cancer (HPC-YS) xenograft previously shown to react specifically with MAb A7. The radioactivity of tumors and normal organs was subsequently measured. The tumor tissue/blood ratio of ¹²⁵I-labeled Fab fragments of MAb A7 was 1.00±0.24 and 9.68±2.54 at 2 and 24 h after injection, respectively. The tumor tissue/blood ratio of radioactivity was significantly higher than those of normal organs at 24 h after injection. Moreover, the tumor tissue/blood ratio of ¹²⁵I-labeled Fab fragments of MAb A7 was greater than that of intact MAb A7, although the ¹²⁵I-labeled Fab accumulation level was much less than that of ¹²⁵I-labeled intact MAb A7 in the tumor. When mice bearing tumors which did not react with MAb A7 were studied, ¹²⁵I-labeled Fab fragments did not specifically localize to the tumors. These results suggest that Fab fragments of MAb A7 may be suitable carriers of radionuclides for the immunodetection of human pancreatic cancer.     

Resection margin in patients with gastric cancer associated with esophageal invasion: Clinicopathological study

We investigated the correlations between resection margin involvement by carcinoma and a number of clinicopathological features in patients with gastric cancer and esophageal invasion. From January 1968 to December 1988, 1,040 patients with carcinoma of the stomach underwent gastric resection. Thirty-nine patients had tumor infiltration of the esophagus on histological examination of the resected specimens. The patients were divided into two groups on microscopic examination: those in whom the resection margin was less than 5 mm wide, and those in whom it exceeded 5 mm microscopically. There were 6 and 33 patients in the narrow and wide margin groups, respectively. There were statistically significant differences in tumor size, depth of cancer invasion, and macroscopic appearance between the two groups. The risk of resection margin involvement was high in tumors with the following features: large Borrmann type 4 tumor (macroscopic appearance and size) and infiltrative carcinoma (depth of invasion). © 1993 Wiley-Liss, Inc.     

Enhanced oncogenicity of human papillomavirus type 16 (HPV16) variants in Japanese population

To investigate whether HPV16 E6 variants carry an elevated risk for cervical cancer in Japanese population, we investigated the E6 sequence variation in 40 cervical intraepithelial neoplasias (CINs) I-III and 43 invasive cervical cancers (ICCs), all positive for HPV16. HPV16 E6 variants were frequently found in ICCs than in CINs (88 vs. 65%, P=0.01). The E6 D25E, a rare variant in Western countries, was most frequently observed in ICC (44%). CIN I/II lesions with HPV16 variants were less likely to regress than those with HPV16 prototype (P=0.048). The finding that HPV16 E6 variants represent a significant risk factor is common between Western and Japanese women despite the different distribution of each variant.     

Atelosteogenesis Type 3: The First Patient in Japan and a Survivor for more than 1 year

We report the first patient of atelosteogenesis type 3 (AO₃) in Japan. The patient had multiple craniofacial abnormalities at birth, including ocular hypertelorism, a flat nasal bridge, micrognathia and a cleft palate. There was rhizomelic shortness of the limbs and a club-foot. The infant had short broad thumbs in the hands similar to those observed in the feet. There were no chromosomal abnormalities. Radiological examination demonstrated striking hypoplasia of the humerus with proximal rounding and distal tapering giving a 'drumstick' appearance, 'S'-shape configuration of the cervical spine, scoliosis and coronal cleft in the thoracolumbar vertebral bodies. The infant experienced recurrent apnea and persistent severe tracheomalacia, which necessitated tracheostomy at 5 months of age. Despite his multiple skeletal deformities and respiratory problems, this patient survived more than 1 year with motorneuronal developmental delay.     

Haemodynamic effects of induction of general anaesthesia with propofol during epidural anaesthesia

PURPOSE: To clarify whether propofol administration during thoracic or lumbar epidural anaesthesia intensifies the haemodynamic depression associated with epidural anaesthesia. METHODS: Patients (n = 45) undergoing procedures of similar magnitude were randomly divided into three study groups: a control group (n = 15) receiving general anaesthesia alone and two study groups undergoing thoracic (n = 15) and lumbar epidural anaesthesia (n = 15) before induction of general anaesthesia. All patients received 2 mg.kg-1 propofol at a rate of 200 mg.min-1, followed by a continuous infusion of 4 mg.kg-1.hr-1. Mean arterial blood pressure (MAP) and heart rate (HR) were measured at baseline, three minutes after induction, and one minute after tracheal intubation in all three groups and at 20 min after epidural anaesthesia was established in the thoracic and lumbar groups. RESULTS: Following epidural anaesthesia, MAP decreased from 94 +/- 14 (SD) at baseline to 75 +/- 11 mmHg (P < 0.0001) in the thoracic group and from 92 +/- 12 to 83 +/- 15 mmHg in the lumbar group. After propofol administration, MAP decreased further in the thoracic group to 63 +/- 9 mmHg (P = 0.0077) and to 67 +/- 10 mmHg (P = 0.0076) in the lumbar group. The MAP following propofol induction in the thoracic group (P < 0.0001) and in the lumbar group (P = 0.0001) was lower than MAP in the control group (81 +/- 9 mmHg). HR decreased only in response to thoracic epidural anaesthesia (P = 0.0066). CONCLUSION: The hypotensive effects of propofol are additive to those of epidural anaesthesia, resulting in a profound decrease in mean arterial pressure.     

Effects of extrinsic horizontal cell polarization on spike discharges in the carp retina

The effects of horizontal cell polarization on spike discharges were explored in superfused preparations of the carp retina. Light-induced discharge patterns of individual units were determined with spot and annulus stimuli of white light. The effects observed were classified in three response modes (common, reversed and transient). They were consistently observed as the tangential distance between the recording and current-injection electrodes was increased up to 400 μm. The common mode of response consisted of off-discharges upon depolarization and on-discharges upon hyperpolarization of horizontal cells. The reversed mode was opposite to the common. The transient mode consisted in transient spike discharges at the on- and off-sets of extrinsic currents injected into horizontal cells. The common mode of response was observed in 3 of 9 ON-center units, all of 20 OFF-center units and in 3 of 21 ON-OFF units. The reversed mode was seen in 6 of 9 ON-center units and in 4 of 21 ON-OFF units. The transient mode was only found in ON-OFF units. ON-center units can be divided into two subgroups: some responded with the common and others with the reversed mode. All OFF-center units showed exclusively the common mode. On the other hand, all 21 ON-OFF units showed the transient mode, but 9 exhibited one or two additional modes of response; 5 of them showed two (common and transient) modes and 4 showed all three modes, depending upon horizontal cells into which polarizing currents were injected.     

Epidemiological analysis of deaths caused by burns in Osaka, Japan

By referring to all of the death cards recorded for the year of 1978 in the whole area of Osaka Prefecture, we examined deaths due to burn injuries, electric injury and heatstroke, and obtained the following results.

1. 1. Of the total 41 737 deaths, externally induced death took place in 3207 cases (8 per cent), and death due to burn injuries including electric shock and heatstroke took place in 215 cases (2–60 cases against 100 000 population), accounting for 6.7 per cent of all externally induced deaths. In those aged under 40 years, externally induced death ranked highest as the cause of death, and burn injury was one of the chief causes.

2. 2. The sex ratio of burn-induced death was 3: I for males and females, respectively. However, if burn injuries resulting from social factors and suicide were excluded, the sex ratio was not significantly different at 1-3:1. The causes of injury were work accidents, suicide and other accidents at a rate of I: 2: 3.

3. 3. The monthly incidence of injuries was larger in winter when there were many cases of on-the-spot death due to fire, but there was no significant difference in the monthly incidence of post-treatment death.

4. 4. Of the 215 cases, 158 (73–5 per cent) died on the spot, while only 57 cases died after treatment. There were apparent regional differences in the total casualties. Post-treatment death probably occurred in 30 per cent of the total deaths induced by burn injuries.

5. 5. Medical institutions receiving burn victims could be divided into private and public ones at a nearly equal ratio. Public institutions took a significantly larger proportion of this type of casualty than following road accidents.

6. 6. Supplementary investigations revealed that two to three times as many people died at the scene of the accident than died after treatment from severe burns, this amounted to 140 cases a year in the whole area of Osaka Prefecture.