Clinical application of18F-FUdR in glioma patients — PET study of nucleic acid metabolism

Summary Positron emission tomography was used to investigate the metabolism of nucleic acids by¹⁸F-fluoro-2-deoxyuridine (¹⁸F-FUdR) in 22 patients with gliomas. Sixteen cases of high grade glioma clearly demonstrated a region of high activity with a differential absorption rate (DAR) of 0.64 ± 0.34. Six cases of low grade glioma failed to reveal a positive image of the tumor and the DAR in tumor was 0.21 ± 0.042 (p < 0.01). This PET-¹⁸F-FUdR study succeeded in differentiating high and low grade gliomas from the view point of nucleic acid metabolism.     

Tumor scintigraphy by the method for subtracting the initial image with technetium-99m labeled antibody

The method for subtracting the initial image from the localization image was evaluated for radioimmunoscintigraphy of tumors with technetium-99m (Tc-99m) labeled antibodies. Monoclonal antibodies were parental mouse and mouse-human chimeric antibodies to carcinoembryonic antigen (CEA), designated F11-39 and ChF11-39, respectively, both of which have been found to discriminate CEA in tumor tissues from the CEA-related antigens. After reduction of the intrinsic disulfide bonds, these antibodies were labeled with Tc-99m. In vivo studies were performed on athymic nude mice bearing the human CEA-producing gastric carcinoma xenografts. Though biodistribution results showed selective and progressive accumulation of Tc-99m labeled antibodies at the tumor site, high radioactivity in blood was inappropriate for scintigraphic visualization of the tumors within a few hours. We examined the subtraction of the initial Tc-99m image from the Tc-99m localization image after a few hours. Subtracted images of the same count reflected the in vivo behavior of the Tc-99m radioactivity. The subtracted scintigrams revealed excellent tumor images with no significant extrarenal background. Visualization of the tumor site was dependent on antigen-specific binding and nonspecific exudation. These results demonstrate that a method of subtraction of the initial image may serve as a potentially useful diagnostic method for an abnormal site for agents with a low pharmacokinetic value.     

Scintigraphic demonstration of renal cell carcinoma with I-131-6β-iodomethyl-19-norcholesterol: A case report

Extraadrenal abnormal uptake on adrenocortical scintigraphy has been reported rarely in the normal gallbladder, lipid cell tumor of the ovary, or in clear cell type renal cell carcinoma. Clear cell type renal cell carcinoma contains glycogen and cholesterol like the adrenal gland, but the uptake of the radionuclide I-131 cholesterol has been reported to be low and not sufficient to image it. Right renal and adrenal masses were incidentally discovered on abdominal CT scan in a patient with chronic renal failure resulting in bilateral acquired cystic kidney disease. Adrenocortical scintigraphy done to know the nature of the adrenal mass showed high uptake corresponding to the right renal mass and the right adrenal mass. Clear cell type renal cell carcinoma and adrenal adenoma with prominent clear cells were histologically confirmed on hematoxylin-eosin stain and in an immunohistochemical study with renal cell antibody. Not only low-density lipoprotein receptors mediated uptake but also overall replacement of the right non-tumorous renal parenchyma by acquired cysts may have played a role in imaging the renal cell carcinoma on adrenocortical scintigraphy.     

Mediastinal lymph node metastasis of colon cancer: Report of a case

We herein describe a patient with mediastinal lymph node metastases which occurred after both a primary sigmoid colon cancer and metachronous ovarian metastasis had been resected. The most likely route of metastases to the mediastinum in this case is the paravertebral venous plexus probably connected to the ovarian metastasis, or so-called remetastasis. This case illustrates that the mediastinum is thus a possible metastatic site in patients with colon cancer. Surgeons should therefore pay attention to the mediastinum as well as the lung fields when checking chest X-ray films during a follow-up of patients after a resection of colon cancer.     

Inhibition of cardiac inward-rectifier K current by terodiline

The antispasmodic agent terodiline has cardiotoxic effects that include QT lengthening. To determine whether inhibition of inwardly-rectifying K⁺ current (I_K1) might be a factor in the cardiotoxicity, we measured I_K1 in guinea pig ventricular myocytes. Terodiline reduced outward I_K1 with an IC₅₀ of 7 μM; maximal reduction was 60% with 100–300 μM concentration. Inhibition was independent of current direction, and persisted after removal of the drug. Terodiline (3–5 μM) lengthened action potentials in guinea pig papillary muscles by ca. 10%, primarily by slowing phase 3 repolarization; higher concentrations abbreviated the plateau and markedly slowed late repolarization. Terodiline washout provoked an extra lengthening, consistent with persistent inhibition of I_K1 and rapid recovery of net inward plateau current. The results suggest that inhibition of I_K1 is a likely factor in the cardiotoxicity of the drug.     

Antinociceptive effects of ONO-9902, an enkephalinase inhibitor,after visceral stress condition in rats

Purpose

The present study was designed to examine the antinociceptive effects of orally administered ONO-9902, an enkephalinase inhibitor, on both somatic and visceral pain after visceral stress conditions.

Methods

Twenty six male rats were examined. Tail-flick (TF) and colorectal distension (CD) tests were used to determine somatic and visceral antinociceptive effects, respectively. Measurements were performed in rats under immediate post-stress conditions (group ST; n = 14) and in rats nor under stress conditions (group NST; n = 12). In the stressed group, the same device, CD, for visceral antinociceptive effects was used for visceral stress and was applied with an intracolonic pressure of 60 mmHg for 20 min after drug administration. The TF latency and CD threshold were measured before and at 30, 40, 50, 60 and 90 min after administration of ONO-9902 300 mg · kg^?1 or distilled water.

Results

Orally administered ONO-9902 did not produce any changes in the % maximum possible effect (%MPE) in either TF or CD tests in the unstressed group. In the stressed group, %MPE in the CD test increased 18% and 31% at 30 and 40 min, respectively, after oral administration of ONO-9902 compared with the control group (P < 0.05). However, %MPE to TF test did not alter even after the CD-induced stress condition.

Conclusion

These results suggest that ONO-9902 may have analgesic effects on visceral pain but not on somatic pain under immediate post-stress conditions.     

Assessment of hepatic graft injury by graft effluent in rodents: N-acetyl-β-glucosaminidase and type III procollagen peptide

We studied the significance of N-acetyl--glucosaminidase (-NAG) and type III procollagen peptide (P-III-P) in the effluent of rodent hepatic grafts. After total hepatectomy, the livers were preserved in chilled, lactated Ringer's solution and then divided into five groups (n=10 each): group 1, 4 h preservation only; group 2, 4 h preservation and rewarming; group 3, 6 h preservation only; group 4, 6 h preservation and rewarming; and group 5, minimal preservation only. The -NAG of groups 2 and 4 was significantly higher than that of groups 1 and 3 (0.98±0.5 U/l vs 0.21±0.12 U/l; P<0.01 and 1.76±0.67 U/l vs 0.38±0.25 U/l, respectively; P<0.01), while that of group 4 was significantly higher than that of group 2 (1.76±0.67 U/l vs 0.98±0.50 U/l; P<0.05). The P-III-P of group 4 was significantly higher than that of group 2 (0.133±0.008 U/ml vs 0.110±0.015 U/ml; P<0.01). We conclude that -NAG is a novel parameter of parenchymal and nonparenchymal cells, while P-III-P reflects the integrity of the hepatic sinusoidal extracellular matrix.     

Refilling the lens with an inflatable endocapsular balloon: surgical procedure in animal eyes

In this report we describe the surgical details involved in refilling the lenses of 13 rabbit and 3 primate eyes using an inflatable endocapsular balloon to restore accommodation. The procedure involves endocapsular phacoemulsification through a small buttonhole or dumbbell anterior capsulotomy or minicircular capsulotomy and the simultaneous preservation of capsular integrity, including the zonules and ciliary muscles. An inflatable balloon made of thin silicone membrane is then inserted into the empty capsular bag. A liquid silicone polymer is injected into the balloon through a delivery tube, and the empty capsular bag is refilled by the inflated balloon. The procedure was found to be reproducible, and an accommodation of 6 D was confirmed in one primate eye. Capsular opacification occurred, but the proliferation and migration of residual lens epithelial cells could be hindered by abundant refilling. This lens-refilling technique may provide restoration of accommodation in future cataract surgery. Offprint requests to: O. Nishi     

Availability and limitations of thallium-201 myocardial SPECT quantitative analysis: Assessment as daily routine procedure for ischemic heart disease

To determine the availability and limitations of the detection of ischemic lesions by stress thallium-201 myocardial SPECT as the daily routine procedure, we compared and evaluated the detectability of the quantitative analysis (%uptake and washout rate (WR)) and visual evaluation in 104 patients with effort angina and 17 normal subjects. Visual evaluation combined with WR analysis resulted in significantly higher sensitivity (88.0%) but lower specificity (60.2%) than the other methods. The sensitivity by visual evaluation was quite low in multivessel disease (MVD), and in the regions supplied by mild coronary stenosis or by the left circumflex artery. These were markedly improved by combining visual evaluation and WR analysis, but sensitivity in the MVD group was unsatisfactory even with this analytic method in comparison with the single vessel disease group. One of the causes of low sensitivity in the MVD group might be the "true negative": No induction of the ischemia in the regions of milder stenosis, or the regions supplied by the collateral coronary flow. We therefore conclude that the combination of visual evaluation as a qualitative analysis and WR analysis as a quantitative analysis, is the most useful daily routine procedure as a screening test for detecting ischemia.     

An angiogenesis inhibitor E7820 shows broad-spectrum tumor growth inhibition in a xenograft model: possible value of integrin alpha2 on platelets as a biological marker.

We reported previously that an angiogenesis inhibitor, E7820, inhibits in vitro tube formation of human umbilical vein endothelial cell through the suppression of integrin alpha2 expression. Here we describe the antiangiogenic and antitumor effects of E7820 in mice and discuss the feasibility of using platelet integrin alpha2 expression on platelets as a biological marker of the efficacy of E7820. Oral administration of E7820 significantly inhibited basic fibroblast growth factor-induced angiogenesis in Matrigel implants and human colon WiDr tumor-induced angiogenesis in a dorsal air sac model. Twice-daily treatment with E7820 clearly inhibited the s.c. tumor growth of seven tumor cell lines derived from human colon, breast, pancreas, and kidney, and completely suppressed the growth of human pancreatic KP-1 and human colon LoVo cell lines. Moreover, E7820 significantly inhibited the growth of KP-1 and human colon tumor Colo320DM cells orthotopically implanted in the pancreas and cecum, respectively. The efficacy of E7820 was comparable in the s.c. and orthotopic transplantation models. Immunohistochemical analyses using anti-CD31 antibody showed that E7820 significantly reduced microvessel density in orthotopically implanted KP-1 tumor. E7820 reduced integrin alpha2 expression on a megakaryocytic cell line, Dami cells, induced by phorbol 12-myristate 13-acetate treatment. It also decreased the expression level of integrin alpha2 on platelets withdrawn from mice bearing s.c. KP-1 tumor at a dosage close to that affording antitumor activity. These data demonstrate that E7820 showed a broad-spectrum antitumor effect in mice through inhibition of angiogenesis and indicate that the decrease of integrin alpha2 on platelets might serve as a biological marker for the antitumor efficacy of E7820.