Teruhiko Takayama

Efficacy, toxicity and mode of interaction of combination radioimmunotherapy with 5-fluorouracil in colon cancer xenografts

Purpose:The feasibility of radioimmunotherapy (RAIT) combined with 5-fluorouracil (5-FU) was examined in colon cancer xenografts. The mode of interaction of the two treatments was also investigated. Methods: Mice bearing human colon cancer were treated with a combination of 4.63 MBq (L-RAIT) or 9.25 MBq (H-RAIT) 131I-A7, an IgG1 against 45-kDa glycoprotein, and 5-FU at a dose of 30 mg kg−1 day−1 for 5 days. Myelotoxicity was monitored by blood cell counts and intestinal toxicity was assessed by the dosimetry. The results were compared with those of a single-modality therapy. Results: The combination of 5-FU with H-RAIT enhanced the antitumor effect, improving the tumor quadrupling time from 25.3 ± 9.59 days to 31.3 ± 8.32 days (P < 0.05) and inducing tumor regression in 7 out of 10 mice, compared to 3 out of 9 mice treated with H-RAIT alone. The efficacy of L-RAIT was also improved by the combination. Analysis of the dose/response relationship showed an additive interaction of the two modalities. The combination of 5-FU with RAIT induced slightly more severe myelotoxicity than a single-modality treatment, but blood cell counts recovered similarly. Dose estimation suggested that RAIT does not increase the intestinal toxicity of 5-FU. Conclusion: The combination of two modalities would be feasible for the treatment of colon cancer, increasing antitumor effect with minor effect on toxicity.

Indium-111 transferrin imaging for the diagnosis of protein-losing enteropathy.

For assessment of gastrointestinal protein loss, seven patients suspected of having protein-losing enteropathy were studied by gamma camera imaging using in-111 transferrin. Four patients with a value equal to or more than 20 ml/day on the alpha-antitrypsin clearance test or a high protein content on the gastric juice showed definite intestinal activity on an early image, demonstrating protein loss. The loss site could be determined by observing the movement of radiotracer within the bowel lumen on the subsequent images. The three patients with a value of less than 20 ml/day in the test showed no obvious intestinal activity throughout the study. Therefore, in-111 transferrin abdominal imaging appears to be useful for determining the loss site as well as for establishing the rapid diagnosis of protein-losing enteropathy.

Combination radioimmunotherapy with local hyperthermia: increased delivery of radioimmunoconjugate by vascular effect and its retention by increased antigen expression in colon cancer xenografts

Hyperthermia (HT) may increase tumor targeting of a radiolabeled antibody by its effects on tumor vasculature and antigen expression. Expression of a 45-kDa glycoprotein antigen on LS180 colon cancer cells was 2.7-fold enhanced 2 days after heating at 43 degrees C for 1 h. Preferential tumor accumulation of 125I-A7 recognizing this antigen was doubled and the antitumor effect of 131I-A7 was significantly improved by HT. Hyperthermia also increased tumor uptake of an irrelevant antibody but its radioactivity was rapidly cleared. These results indicate that HT increased the initial delivery of an antibody to a tumor by its vascular effect, and radioactivity was retained in tumors by increased specific binding, resulting in a better radioimmunotherapy outcome.

Advantages of upright position imaging with medium-energy collimator for sentinel node lymphoscintigraphy in breast cancer patients

Objective: To evaluate the advantage of upright position imaging with a medium-energy collimator for the detection of sentinel lymph node (SLN).Methods: Thirty-four patients with operable breast cancer underwent sentinel node lymphoscintigraphy with99mTc-tin colloid. Images were obtained in 5 different positions and paired images from the same patient were compared using side-by-side interpretation. Images were compared in 3 groups: group 1 (anterior view); supine (SAV) vs. upright (UAV), group 2 (oblique view); supine (SOV) vs. upright (UOV), and group 3 (oblique view); modified supine (MOV) vs. UOV. Image quality was evaluated using a 3-grade scale of clear, faint, and equivocal depiction, and correlated to 3 parameters: distance from injection site to lymph node (hot node), counts in hot node, and image contrast. Parameters in group 1 were compared by classifying the primary tumor site into 4 subregions.Results: Image quality in all 3 groups was more enhanced on the image obtained in the upright position than that in the supine position. Obtaining images in an upright position increased the mean distances by 1.5–3.2 cm, and mean contrasts were significantly increased by 0.13–0.31 (p<0.05). It was shown that image quality was more greatly affected by image contrast than by counts in the hot node. Image contrast of 0.5 seemed an appropriate threshold level for detection of the hot node. On comparison of tumor sites, the upper outer quadrant (C) region of the 4 subregions demonstrated greater contrast enhancement on upright position images.Conclusion: Clinical images obtained in an upright position with a mediumenergy collimator were superior to those obtained in a supine position. Use of this procedure is recommended to enhance lymph node detection on sentinel node lymphoscintigraphy.

Enhanced Efficacy of Radioimmunotherapy Combined with Systemic Chemotherapy and Local Hyperthermia in Xenograft Model

We previously found that the efficacy of radioimmunotherapy (RIT) with 131I‐A7, an IgG1 against Mr 45000 glycoprotein on colon cancer, was enhanced by local hyperthermia (HT) or chemotherapy with 5‐fluorouracil (5‐FU). In this study, we aimed to further enhance its efficacy by combining these three modalities. Human colon cancer xenografts (146±12 mm3) in Balb/c nu/nu female mice were treated with 9.25 MBq 131I‐A7 i.v. combined with HT (43°C for 1 h) and 5‐FU (30 mg/kg/day i.p. for 5 days). Tumor growth delay, (Tqtreated‐Tqcontrol)/Tqcontrol where Tq is tumor quadrupling time, in mice treated with RIT+HT+5‐FU was improved to 12.7 from 5.90, 7.55 and 10.1 with RIT alone, RIT+5‐FU and RIT+HT, respectively. Complete response was observed in 4 out of 8 tumors with RIT+HT+5‐FU and 3 out of 10 with RIT+HT. No tumor showed complete response with RIT+5‐FU or RIT alone. 5‐FU slightly increased myelotoxicity of RIT, but HT did not affect it. Body weight loss was not enhanced by the combination. These results indicate that the combination of three modalities is a feasible approach to enhance the antitumor efficacy of RIT without serious increase of toxicity.

Intravascular gas in multiple organs detected by postmortem computed tomography: effect of prolonged cardiopulmonary resuscitation on organ damage in patients with cardiopulmonary arrest

A 76-year-old woman was found in cardiopulmonary arrest with her head submerged in water in a bathtub. Despite cardiopulmonary resuscitation (CPR) for over 1 h by professional emergency technicians and medical doctors, the patient died. Postmortem computed tomography revealed not only pulmonary edema associated with drowning but also the presence of intravascular gas in the pulmonary artery, liver, kidneys, heart (right ventricle), and brain. It was speculated that intravascular gas was generated and spread to multiple organs during CPR procedures via the alimentary tract and lungs, which had been damaged by ischemia after cardiopulmonary arrest. Prolonged CPR procedures may involve the risk of additional organ damage and systemic air emboli.

99mTc colloid and 99mTc IDA imagings in diffuse hepatic disease.

Ninety-six patients with various diffuse hepatic diseases were observed using both 99mTc colloid and 99mTc iminodiacetic acid (IDA), focusing on the potential etiologies of the disease process as well as its chronicity and severity. The presence of acute hepatic disease was more sensitively depicted with 99mTc IDA than with 99mTc colloid. In chronic hepatic disease, on the other hand, 99mTc colloid and 99mTc IDA demonstrated a similar sensitivity. The potential etiology of the disease process (differential diagnosis) and the chronicity of the disease could be evaluated better with 99mTc colloid. Among the patients with different stages of liver cirrhosis, however, 99mTc IDA significantly discriminated the severity of the hepatic disease. These results suggest that 99mTc IDA may be used to determine the degree of functional disorder in acute hepatic disease and evaluate the severity of diffuse hepatic disease, whereas 99mTc colloid can effectively evaluate the potential etiology and chronicity of the disease.

Renal perfusion with Tc-99m DTPA--simple noninvasive determination of extraction fraction and plasma flow.

A simple, noninvasive method for the determination of extraction fraction and renal plasma flow in Tc-99m DTPA studies is presented. This method could be performed in conjunction with the measurement of glomerular filtration rate, providing additional information about renal plasma flow. Graphic analysis of the Patlak plot was employed for the determination of the unidirectional influx rate constant (ku) of Tc-99m DTPA from the blood to the kidney and the initial nonspecific distribution volume (Vn) in the kidney. The first pass extraction fraction was estimated from Ku and Vn, assuming a bolus input to the kidney. The glomerular filtration rate was measured by renal counting corrected for depth and dose. Using the estimated extraction fraction (EF) and glomerular filtration rate (GFR), the renal plasma flow (RPF) was calculated using the formula of RPF = GFR/EF. In a total of 76 kidneys in 38 patients (including 9 patients with normal renal function and without evidence of nephrourologic disease), the value of renal plasma flow showed good correlation with that of effective renal plasma flow measured by renal counting with 1–131 orthoiodohippuran. There was a characteristic tendency for the extraction fraction to show a larger value as the renal plasma flow decreased. These results indicate that this method is valid for renal plasma flow estimation and the determinations of extraction fraction and renal plasma flow in Tc-99m DTPA studies is helpful as an adjunct to the measurement of glomerular filtration rate in order to adequately assess the pathophysiologic changes of renal disorders.

Distinct hepatic retention of Tc-99m IDA in arteriohepatic dysplasia (Alagille syndrome)

An unusual pattern of Tc-99m IDA scintigraphy was observed in a 20-year-old woman with arteriohepatic dysplasia (Alagille syndrome). Although neither hepatic imaging with Tc-99m tin colloid nor radiographic CT revealed any morphologic abnormality in the liver, sequential hepatobiliary imaging demonstrated abnormal radiotracer behavior—specifically, differences in tracer clearance between the peripheral and central portions of the liver. Radioactivity was persistently retained in the periphery of the liver, but the central portion showed normal tracer clearance, resulting in a photopenic center surrounded by a hot peripheral rim on the later images. The gallbladder and small intestine appeared promptly. This image pattern may be characteristic for intrahepatic bile duct hypoplasia.

Localization of Metastases from Malignant Pheochromocytoma in Patients Undergoing 131I-MIBG Therapy with Manually Fused 123I-MIBG SPECT and CT Images

131I-metaiodobenzylguanidine (MIBG) has been used as a therapeutic agent for pheochromocytoma. Tumor localization and precise staging are essential for therapy with high-dose 131I-MIBG. The sites and extent of 123I-MIBG uptake are usually estimated to predict the effectiveness of therapy before administration. However, conventional scintigraphic images provide insufficient anatomic information. Therefore, we tried to manually superimpose 123I-MIBG SPECT and CT images using free software.