Survey of thorotrast-associated liver cancers in Japan.

Data on 93 autopsy cases (group A) of thorotrast-associated liver cancers were obtained from the "Annual of Pathological Autopsy Cases in Japan" from 1958 to 1979, and data on 78 autopsy cases (group B) of thorotrast-associated liver cancers were obtained from the Japanese literature from 1953 to 1980. Cholangiocarcinoma (CLC) constituted 58% of group A and 55% of group B. The curve of the cumulative numbers of patients with CLC versus year in group A was almost linear, showing an increasing risk per surviving patients with advancing time. Angiosarcoma (AGS) occurred in 25% of group A and 24% of group B. The number of patients with AGS increased significantly after 1969 in both groups (P less than 0.05). In group B, age and years after thorotrast injection of patients with AGS were statistically higher than those of patients with CLC (age: P less than 0.05; years after thorotrast injection: P less than 0.0001). Hepatocellular carcinoma (HPC) accounted for 17 and 21% of groups A and B, respectively. When yearly distribution, age, and time after thorotrast injection of patients with HPC were correlated with those of patients with other liver cancers, the only statistically significant difference between patients with HPC and patients with CLC (P less than 0.02) was in the years after thorotrast administration. Since 1977 multiple primary liver cancers including AGS developed in thorotrast-administered patients in both groups.

Chemical assessment of phospholipid and phosphoenergetic metabolites in regenerating rat liver measured by in vivo and in vitro 31P-NMR.

For the assessment of 31P-NMR spectroscopic data, phospholipid precursors (phosphorylethanolamine (PE) and phosphocholine) and catabolites (glycerophosphorylethanolamine (GPE) and glycerophosphorylcholine (GPC)), as well as adenosine phosphates were chemically determined in regenerating rat liver. The data were compared with those obtained by in vivo and in vitro 31P-NMR spectroscopies. Chemical assay revealed a significant increase of PE and a decrease of GPE, GPC and ATP in hepatectomy group compared to sham operation group. The values obtained by in vitro NMR were in good agreements with those of chemical assay, but significant differences between the two groups were observed only in PE and inorganic phosphate (Pi). Noticeable increase in PME was not detected by in vivo 31P-NMR spectroscopy, although the increase of PE was about 2.5-times that of the control and its constitution ratio to the whole phosphomonoester (PME) was less than 15%. On the other hand, in vivo NMR showed a large phosphodiester (PDE) peak occupying approx. 40% of the total phosphorus signal, while the contribution of its constituents, GPE and GPC was about 5% found by both chemical assay and in vitro NMR. The PDE peak in in vivo NMR seemed to reflect the membrane phospholipid itself rather than its catabolites. A slight decrease of phosphoenergetic level in regenerating rat-liver was commonly suggested by all three analytical methods.

Rapid and simple detection of PCR product DNA: a comparison between Southern hybridization and fluorescence polarization analysis.

The essential aim of this study was to compare two different methods, Southern hybridization and fluorescence polarization (FP) assay. They both detect specific hybridization and were examined using common asymmetric PCR products and probes. FP assay clearly showed the hybridization of probe DNAs with the asymmetric PCR products of their target genes. Southern blot patterns presented excellent consistency with the results of FP assay. In both methods, two types of Shiga toxin (vero toxin) genes held in enterohaemorrhagic Escherichia coli (EHEC) were used as target genes. For detection of the two genes, stx1 and stx2, two respective DNA probes were synthesized. Both in FP assay and in Southern hybridization, the probe for stx1 hybridized only with the product of stx1 and vice versa. The results of the DNA detection using different methods were completely in agreement. Moreover, FP assay makes it possible to detect the hybridization rapidly. In our high NaCl concentration condition, hybridization between the probes and the asymmetric PCR products could be monitored within about 15min.

Cancer mortality of thorotrast patients in Japan: the second series updated 1998.

The 150 male patients exposed to Thorotrast who were confirmed by a 1975-1978 national survey with diagnostic X rays of 50,860 war-wounded soldiers were followed up between 1979 and 1998 (Aichi series or second series). Age-adjusted rate ratios of deaths from all causes were 3.0 times higher in Thorotrast patients compared to controls; this was statistically significant. Rate ratios for liver cancer, liver cirrhosis and leukemia were 35.0, 7.5 and 18.2, respectively.

Summary of entire Japanese thorotrast follow-up study: updated 1998.

Updated data from two series in a cancer mortality study for a total of 412 Japanese Thorotrast patients were combined. The rate ratio for all deaths of Thorotrast patients, compared to controls, started to increase after a latent period of 20 years after injection of Thorotrast. Rate ratios for liver cancer, liver cirrhosis, leukemia and lung cancer were 35.9, 6.9, 12.5 and 2.0 times higher, respectively, than those for controls.

Hepatic arterial infusion chemotherapy for liver metastases from breast cancer.

Between 1985 and 1992, 56 patients with unresectable liver metastases from breast cancer were treated by repeated hepatic arterial infusion chemotherapy employing an implantable port system. 5-Fluorouracil (5-FU) at 330 mg/m2 per week. Adriamycin (ADR) at 20 mg/m2 every 4 weeks, and mitomycin C (MMC) at 2.7 mg/m2 every 2 weeks were given to 42 patients. The remaining 14 patients received 5-FU at 330 mg/m2 per week and epirubicin (EPIR) at 20 mg/m2 every 2 weeks. As a rule, the treatment was performed on an outpatient basis. The side effects and complications observed included myelosuppression (41%), hepatic arterial occlusion (23%), and gastric mucositis (20%), but no major toxicity was encountered. The response rate (CR+PR) of the evaluated patients as determined from CT scans was 81%. The overall median survival period was 12.5 months. Only 14% of the patients died due to regrowth of liver metastases, and in 70% of the total cases, death due to liver metastases was avoided by this treatment. Thus, repeated hepatic arterial infusion chemotherapy for liver metastases from breast cancer might be capable of prolonging the survival of patients via avoidance of death due to the liver metastases.

Management of patients with unresectable liver metastases from colorectal and gastric cancer employing an implantable port system.

Between 1985 and 1990, 50 patients with unresectable liver metastases from colorectal cancer and 34 subjects with metastases from gastric cancer were treated by repeated hepatic arterial infusion chemotherapy employing an implantable prot system. A catheter was inserted into the hepatic artery via the left subclavian artery and was connected to the implantable injection port in each patient. 5-Fluorouracil (5-FU) at 330 mg/m2 per week (167 mg/m2 daily given continuously over the initial 3 months for colorectal cancer), Adriamycin (ADR) at 20 mg/m2 every 4 weeks and mitomycin C (MMC) at 2.7 mg/m2 every 2 weeks were given to all 34 patients with gastric cancer and to 31 of the colorectal cancer patients. The remaining 19 patients with colorectal cancer received 5-FU at 1,000 mg/m2 every week. As a rule the treatment was performed on an outpatient basis. The side effects and complications observed included myelosuppression (23%), hepatic arterial occlusion (21%), and gastroduodenal mucositis (12%), although no major toxicity was encountered. The response rate (CR+PR) among the evaluated patients as determined using CT scans was 67% for colorectal cancer and 73% for gastric cancer. The overall median survival was 12 months and 15 months, respectively. Good local control of liver metastases from the colorectal and gastric cancers was achieved by repeated hepatic arterial infusion chemotherapy employing an implantable port system without the need for hospitalization and without producing major toxicity. Thus, the implantable port system is very useful for the management of patients with unresectable liver metastases.

Observation of rat hind limb skeletal muscle during arterial occlusion and reperfusion by 31P MRS and 1H MRI.

31P NMR spectra and 1H MR T1- and T2-weighted spin-echo images were concurrently observed in rat hind limb during arterial occlusion and following reperfusion. With arterial occlusion, phosphocreatine level decreased and inorganic phosphate (Pi) level increased in 31P NMR spectra. Intracellular pH's dropped as a function of time. Beta-ATP started to decrease in three hours. In six hours after the occlusion, any peaks other than Pi were scarcely detected. The signal intensities in the 1H MR images increased homogeneously in both T1- and T2-weighted conditions, but the changes were more profound with T2-weighted images. After the release of the arterial occlusion, the 31P NMR spectra recovered to the preischemic state in several hours. The 1H MR images during reperfusion showed characteristic heterogenous pattern. The signal intensities in the anterior tibial muscle and the gastrocnemius muscle remained high in T1-weighted condition and the intensities further increased in T2-weighted condition, while those in other parts returned to the preischemic level. These changes were found to be irreversible even 12 hr after the release. The high signal intensities suggested the increase of water in the extracellular compartment induced by so-called reperfusion injury. Multinuclear analysis using in vivo NMR was valuable to consecutively detect time-dependent and location-specific response in skeletal muscle during ischemia and reperfusion.

Thorium dioxide-related angiosarcoma of the liver. Pathomorphologic study of 29 autopsy cases.

We describe the pathomorphologic features of 29 autopsy cases of thorium dioxide-related angiosarcoma (AGS) of the liver. The average (+/- SD) latent period after thorium dioxide injection was 36.2 +/- 5.2 years. Macroscopically, thorium dioxide-related AGS was divided into four types as follows: diffuse micronodular, multinodular, massive, and mixed multinodular and massive. Diffuse-micronodular and multinodular types were the most common. Histologically, thorium dioxide-related hepatic AGS was characterized by two cell types (spindle-shaped cells and polyhedral cells) and two structural patterns (sinusoidal and solid). There was no case composed of a solid pattern only. Immunohistochemically, factor VIII-related antigen was found to be positive in the endothelial cells of normal blood vessels and in the hyperplastic endothelial cells of the sinusoids, but negative in the tumor cells. Extramedullary hematopoiesis was found in both the tumorous and nontumorous areas in four cases. Erythrophagocytosis by the tumor cells was found in three cases. In the nontumorous area, varying degrees of sinusoidal dilatation with frequent hyperplastic changes of the sinusoidal lining cells were observed in all cases. These sinusoidal changes were frequently contiguous to AGS foci and were considered as a precursor change. In addition to the dominant sinusoidal changes, nodular hepatocytic hyperplasia was observed in two cases.

Type II citrullinemia associated with neutropenia.

A 37-year-old Japanese man was admitted with delirium and hyperammonemia. He was diagnosed as having type II citrullinemia because of an elevated citrulline level on amino acid analysis and very low hepatic argininosuccinate synthetase activity. He also showed a low neutrophil count and a low serum level of granulocyte colony-stimulating factor. Reduced production of this cytokine and/or impairment of its feedback regulation by the neutrophil count may have played a role in the neutropenia of this patient.

Clinical evaluation of assistant diagnostic system for mammograms using the auto-analyzing method.

Clinical usefulness of a newly developed auto-analyzing system of mammograms to search the abnormal dense areas such as cancer lesions was studied. 345 breasts including 86 cancers, 52 mastopathies, 18 fibroadenomas, 13 cysts, 4 lipomas and 172 normals were analyzed and compared with final diagnosis. 84 of 86 cancer lesions were correctly pointed out (sensitivity: 97.9%). Based on the gradient of the density, the ranking of the cancer or calcified lesions among suspected regions in a mammogram was decided. 55 lesions of them (64.0%) were ordered at the first rank and 83 (96.5%) were in the upper three ranks. 68 of 74 breasts with calcifications were correctly diagnosed and 48 of them were ranked in the upper three ranks. Although further improvement of the system is needed, this system will be a useful assistance for screening the breast cancer in the analyses of mammograms.

[Technique and problems of total parathyroidectomy with autotransplantation in secondary hyperparathyroidism].

Between 1982 and 1990, 20 patients with chronic renal failure underwent total para-thyroidectomies and autotransplantations as treatment for secondary hyperparathyroidism. Fourteen cases were cured of their symptoms and their serum PTH levels was restored to normal. Recurrent hyperparathyroidism developed in 6 cases. In 3 of the 6 cases, excision of parathyroid tissue from the forearm could easily be performed under local anesthesia. Of the other cases, 2 had five and one had six glands. Several localizing methods should be performed before operation, in order to overlook the parathyroid glands in different anatomic positions.

[Transurethral microwave thermotherapy for benign prostatic hyperplasia].

Transurethral microwave thermotherapy (TUMT) of prostate was administered to 10 patients with bladder outlet obstruction due to benign prostatic hyperplasia. The mean age of the patients was 74.4 years (range 63 to 85). The Prostatron device, which provides microwave heating of the prostate and conductive cooling of the urethra was used, and the prostate was heated with a calculated intraprostatic temperature of 45.5 degrees C for 55 minutes. No anesthesia was required for most of the patients. The clinical effects were evaluated at 4-6 weeks and 3 months after treatment. The symptomatic scores improved in the majority of patients. There was no significant change in prostate volume. The maximum flow rate and average flow rate were increased at 6 weeks and 3 months, but there was no significant change. The only side effects were transient hematuria and short-term obstruction secondary to urethral edema. In comparing TUMT with the transurethral resection of prostate (TUR-P), the maximum flow rate after TUMT was lower than that after TUR-P and the improvement of residual urine after TUMT was lower than that after TUR-P.

[Changes in arterial blood flow patterns by patients' posture during hepatic arterial infusion chemotherapy assessed by 99mTc-MAA perfusion scintigraphy].

Hepatic arterial perfusion scintigraphy (HAPS) with 99mTc-macroaggregated albumin (MAA) was performed to reveal the effect of patients' posture for the arterial blood flow patterns in hepatic arterial infusion (HAI) chemotherapy. 20 patients of liver metastases with the percutaneously implanted catheter into the hepatic artery underwent HAPS following administration of 99mTc-MAA at the supine and the upright position under one week interval. 10 ml of the saline with radionuclide was injected at a rate of 1 ml per minute. Acquired two images at the different position of each patient were compared and grouped into three classes; similar, slightly different and different. Of 20 patients, 6 (30%) were judged as similar, 8 (40%) as slightly different, and 6 (30%) as different. These results suggest that the drug distribution can change by patients' posture in case of the slow rate HAI performed with continuous infusion pump.

[Mass screening of breast cancer with imaging diagnosis].

Westernization of our life-style and diet has caused a higher incidence of breast cancer in Japan. Although mass screenings such as anamnesis, visual and palpable examinations are provided by local government in Japan, no curable cancer in the early stage can be detected without the use of imaging diagnosis. Furthermore, the image can be saved as a record. Mammography yields images that are best suited for breast cancer examination in terms of sensitivity, specificity and accuracy. However, the large volume of information collected from the images makes diagnosis extremely difficult. In order to ease the burden on the diagnosing physician and to reduce the examination cost, CRT diagnosis by digital images and image selection by an automatic diagnosis supporting system with neuro-computer must replace the present filming method. On the other hand, 100% accuracy can not be achieved by either mammography or ultrasonic examination due to the limitation in depicting images on a display monitor. The accuracy rates of mammography and ultrasonic examination are 91.5% and 87.5% in our hospital. Imaging diagnosis, however, must be efficiently applied in addition to the visual and palpable examinations in promoting mass screening for breast cancer.

[Early diagnosis of breast cancer].

Despite the increasing incidence of breast cancer in recent years, early detection of breast cancer improves the curative rate and quality of life (QOL). Advances in diagnostic imaging are making early detection increasingly common. Although mammography (MMG) is the most popular examination method and yields excellent image description, diagnosis is influenced by imaging technique and ability to read the images. A clear image can be achieved if the MMG image acquired at 28 Kv using an M0 filter is energy subtracted at 32 Kv using an Rh filter. Ultrasonography can be excellent for qualitative diagnosis of a tumor, but changes in blood flow volume, as demonstrated by Doppler imaging, makes early detection difficult. Breast scintigraphy by 201TlCl can clearly demonstrate palpable breast cancer and also lymph node metastasis, but poor spatial resolution remains a problem. High resolution CT is effective for detection of lymph node metastasis. MRI offers excellent qualitative diagnosis of tumors, but detection of ultra-small lesions is difficult even using contrast medium. The detection rate and proportion of early breast cancer detected on the whole will rise if MMG is introduced into the present mass screening for breast cancer, but its implementation requires improved facilities, imaging capability, and experience in image reading.

[Non vascular interventional radiology--general].

Since last about 20 years, invasive diagnostic procedures have gradually changed the conception to interventional radiology (IVR). Non vascular IVR has been developing steadily by suitable instruments and excellent techniques as well as vascular IVR. The fields of non-vascular IVR is becoming wider and wider in various regions in the body. Non-vascular IVR contains many kinds of drainage and forming inner fistula in the biliary and urinary tracts, for example, occlusive jaundice or hydronephrosis. Drainage for abscess in the thoracic or abdominal cavity is a good indication except peri-pancreatic abscess. In addition, IVR means time saving and cost saving in the aspiration biopsy for malignant neoplasms this is fast decision for reasonable therapies. In the earlier period, aspiration biopsy was considered as dangerous method because of bleeding and dissemination of malignant seeds along the route of aspiration needles. By using fluoroscopic image amplifier and ultrasonic unit, non-vascular IVR has many indications that radiologist's specialty demonstrated. Therefore, radiologist should have heavy responsibility based on understanding of right knowledge and good management for non-vascular IVR.

[Low-dose intermittent intra-arterial infusion chemotherapy].

Arterial infusion chemotherapy is commonly-used modality for controlling cancers located in specific regions. Previously we described a new method of intra-hepatic arterial catheterization through the left subclavian artery using a subcutaneously-implanted silicone reservoir. In the present paper, we report our experience using a low dose-intermittent intraarterial (i.a.) infusion chemotherapy. Since February, 1982, 70 patients including 44 cases of metastatic liver cancer, 16 cases of primary hepatocellular carcinoma and 10 cases of other gastrointestinal malignancies, have been treated with this low dose-intermittent i.a. infusion chemotherapy, the drugs used being as follows. 1) MMC 4 mg, 5-FU 500 mg, AraC 40 mg/2w, 2) MMC 4 mg/w, 3) 5-FU 500 mg/w, MMC 4 mg/2w, ADM 30 mg/4w. Here, we briefly review the effectiveness of this modality for controlling regional diseases including liver metastases. The average hospital-free interval was 156 days and partial responses were observed in 43% (21/49) of cases. Side effects during the therapy were only mild bone marrow suppression and anorexia, which were tolerable in out-hospital care. We also studied the pharmacokinetics of i.a. infusion into the liver in comparison with i.v. infusion using 99mTc-RBC, and found that the ratio of i.a. to i.v. with regard to trans-arterial drug delivery to the liver was 10.0. From the viewpoints of first pass effect and increased local concentration theory, this ratio suggests that the effectiveness of a low-dose anti-tumor agent administered intraarterially is not so low. Accordingly, we believe that low dose-intermittent i.a. infusion chemotherapy is beneficial as an induction and maintenance chemotherapy for patients with regionally located cancers because it is effective, safer and prolongs the hospital-free interval.

[Pharmacokinetics in arterial infusion chemotherapy].

The pharmacokinetics of arterial infusion chemotherapy was introduced. The pharmacokinetic rationales were based on the theories of "first pass effect" and "increased local concentration without first pass effect" advocated by Dr. Collins. These theories can offer much information to select the drug and to determine the administration schedule. However, for most of the drugs, the clinical pharmacokinetic studies are poor, and the optimal dose in bolus intraarterial infusion and the administration schedule is uncertain in terms of the dosage and hours. There are also some differences between pharmacokinetic understanding and clinical effect. Thus, further pharmacokinetic investigations and clinical studies are required to establish effective regimens for arterial infusion chemotherapy.

[Outpatient cancer chemotherapy employing implantable systems].

Outpatient cancer chemotherapy (OCC) employing implantable systems was introduced and the objects, conditions and problems of OCC were discussed based on experiences in 324 cases. The aims of OCC are improved QOL and the continuation of chemotherapy. Our requirements are safety, effectiveness, easy management and non-disturbance of activity. Implantable systems are very useful for OCC, especially continuous infusion combined with ambulatory pumps. However, the improvement of ambulatory pumps and the establishment of methods to evaluate OCC are required to further develop OCC.