Sequential observations on the appearance of neoplastic lesions in the liver and kidney after treatment with N-ethyl-N-hydroxyethylnitros-amine followed by partial hepatectomy and unilateral nephrectomy

Sequential observations were carried out on the induction ofpreneoplastic lesions in the liver and the kidney. Rats wereinitially given N-ethyl-N-hydroxyethylnitrosamine (EHEN) intheir drinking water (0.1%) for 3 days (Group 1), 1 week (Group2) or 2 weeks (Group 3) or tap water (Group 4). Rats in Groups1 – 3 were subjected to partial hepatectomy and unilateralnephrectomy (right side) 2 weeks after the end of EHEN treatment.Rats from these groups were killed in week 10, 20, 30 and 40of the experiment. In the liver, the effect of EHEN in the inductionof -glutamyltranspeptidase (-GT) positive foci and hyperplasticnodules (HN) was clearly dependent on the length of treatment.The preneoplastic lesions increased with the lapse of observationtime. Changes measured as number of -GT positive foci were 10–40times greater than those measured as HN, especially among thesmall size range. Values for changes in Group 1 given 0.1% EHENfor 3 days were very low, indicating that this dose is closeto the threshold. Two rats with hepatocellular carcinoma inGroup 3 given EHEN for 2 weeks survived until week 40. In thekidney, tubular epithelial proliferations composed of cellswith slightly basophilic cytoplasm and slightly atypical nucleiwere tentatively named atypical cell foci (ACF). EHEN inducedACF, renal cell adenomas and renal cell carcinomas. The increasein the induction of ACF was dependent on the length of observationperiod but not on the length of treatment. Even though controlrats (not treated with EHEN) also had ACF, their quantitativevalues were far less than the groups given EHEN and killed atweek 40, indicating that a large number of ACF were inducedby EHEN. Therefore, EHEN is good for experimental inductionof preneoplastic lesions in the liver and kidney of rats. Theexperimental schedule for Groups 1 and 2 could be used as ashort-term screening test for promoters and the schedule forGroup 3 as an assay for inhibitors.     

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.     

Present status of ethics committees of the medical schools in Japan

Present features and functions of ethics committees in 80 Japanese medical schools were surveyed through inquiries to those institutes by the author. Seventy nine schools have already started their own committees in each campus by the end of 1990, and the remaining one is preparing for its start in near future. The major role of the ethics committee may be said to roughly correspond to that of the Institutional Review Boards (IRB) in the USA, although a role of the hospital ethics committee has been played in addition to its proper functions in many schools. Among many problems two major drawbacks seem necessary to be removed urgently. The first one is an inappropriate composition of the committee in the majority of schools. More members from the outside of the campus, younger generations, and female reviewers should be added to the committee. The second point is the essentially closed review systems in most schools. The process of the review has not been effectively opened to the public yet, even in case in which no privacy of the patients or volunteers appears in the discussion. Several schools are preparing for opening now and the situation will be improved gradually. It was fortunate that the ethics committees in Japanese medical schools were founded by wills and efforts of members of each campus without having any suggestions, recommendations, or orders from the national government or other officials.     

Management of Hyperthyroidism Due to Graves' and Nodular Diseases

Endocrine surgeons have had an important role in the management of hyperthyroidism due to either Graves' disease or toxic nodule(s). Since alternative treatments such as antithyroid drugs or radioiodine are also available, the decision-making for management should be based on clear assessment of advantages and limitations of each of the treatment options. Surgery provides rapid resolution of these conditions, and cure rates are high, although it may be associated with perioperative complications and postoperative thyroid dysfunction. The authors' experience in the surgical treatment of hyperthyroidism and a review of the recent literature are outlined in this report.     

Surgical anatomy of the hepatic hilar area

It is important to understand the main variations of the biliary and vascular elements inside the plate system for hilar bile duct carcinoma because all variations of these elements occur in this plate system. The plate system consists of the hilar plate, cystic plate, and umbilical plate which cover the extrahepatic vascular system and are fused with the hepatoduodenal ligament. The bile duct and vascular system that penetrate the plate system form Glisson's capsule in the liver, but the caudate branch and the medial segmental branch are exceptions. The bile duct and hepatic artery accompanying the plate system can be exfoliated from the portal vein with numerous lymph ducts and nerves. The bile ducts in the right hepatic lobe are classified into 4 types, and the standard type is present in 53-72% of cases. In the left bile duct, the medial segmental bile duct is connected in the vicinity of the hilar area in 35.5% of cases, and these cases should be treated the same as the caudate lobe in hilar bile duct carcinoma. Generally, there is little main variation of the portal vein (16-26%), but more variation in the hepatic artery (31-33%). During surgery for hilar bile duct carcinoma, it is important to observe the plate system and the many variations of the bile duct and vascular system.     

Gastric Acidity following Pancreaticogastrostomy with Pylorus-preserving Pancreaticoduodenectomy

Pancreaticogastrostomy (PG) has been reintroduced and employed occasionally as a useful alternative to pancreaticojejunostomy (PJ) after Whipple resection or pylorus-preserving pancreaticoduodenectomy (PPPD). Although the physiologic alteration in the stomach is important for the correlation between gastric and pancreatic functions, the actual intragastric pH profile after PG is still unclear. This study was conducted to investigate the physiologic changes in gastric pH and serum gastrin and secretin levels before and after PPPD reconstructed with PG (PPPD-PG) in humans. Twenty-four hour continuous intragastric pH and serum gastrin and secretin levels in the fasting state were examined in 25 patients who had undergone PPPD-PG. No peptic ulcer was detected after the operation. After PG, serum gastrin and secretin levels were unchanged. Twenty-four hour gastric pH monitoring revealed two distinct patterns during the nocturnal period before the operation: patients with acid-type secretion (n= 11) exhibited a persistent acid pH, whereas those with alkaline-type secretion (n= 14) had cyclic variations between an acid and an alkaline pH value. After PG, in both acid- and alkaline-type patients, median pH and percentages of time that the gastric pH was less than 4 (% pH < 4) and more than 6 (% pH > 6) did not change, and circadian pH patterns also remained unchanged. These results suggest that PPPD-PG has little influence on gastric acidity, and the neurohumoral relation between the stomach, duodenum, and pancreas is preserved after PG. Therefore, physiologically, PG can be recommended as a reconstructive procedure after PPPD.     

Prognostic significance of loss of heterozygosity on chromosome 9p21–22 in human esophageal cancer

Background Deletions involving chromosome 9p21, on which the tumor suppressor genep16/MTS1 is located, have been noted in esophageal cancer. We investigated the relationship between the deletion of chromosome 9p21–22 and the clinical features of esophageal cancer. Methods We examined the loss of heterozygosity (LOH) on chromosome 9p21–22 in 56 esophageal cancers using polymerase chain reaction (PCR) analysis and 2 microsatellite markers (RPS6 and IFNA). Results In 18 out of 50 informative cases (36%), LOH had occurred at 1 or 2 loci on chromosome 9p21–22. We found no relationship between LOH on chromosome 9p21–22 and patient sex, age tumor length, location, histologic differentiation, depth of tumor invasion, the extent of lymph node metastasis, histologic stage, or curability. Among 35 patients without an absolute noncurative resection, the mean survival of 11 patients with LOH on chromosome 9p21–22 was 19.3 months, compared with 42.3 months for 24 patients with a normal allele; thus, the survival rate of those with LOH was significantly lower than that of patients without LOH on chromosome 9p21–22 (log-rank test;P=0.03). Conclusion These data suggest that LOH on chromosome 9p21–22, on which the cell-cycle regulatorp16/MTS1 gene is located, may be related to cancer development, and probably can serve as a clinical marker for evaluating a patient's prognosis.     

Truncated midkine as a marker of diagnosis and detection of nodal metastases in gastrointestinal carcinomas.

Midkine (MK) is a growth factor identified as a product of a retinoic acid-responsive gene. A truncated form of MK mRNA, which lacks a sequence encoding the N-terminally located domain, was recently found in cancer cells. We investigated the expression of the truncated MK mRNA in specimens of 47 surgically removed human gastrointestinal organs using polymerase chain reaction. Truncated MK was not detected in all of the 46 corresponding non-cancerous regions. On the other hand, this short MK mRNA was expressed in the primary tumours in 12 of 16 gastric cancers, 8 of 13 colorectal carcinomas, five of nine hepatocellular carcinomas, two of two oesophageal carcinomas and one ampullary duodenal cancer. In addition, truncated MK was detectable in all of the 14 lymph node metastases but in none of three metastatic sites in the liver, suggesting that truncated MK mRNA could become a good marker of nodal metastases in gastrointestinal tract.     

Role of cyclin E and p53 expression in progression of early gastric cancer

Background. To elucidate the role that cyclin E overexpression plays in the progression of early gastric cancer, we examined the expression of cyclin E and p53, as abnormal p53 expression is linked with cyclin E overexpression in exerting adverse affects on the cell cycle. Methods. Specimens from 108 early gastric cancers were stained by an immunohistochemical method, using anti-cyclin E and anti-p53 antibodies. Results. The positivity rate of cyclin E expression in early gastric cancer was 33% (36/108). Cyclin E-positive tumors invaded more deeply (P < 0.05), infiltrated lymphatic vessels more frequently (P < 0.01), showed a higher incidence of differentiated cancer (P < 0.01), and more often expressed p53 (P < 0.01) than cyclin E-negative tumors. Differentiated cancers showing coexpression of cyclin E and p53 were more likely to metastasize to the lymph nodes. Conclusions. Overexpression of cyclin E may promote the progression of early gastric cancer. Received for publication on Apr. 27, 1998; accepted on Nov. 17, 1998