Effects of the prostaglandin synthetase inhibitor indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor contents of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in Sprague-Dawley rats fed a high- or low-fat diet.

The effects of indomethacin on tumorigenesis, tumor proliferation, cell kinetics, and receptor content of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma have been examined in female Sprague-Dawley rats. The rats were fed either a high-fat (20% corn oil) or low-fat (0.5% corn oil) diet with or without 0.005% indomethacin starting 7 days after intragastric administration of a single dose of 5 mg 7,12-dimethylbenz(a)anthracene. The results demonstrated that indomethacin completely blocked the stimulatory effect of fat on tumorigenesis, as demonstrated by a decreased tumor incidence, a decreased number of tumors per group, and an increased latency. Contrary to what had been expected, however, indomethacin promoted tumor proliferation in both the high- and low-fat diet groups, as evidenced by an increased tumor size, an increased bromodeoxyuridine-labeling index, and a decreased potential tumor-doubling time. No significant difference in either the estrogen receptor or progesterone receptor content of the tumor was noted. It can be concluded, therefore, that indomethacin significantly reduced tumorigenesis in the high-fat diet group but significantly promoted tumor proliferation in both the high- and low-fat diet groups.

Bilateral cervical lymph node metastases in well-differentiated thyroid cancer.

We analyzed the regional lymph node metastases of 98 patients with thyroid cancer who underwent bilateral modified neck dissection. Bilateral jugular lymph node metastases were frequent in patients with papillary carcinoma of the thyroid, especially in those patients with obvious carcinoma in both lobes of the gland, cancer arising in the isthmus, clinically detectable bilateral lymphadenopathy, and recurrent thyroid cancer. In patients whose cancer was clinically confined to one lobe, and where there were no obviously enlarged contralateral lymph nodes, the occurrence of contralateral jugular lymph node metastasis was significantly correlated with the contralateral paratracheal lymph node metastasis. The bilateral lymphadenectomy appears to be appropriate in these instances.

Breast cancer and regional lymph node dissections.

Regional lymph node metastases were evaluated in 289 patients with operable breast cancer. The metastases of the axillary and internal mammary lymph node were shown to be closely related to the survival of patients, but the status of these nodes was shown to be impossible to estimate before the operation. Thus, axillary and internal mammary node dissections seem to be very important in order to attain an acceptable amount of information for staging of certain breast cancer patients. Due to the radicality of operations including internal mammary node dissection, the use of modified extended mastectomy is proposed as the staging operation. In this manner, the anterior chest deformity created by an extended radical mastectomy can be avoided and the pectoralis major muscle spared in patients without internal mammary lymph node involvement. Also found in this study, was some evidence of the beneficial use of en bloc extended radical mastectomy for the survival of a selected group of patients.

Impact of neck dissection on survival in well-differentiated thyroid cancer: a multivariate analysis of 218 cases.

The management of cervical lymph node metastases in well-differentiated carcinoma of the thyroid has been highly controversial. In the Department of Surgery (II), Kanazawa University Hospital, the surgical management of cervical lymph node metastases in curable well-differentiated carcinoma of the thyroid has been changed from a conservative approach to an aggressive one since 1973. In order to determine whether an aggressive approach for cervical lymph node metastases is adequate, a retrospective multivariate analysis was carried out of 218 cases of well-differentiated thyroid cancer. The patients have been followed up from 5 to 30 years. Multivariate analysis was conducted following Cox's model. As for the results, the aggressive management of cervical lymph node metastases appeared to have an impact on survival. Furthermore, age and sex were confirmed to be important prognostic factors and a partial lobectomy was confirmed to be inadequate as a type of thyroidectomy.

[A case of cutaneous and brain metastasis of gastric carcinoma, treated effectively by chemotherapy with CDDP, MMC, etoposide and 5'-DFUR].

A case of cutaneous and brain metastasis of gastric carcinoma, treated effectively by chemotherapy, is reported. The patient was a 67-year-old female. She underwent total gastrectomy for advanced gastric carcinoma with direct invasion to liver. Six months later, she was admitted with headache and multiple skin nodules on the trunk. CT showed two round tumor shadows on the left side of brain, and a skin biopsy specimen revealed poorly differentiated adenocarcinoma. Chemotherapy with 10mg of CDDP, 2mg of MMC, 150mg of etoposide and 300mg/day of 5'-DFUR was performed. After the third course of chemotherapy, cutaneous and brain metastasis disappeared. Although the patient died of pulmonary metastasis 24 weeks after, cutaneous and brain metastasis disappeared 12 weeks.

[Intra-arterial infusion chemotherapy using an implantable reservoir in the treatment of hepatic metastases in colorectal cancer].

With colorectal cancer, the therapeutic outcome for multiple hepatic metastasis extending to the bilateral lobe, even when various chemotherapies are administered, is extremely poor. For multiple hepatic metastases at our clinic, from November, 1985, through February, 1991, we used an implantable reservoir to administer intra-arterial infusion chemotherapy and reviewed the results. We treated 16 patients with hepatic metastases of colorectal cancer, H2 in 3 cases and H3 in 13 cases. When we used the reduction rate of the tumor diameter as seen by CT scan as a criteria for antitumor effectiveness, 1 case was CR and 3 cases were PR, for an efficacy rate of 25.0%. Changes in the serum CEA level were related to antitumor effectiveness. Among the evaluable cases, the 1-year survival rate was 60.0%, which was significantly more favorable than the 20.0% obtained in the systemic chemotherapy group (p less than 0.05). Given the above, although there are a few problems such as the kind and dose of drugs, the use of intra-arterial infusion chemotherapy with an implantable reservoir to treat hepatic metastases of colorectal cancer permits a form of chemotherapy providing a better QOL out of hospital.

[Effect of high dietary fat on the total DNA and receptor contents in rats with 7,12-dimethylbenz[A]anthracene-induced mammary carcinoma].

The influences of high dietary fat on the malignant intensity and the hormone receptors of DMBA-induced mammary breast carcinoma were analyzed in female Sprague-Dawley rats. The rats were fed either a low-fat diet or high-fat diet after the DMBA administration. As the results, incidence, size, average latent period, DNA histogram, DNA index and % of S-phase fraction of tumor were significantly different between both groups. But the ER and PgR contents were not different between both groups. The results suggest that a high dietary fat could increase the malignant intensity of the tumor but does not influence the receptor contents of the tumors.

[Influence of endocrine therapy on the proliferation of estrogen (ER) positive cells and ER negative cells of human breast cancer (MCF-7)].

The influence of endocrine therapy on the proliferation of estrogen receptor (ER) positive cells and ER negative cells of human breast cancer (MCF-7) serially transplanted into nude mice was analyzed by tumor growth, dextran-coated charcoal (DCC) method, ER-immunocytochemical assay (ER-ICA) and ER-immunocytochemically stained 3H-thymidine autoradiography. In the tamoxifen (TAM) group and the medroxyprogesterone acetate (MPA) group, tumor growth was inhibited, but it was promoted in the 17 beta-estradiol dipropionate (E2) group. The ER level by the DCC method significantly decreased in the TMA, the MPA and the E2 groups. The ER-ICA showed that the ER positive cells rate in the TAM and the MPA group decreased, but it increased in E2 group. However, the ER-immunocytochemically stained 3H-thymidine autoradiography showed that not only the labelling index of ER-positive cells but also that of ER negative cells significantly decreased in the TAM and the MPA groups, but significantly increased in the E2 groups. Therefore it was concluded that endocrine therapy affected the proliferation of both ER positive cells and ER negative cells of ER positive breast cancer.

Effects of high dietary fat on the total DNA and receptor contents in rats with 7,12-dimethylbenz[a]anthracene-induced mammary carcinoma.

The influence of high dietary fat on the malignant intensity and the hormone receptors of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinoma in female Sprague-Dawley rats were analyzed by the tumor incidence and growth, the DNA histogram type, the DNA index, the S-phase fraction, and the estrogen receptor (ER) and progesterone receptor (PgR) assays. The rats were fed either a low-fat (0.5% corn oil) diet or a high-fat (20% corn oil) diet after the DMBA administration. Tumor incidences in the low-fat and the high-fat diet groups were 46 and 86%, respectively (p less than 0.01). Tumors in the high-fat diet group were also significantly larger than those in the low-fat group. Average tumor latent period was significantly shorter in the high-fat diet group, comparing with that in the low-fat diet group (p less than 0.01). Sixty-nine percent of the tumors in the high-fat diet group had aneuploid type, while only 8% of those in the low-fat diet group had aneuploid type. The DNA index and S-phase fraction also were significantly higher in the high-fat diet group (p less than 0.01). But the ER and PgR contents were not different between both groups. Therefore, these results suggest that a high dietary fat could increase the malignant intensity of the tumor but does not influence the hormonal responsiveness of these tumors.

Antithrombogenicity and oxygen permeability of block and graft copolymers of polydimethylsiloxane and poly(alpha-amino acid).

A-B-A-type block copolymers consisting of poly(alpha-amino acid) as A component and polydimethylsiloxane as B component and graft copolymers consisting of polydimethylsiloxane as trunk polymer and poly(alpha-amino acid) as branch polymer were synthesized. gamma-Benzyl-L- or DL-glutamate, epsilon-benzyloxycarbonyl L-lysine, and sarcosine were used as alpha-amino acid. Different microphase-separated structures were found on the film surface according to the copolymer composition and the casting conditions. In vitro antithrombogenicity test showed higher antithrombogenicity of block or graft copolymers than homopolymers. The best antithrombogenicity was independent of the kind of alpha-amino acid and the degree of polymerization of copolymers. The best ratio was 65-75% in block copolymer and 40-50% in the case of graft copolymer. The oxygen permeability of block and graft copolymer film was intermediate between those of homopolymers and varied with changing the composition of the copolymer. These experiments showed that the microphase-separated structure on the film surface was most important both for the antithrombogenicity and oxygen permeability of these copolymer films.

[Prognosis of mitral valve prolapse related to the changes in the grade and ventricular arrhythmias].

Eighty-four cases with idiopathic mitral valve prolapse (MVP) were followed for 3.1 years in average (1 to 6 years). Left ventricular end-diastolic and end-systolic dimensions and/or left atrial dimension increased in 72.4% of the cases with severe grade of MVP, while in only 14.3% of the cases with mild grade of MVP during follow-up period. Incidence of ventricular arrhythmias was 70% including about 10% each of grade III, IVa, and IVb in Lown's classification. Repeated examination using 24-hour Holter monitoring showed ventricular arrhythmias of long duration in a majority of the cases, and 66.7% of the cases with III and IV in Lown's classification revealed IVa and IVb frequently including one case of sudden death occurred during follow-up period.

[Investigation of gastric cancers detected at a medical check-up center].

Most of the gastric cancers investigated in this study were detected during mass screening at a Medical Check-up Center. The research period was 5 years, from 1990 to 1994. The total number of patients undergoing initial gastric examinations was 300,658. Four point eight percent of these needed detailed examinations, and 77.2% actually underwent detailed examinations. Over the 5 years, the number of gastric cancers detected was 253. The rate of detection of these cancers was almost unchanged every year, with the average rate of change being 0.11%. The rate of detected gastric cancers was investigated according to age and sex. No cancers were found below age 29, and the rate gradually rose over age 30. Over age 50, the rate in males was twice that in females. The rate of early gastric cancers was 66.4% of all reported cancers. As regards location of 253 cases, 16.5% were in the C-area, 45.8% in the M-area, 36.2% in the A-area; 19.2% were in the greater curvature, 33.9% were in the lesser curvature, 17.3% in the anterior wall, and 26.1% in the posterior wall. The sizes of the lesions were as follows: 11.5% were below 1.0 cm, 29.6% were from 1.1 cm to 2.0 cm, 46.6% were from 2.1 cm to 5.0 cm, and 12.3% were over 5.1 cm. It was considered that indirect X-rays were slightly inferior to direct X-rays in detecting early gastric cancer. The X-ray positionings in which cancers were detected were: 75.7% by supine double contrast and 48.6% by compression in 144 cases of early cancer. On the other hand, the rate were 75.6% by supine double contrast, and 51.2% by compression in 82 cases of advanced cancer. A similar tendency was found in one-shot X-ray positioning which revealed cancers. The rate of gastric cancer notdetected by X-ray pictures was 5.9% of the 253 cases. The size of the cancers notdetected by X-ray was within 2.0 cm in all cases. 58.7% of the 155 early cancer patients and 48.2% of the 83 advanced cancer patients had examinations the previous year. Therefore, it is clear that some cases of advanced cancer were not detected in the mass gastric screenings. Endoscopically, 7 cases of gastric cancer were diagnosed correctly by means of repeated biopsies which were needed 3 or 4 times over 3 to 18 months owing to pseudonegative findings on the first bioptic examination. Consequently, it is necessary to make naked eye diagnosis by endoscopic examination. Six cases of death from gastric cancer were certified within one year after normal diagnosis during the mass screening. Three cases were Borr. 4, 2 cases Borr. 3, and 1 case was Borr 2. A retrospective investigation of X-ray pictures showed that it would have been difficult to identify the lesions in these cases. The above results show that the accuracy of examinations and diagnosis must be raised in mass gastric screenings, but it is doubtful whether relying on the present methods of screening will lead to a marked improvement. For the purpose of increasing the effectiveness of mass gastric screening, we would emphasize the necessity of the following new tests; serum pepsinogen measurement, reinvestigation of patient's ages, shortening the intervals between examinations in high risk groups, using direct X-rays rather than indirect X-rays, and intermitted endoscopic examinations.

Clinical and exercise echocardiographic findings in patients with mitral valve prolapse.

To assess the relationship between left ventricular functional reserve and prognosis in patients with idiopathic mitral valve prolapse, ergometer exercise echocardiography was performed in 10 normal subjects and 30 patients with mitral valve prolapse having either mild, or no mitral regurgitation. These 30 patients with mitral prolapse were followed for 2 to 8 (mean 4.5) years. Increment of % fractional shortening during maximum exercise at the initial study in patients with mitral valve prolapse and normal subjects were 7 +/- 7 and 11 +/- 3%, respectively. Based on increment of % fractional shortening, patients with mitral valve prolapse were divided into 2 groups; Group I: 13 cases with delta% fractional shortening less than 5%, Group II: 17 cases with delta% fractional shortening greater than or equal to 5%. The incidence of cardiac symptoms was higher in Group I than in Group II (85 vs 41%, p less than 0.05). ST-T changes and life-threatening arrhythmias were more frequently observed in Group I. During the follow-up period, M-mode echocardiographic measurements did not vary in Group II, but left ventricular and left atrial dimensions increased significantly (p less than 0.05, p less than 0.01, respectively) and % fractional shortening decreased significantly (p less than 0.01) in Group I without any change in mitral regurgitation severity. Thus, some patients with mitral valve prolapse not having significant mitral regurgitation may develop progressive deterioration of the cardiac function, which may be predicted by exercise echocardiography.

[Exercise echocardiography and clinical features in patients with mitral valve prolapse].

To assess left ventricular (LV) functional reserve and prognosis in patients (pts) with idiopathic mitral valve prolapse (MVP), we performed ergometer exercise echocardiography for 10 normal subjects and 30 MVP pts without or with mild mitral regurgitation (MR). These 30 pts were followed for 2-8 years (mean 4.5). Percent changes (delta%FS) of % fractional shortening (%FS) during exercise at initial study in MVP pts and normal subjects were 7 +/- 7 and 11 +/- 3%, respectively. Based on delta%FS, MVP pts were divided into two groups; Group I: 13 cases with delta%FS less than 5%, Group II: 17 cases with delta%FS greater than or equal to 5%. The incidence of cardiac symptoms was higher in Group I than in Group II (85 vs 41%, p less than 0.05). ST-T changes on standard 12 lead ECG and life-threatening arrhythmias on Holter ECG were more frequently observed in Group I (38 vs 18%, 58 vs 20%). During follow-up period, M-mode echo measurements did not change in Group II, but LV end-diastolic dimension, LV end-systolic dimension and left atrial dimension significantly increased (p less than 0.05, p less than 0.01, p less than 0.01, respectively), and %FS significantly decreased (p less than 0.01) in Group I without any changes of MR severity. Thus, some MVP pts with impaired cardiac reserve detected by exercise echo may develop progressive deterioration of cardiac function even without significant MR.

[Right ventricular endomyocardial biopsy findings in idiopathic mitral valve prolapse: comparison with clinical findings].

Right ventricular endomyocardial biopsies were performed in nine patients with mitral valve prolapse (MVP), and the histological features were compared with the clinical findings. All of them had atypical anterior chest pain and/or dangerous ventricular arrhythmias, but the grade of MVP was mild. Five patients had non-specific ST-T changes on resting 12 leads ECG, four had ischemic ST depression on treadmill exercise ECG, and five had dangerous arrhythmias on 24 hour Holter monitoring ECG. Resting echocardiography showed normal left ventricular function in all, but exercise echocardiography revealed reduced increment of % fractional shortening (delta % FS) in five patients. Right ventricular endomyocardial biopsy findings disclosed endocardial thickening and interstitial myocardial fibrosis in eight patients, myocardial hypertrophy in two, myocardial degeneration in five, and myocardial disarray in five, although these changes were mild. These results suggest that in patients with MVP, there is a subgroup with endomyocardial abnormalities, and these might have some relations to the variety of clinical findings in MVP.

Cardiac thrombus in dilated cardiomyopathy. Relationship between left ventricular pathophysiology and left ventricular thrombus.

The relationship between left ventricular thrombus and left ventricular dynamics in dilated cardiomyopathy (DCM) was studied by echocardiography and postmortem examination. The subjects were 57 patients with DCM, 40 were survival patients examined by echocardiography and 17 were autopsy patients. Systemic or pulmonary embolism occurred in 10 of 57 patients, 4 of 40 survival patients and 6 of 17 autopsy patients. Intracardiac thrombus was detected in 11 of 40 survival patients and was found in 8 of 17 autopsy patients. Left ventricular segmental wall motion abnormalities were observed in all 40 patients examined by two-dimensional echocardiography and apical dyskinesis or akinesis was observed more frequently in patients with left ventricular thrombus than in patients without left ventricular thrombus. Of 33 patients examined by pulsed Doppler echocardiography, Doppler ejection flow signals in the apical long axis view were recorded in 9% at the apex, in 17% at the middle portion and in 57% at the portion near the interventricular septal center. The signals at the portion near the interventricular septal center were recorded in only 2 patients with left ventricular thrombus but in 66% of patients without left ventricular thrombus. Systemic or pulmonary embolism and intracardiac thrombus occurred less frequently in patients treated with warfarin than in patients without warfarin. These results indicate that endomyocardial and blood flow disorders of the left ventricle play important roles in the occurrence of left ventricular thrombus and that anticoagulant therapy is useful for the prevention of systemic or pulmonary embolism and cardiac thrombus.

[Two-dimensional echocardiographic findings of patients with papillary muscle dysfunction].

Two-dimensional echocardiographic examination was performed to investigate pathophysiological mechanism of mitral regurgitation due to papillary muscle dysfunction in 6 patients with myocardial infarction (anterior : 3, inferior: 2 and subendocardial: 1) and 13 patients with dilated cardiomyopathy. The patients were divided into 2 groups; Group I was 9 with mitral valve prolapse and Group II was 10 without mitral valve prolapse (MVP). In Group I MVP was observed in the posterior leaflet in 6 and in both leaflets in the remainder. The apical four-chamber view of all patients in Group II showed that the point of mitral valve coaptation displaced toward the apex of the left ventricle during systole and the both mitral leaflets were convexed toward the left ventricle. Follow-up observation in a patient with dilated cardiomyopathy revealed that the heart was not enlarged (CTR 50%), no murmur was heard and mild anterior mitral leaflet prolapse was observed in 1979, but, in 1981, CTR became 63%, and a grade IV systolic murmur suggesting mitral regurgitation was noted. Two-dimensional echocardiography revealed that mitral leaflets became convex toward the left ventricle and coaptation point of the mitral closure shifted to the apex of the left ventricle below the level of mitral annulus. Thus, the transition to Group II from Group I was suggested. Echocardiographic measurements revealed that left ventricular end-diastolic dimension was 71 +/- 11 mm in Group I and 74 +/- 10 mm in Group II, left ventricular end-systolic dimension was 61 +/- 11 mm in Group I and 62 +/- 11 mm in Group II, and anterio-posterior mitral ring dimension was 31 +/- 3 mm in Group I and 35 +/- 3 mm in Group II (p less than 0.05). In conclusion, it was suggested that two mechanisms of mitral regurgitation are present in papillary muscle dysfunction; 1) mitral valve prolapse and 2) shift of mitral coaptation point toward the apex of the left ventricle associated with marked dilatation of the mitral annulus.

[Evaluation of left ventricular function in patients with dilated cardiomyopathy by exercise echocardiography].

In order to evaluate left ventricular function of dilated cardiomyopathy, 24 patients and ten healthy subjects were studied by exercise echocardiography. The patients with dilated cardiomyopathy were classified into 3 groups according to the presence or absence of mitral regurgitation and the severity of left ventricular dilatation: Group I was consisted of five cases with mitral regurgitation. Group II was consisted of seven cases without mitral regurgitation who had marked left ventricular dilatation, where the left ventricular end-diastolic dimension index (DdI) was greater than 46 mm/m2 and left ventricular end-systolic dimension index (DsI) was greater than 40 mm/m2. Group III was consisted of 12 cases without mitral regurgitation who had moderate left ventricular dilatation, where the DdI was less than 46 mm/m2 or DsI was less than 40 mm/m2. The ergometer exercise tests were performed for 3 min at 25 watts in a supine position. There was no significant differences of exercise-induced increases in heart rate, elevations of systolic blood pressure and increases of rate pressure product, respectively, between healthy subjects and each group of dilated cardiomyopathy. In healthy subjects, both DdI and DsI were unchanged on exercise. In Group I, DdI was unchanged but DsI decreased (p less than 0.02), thus percent fractional shortening of the left ventricle (delta D) was increased (p less than 0.05). In Group II, both DdI and DsI were unchanged. In Group III, DdI was increased (p less than 0.05) while DsI was unchanged, thus delta D was increased (p less than 0.02). These results suggested that the left ventricle is able to respond to exercise by its further dilatation (increase of preload) in mild to moderate dilated cardiomyopathy (Group III). On the other hand, in cases with marked left ventricular dilatation (Group II), the further dilatation is not induced. The same was true in dilated cardiomyopathy with mitral regurgitation (Group I), where the left ventricle had almost the same size as in Group II, although changes in DsI and delta D were not evaluated precisely because of the associated regurgitation.

[Diagnosis of idiopathic mitral valve prolapse by two-dimensional echocardiography: evaluation of its clinical significance in the prospective follow-up study].

One hundred and five cases with idiopathic mitral valve prolapse (MVP) diagnosed by two-dimensional (2-D) echocardiography were classified into 5 groups according to the grade of prolapse (Fig. 1), 47 cases of which were followed prospectively for average 2.9 years. 1) Most of the cases with MVP of grade 3 or less showed normal left ventricular diastolic dimension (LVDd) and left atrial dimension (LAD) throughout the follow-up period, while the majority of the cases with MVP of grade 4 revealed increased LVDd and LAD. Thus the mitral regurgitation due to MVP seemed to be insignificant in cases of grade 3 or less, while it is significant in cases of grade 4. 2) During the follow-up period cases of grade 1, 2 and 3 showed the transition of the grade of prolapse each other. On the other hand, most of the cases of grade 4 at the initial examination did not show the change in its grade of prolapse. 3) Fifty-eight cases (55.2%) had symptoms such as chest pain, palpitation and dizziness, and various electrocardiographic abnormalities such as ST and T wave changes, prolongation of QT interval and arrhythmias were also frequently observed. However, the incidence of these symptoms and signs was independent from the grade of MVP. It was concluded that MVP with grade 4 or more is hemodynamically significant, while it was insignificant in cases of grade 3 or less. Therefore, those with symptoms and/or electrocardiographic abnormalities in cases with MVP of grade 3 or less will not require any treatment but only a follow-up observation.