[Mismatches in the treatment for gastric cancer and their correction].

Mismatches in the treatment of gastric cancer to date in Japan are as follows: 1. Difference in the definitive pathological diagnosis even among well-known, experienced pathologists. The case of a patient who was successfully treated by the authors is reported in this paper. 2. The insufficient number of medical oncologists for gastric cancer. 3. The administration of adjuvant chemotherapy after surgery without obvious evidence that it is needed. 4. Inadequate preventive measures, i.e. refrainment from smoking and eradication of Helicobacter pylori. 5. The application of standard surgery, which is designed basically to treat advanced gastric cancer with serosal and nodal involvement, in cases of early gastric cancer. These mismatches have been corrected recently by the adoption of modified surgery and an endoscopic approach to the early gastric cancer. These modifications could be attained through our pioneering effort to find a balance between the two contradictory approaches of radical treatment and preservation of organic function, which are often irreconcilable in cancer treatment in general, after the accumulation of sufficient data on early gastric cancer in a Japanese nationwide study.

Multiple giant angiomyolipomas with a polygonal epithelioid cell component in tuberous sclerosis: an autopsy case report.

A recent case of angiomyolipoma (AML) with a prominent component of polygonal epithelioid cells is described. A 27-year-old Japanese male with tuberous sclerosis presented with massive abdominal tumors increasing progressively in size. The patient died of respiratory disturbance and the autopsy revealed massive tumors in the bilateral kidneys, liver and lymph nodes, subependymal giant cell glioma of the brain and lymphangiomyomatosis of the lungs. The giant tumors were an unusual type of AML with a component of polygonal epithelioid cells, which showed a hepatocellular carcinoma-like pattern in some areas. Smooth muscle components comprising spindle cells, short or plump spindle cells and polygonal epithelioid cells frequently exhibited positive staining for HMB-45 but negative staining for epithelial cell markers. The unusual AML presented in this case was thought to be of low-grade malignancy and slow growing. It has been suggested that angiomyolipomas with diffuse areas of epithelioid cell component are potentially malignant. Immunostainings positive for HMB-45 but negative for epithelial cell markers are considered to be useful in differentiating AML with polygonal epithelioid cell component from other tumors, especially from renal cell carcinoma and hepatocellular carcinoma.

Combined treatment of probucol with diltiazem regresses atherosclerosis induced by 196 cholesterol diet in rabbit aorta.

To clarify whether probucol, an antioxidant, or diltiazem, a Ca2+ antagonist, favorably affect the regression of established atherosclerosis, rabbits were fed a 1% cholesterol diet for 10 weeks, then a standard diet for an additional 25 weeks (regression period). During the regression period, rabbits were grouped into a saline (S) group (n=8, 1 ml saline/d), a probucol (P) group (n=8, 1000 mg/d probucol), or a probucol and diltiazem (P+D) group (n=8, probucol 1000 mg/d in diet and diltiazem 30 mg/d). We measured cholesterol in serum, lipoprotein fractions, and serum triglyceride or phospholipid concentration and found no significant differences among the three groups at 10, 15, or 35 weeks. After 10 weeks of the atherogenic diet, the ratio of macroscopic atherosclerotic lesions in aortic intima rose to 36.6 + or - 5.6%. After the regression period, the S group developed more atherosclerotic lesions (48.6 + or - 6.4%). The P+D and P groups, however, had decreased scores of 24.3 + or - 5.5% (p<0.05 vs. S) and 32.3 + or - 5.6%, respectively. Moreover, these decreased scores were well correlated with the decrease in aortic tissue lipid compositions, but not the parameters for extracellular matrices. We concluded that P+D or P therapy might be effective in regressing established atherosclerosis by removing lipid contents but not extracellular matrices.

Epididymal lymphangiectasis.

We report on a 59-year-old man with epididymal lymphangiectasis. The patient had noticed somewhat intermittent intrascrotal painless swelling. The interstitium of the right caput epididymis exhibited a number of large, dilated lymphatic vessels forming irregular channels among and around the epididymal ducts. The afferent epididymal ducts showed dilatation similar to that of the lymphatic vessels except for focal cuboid epithelial linings. Spermatogenesis in the right testis was preserved. Lymphangiectasis in the epididymis is infrequent and needs to be differentiated from other intrascrotal lesions.

Reversibility of ethylene oxide-induced testicular damage evaluated by the hemiorchiectomy method.

In the present study, we tried to use the hemiorchiectomy method to examine a reversibility of the testicular damage induced by ethylene oxide (EtO). Wistar male rats were exposed to EtO at a concentration of 500 ppm, 6 hours a day, 3 days a week for 8 weeks. Thereafter we evaluated the reversibility after 13-week recovery period. From the result about a propriety of the hemiorchiecyomy method for recovery study, it was suggested that hemiorchiectomy did not affect remaining testis and epididymis after the recovery period and there was no laterality about the testicular damage just after the exposure period. Therefore we concluded that the hemiorchiectomy method could be used for recovery study for EtO-induced testicular damage. The reversibility was evaluated by comparing the damages of hemiorchiectomized testis just after the exposure period and those of remaining testis removed after the recovery period in the same rat. The result indicated that the reversibility of EtO-induced testicular damage may depend on a degree of damage just after the exposure.

Cell death and regeneration of renal proximal tubular cells in rats with subchronic cadmium intoxication.

Male Sprague-Dawley rats were injected subcutaneously with 0.6 mg cadmium (Cd)/kg/day for 8 wk. The subsequent changes in renal proximal tubules were studied histologically, histochemically, and ultrastructurally. The urinary and tissue Cd concentrations were determined by atomic absorption spectrophotometry. After 4 wk of exposure, apoptosis was observed predominantly in segment S3 along with epithelial regeneration in the affected tubules, and these changes gradually became more pronounced as the experimental period was prolonged. The apoptotic cells were shed into the lumen and were found to contain a large quantity of Cd. Apoptotic cells were counted in paraffin sections after various periods of exposure to Cd. Nuclear bromodeoxyuridine uptake, mitotic count, and nuclear density were used as indicators of tubular regeneration. A correlation was found between the numerical increase of apoptotic cells and the rate of urinary Cd excretion, and the rate of increase in the tissue Cd concentration had a tendency to reduce after 4 wk as the rate of urinary Cd increased. These observations suggest that apoptosis might be helpful for the efficient excretion of Cd into urine. Progressive increases in the preceding indicators of regeneration were observed. From our results, it appears that Cd-induced tubular damage, i.e., cell deletion due to apoptosis, is reversible as a result of marked epithelial regeneration. On the basis of these histological changes, the critical concentration of Cd required to produce renal tubular damage was estimated to be 600 micrograms/g dry tissue.

Changes in spermatozoa due to large doses of pyridoxine (vitamin B6).

To investigate the changes of spermatozoa by high doses of vitamin B6 (B6), the alterations in spermatozoa and testis of rats after the administration of high doses of B6 were evaluated quantitatively and morphometrically. Wistar rats of 11 weeks of age were intraperitoneally injected with 63, 125, 250 and 500 mg/kg of B6 daily 5 times per week for 6 weeks. Using the spermatozoa taken from the epididymis and ductus deferens, the number, motility and nuclear morphology of spermatozoa were examined. After preparing 7 parameters for the nuclear morphology, the morphometry was performed by an IBAS version 2 (Zeiss) image analysis system. The number of spermatocytes and spermatids in representative stages of spermatogenesis was counted per Sertoli cell histologically. Mild deformation of spermatozoa nuclei occurred in the 63 mg or more exposure groups. In the 125 and 250 mg groups, the decrease in number as well as motility of spermatozoa together with slight decrease of spermatids in late maturation phase (mature spermatids) and the delay in spermiation appeared. Phagocytosis of mature spermatids by Sertoli cells was clearly increased in the 250 mg group. The alteration and the decreased number of spermatozoa are suggested to have mainly resulted from alteration of mature spermatids and the increased phagocytosis of mature spermatids by Sertoli cells. Computer-assisted morphometry of spermatozoa nuclei was useful not only to evaluate morphological changes objectively but also to discern them early.

Hepatic lymphangiomatosis: report of two cases, with an immunohistochemical study.

Two cases of hepatic lymphangiomatosis were examined. One tumor was noted incidentally at autopsy, and the other tumor was removed by operation. These liver tumors could not be detected by the naked eye, but ill-defined lace-like areas were seen. Microscopically, small cystic spaces were irregularly aggregated in the hepatic parenchyma and, in part, in the portal tracts. Faintly stained lymph-like material without any erythrocytes was found in the spaces. The silver impregnation method confirmed that most of the cystic lumina were dilated Disse's spaces. Also, some of them were directly connected with lymph vessels in the portal tracts. Thin lining cells along the internal surface of these cystic channels could not be positively stained by Ulex europaens 1 or factor 8-related antigen, both of which were present in the endothelium of the blood vessels in the portal tracts. We describe herein this rare lymphangiomatosis of the liver, with special reference to its immunohistochemistry.

Effects of megadoses of pyridoxine on spermatogenesis and male reproductive organs in rats.

Although it has been indicated that many neurotoxicants also cause reproductive toxicity, the reproductive toxicity of megadoses of pyridoxine, which is a neurotoxicant, has not been studied. In this paper, we studied the effects of megadoses of pyridoxine on male reproductive organs. Pyridoxine hydrochloride, 125 mg/kg, 250 mg/kg, 500 mg/kg or 1000 mg/kg, daily, was intraperitoneally injected into Wistar male rats 5 days a week for 2 or 6 weeks, and its effects on the male reproductive organs were investigated. After 2 weeks of administration, absolute weights of the testis in the 500 and 1000 mg/kg epididymis in all the exposed groups and prostate gland in the 1000 mg/kg group decreased, and mature spermatid counts in the testis decreased in the 1000 mg/kg group. After 6 weeks administration, the absolute and relative weights of the testis, epididymis, prostate gland and seminal vesicle decreased in the 500 mg/kg and 1000 mg/kg groups, and mature spermatid counts in the testis and sperm counts in the epididymis decreased in these groups. Among the marker enzymes of the testicular cells, LDH-X activity decreased, and beta-glucuronidase activity, cytochrome P-450 content and cytochrome b5 content increased in the 1000 mg/kg group. Plasma testosterone concentration did not significantly alter in all the exposed groups. From these results, it was concluded that megadoses of pyridoxine affected the spermatogenesis and decreased reproductive organ weights in the rat.

Testicular damage caused by inhalation of ethylene oxide in rats: light and electron microscopic studies.

Although testicular damage caused by ethylene oxide vapor (EtO) has been previously reported, the morphological changes occurring in seminiferous tubules remain unclear. We examined the time course of the testicular lesion induced by EtO in order to clarify its morphogenesis. Wistar rats were exposed to 500 ppm EtO for 6 hr per day, 3 times per week for 2, 4, 6, or 13 weeks through inhalation. In the 2-week exposure group, Sertoli cells often showed condensation and retraction of the cytoplasm, and dilatation of the endoplasmic reticulum (ER). In apical Sertoli cells, processes which encapsulated the heads of elongate spermatids, ectoplasmic specializations, and tubulobulbar complexes were often deformed and many elongate spermatids were degenerated. In the 4- and 6-week exposure groups, many degenerated Sertoli cells were present, and deformed germ cells, sometimes with multinucleation, appeared to make direct contact with each other without interlocation of Sertoli cell lateral processes. A few scattered immature Sertoli cells were evident in the 6-week exposure group. In the 13-week exposure group, seminiferous tubules containing almost all types of germ cells reappeared, mixed with atrophic tubules containing Sertoli cells only. In the former tubules, Sertoli cells often possessed regularly regenerated lateral processes, which were interposed between germ cells. These results indicate that the germ cell damage may be associated with damage to Sertoli cells. In spite of the intermittent exposure, focal regeneration of Sertoli cells appeared after 6 weeks of exposure to EtO and preceded patchy recovery of germ cells. Therefore, the data suggest that Sertoli cell regeneration may permit regeneration of germ cells.

Testicular damage by high doses of vitamin B6 (pyridoxine) in rats: a light and electron microscopical study.

Male Wistar rats were administered daily intraperitoneal injections of 125, 250, 500, and 1000 mg/kg/day of vitamin B6 for 2 and 6 weeks and the histogenesis of the testicular damage was investigated. A reduction of germ cells was not prominent in the 2-week groups, whereas a delay in spermiation, degeneration of elongated spermatids, and Sertoli cell alterations were observed in the 500- and 1000-mg groups, although generally, these were relatively mild. Ectoplasmic specializations (ES), tubulobulbar complexes, and endoplasmic reticulum (ER) in the apical processes of Sertoli cells were irregularly arranged and their disappearance was also retarded. The Sertoli cell cytoplasm was often retracted and condensed. In the 6-week groups, no histological change in the testis was noted with the 125-mg dose. The retardation in spermiation and Sertoli cell alterations similar to those in the 500-mg dose 2-week group were observed in the 250-mg group. In the 500- and 1000-mg groups, germ cells were generally degenerated and markedly reduced in number. Multinucleate germ cells were mingled with anisocytotic germ cells, and openings of intercellular bridges were occasionally found. Sertoli cells also showed more severe alterations, such as focal disappearance of ES in earlier than ordinary stages, marked dilation of the ER, and markedly condensed or electron-lucent cytoplasm. These results suggest that the Sertoli cell damage may induce diverse germ cell degeneration in which retardation of spermiation occurs first.

Dose dependent effects of inhaled ethylene oxide on spermatogenesis in rats.

Male Wistar rats were exposed to ethylene oxide (EO) at concentrations of 50, 100, or 250 ppm for six hours a day, on five days a week for 13 weeks. Dose effect relations of inhaled EO on spermatogenesis were evaluated from testicular and epididymal weights, histopathological changes and lactate dehydrogenase X (LDH X) activity in the testis, and sperm counts and sperm head abnormalities in the epididymis. At 250 ppm, a decrease in epididymal weights, slight degenerations in the seminiferous tubules, decreased sperm counts, and increased numbers of abnormal sperm heads in the tail of the epididymis were found; these were not seen at lower doses. When the abnormal sperm heads were classified into immature types and teratic types, the number of immature heads increased only at 250 ppm. On the other hand, the teratic type had increased at doses of 50 and 100 ppm EO when compared with the control group. Hence, subchronic inhalation of EO at low concentrations affects spermatogenesis in rats.

Preventive effects of methylcobalamin on the testicular damage induced by ethylene oxide.

In this study, the effects of methylcobalamin on testicular damage induced by ethylene oxide (EtO) were studied. When Wistar male rats inhaled EtO at 500 ppm, 6 h a day, 3 days a week, for 6 weeks, testicular damage was observed histopathologically and by some other parameters. Subcutaneous injection of methylcobalamin at 500 micrograms/kg, 5 times/week was found to ameliorate the damage. However, the degree of the methylcobalamin effect differed among the parameters examined in this study. Decrease in testicular weight due to EtO exposure was completely prevented by methylcobalamin, and decrease in testicular mature spermatid count and LDH-X activity was fairly well prevented. The degree of prevention of alteration in the epididymis, such as epididymal weight, epididymal sperm count and sperm abnormality rate, was significant but not complete. EtO caused apparent alterations in glutathione metabolism in the testes, but methylcobalamin did not affect such alterations induced by EtO. From these results, it has been determined that methylcobalamin has definite preventive effects on testicular toxicity of EtO.

Pathological study on beagles after long-term oral administration of cadmium.

Histopathological, histochemical, and electron microscopic examinations were performed on beagles after a long-term oral cadmium (Cd) administration of greater than 8 years. Although renal atrophy was remarkable in groups receiving doses of 50 and 100 mg/kg body weight/day, bone lesions could not be demonstrated by roentgenological and histopathologic examination. It was noticed that concomitant regeneration or recovery and cell death of the epithelium occurred in the proximal convoluted tubules. The cell death was consistent with apoptosis, a special feature of cell death, which was shown to play a major part in the tubular damage of cadmium by electron microscopic examination. Fatty degeneration of the pars recta tubules was seen to show dose-dependence. The intrarenal cadmium was localized predominantly in the cytoplasm of the proximal tubular epithelium by histochemical and ultracentrifugal cell fractionation examinations. Although no remarkable changes were found in the other organs, aggregates of siderophages in the liver and focal hemorrhage in the spleen, known as spontaneous lesions, might be related to Cd intoxication. In conclusion, the present study revealed that no bone lesions occur with Cd administration in adult beagles in spite of long-term administration. An excessive cell death to regeneration or recovery in the proximal tubules might result in the renal cortical atrophy. No remarkable changes were seen in the glomeruli and distal nephrons, which were in good agreement with Cd distribution.

[An autopsy case of acute interstitial pneumonia].

An autopsy case of a 77-year-old male with acute interstitial pneumonia (AIP) is reported. The patient died of respiratory failure in the extremely rapid course of 8 days. The histogenesis of the thickening of the alveolar wall and the intraluminal lesions were noticed. Incorporation of the hyaline membrane as well as the intraseptal edema and septal cell proliferation played an important role in the fibrous thickening of the alveolar wall. The intraluminal granulation tissue was observed in the alveolar space and the alveolar duct, often extending into the respiratory bronchioles. Intraluminal granulation tissues in the alveoli frequently had the appearance of intraluminal buds of mesenchymal cells, so-called Masson's bodies, and there was little remodeling of pulmonary structures in this case. These findings suggest an acute, diffuse and severe damage of the peripheral respiratory tract and are consistent with bronchiolitis obliterans with classical interstitial pneumonia (BIP) by Liebow and AIP by Katzenstein. This patient had suffered from suspected "Bronchiolitis obliterans organizing pneumonia" (BOOP) one and half years ago. The relationship between AIP, BIP and BOOP is discussed.

Multiple primary cancers in a case of chronic arsenic poisoning--an autopsy report.

This is an autopsy report of multiple primary cancers observed in a patient who had clinically been diagnosed as chronic arsenic poisoning. An 88-year-old man, non-smoker, had worked in an arsenic mine for 6 years from the age of 47. He had undergone operations for Bowen's disease and gastric cancer at ages 80 and 86, respectively. At autopsy, squamous cell carcinoma of the lung and a polypoid lesion in the piriform recess were found. Furthermore, microscopic examination revealed latent prostatic adenocarcinoma and oncocytoma in the kidney. The polypoid lesion of the piriform recess appeared to originate from the duct of the minor salivary gland in the pharynx, showing an adenoid cystic carcinoma-like pattern with squamous cell carcinoma in part. The cause of death was thought to be respiratory failure due to bronchopneumonia and pulmonary edema as well as hydrothorax, and chronic heart failure following ischemic heart disease. Bowen's disease was followed by four internal malignant tumors, even though the etiological relation between these cancers and arsenic is not clear.

Effects of polysulfated glycosaminoglycans obtained from bovine lung tissue on hypercholesterolemic rabbits.

Sixteen rabbits were fed a 1% cholesterol diet with an intraperitoneal injection of saline (n = 8) (cholesterol-diet group), or 50 mg glycosaminoglycans-polysulfate (GAG-PS) (n = 8) (GAG-PS group). After 10 weeks all rabbits were sacrificed and studied. Eight rabbits on a standard diet with an intraperitoneal injection of saline (n = 8) (standard-diet group) were processed in the same manner. After 10-weeks of feeding, the plasma total cholesterol of the GAG-PS group was significantly lower than that of lower than that of the control group (P less than 0.02). The VLDL cholesterol of the GAG-PS group was also significantly lower than that of the cholesterol-diet group. There were no differences in LDL-cholesterol, HDL-cholesterol or plasma triglycerides between the groups. Total lipoprotein lipase activity (T-LPL) (LPL + HTGL) of the GAG-PS group at 10 weeks was higher than that of the cholesterol-diet group. These elevated T-LPL levels were mainly due to an increase in the LPL from peripheral tissues. ADP-induced platelet aggregability of the GAG-PS group significantly decreased at 10 weeks when compared to the cholesterol-diet group, and antithrombin-III activity of the GAG-PS group was inversely increased when compared to the cholesterol-diet group. Although there were no differences in aortic levels of total cholesterol and uronic acid between the GAG-PS group and the cholesterol-diet group, the surface involvement of the aorta in the GAG-PS group was significantly lower than that in the cholesterol-diet group. The aortic levels of free cholesterol, hydroxyproline and calcium of the GAG-PS group were significantly decreased when compared to the cholesterol-diet group. These findings suggest that GAG-PS has antiatherosclerotic effects.

Diffuse pleural rhabdomyosarcoma with persistent pleural effusion.

A unique case of embryonal rhabdomyosarcoma arising at the left pleura of a 7-year-old Japanese girl is reported. The present case was characterized by persistent pleural effusion, and the malignant cells incidentally found in it were the first diagnostic clue. The tumor showed a rare growth pattern involving diffuse thickening of the parietal pleura. Biopsy of the thickened parietal pleura upon thoracotomy revealed embryonal rhabdomyosarcoma largely composed of immature mesenchymal cells. Immunohistochemical demonstration of creatinine phosphokinase-MM was most helpful among several types of immunostain for the histopathological diagnosis. Ultrastructurally, thin filaments with primitive Z bands could be seen in some tumor cells. Intensive clinical examination revealed only diffuse thickening of the parietal pleura, which was reduced by chemotherapy. This is the first documented case of rhabdomyosarcoma arising at the pleura. Previous reports of rhabdomyosarcoma arising at unusual sites are reviewed and the histogenesis of this tumor is briefly discussed.

Hyperechoic pattern in breast cancer--its bio-acoustical genesis and tissue characterization.

Clinical breast echography is increasingly being used as it offers a high degree of diagnostic accuracy rate. Internal echoes of usual breast cancer is hypoechoic in the majority of cases, however hyperechoic mass lesion may appear in rare instances. This echo-pattern was seen in a 38-year-old housewife with invasive ductal carcinoma. Also, its bio-acoustical mechanism, that is, why hyperechoic pattern appears, was investigated from the viewpoint of ultrasonic tissue characterization and its related papers were reviewed. Tumor heterogeneity in cellularity such as cribriform pattern, tubular structure, solid nests and a scirrhous pattern of cancer cells may play an important role in producing the hyperechoic breast pattern.