Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody.

Immune regulation has been shown to be involved in the progressive growth of some murine tumors. In this study, we demonstrated that a single in vivo administration of an amount less than 0.125 mg of anti-CD25 interleukin 2 receptor alpha monoclonal antibody (mAb; PC61) caused the regression of tumors that grew progressively in syngeneic mice. The tumors used were five leukemias, a myeloma, and two sarcomas derived from four different inbred mouse strains. Anti-CD25 mAb (PC61) showed an effect in six of the eight tumors. Administration of anti-CD25 mAb (PC61) caused a reduction in the number of CD4+ CD25+ cells in the peripheral lymphoid tissues. The findings suggested that CD4+ CD25+ immunoregulatory cells were involved in the growth of those tumors. Kinetic analysis showed that the administration of anti-CD25 mAb (PC61) later than day 2 after tumor inoculation caused no tumor regression, irrespective of depletion of CD4+ CD25+ immunoregulatory cells. Two leukemias, on which the PC61-treatment had no effect, seemed to be incapable of eliciting effective rejection responses in the recipient mice because of low or no antigenicity.

Generation of multiple angiogenesis inhibitors by human pancreatic cancer.

A primary inoculum of human pancreatic cancer cells (BxPC-3) has the ability to inhibit the growth of a secondary tumor in an in vivo animal model. Such ability suggests that the primary tumor is producing inhibitors that act at the site of the secondary tumor. Accordingly we attempted to discover which inhibitors are produced by pancreatic cancer cells. We determined that pancreatic cancer cells process angiostatin isoforms from plasminogen. Additionally, we isolated and characterized an uncleaved "latent" antiangiogenic antithrombin (aaAT) molecule processed from systemically available AT by pancreatic cancer cells as well as a cleaved form of aaAT processed from systemically available AT by pancreatic cancer cells. Human AT, cleaved with human neutrophil elastase, inhibits angiogenesis in the chorioallantoic membrane assay. This human aaAT molecule is able to inhibit the growth of pancreatic tumors in immune-compromised mice. Our work represents the first demonstration of multiple angiogenesis inhibitors from a single tumor and suggests that antiangiogenic therapies may provide an avenue for future treatment of pancreatic cancer.

Extraskeletal myxoid chondrosarcoma arising from the retroperitoneum.

A case of extraskeletal myxoid chondrosarcoma is presented. The tumor occurred in the retroperitoneum and systemic metastases were found at autopsy. The primary and metastatic tumors were soft and strikingly myxoid on gross appearance. Microscopic observation revealed undifferentiated malignant tumor having large amounts of myxoid substance and a small amount of well-differentiated chondrosarcoma element in the primary lesions. The authors obtained an immunohistochemical result that the tumor cells showed positivity for alpha-1-antitrypsin and alpha-1-antichymotrypsin. Regarding S-100 protein, the well-differentiated chondrosarcoma element revealed intense positivity, whereas the poorly differentiated myxoid areas were not positive except for a few tumor cells. This is the first case, to our knowledge, of extraskeletal myxoid chondrosarcoma arising from the retroperitoneum, and immunohistologic findings suggest that alpha-1-antitrypsin and alpha-1-antichymotrypsin may be available markers in poorly differentiated chondrosarcomas showing a negative reaction for S-100 protein.

A phase II study of prophylactic intravesical chemotherapy with epirubicin in the treatment of superficial bladder cancer. Tokyo Women's Medical College Bladder Cancer Collaborating Group.

Intravesical instillation of epirubicin was carried out to investigate the efficacy of this treatment in preventing postoperative recurrence of superficial bladder cancer. The subjects were 100 patients who had been treated with transurethral resection (TUR) for superficial transitional-cell carcinoma of the bladder (classified as primary or recurrent superficial bladder cancer of pathological stage Tis, Ta, or T1 and histological grade G1, G2, or G3) at Tokyo Women's Medical College Hospital and its affiliated hospitals during the 2-year period ranging from April of 1990 through March of 1992. A solution of epirubicin was prepared by dissolving 20 mg in 30 ml physiological saline, and this was instilled into the bladder a total of 17 times during 1 year: once immediately after TUR, once every 2 weeks for the next 4 months, and then once per month for the following 8 months. Thereafter, the course of each patient was followed by performing urinary cytodiagnosis once each month and cystoscopy once every 3 months. Of the 100 patients, 83 were evaluable. The mean duration of follow-up was 461 +/- 222 days, and the recurrence rate was 30.1% (25/83 cases). The recurrence rate determined for primary cases was 19.7%, whereas that recorded for recurrent cases was 61.9%. Adverse effects occurred in 9.3% (9/97) of the patients, but these side effects were mild in severity and the instillation regimen did not have to be discontinued in any of the patients. Analysis of the risk factors for recurrence revealed significantly higher recurrence in the recurrent-patient group and the multiple-tumor group. On the basis of these findings, the authors surmised that when given in an intravesical instillation regimen, epirubicin causes few adverse effects, and its efficacy in the prophylaxis of recurrence of superficial bladder cancer is equivalent to that thus for reported for other drugs. At present, the authors are carrying out a controlled clinical study on epirubicin that takes into account the risk factors for recurrence of superficial bladder cancer.

Spontaneous pancreatitis in spontaneously hypertensive rats.

The pancreatic lesions in 6- to 36-week-old spontaneously hypertensive rats (SHR), stroke prone SHR (SHRSP) and Wistar-Kyoto rats (WKY) were examined histopathologically. Inflammatory cell infiltration with hemorrhage and stromal fibrosis became evident in 12-week-old SHR and SHRSP together with acinar atrophy and/or degeneration and ductular proliferation. These changes in SHR and SHRSP were even more prominent at the age of 24 weeks and extremely severe at 36 weeks. In addition, in SHR and SHRSP over 12 weeks of age, small necrosis of acinar cells was found occasionally together with fibrosis and arteriosclerosis. Pancreatic arteriosclerosis was marked in SHR and SHRSP over 24 weeks of age at the level of arterioles < 200 microns in diameter. Adrenergic nerve fibers stained by fluorescence histochemistry were present around the pancreatic arteries and ducts and within the parenchyma, and they were denser in SHR and SHRSP than in WKY, indicating hyperinnervation of the sympathetic nervous system in SHR and SHRSP. It is suggested that the pancreatic ischemia caused by arteriosclerosis due to facilitation of the sympathetic nervous system is an important factor in the pathogenesis of the spontaneous pancreatitis of SHR and SHRSP.

Antimutagenicity of Tochu tea (an aqueous extract of Eucommia ulmoides leaves): 1. The clastogen-suppressing effects of Tochu tea in CHO cells and mice.

The suppressing effect of crude extracts of Tochu tea, an aqueous extract of Eucommia ulmoides leaves and a popular beverage in Japan, on the induction of chromosome aberrations in CHO cells and mice was studied. When CHO cells were treated with Tochu tea crude extract after MMC treatment, the frequency of chromosome aberrations was reduced. Out of 17 Tochu tea components, 5 irridoids (geniposidic acid, geniposide, asperulosidic acid, deacetyl asperulosidic acid, and asperuloside) and 3 phenols (pyrogallol, protocatechuic acid, and p-trans-coumaric acid) were found to have anticlastogenic activity. Since the anticlastogenic irridoids had an alpha-unsaturated carbonyl group, this structure was considered to play an important role in the anticlastogenicity. The anticlastogenic effect of Tochu tea extracts was examined in mice using a micronucleus assay. When mice received 1.0 ml 4% Tochu tea extract by oral gavage 6 h before intraperitoneal injection of MMC, a decrease in the frequency of micronuclei was observed. This decrease was not due to a delay in the maturation of micronucleated reticulocytes.

Antimutagenicity of Tochu tea (an aqueous extract of Eucommia ulmoides leaves): 2. Suppressing effect of Tochu tea on the urine mutagenicity after ingestion of raw fish and cooked beef.

The effect of Tochu tea, which is an aqueous extract of Eucommia ulmoides leaves and a popular-beverage in Japan, on the urine mutagenicity before and after ingestion of raw fish and cooked beef was studied using Salmonella typhimurium YG1024. Urines were collected from seven healthy, non-smoking Japanese women before and after ingestion of raw fish and cooked beef. In experiment 1,3 were in a control group and 4 were in a Tochu tea-drinking group (2000 ml per day). The mutagenicity of urine from the Tochu tea-drinking group was much lower. In experiment 2 the 7 women switched groups; the tea-drinking group became the control group, and the control group became the Tochu tea-drinking group. Again, the mutagenicity of urine collected from the Tochu tea-drinking group was much lower. These results suggest that the decrease in the mutagenicity of the urine from the Tochu tea-drinking group was due to the intake of Tochu tea, but not to individual differences. Thus, the ingestion of Tochu tea may reduce human exposure to dietary mutagens.

Linkage of persistent cholangitis after bilioenterostomy with biliary carcinogenesis in hamsters.

Biliary carcinoma occurring after bilioenterostomy has been reported as a late complication of this surgical procedure. The present study was designed to determine if bilioenterostomy promotes biliary carcinogenesis, and also to clarify the relationship between biliary inflammation and biliary carcinogenesis in hamsters. Syrian hamsters underwent a simple laparotomy (SL), choledochoduodenostomy (CD) or choledochojejunostomy (CJ). All hamsters received subcutaneous injections of the chemical carcinogen, N-nitrosobis (2-oxopropyl) amine (BOP), and were sacrificed 20 weeks after surgery. Neoplastic lesions in the biliary tree were histologically examined, and the presence and degree of cholangitis was also evaluated with special reference to biliary carcinogenesis. The incidence of bile duct carcinoma was not significantly different among the three groups. Numerous bile duct carcinomas, however, were recognized in the bilioenterostomized animals, especially in the CJ group. Moreover, significant correlations between biliary carcinogenesis and the presence of cholangitis were noted in both the CD and CJ groups, but not in the SL control group. Severe cholangitis was evident in the CJ group, and the number of biliary carcinomas was well correlated with the degree of cholangitis. In conclusion, the risk of carcinoma in the biliary tract may increase when persistent cholangitis is present after biliary reconstruction.

A case of ornithine transcarbamylase deficiency with acute and late onset simulating Reye's syndrome in an adult male.

A 15-year-old male was admitted to the hospital because of a disturbance of consciousness. He was in good mental and physical condition until the previous day, when he vomited and experienced a reduction of consciousness. He was brought to the hospital the day following the onset of symptoms. On admission the patient was stuporous. Neurological focal signs were not demonstrated. Computed tomographic (CT) scanning on admission showed no definite abnormality. Cerebrosprinal fluid had no pleocytosis. At this time, Reye's syndrome was suspected because of the acute change of consciousness and the presence of hyperammonemia. The disturbance of consciousness progressed and he became comatose on the day following admission. CT scanning showed that the suprasellar, ambient and quadrigeminal cisterns could almost not be detected and the bilateral ventricles were narrowed. The plasma aminogram demonstrated an elevation of alanine, lysine, glutamine, glutamic acid, aspartate and proline. Ketonuria was negative, but the urinary excretion of orotic acid was markedly increased. This data was indicative of the existence of an ornithine transcarbamylase (OTC) deficiency. The patient was died on the third day after hospitalization. The OTC activity in the liver was 10% of normal. Activities of other enzymes in the urea cycle were within normal limits. It is unusual that the symptoms of the enzyme deficiency occurred, both acutely and late at an adult age, as in this case. This case demonstrates that OTC deficiency should be considered in the differential diagnosis of hyperammonemia of adult onset.

[Decrease of nosocomial bacteremia and nosocomial pneumonia after introduction of preventive measures of hospital infection].

In the early 1980's methicillin-resistant staphylococcus aureus (MRSA) was reported as a major pathogenic organism of geriatric hospital infection in Japan. At the same time in the A geriatric hospital MRSA infection was prevalent. To decrease nosocomial infections some active preventive measures against hospital infection were taken since Oct. 1991. About a year before introduction of prevention of hospital infection in the geriatric ward (190 beds) of A hospital 193 episodes of nosocomial bacteremia were observed. However a year after introduction of preventive measures episodes of nosocomial bacteremia were decreased to less than a half (45.6%) in comparison to the number before introduction of prevention. As a causative organism gram-positive bacteria including MRSA were markedly decreased. Major portals of entry of bacteremia (74.9%) were urinary-tract system, intravenous hyperalimentation (IVH) catheter, and pressure sores. MRSA-positive pressure sores were decreased to 20.4% of those before prevention. On the other hand 87 episodes of nosocomial pneumonia were observed before prevention. However a year after introduction of preventive measures episodes of nosocomial pneumonia were decreased to less than a half (44.8%) in comparison to the number before introduction of prevention. After prevention MRSA and mixed infection of P. aeruginosa and MRSA were markedly decreased. The decrease of bacteremia and nosocomial pneumonia were caused by cleaning hands, the preventive measures for decrease and improvement of pressure sores, cleaning the upper respiratory tract for prevention of lower respiratory-tract infection cleaning floors and education of the staff, etc.

[Coagulase typing of Staphylococcus aureus in the geriatric wards after introduction of preventive measures of hospital infection].

In the early 1980's methicillin-resistant Staphylococcus aureus (MRSA) was reported as a major pathogenic organism of geriatric hospital infection in Japan. At the same time in our geriatric wards, including 190 beds, MRSA infection was prevalent. In the early 1980's in our geriatric wards minocycline was one of the most sensitive antibiotics to MRSA isolated in our wards and used frequently against MRSA pneumonias and bacteremia. In the late 1980's resistant strains of MRSA to minocycline rapidly increased because vancomycin was not allowed to introduced for treatment of MRSA before 1991 in Japan. At the same period the predominant coagulase type changed from type II to type VII. To decrease minocycline-resistant strains to MRSA after 1987, use of minocycline was limited. Moreover since Oct. 1991 to decrease nosocomial infections some active preventive measures against hospital infection, including limited use of 2nd and 3rd cephems, were taken. In this study changing patterns of coagulase type of Staphylococcus aureus were discussed. At least 4 years was needed to find out that the predominant coagulase type changed from type VII to type II again in 1991. In this study about 22 antimicrobial agents MICs of 313 strains of Staphylococcus aureus isolated between March 1992 and June 1993 were determined and compared with the data of MICs before introduction of preventive measures. The pattern of susceptibility to MINO was in part improved. Thus the some sensitive strains of S. aureus were observed again in our geriatric wards. Interestingly indeed it took approximately 5 years to find out the emergence of sensitive strains to MINO since limitation of use of MINO in 1987.

[A case of xanthogranuloma of the urinary bladder].

A case of xanthogranuloma of the urinary bladder is reported. A 68-year-old man was referred to our hospital for the evaluation of microscopic hematuria. At that time, he did not have an abdominal tumor and ultrasonography showed no abnormality of the kidneys and the bladder wall. Two months later, he was admitted with the chief complaints of perineal discomfort and non tender fist size mass was palpable in the lower abdomen. Ultrasonography, computed tomographic scan and magnetic resonance imaging MRI demonstrated a supravesical mass which was strongly suspected as urachal tumor. Total cystectomy with urachal resection was performed. The histological diagnosis was xanthogranuloma. The patient has been in good health without recurrence, 4 years after surgery. We discuss xanthogranuloma of the urinary bladder in the literature.

[Utility of prostate specific antigen (PSA) density in detecting prostate cancer in men showing gray zone serum PSA levels].

The efficacy of prostate specific antigen density (PSAD) in diagnosing prostate cancer was assessed in 98 patients with serum prostate specific antigen (PSA) levels between 2 and 10 ng/ml who had a pathological diagnosis made by prostate biopsy or transurethral resection of the prostate. Of the 98 patients, 22 (22%) had prostate cancer. The PSA (based on a cut-off value of 4.5 ng/ml) had a sensitivity and positive predictive value (PPV) of 82% and 38%, respectively, for diagnosing prostate cancer, while the results for PSAD (based on a cut-off value of 0.13) were 91% and 61%. The PSAD was more efficient than the PSA levels and was also superior to digital rectal examination (DRE) combined with transrectal ultrasonography (TRUS), for which the sensitivity and PPV were 73% and 39%, respectively. Six (11%) out of 57 patients who were normal on DRE and TRUS had prostate cancer. In these 57 patients, the PSA (cut-off value: 4.5 ng/ml) had a sensitivity of 50% and PPV while the values for PSAD (cut-off value: 0.13) were 83% and 36% respectively. The PSAD could effectively detect even impalpable prostate cancer not visible on TRUS.

[A juxtaglomerular cell tumor. Analysis of immunohistochemistry, electron microscopy and in situ hybridization].

We present a case of juxtaglomerular cell tumor measuring 8 mm in diameter in the right kidney. The hypertension was cured and plasma renin activity returned to normal level following tumor resection with partial nephrectomy. We studied histopathologic, electron microscopic, and immunohistochemical findings of the tumor. The majority of tumor cells stores renin granules in cytoplasm. In situ hybridization confirmed us that the most tumor cells produce renin. We use the digoxigenin labeled 0.6-kb length RNA probe of human renal renin, the specificity was analyzed by competition assay (1:50).

[A comparison of bullard laryngoscope and intubating laryngeal mask using fiberoptic guidance for tracheal intubation].

The purpose of this study is to compare the success rate of tracheal intubation, intubation time and laryngoscopic view of the larynx by Bullard laryngoscope or by intubating laryngeal mask using fiberoptic guidance in 50 patients. Following a standardized induction protocol, conventional laryngoscopic view by Macintosh's laryngoscope was obtained and classified by Cormack's grades. We measured the times from incertion of laryngoscopy or laryngeal mask until obtaining the best view of the larynx and until tracheal intubation. A best view by Bullard laryngoscopy or by fiberoscopy through the laryngeal mask was classified by Cormack's grades. The success rate of tracheal intubation was higher by Bullard laryngoscopy than by intubating laryngeal mask. The durations of laryngoscopy and tracheal intubation were significantly shorter and Cormack's grades were significantly lower by Bullard laryngoscopy than by laryngeal mask and fiberscopy. These results demonstrate that tracheal intubation by Bullard laryngoscope is faster and more successful compared with intubating laryngeal mask using fiberoptic guidance.

[Comparison of the effect of rapid infusion of lactated and that of acetated Ringer's solutions on maternal and fetal metabolism and acid-base balance].

The maternal and neonatal metabolism and acid-base balance were investigated in 20 parturients undergoing combined spinal and epidural anesthesia for cesarean delivery. Patients received intravenous infusion at a rate of either 25 ml.kg-1.h-1 of lactated (LR group, n = 10) or acetated (AR group, n = 10) Ringer's solution before anesthesia, to prevent hypotension during anesthesia. We obtained venous blood samples as follows; maternal control before anesthesia, maternal sample A after the infusion, umbilical sample B, and neonatal pedal sample C 5 h after birth, and determined lactate, pyruvate, bicarbonate, and base excess concentrations, and pH in each sample. In sample A, the lactate level was significantly higher and base excess level was significantly lower in the LR group than in the AR group. The pH of sample A and B was significantly higher in the AR group than in the LR group. However, no differences in all parameters of sample C between the two groups were observed. These results demonstrated that acetated Ringer's solution is better than lactated Ringer's solution in rapid infusion before cesarean section because of the correction of neonatal lactic acidosis.

[Depressive effect of dibucaine and bupivacaine on the growth of axons from cultured neuron of Lymnaea stagnalis].

The depressive effect of dibucaine (n = 8) was compared with that of bupivacaine (n = 9) using identified cultured neurons (A cluster) of Lymnaea stagnalis. Cultured interneurons exhibit extensive neurite outgrowth within 14-20 hours when placed in brain conditioned media. The changes of cultured neuron were recorded using a color video camera directly connected to an inverted microscope and the images were stored on digital video tape. Local anesthetics were added to the culture dish, with final concentrations of 1 x 10(-6) M-8 x 10(-4) M of dibucaine and 1 x 10(-5) M-8 X 10(-3) M of bupivacaine. We examined the damage of growth cone before and 30 minute after local anesthetics administration. Histologic damage were scored from moderate to severe compared to the control before dibucaine or bupivacaine administration. Dibucaine or bupivacaine damaged the growth cone moderately in the concentration of 1 x 10(-5) M or 4 x 10(-4) M, respectively. While dibucaine or bupivacaine damaged it severely in the concentration of 8 x 10(-5) M or 2 x 10(-3) M, respectively. These results suggest that bupivacaine is safer than dibucaine with the concentration we use in clinical practice.

Dural puncture with a 26-gauge spinal needle affects spread of epidural anesthesia.

Combined spinal and epidural anesthesia may increase the risk of epidurally administered drugs spreading into the subarachnoid space through the dural hole. We studied the effect of dural puncture with a 26-gauge needle on the spread of analgesia induced by epidural injection of local anesthetics. Forty patients were randomly assigned to control and dural puncture groups. In the dural puncture group, the dura was punctured with a 26-gauge Whitacre spinal needle at L2-3 but no drug was injected. In both groups, an 18-gauge epidural catheter was inserted 4 cm cephalad into the epidural space at L2-3 and 15 mL of 2% mepivacaine without epinephrine was injected. Analgesia was assessed by pinprick at 5, 10, 15, and 20 min after injection and at the end of surgery. The caudal spread of analgesia was significantly greater in the dural puncture group than in the control group 15 and 20 min after injection (P < 0.01), but the cranial spread of analgesia was not different between the two groups. We conclude that dural puncture (without drugs) using a 26-gauge Whitacre spinal needle before epidural injection increases caudal spread of analgesia induced by epidural local anesthetics.

Aortic dissections complicating open cardiac surgery: report of three cases.

Between June 1991 and February 1999, three patients suffered ascending aortic dissection as a complication of cardiopulmonary bypass operations with aortic cannulation at our hospital. The dissection occurred during the operation in two of the three patients and several months after the operation in one. Among a total of 2207 cardiac operations performed during this period, the incidence of perioperative ascending aortic dissection was 0.14%. In addition to visual inspection and palpation, either epicardial or transesophageal echocardiography proved extremely useful for establishing an intraoperative diagnosis of ascending aortic dissection as a complication of open cardiac operation. One of the three patients underwent closed plication but subsequently died of vital organ ischemia. In this case, failure of reapproximation of the injured intima by closed plication might have led to extension of the dissection. Despite prolonged cardiopulmonary bypass and myocardial ischemic time, graft replacement of the ascending aorta was successfully carried out in the other two patients. Thus, we believe that graft replacement of the ascending aorta should be performed for patients with extensive aortic dissection complicating an open cardiac operation.