A total of 74 primary cell cultures were made on the tissue specimens collected by (1) open surgery, (2) TUR and (3) biopsy from 48 patients with benign prostatic hyperplasia (BPH) and 6 with carcinoma of the prostate; and 11 subcultures of cells from the patients with benign prostatic hyperplasia (8 of cells from thee specimens collected by open surgery, 1 by TUR, and 2 by biopsy) and 3 of cells from the patients with carcinoma of the prostate (all by biopsy) were successfully made. These subcultures were all prepared by explant culture. A few sex hormons (testosterone, estrone, 5α-dihydrotestosterone, diethylstilbestrol diphosphate) at various concentrations (0.1, 1.0 and 10.0μg/ml) were allowed to act on these successfully subcultured cells in order to study their effects on the culture cells from benign prostatic hyperplasia and carcinomas of the prostate in terms of (1) cell count, (2) DNA synthesis by the cells with ³H-thymidine (by the cover slip method), and (3) morphologic changes (by light-microscopic or electron-microscopic observation).
A) The protease extracted from bacillus polymixa proved better in cell dispersion in the primary cell culture by suspension culture than trypsin; and it gave the highest yield of viable cells when cultured at 1000PU/ml and at 37°C for 90 minutes.
B) The doubling time of the cells from BPH was shorter than that of the cells from the carcinomas of the prostate, that is, the former being about 10-12 hours, and the latter about 26 hours.
C) Both fibroblastic cells and epithel-like cells were found in the culture cells from the carcinomas of the prostate as well as in those from BPH; however, there was no marked morphologic difference between the culture cells from the two origins.
D) Effects of sex hormones on culture cells.
a) Testosterone
Testosterone, at a concentration of 1.0μg/ml, accelerated the growth of the cells from the carcinomas of the prostate and also increased DNA synthesis by the cells. The same hormone, at a concentration of 10.0μg/ml, inhibited the growth of the cells from both of the two origins and also suppressed DNA synthesis by them. These growth inhibition and DNA synthesis suppression appear attributable to the “toxic effect” of the agent.
b) Estrone
Estrone, at concentrations of 0.1 and 1.0μg/ml, proved inert on the growth of cells from BPH; while the same hormone, at 10.0μg/ml, markedly inhibited DNA synthesis by the cells. This hormone, at higher concentrations, proportionally suppressed DNA synthesis by the cells.
c) 5α-Dihydrotestosterone
This hormone, at concentrations of 0.1 and 1.0μg/ml, increased DNA synthesis by the cells from BPH, and it was characteristic of this agent that the agent at the latter concentration increased the synthesis by about 20%, as compared with the control.
The same sex hormone, at a concentration of 10.0μg/ml, markedly suppressed DNA synthesis by the culture cells from the carcinomas of the prostate, and this suppression also appears attributable to the “toxic effect” of the agent.
d) Diethylstilbestrol diphosphate
Diethylstilbestrol diphosphate, at a concentration of 10.0μg/ml, moderately inhibited the growth of culture cells from BPH, and suppressed DNA synthesis by the cells, while the same hormone, at higher concentrations, proportionally inhibited the growth of culture cells from the carcinomas of the prostate and suppressed DNA synthesis by the same cells. These inhibition and suppression were particularly marked with the hormone at 10.0μg/ml, and it appears that besides its “toxic effect, ” its “hormonal effect” is also involved.
At the light-microscopic level, diethylstilbestrol diphosphate at a concentration of 10.0μg/ml gave rise to morphologic changes in the culture cells from the carcinomas of the prostate, that is, (1) distension of cytoplasm, and (2) enlargement

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Various clinical manifestations of human renal cell carcinoma have been reported by many authors and it is currently maintained that different functional and morphological characteristics of individual tumor are responsible for this.
An attempt to establish cell line has been made for suitable in vitro experimental system. Attempts have also been made to transplant human renal cell carcinoma to nude mouse for further functional and morphological study.
Materials and methods:
Thirty-six surgical specimens of renal cell carcinoma obtained at Keio University and its affiliated hospitals from September '73 through March '77 were used. Those specimens, after being cultured, transplanted to nude mouse, were examined from different points of view including light and electron microscopic observation, cell growth, chromosomal analysis and determination of erythropoietin activity.
Results:
1) Thirtysix cases of direct cell culture were performed in which primary culture and successive culture were successful in 11 and 2 cases, respectively.
2) Six out of 12 transplanted tumors to nude mouse were successful, and 4 of the 6 transplanted tumors were still in growth at present time. Among them included is a tumor capable of producing erythropoietin, which was originally derived from metastatic foci in the lung from renal cell carcinoma.
3) Histopathological findings of the transplanted tumor and original tumor were basically identical, and that of tumors successively cultured also carried the similar characteristics.
4) Indirect culture through nude mouse also succeeded, and among them included was a cell line established and named KU-2 in November 1976.
5) Histopathological characteristics of the established cell line, even after being transplanted back to nude mouse remains unchanged.
6) Presence of brush-border like structure in the transplanted tumor and radially arranged microvilli in cultured cells observed under electron microscopy is a proof for the current thought that renal cell carcinoma is originated in proximal tubular cell.
7) Erythrocytosis transfered to tumor bearing nude mouse as well as determination of erythropoietin activity in the tumor tissue raised the possibility that the tumor per se was capable of producing erythropoietin.
Development of hepatomegaly in the nude mouse with this particular tumor, in addition to the above observation, can explain the unique functional characteristics of this tumor.

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Recently, a concept of a renal pelvic pacemaker activity controlling ureteral peristalsis has been put forward by several workers (Constantinou 1974, Hrynczuk & Schwartz 1975, Tsuchida & Yamaguchi 1977, Constantinou & Hrynczuk 1977). However, the data is very meagre about the origin and propagation of contraction waves in the renal pelvis. Furthermore, the relation between electrical activity and pressure changes of the renal pelvis has not been understood. To examine these problems, the present paper describes a new method which enables one to record electromyogram continuously on various regions of the renal pelvis and ureter, and to measure simultaneously pelvic pressure changes associated with those electrical activities in vitro.
At the proximal end of the renal pelvis, the interval of EMG was constant throughout the recording period. Pressure variations of the renal pelvis were also rhythmic, and the mean value of the interval between the pressure complexes was the same as that of EMG on the proximal end of the renal pelvis.
These electrical waves generally propagated toward the ureter through the pelviureteric junction. However, some waves faild to conduct within the pelvis as well as at the pelviureteric junction. The ratio of discharge interval between the proximal end and the center of the pelvis were in order of 1:1, 2:1, 3:1 etc., and that between the proximal end and the pelviureteric junction were 1:1, 2:1, 3:1 etc. Thus the discharge interval at the pelvic center, pelviureteric junction and the. ureter were found to be a multiple of the pacemaker interval at low perfusion rate into the renal pelvis. However, at such a high perfusion rate as 1.22ml/min, pacemaker discharge always propagated toward the ureter.

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The measurements of arterial blood flow of transplanted kidney by directional ultrasonic Doppler technique were carried out 52 times in 40 recipients and the output of the flow meter was displayed on soundspectrogram.
The ultrasonic probe was placed over the confirmed site of the transplanted renal artery as follows; the position of the graft artery was identified through the operative procedures and/or by ultrasonotomography, especially using electronic scanning and/or by graft angiography.
The signals from transplanted renal artery were easily distinguished on soundspectrogram from the signals which were reflected from the external iliac artery.
In the transplanted renal artery, the blood flow pattern showed a rapid forward phase in systole (s) and a slow forward phase in diastole (d) but not a reverse flow.
Problems originating from the angle of the probe to the vessel would be resolved by calculation of d/s. Value of d/s, acceleration time and appearance time in the pattern were proved to bee specific to each case. Therefore, evaluation and comparison of these values were significant in analysis of the flow pattern.
Significant correlation between acceleration time and graft function was observed. But no correlation among d/s, appearance time and graft function were observed.
Arterial blood flow patterns of the graft were classified into three groups based on acceleration time. Group 1, group 2 and group 3 corresponded to excellent, intermediate and poor in graft function, respectively.
This method is a safe, simple and noninvasive technique that produces no discomfort on the patient. Therefore, serial blood flow determination by this method is applicable as a diagnostic procedure for follow-up study of the transplantation patients.

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To investigate the relation between changes in ultrasonic Doppler flow pattern in transplanted renal artery and morphological findings in allotransplanted kidney, histopathological and angiographical examinations were simultaneously carried out.
Light microscopic examinations were performed in twenty recipients; open biopsies were done in 17 patients and autopsies in the remainder. Several stain techniques were prepared for evaluating particular features of graft change; vessels, interstitial tissue, tubuli and glomeruli.
Angiograms were obtained from 15 renal homografts of 20 histopathologically examined. The arteriograms were carefully evaluated for abnormalities of the anastomoses and intrarenal arterial branches. The presence or absence of preexisting arterial disease was evaluated by reviewing preoperative donor arteriograms.
Histopathological and angiographical findings were well coincident in far-deteriorated grafts. For example, the histologic vascular changes with interstitial damage were responsible for the angiographical findings such as the sparse arbolization, beading and blocking of the peripheral vasculature. On the other hand, the graft biopsies showed possibility of clinically inactive rejection even in the grafts which were angiographically normal.
These survey revealed that changes in Doppler flow pattern were secondary to morphological changes in allograft mainly induced by rejection. It is possible to speculate about morphological features in graft according to evaluation of the Doppler flow pattern in the graft artery.

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The rationale of the treatment of bladder carcinomas by a hydrostatic pressure technique has been based on the concept that increased intravesical hydrostatic pressure induces a reduction of blood circulation, thus causing ischemic damage on the carcinoma tissues, without affecting the normal bladder wall. The purpose of this study was to determine if an increased hydrostatic pressure induces a significant reduction of the blood flow within the normal bladder wall. Such a study is prerequisite for a better understanding of the hydrostatic treatment of bladder carcinomas.
Twenty dogs weighing 7 to 31kg were used in this study. Under thiamylal-Na anesthesia, the bladder and abdominal aorta were exposed by a median incision in the lower abdomen. intravesical hydrostatic pressure was increased by saline infusion via a catheter secured through a bladder fistula.
Bladder wall PO₂, an index of blood flow, was continuously measured by the Yagi's polarographic oxygen electrode implanted in the muscular layers of bilateral and posterior bladder walls. Changes in the polarographic amplitudes with the increasing hydrostatic pressure were expressed as percent of the control level obtained from the same but empty bladder.
The results obtained were as follows:
1) The mean increments of the bladder wall PO₂ during 100% oxygen breathing were 90±62% (1 S. D.) in the left lateral wall, 54±42% in the right lateral wall and 80±48% in the posterior wall. Thus, the Yagi's polarographic PO₂ measurement was proved to be a potentially useful tool for monitoring bladder wall PO₂ in situ.
2) During an elevation of intravesical hydrostatic pressure, the bladder wall PO₂ was decreased to 50±19% in the left lateral wall, 49±25% in the right lateral wall and 61±24% in the posterior wall, indicating a marked reduction of the blood flow within the bladder wall. The response of bladder wall PO₂ to 100% oxygen breathing was also markedly reduced, suggesting a total obstruction of blood vessels in the bladder wall.
3) The response time, a time between the beginning of O₂ breathing and the onset of PO₂ elevation was prolonged two to five folds that of the control (empty bladder) by the increased intravesical hydrostatic pressure. This is a further evidence of a marked reduction of blood flow in the bladder wall.
4) The PO₂ levels measured at various sites of the bladder did not significantly differ from one another, suggesting a uniform hydrostatic pressure effect on blood flow in the bladder wall.
5) The bladder wall blood flow was restored by reducing intravesical hydrostatic pressure. This suggests that a reduction in the bladder perfusion is reversible and gives no ischemic damage to normal bladder wall.
These results indicate that the therapeutic effect of hydrostatic treatment is probably due to the ischemic insult selective to the carcinoma tissue which is known to be highly vulnerable to the ischemic condition.

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The in vitro reactivity of normal lymphocytes with various serum was determined by quantitation of phytohemagglutinin (PHA)-induced tritiated thymidine incorporation (cpm).
A rate of blastogenesis of lymphocytes was expressed as stimulation index (SI) that was calculated dividing cpm with PHA by that without PHA.
Effects of sera on blastogenesis of normal lymphocytes was expressed as percent change (%SI) per SI with fetal calf serum.
SI of normal lymphocytes showed almost equal value with any one; autologous serum 26.7±11.6 (mean±SD), fetal calf serum 25.4±11.8 and inactivated homologous AB serum 28.8±11.4. But SI of normal lymphocytes with serum from the patients with bladder carcinoma was 14.0±7.9. It was significantly lower than that with fetal calf serum or homologous normal AB serum.
The inhibition of transformation of normal lymphocytes was more significant with serum from the preoperative patients with bladder carcinoma (%SI 57.5±18.9) than the post-operative ones (%SI 85.6±15.6). %SI was lower with serum from the high grade and high stage bladder carcinoma group than the low grade and low stage one.
On the other hand, SI of lymphocytes from patients with other malignant disease, such as prostatic carcinoma and embryonal cell carcinoma of testis, showed significantly lower level with autologous serum than fetal calf serum or homologous normal AB serum. SI of the same lymphocytes was also low with serum from patients with bladder carcinoma as well as autologous one. Therefore, it was likely that the inhibitory effect of serum from the patients with bladder carcinoma was not specific to bladder carcinoma.
Serum globulin fraction was also studied by means of cellulose acetate electrophoresis in 34 patients with bladder carcinoma and 14 patients without carcinoma. There was no difference in the practical pattern of serum globulin between the patients with carcinoma and those without carcinoma. In the former, serum globulin fraction was as follows, α₁ 3.34±0.89, α₂ 8.92±1.67, β 11.13±1.38 and γ 18.21±3.99%. In the latter, each fraction was 3.09±0.57, 8.63±1.76, 10.73±1.03, and 18.36+4.09%, respectively.

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The survival rates were studied in 82 patients with renal cell carcinoma comparing nephrectomy alone to nephrectomy combined with radiation therapy and/or chemotherapy.
The 3-year and 5-year survival rates of all 82 patients were 44% and 39%, respectively.
In 69 patients capable of undergoing nephrectomy of these 82 patients, the 3-year and 5-year survival rates were 50% and 46%, respectively. Surgical procedures in these 69 patients undergoing nephrectomy were transperitoneal nephrectomy in 47 patients, translumbar nephrectomy in 20 patients and thracoabdominal nephrectomy in 2 patients. Examining the relationship between surgical procedures and survival rates in 33 patients with stages II and III to which surgical procedures were considered to be important, the survival rate of 25 patients undergoing transperitoneal nephrectomy was more favorable in comparison with that of 8 patients undergoing translumbar nephrectomy up to 2 years after operation, but no difference was found between both surgical procedures after 3 years or thereafter.
Of 65 patients undergoing nephrectomy and survived more than 2 months after operation, 44 patients received radiation therapy and 38 patients received chemotherapy. And, 28 of these patients received both radiation therapy and chemotherapy.
31 patients received 4, 000-6, 000 rads postoperatively and 13 patients received 3, 000-4, 000 rads preoperatively. The survival rate of these 44 patients were apparently favorable compared with that of 21 patients who received no radiation therapy, and its favorable effect was more prominent in patients with stages II and III.
However, the survival rate was not improved further even if chemotherapy was further added. As chemotherapy, first 3 cases were administered 5-10mg of thio-Tepa, 10-20 times, 10 patients 2-4mg of mitomycin C 10-20 times, and the rest 25 patients 2-4mg of mitomycin, 250-500mg of 5-fluorouracil and 20-40mg of cytosine arabinoside twice a week, totally 10 times after operation.
The survival rate of these 38 patients who received chemotherapy was similar to that of 27 patients who received no chemotherapy. No improvement of the survival rate due to chemotherapy was obtained in patients at every stage.

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In 34 cases of cancers of the urogenital tract such as the bladder, the prostate, and the kidneys, the total hemolytic complement (CH₅₀), the proteins of the complement-system (C_1q, C₁₅, C₄, C₃, C₅, C₉, C_3a and C₃-A) and the proteinase inhibitors (C_1s-INH, AT-III, α₁-AT and α₂-M) in the serum were measured.
Our results are summarized in the following. 1) Among the proteins of the complement-system, C₉ was found to be remarkably elevated in the cases of cancer in the urogenital tract, and its elevation became more predominant as the stage of the illness progressed. 2) C_1s-INH showed a significant increase along with the progression of cancer. The presence of a close correlationship between C_1s-INH and C₄ was documented. 3) C₃-A also demonstrated a tendency to increase as the stage of cancer progressed. A close correlationship between C₃-A and C_3a was observed. 4) AT-III, which showed a generalized tendency to decrease in the cases of cancer, demonstrated a marked decrease in the cases of cancer of the prostate. 5) α₁-AT showed a tendency to increase in all cases and α₂-M showed the same tendency only in male cases of cancer.
From these studies, it is concluded that the presence of a generalized increase of the complement-system in the serum of the cases of cancer in the urogenital tract is confirmed and these findings should be considered pathophysiologically in close association with previously well-documented findings of a decrease of fibrinolytic activity and an increased activation of coagulation system in the blood in the cases of cancer, and it is also speculated that these changes might possibly be supplying a favorable environment for the progression of cancer.

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A clinical study with periodic check-ups of 84 patients who had TUR, TUC or partial cystectomy for cure or control of bladder tumor and in whom there were one or more recurrences is reported.
The results were as follows:
1) Primary recurrences were found in 49 out of the 84 cases (58%). The number of repeated recurrences was one to 8, averaging 1.9.
2) There were two peaks of incidence of recurrence, within 6 months and between one and three years after the treatment. The time of recurrence after TUR and TUC is rather later than that after partial cystectomy.
3) The recurrence was most frequently found solitary and at the same place as the original tumor.
4) The incidence of recurrence was generally high in cases with multiple tumor and tumor with atypical histology.
5) The frequency of recurrences in other part of the bladder was higher in multiple recurrent cases than in single recurrent cases,
6) Histological examination of the specimen obtained in partial cystectomy demonstrated proliferative changes with epithelial hyperplasia close to the tumor. The incidence of such changes developing 5mm or more from the tumor margin was 71 and 23 per cent in recurrent and non-recurrent cases, respectively.
7) There were no recurrence in 3 cases who had bladder irrigation with anticancer drug after TUR
8) There were 4 cases with total cystectomy after repeated conservative treatment.
From the results above mentioned it was stressed that bladder irrigation of anticancer drug after TUR and TUC and sufficient resection of the bladder wall in partial cystectomy is of utmost importance.

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In order to evaluate objectively clinical efficacy and appearance of adverse reactions of amikacin (AMK), a double-blind controlled trial was carried out in patients with complicated urinary tract infections in comparison with gentamicin (GM).
The results obtained are follows:
1) Of 212 patients given AMK and GM, 24 were excluded due to inadequacy for entry criteria, and 14 were due to discontinuation of therapy and other incompliances. The remaining 174 patients were completely eligible for evaluation, each of the 87 patients being treated by AMK or GM.
2) No significant differences were noted between the two treated groups, so far as the background factors and baseline data of the patients are concerned. The two drug groups are considered to be similar and comparable.
3) Clinical evaluation was made after five day administration of 400mg/day of AMK and 80mg/day of GM in two divided intramuscular doses. The overall favorable response rate was 58.6% for AMK treated group and 54.0% for GM treated group, and no significant difference at 5% level was observed. The effect on pyuria and bacteriuria, bacteriological response and improvement in subjective symptoms were also comparable each other.
4) No significant differences were noted between the two treated groups in the stratified analyses. It was, however, noteworthy to see relatively higher cure rate by AMK in such patients generally supposed to be refractory as with the indwelling catheter, mixed infection, and post-prostatectomy infection. Also, AMK is characterized by being effective on the urinary tract infections induced by GM-resistant organisms.
5) Adverse reactions were assessed in 106 patients of each of two treated groups. Frequency of subjective adverese reactions and that of abnormal values in laboratory examination were 1.9% for the two treated groups. however, when AMK is to be given to aged patients or patients with impaired kidney function, careful observation is mandatory as with other aminoglycoside antibiotics.
6) As to the utility assessed by the attending physcians no significant difference was noted between the two drug groups.
7) On the basis of the results AMK is considered to be an agent widely indicated for the treatment of complicated urinary tract infections, whatever the types of infections, morbid conditions and pathogens might be.

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