Eighteen patients with renal cell carcinoma subjected to nephrectomy were examined for expression of major histocompatibility complex (MHC) class-I and -II antigens by staining with monoclonal antibodies. The neoplastic tissue and normal tissue were examined by the indirect immuno-peroxidase method. Only four of the eighteen patients expressed class-I antigen and no patient expressed class-II antigen in the neoplastic tissue. The normal tissue of all patients expressed class-I antigen. Subsequently, carcinoma tissue was incubated in the tissue culture medium RPMI1640 containing various concentrations of interferon (IFN)-α (0, 10, 30, 100IU/ml) for 24 hours. The incubation of the renal cell carcinoma tissue with the medium without IFN-α did not affect the expression of class-I. Furthermore, the relationship between IFN-α concentration and the expression of MHC antigens was investigated. Groups incubated with 10, 30, and 100IU/ml interferon showed enhanced expression of class-I compared with the control group (p<0.05, p<0.001, p<0.05, respectively). The expression in the 100IU/ml group tended to decrease. Staging and grading in patients did not correlate with class-I expression statistically. The expression of MHC class-II antigen remained unexpressed by IFN-α treatment. There results suggest some relationship between the expressed MHC class-I antigen and IFN-α therapy in renal cell carcinoma. Further, the interferon concentration giving the greatest degree of class-I expression was suggested to be the best therapeutic dose of IFN-α, and the expression level of MHC class-I antigen was considered to be of prognostic value.
Investigation into the clinical application of LAK cells for treating renal cell carcinoma was carried out. LAK cells were induced from peripheral blood mononuclear cells of healthy adults or renal cell carcinoma patients by incubation of peripheral blood mononuclear cells in complete medium (RPMI1640 containing 10% heat-inactivated human AB serum) or serum-free medium (AIM-V) supplemented with IL-2. Then the characteristics of the LAK cells thus produced were studied. When cultured in complete medium, peripheral blood mononuclear cells isolated from healthy adults, recovered to 60% of the initial level on day 4 of incubation. Both NK and LAK activity were markedly enhanced before day 4. On day 4, a similar number of peripheral blood mononuclear blood cells and a similar cytotoxicity were observed in serum-free culture. The cells with a high growth rate during the 4 days of incubation were CD25, HLA-DR, CD3, CD16 cells in both cultures. The supernatant of LAK generation cultures had detectable levels of interferon (IFN)-γ, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α on day 4. IFN-γ and IL-1β both showed significant concentrations in the LAK culture supernatant, which increased progressively with further culture. TNF-α was not produced by LAK cells alone. IFN-γ and IL-β production by the LAK cells was enhanced by stimulation with the Caki-1, ACHN and K-562 tumor cell lines, while TNF-α production was stimulated by Caki-1 and K-562 cells. LAK cells produced an additional effect that was due to cytokine production by the LAK cells in addition to the direct cytotoxicity of them. The recovery rate on day 4 of peripheral blood mononuclear blood cells in the serum-free culture from renal carcinoma patients was equivalent to that from healthy adults. The cultured LAK cells showed a broad-spectrum antitumor effect covering both autologous tumor cells and cultured renal carcinoma cell lines. These results supported that LAK cells inducted by serum-free medium with IL-2 have clinical utility.
We evaluated adoptive immunotherapy using LAK cells combined with systemic administration of interleukin-2 (IL-2) in 11 patients with metastatic renal cell carcinoma. The LAK cells were generated by incubation in serum-free medium (AIM-V) supplemented with IL-2 (1, 000U/ml) for 4 days and were generally administered twice weekly (4 times/cycle). Daily administration of IL-2 (50×105U) was started 3 days prior to the first LAK infusion and continued throughout the cycle. Each course of therapy comprised 1-6 cycles, with the total dose of LAK cells and IL-2 varying from 3.3-52.6×109 cells and 140-900×105U, respectively. Clinical response was evaluated in terms of metastasis to specific organs (lung only: eight cases, lung and brain: one, lung and lymph nodes: one, lung and bone and pleuropericardium: one). The outcome was complete response in one patient, partial response in one, no change in six and disease progression in three. The response rate was 18.8%. This therapy was most effective against pulmonary metastases. Adverse reactions to LAK cell infusion included fever, headache, and chills. Eosinophilia and weight gain due to IL-2 administration were also observed. However, all of these symptoms were transient and no serious side effects occurred. In these patients, the propotion of natural killer (NK) cells (CD16) and cells with IL-2 receptor (CD25) among PBL was increased markedly in the early phase of therapy, and activated T cell (CD3+DR+) and supressor T cells (CD8+11+) increased significantly at a later phase. It was suggested that the clinical response would be expected in case of increasing of CD16 cells or CD25 cells and augmentation of NK or LAK activity. Our results indicate that this regimen of adoptive immunotherapy shows some promise for the treatment of advanced renal cell carcinoma.
Matrixmetalloproteinases (MMP), such as type IV collagenases and interstitial collagenases, play an important role in tumor invasion and metastasis. And tissue inhibitor of metalloproteinases (TIMP) inhibit collagenolytic activity of these enzymes. We investigated the gene expressions of MMP-9 (92kDa type IV collagenase), MMP-2 (72kDa type IV collagenase), TIMP-1 and TIMP-2 in bladder cancers by Northern blot and slot blot hybridization. The mRNA levels of MMP-2, TIMP-1 and TIMP-2 increased in the cases with invasion and metastasis of bladder cancers. These findings suggest that MMP-2 acts as a regulator of the invasion and metastasis of bladder cancers. The MMP-2/TIMP-2 ratio increased as tumor invasion and metastasis progressed, suggesting that an imbalance in the MMP and TIMP ratio promote the invasion and metastasis of bladder cancers. And we also investigated the gene expressions of c-fos that activate the collagenase genes, and there was a correlation between c-fos and MMP-2 in gene expressions. It is suggested that fos gene may play an important role for the invasion and metastasis in bladder cancers.
Recently several authors have observed tissue damages in ESWL treated kidneys, such as interstitial hemorrhage and edema, cavitation of renal tubular cells and vascular spasms. Examination using renal scintigraphy suggested that these damages could cause a decrease of renal blood flow in the treated kidney. Trying to confirm and further investigate this possibility, we studied on changes of renal blood flow velocity using ultrasound color doppler method in 23 consecutive patients with renal stones who underwent ESWL. The studies were conducted before, immediately after and 1 week after an ESWL treatment. Results were as follows; renal blood flow velocity decreased significantly in the area exposed to shock were immediately after the treatment and returned to the pretreatment levels after 1 week. The changes were not significant in the non-exposed area. In parallel with this decrease of renal blood flow velocity, significant increases of resistive index, pulsatility index and significant decreases of ratio were observed. These parameters calculated by mesuring of renal blood flow velocity are known to well correlate with parenchymal vascular resistence. We speculate that these changes in renal parenchymal blood flow velocity are triggeted by the tissue damages caused by the exposure to shock wave. The recovery of renal blood flow velocity may depend on the recovery of the tissue damages. Ultrasuond color doppler method may make it possible to monitor the recovery of tissue damages induced by shock wave and may provide us with an useful information to determine when to repeat ESWL if needed.
The protective effect of prostaglandin I2 derivative (OP-41483), which has actions of antiaggregation of platelets and vasodilatation, to damage by warm ischemia was investigated in rabbit kindeys. Experiment 1) Two weeks after the right nephrectomy, the left renal artery and vein were temporarily clamped for 180 minutes. Before and/or after the clamp was released, OP-41483 was given by i. v. drip (100-1, 000ng/kg/min) for 10 minutes. Renal blood flow (cortical flow and medullary flow) was measured before and after warm ischemia. Changes of blood urea nitrogen and serum creatinin level were measured after warm ischemia. Experiment 2) Bilateral renal arteries and veins were clamped for 180 minutes. OP-41483 (300ng/kg/min) was administered before and/or after clamping the aforementined vessels. The left kidney was removed after warm ischemia of 180 minutes, the other one was removed 60 minutes after the clamp was released, and histological examination was studied. Results were as follows: The blood urea nitrogen and serum creatinin level of OP-41483 treated group were lower than that of non-treated group. The best protective effect was seen when 1, 000ng/kg/min OP-41483 was administered before and after the ischemia. No significant decrease of the renal blood flow was demonstrated after the warm ischemia in the OP-41483 treated group. Histopathologically, OP-41483 has the inhibit effect on detachment of tubular cell from the basal lamina, Bowman's space exudate and swelling of mitochondria.
To study a clinical problem in urolithiasis complicated with bacteriuria treated by extracorporeal shock wave lithotripsy (ESWL), we studied relationships between the frequency of bacteriuria and some clinical factors such as sex, location of, size of and composition of calculi in patients with upper urinary tract calculi. We also evaluated whether bacteriuria caused fever elevation after ESWL monotherapy. Six hundred seventy patients with upper urinary tract calculi, 440 renal calculi and 230 ureteral calculi, were subjected to the present study. The results were summarized as follows: 1) Bacteriuria was found in 40 of 440 patients with renal calculi (9%) and 12 of 230 patients with ureteral calculi (5%). 2) The frequency of bacteriuria was significantly higher in female (11%) than in male (6%) (p<0.05). 3) Ten strains of Pseudomonas aeruginosa, 7 of Escherichia coli and 6 of Proteus mirabilis were isolated in patients with bacteriuria. 4) On the location of renal calculi in patients with bacteriuria, 37 out of 40 patients (93%) were found in R2. In contrast, bacteriuria was the most frequently found in DS 6 (19%), whereas the positive rates were about 10% in DS 3 (7%), DS 4 (7%) and DS 5 (9%). The presence of bacteriuria was not related to the location of calculi or the size of calculi in patients with ureteral calculi. 5) Most of the calculi with bacteriuria were composed of magnesium ammonium phosphate or the mixture of calcium phosphate and carbonate with or without oxalate. 6) Patients with bacteriuria had a significantly higher rate of fever elevation after ESWL than those without bacteriuria (p<0.01).
Transurethral endoureteropyelotomy was performed in a total of 37 patients with primary ureteropelvic junction obstruction or various ureteral strictures. Thirty-one (84%) of the 37 evaluable patients showed a radiographical improvement of hydronephrosis with a mean follow-up period of 15.8±10.5 months (range: 3-40). The clinical success rates were as follows: primary ureteropelvic junction obstruction, 11/12 92%); upper ureteral stricture, 6/7 (86%); lower ureteral stricture, 14/18 (78%). This endourological procedure required a mean operation time of 68.0±27.7 minutes and hospital stay of 7.3±4.9 days. No major complication has been identified. This retrograde procedure has a straight access to the strictured segment of ureteropelvic junction. It is safe and less invasive to the renal parenchym as it does not require percutaneous nephrostomy. Therefore, it might be clinically useful for the treatment of primary ureteropelvic junction obstruction and other ureteral strictures.
We examined pressure-flow test results in 28 male patients with micturition disturbance in whom it is difficult to determine whether bladder outlet obstruction or impaired detrusor contractility is the cause. One reason that some patients do not improve after prostatectomy is that detrusor contractility was not estimated before preoperatively. The degree of infravesical obstruction and of detrusor function were assessed by the method of Griffiths' diagram (maximum flow rate versus corresponding detrusor pressure). Three patients showed infravesical obstruction, 11 equivocal obstruction, and 14 no obstruction. No patients showed strong detrusor function, 14 normal function, and 14 weak function. Eleven patients underwent TU-procedure. Two patients with normal detrusor function and infravesical obstruction showed good postoperative improvement of uroflowmetry results, but 4 patients with weak detrusor function and no infravesical obstruction showed no improvement. Preoperative assessment of the degree of infravesical obstruction and of detrusor function by pressure-flow testing is therefore considered useful. We emphasize that preoperative evaluation of detrusor function is an important aspect of treatment of male micturition disturbance.
To predict histological grade of renal cell carcinoma preoperatively, an equation using plasma immunosuppressive acidic protein (IAP) level and tumor diameter was proposed. Between April 1977 and December 1991, 281 patients, 195 males and 86 females, aged between 20 and 84-year-old, were operated at our institutions. Multivariate analysis was performed to detect relationship between tumor grade and various factors that have continuous quantity. Among plasma components tested, plasma IAP levels showed the best correlation with grade (r value=0.526, n=157). Tumor diameter also showed correlation with grade (r value=0.476, n=273). Therefore, these two factors were used as variates. Discriminant analysis was applied to differentiate the patients with grade 1 or grade 2 tumor from those with grade 3 ones. From this analysis the linear function was obtained; z=6.9429-0.0048x1-0.4118x2 (x1: IAP (μg/ml), x2: diameter (cm)). Tumor was assumed to be grade 1 or grade 2 when z value was positive, and it was assumed to be grade 3 when z value was negative. Overall accuracy was 87.7%. Positive predictive value of grade 1 or grade 2 tumor, and grade 3 tumor was 91.7% and 77.8%, respectively. Sensitivity was 90.9% for grade 1 or grade 2 tumor, and 79.5% for grade 3 tumor. As a result, it's possible to estimate tumor grade before operation using discriminant analysis in patients with renal cell carcinoma.
During the past 20 years from August 1971 to July 1991, 3215 cases of transurethral resection were performed at Kitasato University Hospital, and consisted of 2008 benign prostatic hyperplasias, 692 bladder tumors, 258 prostate cancers, 167 bladder neck contractures, 38 urethral strictures, 20 chronic prostatites and 32 various urologic diseases. On 2266 transurethral resections of the prostate including 2008 benign prostatic hyperplasias, and 258 prostate cancers analysis was conducted. Patient age ranged from 44 to 97 (mean, 70.1). Resected tissue varied from 1 to 177 (mean, 26.9) grams. The time required for resection was from 9 to 245 (mean, 73.0) minutes. The volume of irrigation fluid was from 4 to 92 (mean, 25.0) liters. The duration of catheter placement after operation was 3 to 44 (mean, 4.1) days and hospitalization, 10 to 81 (mean, 12.1) days. The number of complications and blood transfusions were 308 (13.6%) and 381 (16.8%) resectively. Resected amount of tissue, volume of irrigation fluid, duration of catheter placement and frequency of complication in the benign prostatic hyperplasia group exceeded those in prostate cancer group. The length of hospitalization and blood transfusion rates were higher in the prostate cancer group. The rate or frequency of each item increased with the operating time and amount of resected tissue. Today, 60 minutes of operating time as a limiting factor of transurethral resection is not considered a important factor. Based on the results of the 2266 TURP cases, an attempt will be made to establish safer methods of treatment.
Pre-operative and operative complications in 2266 patients having undergone transurethral resection of prostate (TURP) for the past 20 years at Kitasato University Hospital were analyzed. They consisted of 2008 benign prostatic hyperplasia and 258 prostate cancer patients. Seven hundred and fifty four patients showed some of physical disorders prior to TUR: hypertension in 147 cases, diabetes mallitus in 87, ischemic heart disease in 46, chronic obstructive lung disease in 41 and others. Operative and postoperative complications of TURP were seen in 308 cases (13.6%). Perforation of the prostatic capsule was seen in 100 cases (4.4%) and bladder perforation into intraperitoneal cavity in 6 cases (0.3%). Transurethral fulgulation for postoperative hemorrhage was conducted on 79 cases (3.5%). Hyponatremia lower than 130mEq/L was noted in 14 cases (0.6%). Severe urinary tract infection leading to bacteremia was observed in 9 cases (0.4%). Postoperative epididymitis was evident in 20 cases (0.8%). There was postoperative urinary incontinence in 19 cases, 3 of which was treated with Teflon-paste injection successfuly. One patient had to undergo AMS-800 artificial sphincter implantation. The number of postoperative urethral stricture patients requiring urethral dilatation or internal urethrotomy was 12 (0.5%) and postoperative bladder neck contracture was seen in 20 cases (0.9%). One patient (0.04%) who developed DIC after profuse postoperative hemorrhage died on the 37th postoperative day. The efficiency of TURP depends not so much on the skill of cutting as on the speed and accuracy of orientation and haemostasis. The quick recognition of anatomical landmarks will assure effective and safe resection.
Testicular malacoplakia is an extremely rare condition; only 37 cases have been reported in the world literature. We hereby report a case of testicular malacoplakia. In over half of the cases of testicular malacoplakia, a preceding bacterial infection of a gramnegative rod has been known to occur, most commonly Escherichia coli from urine or a suppurative lesion. This evidence may well be significant in explaining a possible initiative or contributing cause of malacoplakia. Orchiectomy is thought necessary to distinguish testicular malacoplakia from other scrotal conditions such as testicular cancer and granulomatous orchitis.