Efficacy and safety of systemic chemotherapy and intra-arterial chemotherapy with/without radiotherapy for bladder preservation or as neo-adjuvant therapy in patients with muscle-invasive bladder cancer: a single-centre study of 163 patients.

INTRODUCTION: Patients with muscle-invasive bladder cancer (MIBC) often undergo various preoperative treatments to improve survival; however, their efficacy and safety remain unclear. MATERIALS AND METHODS: The anti-tumour effects and adverse events were evaluated in 163 MIBC patients who received systemic chemotherapy (SC, n = 34), intra-arterial chemotherapy (IAC, n = 50), or combined IAC and radiotherapy (IAC + R, n = 79). RESULTS: Pathological complete responses were observed in 17.6%, 22.0%, and 43.0% of patients in the SC, IAC, and IAC + R groups, respectively, with respective 5-year overall survival rates of 42.0%, 46.7%, and 50.3%. Multivariate analysis showed that successful IAC + R protocol administration was a significant predictor for survival (hazard ratio = 0.16, p = 0.028). The incidence of severe adverse events was higher in the IAC + R group (36.7%) than in the SC (9.8%) and IAC groups (16.0%). CONCLUSIONS: IAC + R was useful for patients with MIBC. Successful completion and optimal patient selection were important for this treatment strategy.

All-trans retinoic acid enhances gap junctional intercellular communication among renal epithelial cells in vitro treated with renal carcinogens.

Epidemiological and clinical studies imply that retinoids have a chemopreventative action against cancer and can suppress the growth of cancer cells. The regulation of connexin (Cx) expression by retinoids varies among tissues and organs. In this study, we investigated whether all-trans retinoic acid (ATRA) upregulates gap junctional intercellular communication (GJIC) in renal epithelial cells exposed to renal carcinogens. Madin Darby canine kidney (MDCK) cells were incubated with ATRA for 3 days, then briefly exposed to 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or renal carcinogens potassium bromate (KBrO3) and dimethylnitrosamine (DMN). ATRA increased the expression of connexin 43 mRNA and protein without affecting Cx 43 phosphorylation and prevented inadequate Cx 43 localisation caused by TPA/KBrO3 or DMN. Consequently, ATRA prevented the disruption of GJIC in MDCK cells. These data suggest that ATRA enhanced GJIC by upregulating Cx 43 expression and that ATRA might be useful for prevention of renal cell carcinoma.

The expression of platelet-derived endothelial cell growth factor in human bladder cancer.

Platelet-derived endothelial cell growth factor (PD-ECGF) is an angiogenic factor and in some studies PD-ECGF/dTdRPase expression levels in several kind of cancers were higher than in their surrounding normal tissues. In this study, we evaluated PD-ECGF/dTdRPase expression in bladder cancer by an immunohistological method and determined whether it correlated with tumor stage, grade and recurrence. PD-ECGF/dTdRPase expression was correlated with tumor grade and stage. Furthermore, among the superficial tumors, PD-ECGF/dTdRPase expression was correlated with a recurrence-free rate and thus it might be a prognostic factor for the recurrence of superficial bladder cancer.

Changes in the gap junctional intercellular communication in renal tubular epithelial cells in vitro treated with renal carcinogens.

Gap junctional intercellular communications (GJIC) are known as the channels for the direct transfer of cytoplasmic molecules between neighboring cells and are lost during transformation of normal cells. To study the function and the molecular mechanism for the loss of GJIC, the effects of dimethylnitrosamine, KBrO3 and FeSO4 x 7H2O, which are known as chemical tumor promoters of the kidney on the GJIC function and the expression of connexin 43 of Madin-Darby canine kidney (MDCK) epithelial cells, were examined. These tumor promoters inhibited the GJIC in MDCK cells. The expression of connexin 43 mRNA and connexin 43 protein was not altered by these treatments, whereas immunocytochemical study revealed that the distribution of connexin 43 protein was changed from the cell surface to the cytoplasma. These data suggest that blockage of GJIC in MDCK cells treated with renal carcinogens support the hypothesis that loss of GJIC might be important in renal carcinogenesis.

Cooperative effects of v-myc and c-Ha-ras oncogenes on gap junctional intercellular communication and tumorigenicity in rat liver epithelial cells.

The objective of this study was to isolate and partially characterize several rat liver epithelial cell clones containing myc, ras and myc/ras oncogenes in order to study their roles in apoptosis and to test the hypothesis that gap junctional intercellular communication is necessary for apoptosis in solid tissues and that the loss of junctional communication leads to tumorigenesis. The co-transfection of the myc and ras oncogenes in the normal rat liver epithelial cell line (WB-F344) resulted in a loss of functional channels and normal growth regulation; cell-cell communication was significantly decreased and tumorigenicity determined in adult male F344 rats was induced. We examined cell growth properties, gap junctional intercellular communication (GJIC), using the scrape-loading-dye transfer and fluorescence-redistribution-after-photobleaching assays, and tumorigenicity in a series of normal and v-myc-, c-Ha-ras- and v-myc/c-Ha-ras-transfected WB-F344 cell lines. The c-Ha-ras- and the v-myc/c-Ha-ras-transduced cell lines appeared distinctly different from the other lines, having spindle-shaped morphology, shorter generation time and contact insensitivity. On the other hand, the normal WB-F344 cell line and the v-myc-transduced cell line showed excellent GJIC. Moreover, the c-Ha-ras-transduced cell lines displayed decreasing levels of GJIC associated with their increasing tumorigenicity. The v-myc/c-Ha-ras-transformed cell lines showed the lowest levels of GJIC and were also the most tumorigenic. These findings suggest that the reduction of GJIC in c-Ha-ras- and v-myc/c-Ha-ras-transformed WB-F344 cells is linked to their tumorigenic potential. These cell lines should provide valuable tools to study the role of GJIC in apoptosis during tumorigenesis.

Stimulation of cell proliferation and inhibition of gap junctional intercellular communication by linoleic acid.

The effect of linoleic acid (LA) on gap-junction permeability, connexin 43 mRNA level, protein level, and phosphorylation, and the numbers of gap-junctional membrane plaques were studied in the rat liver epithelial cell line WB-F344 to determine whether changes in these parameters correlated with the enhanced cell growth and the inhibition of gap-junction function. When cultured in a medium with low serum (1%), these cells exhibited a slower growth rate than in the high serum medium (7%). Addition of linoleic acid (0.01-3 mg/ml) to the low serum medium increased the growth rate and inhibited gap junctional intercellular communication (GJIC) in a dose-dependent manner. In a comparison of short-term and long-term treatments with LA, GJIC in short-term treated (1 h) WB cells was inhibited at 3 mg/ml LA but readily recovered by washing and removing LA from cells, whereas GJIC in long-term treated (6 days) WB cells did not recover by washing and removing LA from WB cells. Western blot analysis of connexin 43 showed that a short-term incubation with linoleic acid increased the relative amount of unphosphorylated connexin 43 protein, but a long-term incubation with linoleic acid decreased the amount of unphosphorylated connexin 43 protein and increased the relative amount of hyperphosphorylated connexin 43 protein. Connexin 43 and p53 mRNA levels decreased in a time- and dose-dependent manner in linoleic acid-treated cells. These results suggest that growth stimulation and gap junctional intercellular communication inhibition of rat liver epithelial cells by linoleic acid may be mediated in part through modulation of p53 expression and function.

Preparation of monoclonal antibodies against N-(gamma-maleimidobutyryloxy)succinimide (GMBS)-conjugated acetylspermine, and development of an enzyme-linked immunosorbent assay (ELISA) for N1,N12-diacetylspermine.

We have developed three mouse monoclonal antibodies (mAb) of types IgG1 and IgG2b, i.e. anti-acetylspermine (Ac-Spm)-1 and 2 (ACSPM-1 and 2), and anti-acetylspermine (Ac-Spm)-3 (ACSPM-3), respectively, against Ac-Spm conjugated to bovine serum albumin via a heterobifunctional cross-linker, N-(gamma-maleimidobutyryloxy)succinimide (GMBS). Among these mAbs, ACSPM-2 was the most useful for the development of an enzyme-linked immunosorbent assay (ELISA) for acetylpolyamines (Ac-PAs) with glutaraldehyde (GA)-conjugated N1,N12-diacetylspermine (2Ac-Spm) or acetylspermine (Ac-Spm) as the solid phase antigen. However, GMBS-conjugated Ac-Spm did not behave as a solid phase antigen in the competitive ELISA. The ELISA is based on the principle of competition between an analyte and the conjugated antigen for the mAb, followed by immunoreaction with biotinylated anti-mouse immunoglobulin and horseradish peroxidase-streptavidin. The ACSPM-2 mAb reacted with 2Ac-Spm to the highest degree, followed by Ac-Spm, N1-acetylspermidine (N1-Ac-Spd), N8,N8-diacetylspermidine (2Ac-Spd), and spermine (Spm), the EC50 values being 0.06, 0.25, 7.0, 10, and 60 microM, respectively, but exhibited almost no cross-reaction with other polyamine-related compounds or amino acids. The method was used to determine the urinary Ac-PA levels in healthy subjects, the average value of 0.36 microg of 2Ac-Spm/g creatinine (n = 16) being obtained. The ACSPM-2 ELISA for 2Ac-Spm, which was the PA most relevant to the analysis of human urine among the five PA analogs mentioned above, might have potential for elucidation of the correlation of urinary 2Ac-Spm levels in cancers.

Disruption of gap junctional intercellular communication in human renal cancer cell lines.

OBJECTIVES: Gap junctional intercellular communication (GJIC) is believed to play an important role in the maintenance of cell homeostasis, and its disruption may be associated with carcinogenesis. However, GJIC has not been detected in many human cancers. We therefore studied the regulation of GJIC in human renal cancer cell lines. METHODS: We examined the human renal cancer cell lines, ACHN and NT, as well as Madin-Darby canine kidney (MDCK) cells as a positive control, using GJIC assays, Northern blotting to detect connexin 43 mRNA, immunofluorescent staining, and Western blotting of connexin 43 protein. RESULTS: GJIC of ACHN and NT was completely blocked. In ACHN cells, connexin 43 mRNA was not altered. However, connexin 43 protein was aberrantly localized and phosphorylated connexin 43 protein had disappeared. Both connexin 43 protein and its mRNA were undetectable in NT cells. CONCLUSIONS: GJIC in human renal cancer cell lines is impaired and various pathways may inhibit this mechanism in renal cancer. We believe that connexin plays an important role in renal carcinogenesis.

HTLV-I-associated myelopathy associated with multi-organ inflammatory disease: a case report.

We report a 73-year-old man with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM) complicated with multi-organ inflammatory disease, including Sjögren's syndrome, interstitial cystitis, and uveitis. The presence of HTLV-I proviral DNA in peripheral blood mononuclear cells (PBMC), cerebrospinal fluid, salivary gland, mucosa of urinary bladder, and aqueous humor was confirmed by polymerase chain reaction using HTLV-I pX region primer. Western blot analysis revealed the presence of anti-HTLV-I antibodies in serum, CSF, saliva, and urine, suggesting replication of HTLV-I in each tissue. A high load of HTLV-I proviral DNA (20 copies out of 100 PBMC) was present, associated with increased spontaneous proliferation of peripheral blood lymphocytes (24,747 cpm). Our results suggest that the high load of HTLV-I in patients with HAM may potentially induce systemic inflammation in several organs.

TAC-101, a novel retinobenzoic-acid derivative, enhances gap junctional intercellular communication among renal epithelial cells treated with renal carcinogens.

[4-3,5-Bis(trimethylsilyl)benzamido] benzoic acido] (TAC-101), which exhibits an anti-tumor effect, can bind to retinoic acid receptors (RARs). It has retinoid-like properties, such as chemopreventive action against cancer cells. The up-regulation of connexin (Cx) expression by retinoids is well known in various epithelial cells. In this study, we investigated whether TAC-101 up-regulates gap junctional intercellular communication (GJIC) in renal epithelial cells exposed to the renal carcinogens. Madin Darby canine kidney (MDCK) cells were incubated with TAC-101 for 3 days, then briefly exposed to renal carcinogens potassium bromate (KBrO3) or dimethylnitrosamine (DMN). TAC-101 increased the expression of connexin 43 protein without affecting Cx43 phosphorylation and prevented inadequate Cx43 localisation caused by KBrO3 or DMN. Consequently, TAC-101 prevented the disruption of GJIC in MDCK cells. These data suggested that TAC-101 enhanced GJIC by up-regulating Cx43 expression and that TAC-101 might be useful for the prevention of renal cell carcinoma.

[A case of testicular rupture].

A case of testicular rupture is reported. A 26-year-old man was referred to our hospital because of testicular trauma. Ultrasound of the testis was performed preoperatively. Ultrasonography revealed a disruption of the tunica albuginea and dense clusters of echoes in the tunica vaginalis. In the case of acute testicular trauma, this echo pattern suggests testicular rupture.

Angiogenin expression in superficial bladder cancer.

The concentration of angiogenin in the tumor tissues and corresponding normal tissues of 20 superficial bladder cancer patients was measured using a sandwich enzyme immunoassay (ELISA). In addition, immunohistochemical assays were performed in order to clarify the localization of angiogenin expression in bladder tissue. The mean concentration of angiogenin in the carcinoma tissues was significantly lower than that in the corresponding normal tissues (P < 0.001). Angiogenin expression was weak in the bladder cancer cells. The present results show that the expression of angiogenin is lower in superficial bladder cancer tissues than in corresponding normal tissues. The biological role of angiogenin in carcinogenesis of bladder cancer may be different from those of other angiogenic factors.

Malignant lymphoma of the testis presenting as primary testicular tumor.

A case of malignant lymphoma of the testis is presented. A 49-year-old male presented with swelling and dull pain of his left scrotal content. The initial clinical diagnosis was left testicular tumor. Left high orchiectomy was performed immediately after admission and histopathology showed malignant lymphoma, large cell type, B-cell type according to the Lymphoma Study Group (LSG) classification. Extensive investigations revealed clinical stage lE, with no evidence of metastasis. Chemotherapy was initiated with vincristine, prednisolone, adriamycin and methotrexate (VEPA-M). After therapy, the patient is doing well without any evidence of metastasis.

Non-specific granulomatous prostatitis treated with steroids.

A case of non-specific granulomatous prostatitis is reported. The patient, who had a history of sudden onset of high fever and acute urinary retention, had a hard prostate on digital rectal examination that gave us an impression of prostatic cancer. Since repeated biopsy specimens from the prostate showed granuloma formation with fibrinoid necrosis, the case was diagnosed as non-specific granulomatous prostatitis. Steroid therapy promptly resolved clinical symptoms along with marked histopathologic improvement.

[A case of pyonephrosis caused by ureteral stones with elevated serum levels of CA19-9].

A case of pyonephrosis with high levels of serum CA19-9 antigen is reported. A 71-year-old woman was admitted with right flank pain. Computed tomography and ultrasonography showed severe hydronephrosis and hydroureter due to a right ureter stone. Laboratory data revealed a high level of serum CA19-9. However, no tumor was found in the pancreas, gallbladder, liver, gastrointenstinal tract or genitourinary tract. Drip infusion pyelography showed a non-functioning pattern of right kidney. Therefore, right nephroureterectomy was performed for right pyonephrosis. Histological examination revealed chronic inflammation. Malignant cells were not seen in the resected specimen. The serum CA19-9 levels before and after operation were 102.9 U/ml and 24 U/ml, respectively, being normal after the operation. Immunohistochemical examination revealed the presence of CA19-9 antigen in the urethelium, indicating its expression in the specimen. To our knowledge this might be the first case of pyonephrosis associated with high levels of serum CA19-9 antigen.

[A case of prostatic carcinoma presenting as a metastatic orbital tumor].

A 66-year-old man presented with progressive proptosis of the left eye associated with ocular pain. A computed tomographic scan showed a high density mass in the posterolateral portion of the left orbit. The patient underwent surgical removal of the tumor and histopathological examination revealed adenocarcinoma of unknown origin. To find out the primary focus of the tumor the patient was referred to our department, where biopsy of the prostate revealed adenocarcinoma. Further, immunohistochemical examination of the orbital tumor was performed and prostatic acid phosphatase was identified. Finally, we made a diagnosis of orbital metastasis from prostatic carcinoma. This paper presents a rare case of prostatic carcinoma with orbital metastasis and reviews the literature of the subject.

[Transitional cell carcinoma of the renal pelvis in a woman discovered at childbirth].

We report a case of transitional cell carcinoma of a renal pelvis in a woman discovered after childbirth. A 38-year-old woman, who delivered an immature male infant in cesarean section 29 days prior to hospitalization, was admitted complaining of asymptomatic gross hematuria. Excretory urography and retrograde pyelography showed a filling defect of the right renal pelvis, Spontaneous urine cytology indicated class 5. Renal computed tomographic scan demonstrated a mass lesion in the right kidney. Right total nephroureterectomy and partial cystectomy was performed for diagnosis and treatment. Pathological diagnosis was papillary transitional cell carcinoma (grade 2). This is the first case of transitional cell carcinoma of the renal pelvis occurring in a childbearing woman in Japan.

[Induction therapy with CDDP and ADM for stage D prostatic cancer and its clinical response].

From September 1983 to September 1989, 20 patients with newly diagnosed stage D prostatic cancer were treated with cis-platinum (CDDP) and adriamycin (ADM) as the induction therapy. Analysis of histological and clinical effects on the induction therapy revealed partial response (PR) in 13 cases and no change (NC) in 7 cases according to Shimazaki's response criteria, and PR in 4 cases, NC in 15 cases and progression (PD) in 1 case according to NPCP criteria. Histological Ef 0-b effect was found in 2 cases, Ef 1 in 7 cases, Ef 2 in 3 cases, Ef 3 in 2 cases and Ef 4 in 2 cases. Analysis of long-term results revealed relapse in 9 cases and cancer death in 6 cases. The 1-year, 3-year and 5-year continued response rates for all cases were 85.7, 40.2 and 32.1%, respectively. The 1-year, 3-year and 5-year survival rates were 100, 64.3 and 53.6% respectively. Histologically, low responsive cases showed a tendency of relapse and cancer death more frequently than high responsive cases. These results suggest that CDDP and ADM therapy is more effective than hormone therapy in newly diagnosed stage D prostatic cancer as an induction therapy.

[The Cohen cross-trigonal technic for vesicoureteral reflux with contracted bladder in children].

A 8-year-old girl was referred with both vesicoureteral reflux and repeated urinary infection since she was 30 months old. At 5 years old, she had had cystoscopy. Her excretory urogram (IVP) was almost normal; her voiding cystogram showed both vesicoureteral reflux of grade III and a maximum bladder capacity of 75 ml. At cystoscopy the ureteral orifices were in normal position of the trigone and the orifices were dilated like a golf-hole. Both ureters were reimplanted without ureter stents by the Cohen cross-trigonal advancement technique. Her IVP and a renograms postoperatively have shown normal kidney function and no urinary retention in either kidney. Her voiding cystograms have shown no vesicoureteral reflux. For 15 months after operation she has had no urinary infection. The Cohen cross-trigonal technique is a simple, safe and more applicable method than other anti-vesicoureteral reflux operations in cases of vesicoureteral reflux with contracted bladder.

[Bladder involvement in HTLV-I associated myelopathy].

The HTLV-I infection was endemic in south western Kyushu. This human T-lymphotropic virus type I may cause HTLV-I associated myelopathy (HAM), a neurological disease characterized by a spastic paraparesis. And one of the minor diagnostic features of HAM is the presence of cystorectal disturbance. We experienced 35 HAM patients with a neurogenic bladder. A gradually progressive contracted bladder was observed in 3 of them. The main pathological finding in these patients was submucosal infiltration of lymphocytes. These findings suggest that immunologic mechanisms account for the development of bladder lesions.