Overexpression of O-GlcNAc by prostate cancer cells is significantly associated with poor prognosis of patients.

BACKGROUND: O-linked ß-N-acetylglucosamine (O-GlcNAc) is a glycan essential for fundamental cellular processes such as transcription/translation, nuclear transport, protein stability and protein-protein interactions. However, the role of O-GlcNAc in prostate cancer progression of patients remains poorly unknown. Here we investigated the clinicopathological significance of O-GlcNAc expression level in prostate cancer. METHODS: O-GlcNAc expression level in prostate cancer cells was determined by immunohistochemistry of prostate biopsy specimens obtained from 56 patients later treated with hormone deprivation therapy comparing with adjacent normal prostate glands in the same sections. Overall survival was determined by the Kaplan-Meier and Cox proportional hazards methods with univariate and multivariate models. The effects of reduced O-GlcNAc expression level on proliferation and invasion of prostate cancer LNCaP cells were examined using small interfering RNA (siRNA) targeting O-GlcNAc transferase (OGT), the enzyme responsible for O-GlcNAc biosynthesis. RESULTS: Defining cancer cells showing stronger cytoplasmic staining than normal prostate glands as overexpression of O-GlcNAc, 39% of prostate cancer patients were categorized as overexpression. The Kaplan-Meier and Cox proportional hazards methods with univariate model analysis revealed that O-GlcNAc overexpression was associated with overall survival (P=0.0012 for the Kaplan-Meier and P=0.0021 for Cox univariate hazard model analysis). Furthermore, O-GlcNAc was the only item in which a significant difference was observed at overall survival by multivariate analysis (P=0.0475). Finally, siRNA-mediated OGT knockdown in LNCaP cells resulted in decreased expression of O-GlcNAc and promoted decreased proliferation and tumor cell invasion compared with control siRNA-transfected LNCaP cells. CONCLUSIONS: These results indicate that O-GlcNAc expression level in prostate cancer cells is associated with poor prognosis of prostate cancer patients and likely enhances tumor cell proliferation and invasion.

[Complete remission of lung and hepatic metastases from renal cell carcinoma by interferon alpha-2b therapy: a case report].

A right renal tumor was found in a 74-year-old man with multiple metastases to the lungs and liver. Tumor thrombus extending into the inferior vena cava and a right spermatic varicocele were also noted at the first visit. Interferon alpha-2b and interferon gamma were administered for treatment. Partial remission of lung metastases, complete remission of hepatic metastases, and disappearance of the varicocele occurred after 4, 6 and 8 weeks, respectively. Then the primary right renal tumor was resected. Although only interferon alpha-2b was continued twice weekly by self-injection, complete remission of the lung metastases was obtained 13 weeks after the initiation of therapy. No evidence of recurrence or new metastasis has been found after 18 months. These results indicate that even advanced renal cell carcinoma may show a rapid response to interferon alpha. Interferon alpha is worth trying for metastatic renal cell carcinoma and should be continued for at least a few months.

[Augmentation ileocystoplasty as a treatment of vesicoureteral injury following rectal amputation: a case report].

A 65-year-old man underwent transperineal drainage of pelvic abscess after rectal amputation for rectal cancer. The bladder wall and right ureter were injured during this operation, which led to vesicoperineal fistula and contracted bladder. We performed partial resection of the bladder (fistulectomy), augmentation ileocystoplasty (Cup-patch technique), and bilateral ureteral reimplantation (LeDuc-Camey technique). After surgery, the patient was able to void without any residual urine or incontinence. There was no hydronephrosis or resicoureteral reflux postoperatively. Augmentation cystoplasty is usually performed to treat a contracted bladder, but it can also be applied for the reconstruction of complicated lower urinary tract injury, and may improve the quality of life (QOL) dramatically.

[Fatal hepatic failure following hepatitis caused by flutamide: a case report].

A seventy-three year-old patient with prostate cancer underwent radical prostatectomy, followed by total androgen brocking therapy using flutamide and LH-RH agonist. As Hepatic dysfunction (GPT = 3.045 IU/l) was noticed by periodic blood analysis, flutamide was stopped and he was hospitalized immediately without any subjective symptoms. Ten days after the admission, he developed massive bleeding from duodenal ulcer, resulting in duodenal perforation. Following the emergency operation, plasma exchange therapy was repeated against serious hepatic dysfunction. However, he was dead of pneumonia two months after the admission. Autopsy revealed biliary congestion in a small liver, although it was not cirrhotic. In our patient, hepatic dysfunction was irreversible and prolonged. We strongly recommend to perform serial liver function test from the start of treatment with flutamide, especially during the initial three months. Flutamide should be stopped promptly it significant liver abnormalities are detected.

[A case of posterior urethral polyp in a child].

A case of posterior urethral polyp in a child is reported. A 14-year-old boy presented to our hospital with the chief complaint of a sense of residual urine. Ultrasound sonography and cystoscopy showed a posterior urethral tumor (1.5 cm x 1.8 cm). Transurethral resection was performed, and the pathological diagnosis was a fibrous polyp. One year after transurethral resection, the patient showed no signs of recurrence. Only 8 cases of posterior urethral polyp in children have been previously reported in the Japanese literature.

Detection of prostate cancer cells circulating in peripheral blood by reverse transcription-PCR for hKLK2.

Two of the human tissue kallikrein family, hK2 and hK3 (prostate-specific antigen), are primarily produced by the prostatic epithelium under the regulation of androgens. In this study, we detected prostate cancer cells that expressed hKLK2 or hKLK3 mRNA in the peripheral blood of patients with prostate cancer using reverse transcription-PCR (RT-PCR). We then demonstrated some differences in characteristics, such as differentiation of cancer cells and response to antiandrogen therapy, between hKLK2 and hKLK3 mRNA-expressing prostate cancer cells. Total RNA was isolated from 41 patients with known prostate cancer, 7 patients with benign prostatic hyperplasia, and 20 normal volunteers. By RT-PCR, hKLK2 mRNA was detected in 7 patients (33%), and hKLK3 mRNA was detected in 17 (81%) of 21 stage D prostate cancer patients. In contrast, all patients with benign prostatic hyperplasia and healthy volunteers were negative. From comparison of the background of the patients positive for hKLK2 and/or hKLK3 mRNA, it became evident that the response to antiandrogen therapy and the expression of hKLK2 mRNA were reciprocally correlated, in contrast with the expression of hKLK3 mRNA. Additionally, our study clearly demonstrated that the detection of hKLK2 mRNA in the peripheral blood was useful for screening patients with certain prostate cancers that did not express hK3. We conclude that taking advantage of the difference between hKLK2 mRNA and hKLK3 mRNA expression is clinically useful for following up prostate cancer patients.

[Luteinizing hormone-releasing hormone for prostate cancer in a hemodialysis patient: a case report].

An 81-year-old man on chronic hemodialysis was referred to our hospital with urinary difficulty. Transperineal needle biopsy of a hard nodule in the prostate revealed moderately differentiated adenocarcinoma. He was diagnosed to have stage C prostate cancer. A standard dose of luteinizing hormone-releasing hormone (LH-RH) analogue, leuprorelin acetate (3.75 mg), was administered every 4 weeks for 15 months. No adverse effects were observed throughout the period. The clinical response to LH-RH analogue was excellent, with normalization of serum prostate-specific antigen level and relief of dysuria. Thus the standard dosage of LH-RH analogue is considered to be adequate for hemodialysis patients.

[Wilms' tumor with marked calcification in an 8-year-old boy: a case report].

An 8-year-old boy presented with asymptomatic gross hematuria. Clinical investigation revealed an 8-cm left renal tumor accompanied with marked calcification. Radical nephrectomy with lymph node dissection was performed. Pathological diagnosis was Wilms' tumor without lymph node metastasis. He has been free of recurrence 20 months postoperatively. Our case features prominent calcification on radiological examination, which is uncommon in Wilms' tumor. We reviewed the literature on the relationship between renal tumors and calcification.

Sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a kidney transplant recipient.

A case of sarcomatoid renal cell carcinoma with widespread metastases to liver and bones in a cadaver renal transplant recipient is reported in this article. The patient underwent a kidney transplant at the age of 43 and was treated with various immunosuppressive agents after surgery. Twelve months after the transplantation, multiple tumors were found in the liver, and the patient died 8 months later. Pathological examination at autopsy revealed renal cell carcinoma with a sarcomatoid component in the right native kidney and metastases to liver and bones. It is unusual for renal cell carcinoma to undergo sarcomatous transformation and to metastasize to the liver before reaching other organs. We speculate that immunosuppressants may have altered malignant cell proliferation, invasion, and the form of metastasis in this case.

[Clinical evaluation of tandem PSA for the diagnosis and follow-up of prostate cancer].

The Tandem PSA test was performed simultaneously with assay of Markit-M PA and gamma-seminoprotein to determine its usefulness for the diagnosis of prostate cancer in a total of 81 patients with prostate diseases. The diagnosis was untreated prostate cancer in 16 patients including 2 with T1c tumor, benign prostatic hyperplasia in 56 patients, and other diseases in 9 patients. Tandem PSA, Markit-M PA, and gamma-seminoprotein showed a sensitivity of 81.3, 62.5, and 68.8%, respectively, while the specificity was 67.7, 81.5, and 72.3%, respectively. Tandem PSA had the highest sensitivity, although the specificity and accuracy were the lowest. These results were considered to be due to the fact that the PSA level becomes significantly higher with an increase in the weight of benign prostatic hyperplasia. This indicates that the PSA density should be considered to improve the specificity of Tandem PSA. Use of the Tandem PSA/gamma-seminoprotein ratio was also examined as a possible method which might improve the specificity. Patients with benign prostatic hyperplasia and prostate cancer had a ratio of 1.53 +/- 0.966 and 3.21 +/- 1.811 (mean plus standard deviation), respectively, and these 2 groups showed a significant difference (p = 0.0008). This indicates that calculation of the Tandem PSA/gamma-seminoprotein ratio may be useful to improve the specificity of Tandem PSA for the diagnosis of prostate cancer.

[Clinical analysis of 169 patients with prostate cancer].

At Matsumoto National Hospital, 169 patients with prostate cancer were diagnosed between April 1986 and May 1994. The prostate cancer incidence was the highest in the latter half of the seventies, with an average age of 74.3 years. The clinical stage was defined as A1, A2, B, C, and D2 in 24 (14.2%), 38 (22.5%), 39 (23.1%), 23 (13.6%) and 45 (26.6%) patients, respectively. The clinical stage was not correlated with the patient's age. Incidental carcinoma was discovered in 5.8% of the patients who underwent prostatectomy for benign prostatic hypertrophy (BPH). At initial diagnosis, the tumor was well, moderately, and poorly differentiated adenocarcinoma in 71 (42.0%), 64 (37.9%), and 34 (20.1%) patients, respectively. The median follow-up period was 38.7 months. The over all five-year crude survival rate was 54.8%, while the cause-specific five-year survival rate was 80.0%. The five-year crude survival rate was 58.4, 82.0, 55.2, 42.5 and 37.4%, for patients with cancer at stage A1, A2, B, C, and D. The survival rate was higher for patients with cancer at clinical stage A and shorter for those with cancer at clinical stage D than in other stages. Prognosis was also worse in patients with moderately or poorly differentiated adenocarcinoma than in those with well-differentiated adenocarcinoma. The clinical stage and the pathological grade are important as prognostic factors, although the high incidence of death from other diseases shows that the patients' age should be considered to choose the modality of therapy. These findings indicate that intensive treatment of the patients in clinical stage A2, B and C prostate cancer in combination with screening for the men between 50 and 75 years old for early cancer detection is required.

[Bowel anastomosis using valtrac in urologic surgery].

Valtrac, a biofragmentable anastomosis ring, was used in 10 patients who underwent total cystectomy and urinary tract reconstruction. The primary disease was bladder tumor, neurogenic bladder, and sigmoid colon cancer invading the bladder in 8, 1, and 1 of the patients, respectively. There were 8 ileo-ileostomies and 2 ileo-colostomies. No patient developed anastomotic leakage or insufficiency. Symptoms of mild bowel obstruction were observed in 3 patients, but they improved with conservative management. The outcome was good in all the patients without further ileus during a follow-up period of 1 to 12 months (median: 7.3 months). The most important advantage of this device is that precise bowel anastomosis is standardized and can be achieved safely and quickly. Our findings indicate that the Valtrac system offers a reliable and reproducible alternative to conventional anastomotic techniques in urologic surgery.

[A clinical and pathological study of radical prostatectomy for prostate cancer].

BACKGROUND: Thirty-one patients with prostate cancer underwent radical prostatectomy and simultaneous pelvic lymphadenectomy at Matsumoto National Hospital between 1988 and 1994. Prognostic factors are discussed from their clincopathological findings. METHODS: The patients ranged from 54 to 80-year-old, with an average age of 69.9 years. The median follow-up period was 44 months. The diagnosis was confirmed by needle biopsy or transurethral resection of the prostate. All the patients received short-term endocrine therapy preoperatively, and only noncuratively resected patients underwent adjuvant therapy postoperatively. At initial diagnosis, the tumor grades were well, moderately, and poorly differentiated adenocarcinoma in 9, 12, and 10 patients, respectively. The clinical stage was defined as A2, B, C, D1, and D2 in 12, 4, 6, 3, and 6 patients, respectively. RESULTS: A difference of tumor grade was found between the initial diagnosis and the final diagnosis based on the resected prostate in 8 patients (26%), with 7 of them (88%) showing an increase in grade in the final diagnosis. Also revealed was that 11 of the 25 patients (44%) in stage A2, B, C, or D1 had been understaged preoperatively. The five-year actuarial survival rates were 100%, 92%, and 51% for patients with well, moderately, and poorly differentiated adenocarcinoma, respectively, with a significant difference noted between well and poorly differentiated adenocarcinoma (p = 0.03). Recurrence only developed in patients with pathological stage D tumors. However, the presence or absence of lymph node metastasis did not affect the crude 5-year survival rate. Several stage D patients were successfully treated by radical prostatectomy and adjuvant therapy, achieving long survival. CONCLUSION: These results indicate that patients in clinical stage C have tumors which exhibit differing biological behavior. These patients should be analyzed and classified more precisely so that the most appropriate therapy can be chosen.

[Primary malignant lymphoma of the adrenal gland: a case report].

A 65-year-old woman visited our hospital complaining of general fatigue and nausea. CT scan revealed a homogeneous mass in the left adrenal gland, which was seven centimeters in diameter. Mild swelling of the right adrenal gland was also suspected. We failed to find the primary tumor, although a metastatic non-functioning adrenal tumor was suspected. Adrenalectomy was performed under the diagnosis of a non-functioning adrenal tumor. Pathological examination showed a non-Hodgkin's lymphoma. Since a bleeding tendency gradually developed following the operation, a bone marrow biopsy was done, revealing an invasion by tumor cells. Patients with a malignant lymphoma involving the bone marrow should not be operated on because fatal complications may develop postoperatively. A malignant lymphoma should be considered as a possible diagnosis of adrenal tumors, although it is very rare.

Overexpression of a human prostate-specific glandular kallikrein, hK2, in E. coli and generation of antibodies.

The genomic and the cDNA clones of human glandular kallikrein (hK2), a member of the kallikrein family, have been isolated; however, the hK2 protein has not yet been identified and characterized. The deduced sequence of hK2 is highly homologous to prostate specific antigen (PSA), a widely accepted prognostic indicator of prostate carcinoma. Also, hK2 mRNA, like PSA mRNA, is exclusively expressed in prostatic epithelia. These two properties make hK2 a potentially useful marker for studying prostate cancer. In this paper, we describe for the first time the overexpression of the entire hK2 protein (pre-pro hK2:pphK2) in the E. coli system. Our system yields high levels of authentic pphK2 (as determined by partial amino acid sequence analysis) comprising about 40% of total cellular protein. pphK2 was purified to near homogeneity by preparative SDS/PAGE and used to generate anti-pphK2 antibodies in rabbits. The antibodies recognize the recombinant hK2 protein and a major band of approximately 34 kDa in seminal fluid.

[Bladder substitution using ileal neobladder after total cystectomy: report of three cases].

We constructed an ileal neobladder in three patients using Hautmann's technique. The patients were men 51 and 67 years old with invasive bladder cancer and a 45-year-old woman with intractable hemorrhagic cystitis induced by cyclophosphamide. The urethral catheter was removed on the 21st postoperative day. At 2 to 5 months following operation, 3 patients had a vesical capacity of 270 to 500 ml and the maximum volume of urine excreted at one voiding was 130 ml to 400 ml. Voiding cystography disclosed no vesico-ureteral reflux. Two patients required abdominal straining at urination and another patient complained of a slight degree of nocturnal incontinence. Intravesical pressure was retained below 10 cm in hydrostatic height in two patients. On the other hand, it gradually increased as the neobladder was extended in another one. No uninhibited contraction was demonstrated by cystometric examination. The serum chloride level indicated almost the maximum normal value in all patients. Neither hydronephrosis nor residual urine was seen on drip infusion pyelography. The postoperative results indicate that the ileal neobladder using Hautmann's technique may become a very useful way to reconstruct the urinary tract.

Severe cyclophosphamide-induced hemorrhagic cystitis successfully treated by total cystectomy with ileal neobladder substitution: a case report.

A 45-year-old woman with intractable cyclophosphamide-induced hemorrhagic cystitis was successfully treated with total cystectomy and ileal neobladder substitution. To our knowledge this is the first reported reconstruction of the lower urinary tract in a patient with acute hemorrhagic cystitis using a neobladder. Neobladder substitution is contraindicated if the urethra or bladder neck is involved in the disease, although neither was involved in our patient. Whether these lesions are generally left intact has not been discussed previously. If a neobladder can be used, life threatening hemorrhagic cystitis should be treated with total cystectomy accompanied by immediate neobladder substitution.

[Optimal way of administration of granulocyte colony stimulating factor in the treatment of urological cancer].

Granulocyte-Colony Stimulating Factor (G-CSF) was administered to patients with bladder cancer, ureteral cancer and testicular cancer following chemotherapy. Chemotherapy included 23 courses of M-VAC (Methotrexate, Vinblastine, Adriamycin, Cisplatin) therapy to patients with bladder cancer or ureteral cancer and 10 courses of EP (Etoposide, Cisplatin) therapy to patients with testicular cancer. During M-VAC chemotherapy, about a half of the patients experienced leukopenia below 3000/mm3 until the 11th day. Leukopenia failed to improve promptly when G-CSF was started after leukocytes decreased below 3000/mm3. On the other hand, 5-days of prophylactic administrations of G-CSF from the 9th day of M-VAC therapy were able to increase leukocytes promptly. In EP chemotherapy against testicular tumor, G-CSF was started on the 9th day and continued for 5 days. Leukocytes increased immediately and the average duration of leukopenia below 3000/mm3 was only 1.2 day. These results indicate that a short term of prophylactic administration of G-CSF following these chemotherapies is able to accelerate a recovery from leukopenia and decrease a risk of bacterial infection. G-CSF is proposed to be enrolled in the treatment of urological cancer for the improvement of safety and the outcome of therapy.

[Fertility after treatment for testicular tumor].

Thirty-four patients with stage 1 or stage 2A testicular tumor all survived 5 years after the treatment, whereas eighteen patients with stage 2B or 3 testicular tumor, including only nonseminomatous tumor, had a 5-year survival rate of less than 50%. Spermatogenesis returned to normal in 3 patients surviving 22 months after chemotherapy. Five patients who had undergone retroperitoneal lymph node dissection with division of the inferior mesenteric artery developed impaired ejaculation, whereas 3 patients who had undergone the operation without division of the inferior mesenteric artery had normal ejaculation. In 17 patients with right testicular tumor metastases were found in the para-aortic, paracaval and interaortocaval lymph nodes. On the other hand, in 4 patients with left testicular tumor metastases were limited to the para-aortic nodes. These results indicate that impaired spermatogenesis by conventional chemotherapy is reversible in patients with stage 1 or 2 testicular tumor, and patients with stage 1 tumor or stage 2 tumor with localized para-aortic metastases, not involving the inferior mesenteric artery, should undergo retroperitoneal lymph node dissection without division of the inferior mesenteric artery to preserve postoperative fertility.