Atypical multidrug resistance may be associated with catalytically active mutants of human DNA topoisomerase II alpha.

In human cells, atypical drug resistance was previously identified with reduced catalytic activity or nuclear localization efficiency of DNA topoisomerase II alpha (TOP2 alpha). We have shown two etoposide resistant hTOP2 alpha mutants, K798L and K798P confer resistance to etoposide. In this work, we showed these mutants are also resistant against doxorubicin and mAMSA in vivo in the yeast strain ISE2, rad52, top2-4 at the non-permissive temperature. We purified these mutants to characterize the drug resistant mechanism. Purified recombinant proteins were 8- to 12-fold more resistant to etoposide and doxorubicin than wild type TOP2 alpha, and 2-fold more resistant to amsacrine, as measured by accumulation of cleavable DNA. These data show that K798L and K798P may be intrinsically resistant against these drugs in vitro and that this character may confer atypical multidrug resistant phenotype in vivo in yeast.

Endocrinologically active retroperitoneal ganglioneuroma with positive iodine-131-metaiodobenzylguanidine scintigraphy.

BACKGROUND: A case of retroperitoneal ganglioneuroma incidentally found by ultrasonography in a 56-year old woman is presented. METHODS/RESULTS: Computed tomography revealed a solid round tumor 6 cm in diameter on the upper pole of the right kidney. Iodine-131-metaiodobenzylguanidine weakly accumulated in the tumor 24 and 48 h after the injection. Her serum catecholamines were within normal limits apart from slightly elevated norepinephrine at one of the two examinations. During the operation her serum epinephrine and dopamine levels were elevated to about 50 and 800 times higher than pre-operative values, respectively. CONCLUSION: This case is a rare ganglioneuroma in an adult patient that is endocrinologically active.

Advanced testicular germ cell tumor in a hemophilic patient with human immunodeficiency virus infection.

A stage IIIB anaplastic seminoma which occurred in an HIV-infected hemophilia is reported. The patient with hemophilia A was 36 years old and had been seropositive for HIV antibody for 3 years. Inguinal orchiectomy and subsequent chemoradiotherapy for retroperitoneal lymphadenopathy were performed and a marker negative partial response was obtained. In spite of a low initial CD4+ lymphocyte count (90/microliter), the patient tolerated the treatment well without life-threatening opportunistic infection. Although factor VIII supplement was performed, continuous bleeding from the operative wound made postoperative care difficult.

[Management of invasive carcinoma of bladder and abdominal aortic aneurysm (AAA); technique of radical total cystectomy and simultaneous AAA repair].

BACKGROUND: There is no consensus on the optimal surgical treatment for patients with concomitant invasive carcinoma of bladder and abdominal aortic aneurysm (AAA). We experienced two patients who were treated successfully with simultaneous radical cystectomy and AAA repair. The techniques required for the combined procedure and case reports are discussed. PROCEDURE: The goal of the one-stage operation was to minimize the risk of graft infection without compromising postoperative morbidity and mortality secondary to carcinoma of bladder. Initially pelvic lymph node dissection and radical cystectomy were performed. We preferred retrograde cyctoprostatectomy because most of the cystectomy procedure can be performed without opening the peritoneal cavity and the extent of the retroperitoneal dissection can be minimal. A single-stoma ureterocutaneostomy was preferable urinary diversion. Urinary diversions which utilize intestine such as ileal conduit or ileal urinary reservoir may cause contamination of a graft with bowel content and should be avoided. Before or after urinary diversion, aneurysmal resection and a bifurcated graft replacement were performed. The replaced graft was wrapped with the aneurysmal wall. The major omentum was mobilized and fixed in front of the graft, thereby serving as a protective barrier of the graft. A Dacron graft which was sealed with rifampicin-bonding gelatin was used to further reduce the risk of graft infection. RESULT: Two male patients were treated with the one stage radical cystectomy and AAA repair. Single-stoma ureterocutaneostomy and bilateral ureterocutaneostomy were selected as a urinary diversion. No major postoperative complications, except for paralytic ileus in one case, were observed. CONCLUSION: Our experience and reports of others indicate that radical cystectomy and simultaneous AAA repair can be safely performed with less morbidity than staged operations for the management of concomitant invasive carcinoma of bladder and AAA.

Evaluation of transrectal voiding ultrasonography in men with micturition difficulties without apparent organic obstruction of the lower urinary tract.

OBJECTIVE: To examine whether transrectal voiding ultrasonography (TRVUS) can evaluate voiding movement in men with dysfunctional voiding. METHODS: Ninety-nine consecutive men complaining of voiding difficulties without benign prostatic hyperplasia, prostatic cancer, severe bladder neck contracture and urethral stricture received uroflowmetry and TRVUS. Those who had abnormal findings on both uroflowmetry and TRVUS underwent subsequent cystometry combined with electromyography (EMG) to confirm the presence of dysfunctional voiding. RESULTS: Uroflowmetry indicated abnormal findings in 31 of the 99 patients, and TRVUS demonstrated abnormal movements of the posterior urethra during voiding in all of these 31 patients and 11 of the other 68 patients whose uroflowmetry did not indicate abnormality. TRVUS findings of the former 31 were divided into type E (the external urethral sphincter closed or intermittently opened while the bladder neck manifested an opening movement of > 7 mm during voiding in 20) and type I (both the bladder neck and external urethral sphincter manifested an intermittent movement of < 7 mm in 11). Subsequent cystometry combined with EMG in the 31 patients who had abnormal findings on both uroflowmetry and TRVUS revealed overactivity of the external urethral sphincter (OS) and underactivity of the detrusor (UD) in 85 and 35% of type-E group and 55 and 73% of type-I group, respectively. Type E included significantly more OS without UD than type I (65 vs. 18%; p = 0.0233). All of type-E (20/20) and 91% of type-I (10/11) patients had voiding difficulty which resulted from either OS or UD, while a very limited number of patients (4/31) manifested neurological symptoms such as paraplegia except for voiding difficulties. CONCLUSIONS: Both uroflowmetry and TRVUS are easy and useful methods to evaluate dysfunctional voiding in men, especially when neural disorders or organic obstruction of the lower urinary tract are not apparent.

[Relationship between pretreatment serum levels of prostate specific antigen and bone metastasis in prostate cancer].

We retrospectively reviewed pretreatment levels of serum prostate specific antigen (PSA) in 138 newly diagnosed, untreated patients with prostate adenocarcinoma to evaluate the usefulness of serum PSA levels to predict results of radionuclide bone scans. All of the 24 patients with serum PSA levels above 200 ng/ml showed positive bone scans whereas those with serum PSA levels below 10 ng/ml included only three cases (3/51, 5.1%) positive for bone metastasis. All of the three had poorly differentiated adenocarcinoma of the prostate. In conclusion, bone scans may not be necessary in the cases with serum PSA levels less than 10 ng/ml except for those with poorly differentiated adenocarcinoma.

[Study on prevention of flare-up phenomenon following initial LH-RH analogue administration: combination therapy with diethylstilbestrol].

To eliminate the initial testosterone (T) surge and prevent the risk of flare-up induced by the first administration of luteinizing hormone-releasing hormone (LH-RH) analogue, we examined the effectiveness of short-term combination therapy with diethylstilbestrol (DES). Sixteen previously untreated patients with prostate carcinoma (Stage C: 4 cases, Stage D2: 12 cases) were randomly assigned to 4 groups. Each group included 4 patients. Group 1 received DES (500 mg daily injection) for 7 days, staring before the first subcutaneous injection of luteinizing hormone releasing hormone (LH-RH) analogue (3.6 mg of Zoladex depot); Group 2 received 500 mg of DES injection for 7 days prior to the initiation of therapy with the LH-RH analogue, and moreover received a DES injection for 7 days; Group 3 received 500 mg of DES injection for 7 days simultaneously with the first injection of the LH-RH analogue; Group 4 was pretreated with 500 mg of DES injection for 7 days prior to the initiation of therapy with the LH-RH analogue, with additional DES injection for 3 days. In groups 1, 2 and 4 the level of T decreased during the 7 days of DES therapy, and at 3 days after the first injection of LH-RH analogue increased again. The mean T value in groups 1, 2 and 4 decreased by 33.2 +/- 27.6% (mean +/- SE), 20.5 +/- 20.8%, 13.2 +/- 9.8%, respectively, at the day of the first injection of LH-RH analogue, and increased by 75.2 +/- 21.6%, 70.7 +/- 63.4%, 56.7 +/- 46.4%, respectively, at 3 days after the first injection of LH-RH analogue.(ABSTRACT TRUNCATED AT 250 WORDS)

Benign renal tumors detected among healthy adults by abdominal ultrasonography.

Renal ultrasonography was performed on 17,941 healthy adults without any signs suggestive of urinary tract malignancies. Diffusely hyperechoic renal masses indicative of angiomyolipoma were found in 41 (0.23%) of them and those with echogenic image suggestive of renal cell carcinoma in 45 (0.25%). Final diagnosis of the former group included 24 angiomyolipoma, 1 renal cell carcinoma, 9 calculus and 7 normal variants. The latter group included 19 renal cell carcinomas, 1 leiomyoma, 1 cavernous hemangioma and 24 normal variants or cysts. In total, 24 (0.13%) angiomyolipomas, 20 (0.11%) renal cell carcinomas, 1 leiomyoma, and 1 cavernous hemangioma were discovered. The results indicate that asymptomatic benign renal tumors mainly consisting of angiomyolipoma are not uncommon.

Epidermal growth factor binding by membranes of human renal cell carcinomas: establishment of an epidermal growth factor receptor assay for clinical use.

In order to quantitate epidermal growth factor receptors (EGFR) in human renal cell carcinoma (RCC) tissues, the binding of isotope-labeled epidermal growth factor (125I-EGF) to pooled membrane samples from human RCC was studied. Specific EGF binding to membranes at 4 degrees C reached a plateau after 2 h of incubation and remained constant up to 8 h; specific binding at 25 degrees C reached a plateau after 30 min of incubation, then decreased gradually. 125I-EGF binding to the membrane was displaced by both EGF and transforming growth factor-alpha, but not by insulin and basic fibroblast growth factor. Scatchard analysis of the specific EGF binding generated a straight line, indicating a single class of binding sites for EGF, with a dissociation constant (Kd) of 21.1 x 10(-10) M and a maximum number of binding sites of 57.2 fmol/mg membrane protein. When the protein concentration in the incubation medium was adjusted from 0.71 mg/ml to 2.84 mg/ml, Scatchard analysis revealed identical Kd values, and the maximum number of binding sites was proportional to the protein concentration. These results demonstrate the presence of EGFR on RCC membranes and indicate that these receptors can be studied quantitatively.

[Dynamic study of the hormonal levels and tumor markers after the first administration of long-acting LH-RH analogue in patients with prostate cancer].

The dynamics of hormonal levels and tumor markers after the first administration of long-acting luteinizing hormone-releasing hormone (LH-RH) analogue were evaluated in patients with prostate cancer. Eight patients with histopathologically proved prostate cancer who were previously untreated were studied. The surge in plasma testosterone was recognized in 7 patients after the first administration of a long-acting LH-RH analogue, and reached the highest level after the 3rd day in 6 patients and 14th day in 1 patient. The onset of flare-up reaction due to a transient increase in plasma testosterone was recognized in 3 patients, whose clinical symptoms and signs were increased bone pain in 2 patients and acute urinary retention in 1 patient. An abnormal level of serum prostatic acid phosphatase (PAP) and prostate specific antigen (PSA) was observed in 7 of the 8 patients before treatment. The serum PAP and PSA levels slightly increased after treatment in 4 and 3 patients, respectively. These findings suggest that the combination of estrogen or antiandrogen would allow a safer use of long-acting LH-RH analogue to prevent the risk of a flare-up reaction associated with the first administration of long-acting LH-RH analogue.

Epidermal growth factor receptor content in human renal cell carcinomas.

BACKGROUND: The expression of epidermal growth factor receptor (EGFR) mRNA has been demonstrated in human renal cell carcinomas (RCC), but few reports quantitate EGFR in RCC and correlate EGFR content with clinicopathologic findings. METHODS: Using 125I-EGF as a ligand, the maximum binding of EGF in membrane preparations from RCC (EGFR content) was studied by Scatchard analysis. RESULTS: A single class of binding sites for EGF was observed in 74% of RCC and 50% of normal renal tissues. The EGFR content was increased significantly in RCC compared with normal tissues. In all cases in which EGFR was undetectable, there was no evidence of distant metastasis, venous invasion, or regional lymph node involvement, and these patients had a better clinical outcome than patients with detectable EGFR. The EGFR content was significantly lower in nuclear Grade 1 tumors than in tumors of higher nuclear grades. No significant difference between EGFR content and other clinicopathologic findings was detected. CONCLUSION: The determination of EGFR content in RCC may become an important prognostic factor for the biologic behavior of RCC.

[A report of two cases of multilocular cystic renal cell carcinoma: review of 51 cases reported and the results of a prognostic survey].

We report 2 cases of multilocular cystic renal cell carcinoma. One was in a 33-year-old male, presenting with ultrasonic abnormality of the left kidney at an annual employee health care examination. Computerized tomography (CT) demonstrated a 5 cm of multilocular cystic mass adjacent to the lower pole of the left kidney. Another was in a 44-year-old male, presenting with microscopic hematuria at an annual employee health care examination. CT of the abdomen revealed a 6.5 cm of multilocular cystic mass on the upper pole of the right kidney. Both were diagnosed as renal cell carcinoma by the angiography and underwent radical nephrectomy. Gross specimens showed typical multilocular cystic appearance and histopathology showed clear cell carcinoma infiltrating septa and replacing epithelium of the cyst walls. Both patients are alive without evidence of disease at, 21 months and 14 months after operation, respectively. Including our cases, 51 multilocular cystic renal cell carcinoma and multilocular cystic nephroma associated with renal cell carcinoma have been reported. From the review of the literatures and the answer of the questionnaires inquiring about the outcome of the patient to Japanese reporters, the outcome of 38 patients was ascertained. The 10-year survival rates and non-recurrence rate after operation calculated by the Kaphan-Meier formula were 97.3% and 90.3%, respectively. Because of the good prognosis of reported cases, we concluded that we should choose kidney-sparing surgery for the operation of multilocular cystic renal cell carcinoma.

[Asymptomatic multilocular cystic renal cell carcinoma].

From January 1982 to December 1989, we experienced seven multilocular cystic renal cell carcinomas (MLCRCCs) in 36 asymptomatic renal cancers incidentally diagnosed, and none in 23 symptomatic renal cancers (p less than 0.05). No multiocular cystic nephromas (MLCNs) appeared in either group. Though MLCRCCs have been considered to be, in general, extremely rare, they do occur in asymptomatic renal cancers. A multiloculated renal mass with thick septum discovered in an adult by ultrasonography or CT scan should be suspected as being a MLCRCC rather than a MLCN.

[A case of tranilast-induced cystitis with transient ECG changes].

A case of tranilast (Rizaben)-induced cystitis accompanied with possibly hypereosinophilic heart syndrome was described. A 75-year-old male, who had been taking tranilast for allergic dermatitis for two months, was admitted for severe bladder stimulating symptoms which was unresponsive to antibiotic therapies. Clinical examination revealed tenderness of the prostate, aseptic pyuria, eosinophilia, liver dysfunction and electrocardiographic disorders including atrial fibrillation, T-wave inversions and lowered ST segment without any cardiac symptoms. Cystitis symptoms, pyuria, eosinophilia and liver dysfunction improved within several days after discontinuance of tranilast, and ST-T changes on ECG gradually normalized within a few months. Tranilast-induced cystitis has been demonstrated as a type of eosinophilic cystitis. Since pathologic findings of eosinophilic cystitis and hypereosinophilic heart syndrome are markedly similar and all symptoms and signs disappeared after deprivation of tranilast, it appears likely that eosinophilic inflammation was induced to the heart, liver, bladder and prostate of the current patient by tranilast.

Incidence and properties of renal masses and asymptomatic renal cell carcinoma detected by abdominal ultrasonography.

Renal ultrasonography was performed in 45,905 adults, including 41,364 without any signs suggesting urinary tract malignancies, 1,667 with microscopic hematuria only and 2,874 with some signs of malignancy. Renal lesions were found in 355 adults (0.858%) in the asymptomatic, 39 (2.3%) in the microscopic hematuria and 75 (2.6%) in the symptomatic groups, respectively. Renal cell carcinoma was found in 35 (7.5%) lesions: 19 (5.4%) in the asymptomatic, none in the microscopic hematuria and 16 (21.3%) in the symptomatic groups. A total of 47 patients, including 12 other renal cell carcinoma patients transferred from related hospitals, was grouped into 28 without and 19 with symptoms. Primary tumor size and clinical stages were significantly smaller and lower, respectively, in the asymptomatic group than in the symptomatic group. Radical nephrectomy was performed in all but 2 asymptomatic patients. The 5-year survival rates after nephrectomy were 94.7 and 60.9% for the asymptomatic and symptomatic groups, respectively (p less than 0.01). The results indicate that ultrasonography is a useful tool to detect low stage asymptomatic renal cell carcinoma at low cost.

[A bulky mass non-Hodgkin's lymphoma with dysuria in the rectovesical space].

A case of non-Hodgkin's lymphoma is reported. A 71-year-old man presented with complaint of dysuria and urinary frequency. Rectal examination and CT scan revealed a bulky mass in the rectovesical space. Transperineal needle biopsy of the tumor revealed non-Hodgkin's lymphoma, large cell type, diffuse. The patient received combination chemotherapy of adriamycin, cyclophosphamide, vincristine, prednisolone and pepleomycin. After two days the tumor was marvelously reduced in size, and partial response (PR) by CT was achieved after two months. PR was sustained for two months with cyclophosphamide, vincristine and prednisolone. However, the tumor progressed gradually, and he died five months after the first treatment and two additional courses of chemotherapy. Autopsy showed a 1,700 g bulky mass in the rectovesical space. The mass was covered with peritoneum and had a fistula from rectum to central necrosis of the tumor. Nine cases of the non-Hodgkin's lymphoma with complaint of dysuria have been reported in Japan before our case, which seemed to arise from the submucosal tissue of anterior rectal wall, prostate or lymphatic tissue of rectovesical space.

Biological characteristics of a cold-adapted influenza A virus mutation residing on a polymerase gene.

The biological function of a cold-adapted (ca) mutation residing on the PB2 gene of an influenza A/Ann Arbor/6/60 (A/AA/6/60) ca variant virus in the viral replication cycle at 25 degrees C was studied. The viral polypeptide synthesis of A/AA/6/60 ca variant at 25 degrees C was evident approximately 6 hours earlier than the wild type (wt) virus and yielded twice as many products. The quantitative analysis of viral complementary RNA (cRNA), synthesized in the presence of cycloheximide, revealed that A/AA/6/60 ca variant and a single gene reassortant that contains only the PB2 gene of the ca variant with remaining genes of the wt virus produced equal amount of cRNA at 25 degrees and 33 degrees C, which was an amount approximately four fold greater than the wt virus' cRNA synthesized at 25 degrees C. These results strongly suggest that the ca mutation residing on the PB2 gene of A/AA/6/60 ca variant affects the messenger RNA synthesis at 25 degrees C in the primary transcription.