Efficacy of S-1 in patients with castration-resistant prostate cancer: a phase II study.

OBJECTIVES: This study was conducted to evaluate the efficacy and safety of S-1, an oral fluoropyrimidine derivative, in Japanese patients with castration-resistant prostate cancer (CRPC). The primary endpoint was prostate-specific antigen (PSA) response. METHODS: In this open-label phase II study, S-1 was started at a dose of 80, 100 or 120 mg daily based on body surface area (BSA) for 28 days, followed by 14 days of rest. Patients with histological proof of prostate cancer refractory to hormonal therapies were eligible. Patients who received prior chemotherapy were excluded. All patients provided written informed consent. To observe 20% confirmed PSA response, 33 assessable patients were needed. Treatment was continued until disease progression or the development of intolerable toxicity. RESULTS: A total of 35 eligible patients were enrolled. The median number of treatment cycles was 3. PSA response was observed in 8 patients (22.9%, 90% CI 11.9-37.5), including 3 in which (8.6%) the PSA level normalized. The median overall survival was 25.4 months. The most common treatment-related grade 3 toxicity was anorexia (14.3%). There was no death during the study. CONCLUSION: S-1 monotherapy is active against castration-resistant prostate cancer and has acceptable toxicity.

[One-week effects of Tamsulosin on benign prostatic hyperplasia assessed with a daily symptom score].

The early effects of Tamsulosin within one week of administration on lower urinary tract symptoms in patients with benign prostatic hyperplasia (BPH) were investigated. Patients with newly diagnosed BPH were randomized into a Tamsulosin group and a Eviprostat group. Changes in subjective symptoms daily for 7 days after the start of administration and in the 4th week (8 times in total) were evaluated using seven symptoms in the International Prostate Symptom Score (IPSS) and the quality of life (QOL) index entered in a self-scoring diary kept by the patients daily. In the Tamsulosin group, the IPSS total score showed significant improvements. Significant improvements were observed in the incomplete emptying and frequency scores from the day after the start of administration, in the intermittence and straining scores from day 2, in the urgency and weak stream scores from day 3 and in the nocturia score from day 5. The QOL index significantly improved on day 7. In comparison with Eviprostat, Tamsulosin showed a stronger improvement tendency in the total IPSS, voiding symptoms score and incomplete emptying score and the difference was significant. The difference between the two groups was especially marked for the intermittence and weak stream scores and Tamsulosin showed significantly better early effects. Tamsulosin also showed significantly better early effects than Eviprostat in the QOL index. In conclusion, it was clear that Tamsulosin caused significant improvement in lower urinary tract symptoms associated with BPH as a whole from a very early stage within one week after administration.

[A comparative study assessing clinical effects of naftopidil and tamsulosin hydrochloride on benign prostatic hyperplasia with overactive bladder].

PURPOSE: We compared the efficacy of naftopidil with that of tamsulosin hydrochloride for 154 symptomatic benign prostatic hyperplasia (BPH) patients who also suffered from overactive bladder (OAB) symptoms. MATERIALS AND METHODS: Naftopidil and tamsulosin hydrochloride were administered for eight weeks. The international prostate symptom score (IPSS), QOL index, maximum flow rate (Q(max)), residual urine volume (RUV) and side effect profile were determined before the administration and after eight weeks of treatment. RESULTS: In the naftopidil group, seven parameters of IPSS and QOL index were improved significantly at the endpoint compared to the baseline. In the tamsulosin group, all parameters except frequency and straining were also improved. Both drugs improved the Q(max) at the endpoint, too. The RUV did not change in both groups. Naftopidil was also superior to tamsulosin hydrochloride regarding general treatment outcome by the Japanese clinical guideline of urinary disturbance. CONCLUSIONS: This study demonstrated that naftopidil was clinically efficacious in the treatment of BPH patients with OAB.

[Simultaneous renal cell carcinoma and urothelial carcinoma in ipsilateral kidney, report of two cases].

Two cases of simultaneously developed renal tumors (renal cell carcinoma and renal pelvic urothelial carcinoma) in the ipsilateral kidney are reported. These underwent radical surgery under the diagnosis of renal cell carcinoma or renal pelvic urothelial carcinoma, respectively. The risk of incorrect preoperative diagnosis is discussed in terms of insufficient surgical margins. The liberal use of frozen section diagnosis and more radical resection if applicable may be the key to solve such dilemmas.

Metastasis to the orbit from transitional cell carcinoma of the bladder.

PURPOSE: To demonstrate the pathological features of the extremely rare metastatic transitional cell carcinoma (TCC) from the bladder to the orbit, and to review the literature on metastatic TCC to the orbit. METHODS: A 74-year-old man experienced 2 weeks of red eye, proptosis, diplopia, pain, and visual loss in the right eye. Three years previous to the current presentation, the patient had undergone a transurethral resection for superficial and moderately differentiated TCC of the bladder. A transseptal anterior orbitotomy was performed. RESULTS: Histopathological examination of the orbital lesion revealed nests of carcinomatous cells. Atypical pleomorphic cells with vacuolated cytoplasm were evident. The cellular morphology of the orbital lesion was identical to that of the primary TCC. There have been 12 previously reported cases of metastases to the orbit from TCC of the bladder, with the time from onset of primary TCC to observation of ocular symptoms ranging from 3 weeks to 11 years. Mean survival after orbital metastasis developed from TCC was 3.0 months. CONCLUSION: This study presents a detailed description of the pathological features of metastatic TCC in the orbit. In cases of orbital metastasis from TCC, patient prognosis is very poor.

[A case of pheochromocytoma associated with incidental multiple renal cell carcinoma originating from acquired cystic disease of the kidney in hemodialysis].

The patient was a 52-year-old woman maintained on peritoneal dialysis for 9 years and on hemodialysis for 7 years. This patient complained of palpitations and hypertensive attack during the hemodialysis. Computed tomography and magnetic resonance imaging demonstrated the presence of right adrenal tumor(1.5 x 1.5 cm) and bilateral multiple renal cysts. Right adrenal pheochromocytoma was confirmed by elevated serum level of catecholamines and diagnosed by 131I-MIBG scintigram. This patient underwent right adrenalectomy and nephrectomy in consideration of future generation of cancer in the acquired cystic kidney. Histological examination confirmed malignant pheochromocytoma and small multiple renal cell carcinomas. The patient was alive without any recurrence 6 months postoperatively. To our knowledge, this is the fifth case of adrenal pheochromocytoma and renal cell carcinoma associated ACDK in a hemodialysis patient in the Japanese literature.

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients.

Flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide), a nonsteroidal antiandrogen, is used in the treatment of prostate cancer but is occasionally associated with hepatic dysfunction. In the present study, the metabolism of flutamide including the formation of the possible reactive toxic metabolites was investigated using human liver microsomes and 10 isoforms of recombinant human cytochrome P450 (P450). 2-Hydroxyflutamide (OH-flutamide) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) were the main products of flutamide metabolism in human liver microsomes. The formation of OH-flutamide was markedly inhibited by ellipticine, an inhibitor of CYP1A1/1A2, and was mainly catalyzed by the recombinant CYP1A2. FLU-1 was also produced from OH-flutamide, but its metabolic rate was much less than that from flutamide. An inhibitor of carboxylesterase, bis-(p-nitrophenyl)phosphoric acid, completely inhibited the formation of FLU-1 from flutamide in human liver microsomes. A new metabolite, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine (FLU-1-N-OH), was detected as a product of the reaction of FLU-1 with human liver microsomes and identified by comparison with the synthetic standard. The formation of FLU-1-N-OH was markedly inhibited by the addition of miconazole, an inhibitor of CYP3A4, and was mediated by recombinant CYP3A4. Furthermore, FLU-1-N-OH was detected mostly as the conjugates (glucuronide/sulfate) in the urine of prostate cancer patients collected for 3 h after treatment with flutamide. The formation of FLU-1-N-OH, however, did not differ between patients with and without abnormalities of hepatic functions among a total of 29 patients. The lack of an apparent association of the urinary excretion of FLU-1-N-OH and hepatic disorder may suggest the involvement of an additional unknown factor in the mechanisms of flutamide hepatotoxicity.

A case of ganglioneuroma in which 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol scintigraphy showed high uptake in the adrenal gland leading to a misdiagnosis.

We experienced a case in which 131I-6beta-iodomethyl-19-norcholest-5(10)-en-3beta-ol (131I-adosterol) scintigraphy showed high uptake in the right adrenal gland. We diagnosed functional cortical adenoma because of the finding of 131I-adosterol scintigraphy. However, no positive findings for the existence of cortical adenoma were obtained in other examinations and we performed right adrenalectomy. Unexpectedly, pathological finding showed the right adrenal gland was occupied with a large ganglioneuroma. This is an instructive case in which 131I-adosterol scintigraphy showed abnormal high uptake in the adrenal gland, in spite of the fact that the adrenal gland was occupied by a tumor derived from adrenal medulla.

[Roles of BPH impact index in the evaluation of impaired urination in patients with BPH].

OBJECTIVE: To assess the significance and current status of the benign prostatic hyperplasia (BPH) impact index (BII) in the evaluation of subjective symptoms of impaired urination in so-called QOL disease, BPH. PATIENTS AND METHODS: Over the past 2 year-period, in 159 patients with the diagnosis of BPH were asked to reply to each of the international prostate symptom score (I-PSS), QOL index and BII questionnaires. The subjective symptom scores (a total of 246 points) were evaluated from the viewpoint of clinical statistics in the search for any these and to find which questions cover the BII, most. RESULTS: 1) Statistically significant but moderate correlations were observed among I-PSS total score, QOL index and BII. The correlations among Qmax, BII and QOL were very weak. 2) Out of the 11 domains in both IPSS and BII, 2 questions of BII ("bothersomeness caused by urinary problems" and "degree of worry about well-being") and 4 questions of IPSS ("residual sense," " pollakisuria," "weak urinary stream" and "nocturia") were shared as QOL indices. Patient satisfaction was affected also by the questions in the BII. 3) Of the 7 BPH symptoms assessed in IPSS, 4 symptoms ("residual sense," "pollakisuria," "weak urinary stream" and "nocturia") affected the QOL index, and 4 symptoms ("urgency on micturition," "residual sense," "nocturia" and "strain at urination") affected BII. 4) Of the 7 symptoms assessed by IPSS, different symptoms affected each of the 4 BII questions. CONCLUSION: It is needed to assess BPH symptoms not only by the IPSS and QOL index but also based on BII to provide the detailed therapeutic instructions and thorough patients consultation.

Sarcomatoid renal cell carcinoma with a chromophobe component producing beta-human chorionic gonadotropin.

We report a case of sarcomatoid renal cell carcinoma with a chromophobe component showing significant elevation of beta-human chorionic gonadotropin (beta-HCG) in the peripheral blood. A 35-year-old man was hospitalized because of a large tumor of the left kidney and elevated serum levels of beta-HCG. Extended nephrectomy was performed, after which the serum beta-HCG level decreased. However, 3 months later, masses were discovered in the left renal bed and in the lung in association with elevated serum levels of beta-HCG. The patient was rehospitalized and received combination therapy with interferon-alpha and doxorubicin-based multiple chemotherapy (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). The recurrent mass responded extremely well to treatment, and beta-HCG normalized. However, the patient died 14 months after nephrectomy because of eventual resistance to chemotherapy. Sarcomatoid renal cell carcinoma containing beta-HCG positive cells were pathologically diagnosed with immunohistochemical staining in the left kidney. Sarcomatoid renal cell carcinoma is a variant of renal adenocarcinoma which has a poor prognosis. This patient had an extremely rare sarcomatoid renal cell carcinoma associated with serum levels of beta-HCG which were elevated and strongly correlated with morphologic cancer activity. beta-HCG might be a useful serum marker for detecting and monitoring this renal cell carcinoma.

[Primary, nonviral, hepatocellular carcinoma in patients with prostate cancer treated by hormone therapy: 2 case reports].

We studied two cases of primary, hepatocellular carcinoma (HCC) that occurred following hormone therapy (estrogen therapy in one case and total androgen blockade therapy in another) for stage D2 prostate cancer. Prostate cancer is considered to be hormone-dependent, and androgens appear to be important hormonal factors. However, hepatocellular carcinoma has been shown to have both estrogen and androgen receptors, suggesting that this may be dependent on estrogen or androgen. Reported here are two unique cases of hepatocellular carcinoma in patients with prostate cancer; the pathogenesis of HCC in these patients was suspected to be related to diethylstilbestrol (DES) therapy and antiandrogen therapy for their prostate cancer.

[Invasive squamous cell carcinoma of the bladder: report of 18 cases and review of literature].

PURPOSE: This study was undertaken to determine the most effective treatment for improvement of the prognosis of patients with squamous cell carcinoma of the bladder (SCC). MATERIALS AND METHODS: The subjects included 18 cases of invasive SCC (T2 or worse) we have experienced in the past 10 years. While clarifying the clinical patterns of these cases, the association between stage, therapy, and prognosis was studied. Of the cases of invasive SCC reported in Japan in the recent 20 years, 54 cases in which the stage, therapy, and prognosis were documented were selected, and the association between the therapy and outcome in each stage was studied. RESULTS: In our series, 11 cases are alive without cancer for over 2 years. Of the above patients, 7 underwent cystectomy. Cancer death was experienced in 7 patients. Of these patients, 3 underwent cystectomy, and 6 were classified as stage III or higher. As far as our study of the cases reported in Japan is concerned, the prognosis of the cases having undergone TUR or partial resection of the bladder alone was poor. But, even if patients underwent cystectomy, most of the patients was cancer death in the cases whose cancer was stage III or higher. In the patients receiving some supportive therapy, 4 patients receiving radiation plus cisplatin-based chemotherapy were all alive without for over 2 years. CONCLUSIONS: Total cystectomy is most appropriate as the type of operation for the cases of invasive SCC. But, the cases whose cancer was stage III or higher have high recurrence rate, and must be accompanied with some supportive therapy. We concluded that radiation plus cisplatin-based chemotherapy is a candidate of most effective supportive therapy to improve the prognosis of those patients in the supportive therapy.

[Prostatic cancer in a young adult: a report of 2 cases].

Patients younger than 45 years with prostate cancer are rare. Between 1999 and 2002, we studied two cases of prostate cancer in men aged under 45 years. Case 1; a 45-year-old man admitted with the chief complaint of urination disorder. Serum level of prostate-specific antigen (PSA) was 5,000 ng/ml or higher. Transrectal needle biopsy of the prostate revealed moderately differentiated adenocarcinoma. Computed tomography (CT) and bone scan showed para-aorta lymph node metastasis and bone metastasis. Hormone therapy was performed. Case 2; a 37-year-old man admitted with the chief complaint of pollakisuria and sense of residual urine. Serum level of prostate-specific antigen (PSA) was 24 ng/ml. Magnetic resonance imaging (MRI) showed that the prostate tumor invaded the bladder wall. Transrectal needle biopsy revealed poorly differentiated adenocarcinoma. Hormone therapy and radiation therapy were performed. Twenty-one cases reported in Japan in addition to the present cases are reviewed.

[Clinical characteristics of 16 patients suspected preclinical Cushing's syndrome].

PURPOSE: In 1996, Japanese guidelines for the diagnosis of preclinical adrenal Cushing's syndrome were proposed. However, several patients with preclinical Cushing's syndrome (PCS) didn't clearly show that these diagnostic guidelines were universally applicable. The aim of the present study was to evaluate the validity of these diagnostic guidelines on the basis of our clinical experience. PATIENTS AND METHODS: We performed adrenalectomy for adrenal incidentaloma in 16 patients with suspected PCS at our university hospital from 1990 through 2002. Eight patients met the Japanese criteria for the diagnosis of PCS (PC group) and 8 did not (dexamethasone [DXM] suppression group). Clinical characteristics and pathology profiles were compared between the groups. RESULTS: No patients in the DXM suppression group showed responses of serum cortisol levels on a 1-mg overnight dexamethasone suppression test. Twenty-four-hour urinary levels of 17-hydroxycorticosteroids were significantly higher in the PC group than in the DXM suppression group. In all patients of both groups, adrenal scintigraphy showed marked accumulation of radioisotope in the adhesive, atrophic adrenal cortex. One patient of the DXM suppression group had severe adrenal symptoms after adrenalectomy. Several patients in the DMX suppression group showed clinical improvement after adrenalectomy, as well as did several patients in the PC group. CONCLUSION: Endocrine activity may have been higher in the PC group than in the DXM suppression group. However, because patients who failed a 1-mg DXM suppression test may in fact have autonomous cortisol secretion, adrenalectomy may still be indicated. Autonomous cortisol secretion might not be documented with the 1-mg overnight DXM suppression test; therefore, the results must be interpreted carefully.

Usefulness of tamsulosin hydrochloride and naftopidil in patients with urinary disturbances caused by benign prostatic hyperplasia: a comparative, randomized, two-drug crossover study.

BACKGROUND: The aim of the study presented here was to stratify drug therapy for patients with benign prostatic hyperplasia (BPH) displaying various voiding symptoms. METHODS: Two different alpha1-adrenoceptor antagonists; tamsulosin hydrochloride (Tam) and naftopidil (Naf ), were administered to 96 patients with BPH for 8 weeks in a crossover study. RESULTS: With the administration of both drugs, the International Prostate Symptom Score (I-PSS) significantly decreased and the maximum urinary flow significantly increased. Whereas Naf monotherapy decreased the I-PSS for storage symptoms, Tam monotherapy decreased the I-PSS for voiding symptoms. In both the Naf-to-Tam and Tam-to-Naf groups, crossover was effective when the initial drug was judged subjectively and objectively to have been ineffective. Compliance was acceptable with both drugs. CONCLUSION: Our results show that either Naf or Tam can be used to treat patients on the basis of objective and subjective assessment of voiding symptoms. Our findings should be helpful for patient guidance and treatment of BPH.

[Retrospective analysis of uroepithelial malignancies detected in the renal pelvis and ureter over the past decade at the Jikei University Hospital].

The aim of this study was to investigate recent characteristics and alterations of upper urinary tract cancer based on experience at a single institution over the past decade. Ninety-nine patients with renal pelvic and ureteral cancer resected at the Jikei University Hospital from January 1991 through December 2000 were retrospectively analyzed. Cancer-specific survival by pathologic stage, grade, and various clinical parameters were calculated by the Kaplan-Meier method. Prognostic factors for survival were examined with univariate and multivariate analysis. Cox regression analysis was used for multivariate analysis. Twenty-eight percent of cancers had been detected incidentally without having caused any symptoms. The overall 3-year and 5-year cancer-specific survival rates were 78% and 70%, respectively. The 5-year survival rate was 100% in patients with G1 cancer and 38% in those with G3 cancer. The 5-year survival rate was significantly higher in patients with cancers of lower grade (p = 0.0089), and was also higher in patients with cancers of stage pT1 or lower than in patients with cancers of stage pT2 and higher (p = 0.0038). The survival of patients with recurrence in the bladder was significantly longer than that of patients with recurrence in other organs. Multivariate analysis indicated that patient age and pT were the most important prognostic factors, followed by the presence of symptoms at diagnosis. The incidence of asymptomatic upper urinary tract cancer is increasing at institutions in Japan. We conclude that the cancer grade and stage still have classical predictive value, but that the presence of symptoms at the time of diagnosis is also an important prognostic factor.

Flutamide-induced hepatic dysfunction in relation to steady-state plasma concentrations of flutamide and its metabolites.

The frequency, severity, and outcome of flutamide-induced hepatic injury were prospectively evaluated in 55 patients with prostate cancer who received 125 mg of flutamide 3 times a day (daily dose: 375 mg) combined with an agonistic analogue of luteinizing hormone-releasing hormone. In addition, we examined plasma and urine concentrations of flutamide and its major metabolites 4 weeks after the beginning of flutamide therapy, and evaluated their significance in predicting flutamide-induced hepatic dysfunction. Hepatic function could be assessed in 50 patients and hepatic dysfunction during therapy was observed in 9 patients (18%); 3 patients (6%) were classified as having moderate liver dysfunction and 6 (12%) were classified as having mild liver dysfunction. The steady-state plasma levels of flutamide and its biologic active metabolite, hydroxyflutamide (OH-Flu), were not related to hepatic dysfunction. However, the concentration of another major metabolite, 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) was considerably higher in 2 patients who developed clinically significant hepatic dysfunction. These findings suggest that clinically significant hepatic dysfunction could be induced in patients with compromised flutamide metabolism, which leads to a high concentration of FLU-1. Based on results of this study, we propose that plasma FLU-1 levels are one of the predictive factors for flutamide-induced hepatic dysfunction. This hypothesis will be confirmed in a large-scale study.

A new organic superconductor, beta-(BDA-TTP)2GaCl4 [BDA-TTP = 2,5-(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene].

The preparation, crystal structure and physical properties of beta-(BDA-TTP)2GaCl4 has been investigated; the salt exhibits superconductivity at 3.1 K (onset) under a hydrostatic pressure of 7.6 kbar.

Ser217Leu polymorphism of the HPC2/ELAC2 gene associated with prostatic cancer risk in Japanese men.

The HPC2/ELAC2 gene may be associated with hereditary/familial prostate cancer (PCa). Two common missense variants (Ser217Leu and Ala541Thr) have been reported in the gene. We performed mutational, allelotyping and expression analyses and a molecular epidemiological study to clarify the relations between this gene and prostatic diseases, including PCa and benign prostatic hyperplasia (BPH) in Japanese men. We screened for mutations in 109 patients with PCa including 11 patients from 1 hereditary and 9 familial PCa. Loss of heterozygosity and expression were analyzed. An epidemiological study was done in sporadic PCa (n=98) and BPH (n=143) using 1 novel (Ser627Leu) and 2 previously described polymorphisms of the HPC2/ELAC2 gene. Somatic or germline mutations were not confirmed in any cases of PCa. Loss of heterozygosity at 2 microsatellites, D17S1289 and D17S520, was detected in 1 of 38 and 1 of 35 cases, respectively. Expression analysis revealed decreased or absent mRNA expression in 6 of 38 tumors. Epidemiologic analysis showed that a Leu allele at codon 217 was significantly more frequent in patients with PCa than in controls (10.2% vs. 3.5%, odds ratio = 3.11; 95% confidence interval, 1.22-7.90). At codon 541, all patients with PCa or BPH and all control subjects had the Ala/Ala genotype. At codon 627, the incidence of the Leu variant was slightly, but not significantly, higher in patients with BPH than in controls (7.0% vs. 2.8%, odds ratio = 2.59, 95% confidence interval, 0.94-7.13, not statistically significant). We concluded that germline/somatic mutations of HPC2/ELAC2 are uncommon in PCa. Similarly, allelic imbalances at the gene locus and changes in expression are rare. Although no difference in allele frequency at Ser217Leu between patients with PCa and controls has been reported in a Western population, this polymorphism is a potential indicator of PCa risk in Japanese men and it should be examined in other ethnic groups.

[Mucinous adenocarcinoma of the prostate: a case report and review of 32 cases on immunohistochemical study of both PSA and CEA].

Mucinous adenocarcinoma of the prostate is extremely rare and its biological behavior is not well known. We report a case of mucinous adenocarcinoma of the prostate which stained positively for prostate specific antigen (PSA) and negatively for carcinoembryonic antigen (CEA) on immunohistochemical study. Our case contained conventional adenocarcinomas and no signet-ring cells. Thirty two cases of mucinous adenocarcinoma of the prostate which performed on immunohistochemical study of both PSA and CEA, including our case, were reviewed. 17 of the 23 cases of immunoreactive to PSA contained conventional adenocarcinomas, and 3 of the 10 cases of immunoreactive to CEA contained them, respectively. The 6 cases of immunoreactive to CEA only contained signet-ring cells. It indicated that there seemed to be the two types of mucinous adenocarcinoma of the prostate, the one which stained positively for PSA was the subtype of conventional adenocarcinomas, and the other which stained positively for CEA and negatively for PSA was derived from the intestinal metaplasia with atypia of the prostatic urethra.