Endocrine therapy with or without radical prostatectomy for T1b-T3N0M0 prostate cancer

BACKGROUND: We retrospectively compared the 5-year survival rates of T1b-T3N0M0 prostate cancer patients treated either by endocrine therapy plus radical prostatectomy or endocrine therapy alone. METHODS: Clinical T1b-T3N0M0 prostate cancer patients were enrolled at 104 institutions in Japan. They were assigned to study 1 (n = 176), if they were indicated to prostatectomy, if not indicated, they were assigned to study 2 (n = 151). The indication of prostatectomy was based on the clinical judgement of physicians and/or patients. Those assigned to study 1 underwent prostatectomy and adjuvant endocrine therapy with or without preoperative androgen deprivation. Those assigned to study 2 were treated with leuprorelin acetate with or without chlormadinone acetate. They were followed-up every 3 months until death or for 5 years and over. RESULTS: Those assigned to study 1 were younger (mean age 67.2 vs 75.7 years), less advanced in clinical stage, and had lower prostate specific antigen levels (mean 43.8 vs 103.6 ng/mL). Death for any reason was observed less frequently in study 1 (n = 29, 16%) than study 2 (n = 50, 33%), and the 5-year overall survival rate was higher in study 1 (87 vs. 68%). However, prostate cancer deaths were comparatively seldom (9% in study 1 and 7% in study 2), resulting in the identical 5-year cause specific survival rate in both study groups (91%). In both study groups the overall survival was almost equal to the natural survival of age-matched men. CONCLUSIONS: Endocrine therapy offers a reasonable survival rate in T1b-T3 prostate cancer patients within a 5-year follow-up. Observation will be extended to determine 10-year outcomes.     

Stimulation of Prostaglandin Production by Quinolone Phototoxicity in Balb/c 3T3 Mouse Fibroblast Cells in Vitro

Sparfloxacin (SPFX) and levofloxacin (LVFX) with ultraviolet-A(UVA) irradiation have been reported to induce skin inflammationdue to phototoxicity in Balb/c mice. We examined the productionof arachidonic acid metabolites induced by quinolone phototoxicityin Balb/c 3T3 mouse fibroblast cells in vitro. The cells weresimultaneously treated with SPFX or LVFX at 1,10, or 100 µMand UVA irradiation for 5 min (0.5 J/cm²). They were then culturedin quinolone-free medium for 24 hr, and the concentrations ofprostaglandin E₂ (PGE₂ 6-ketoprostaglandin F₁ (6-keto-PGF₁),and leukotriene B₄ (LTB₄) in the incubation medium were measured.Furthermore, the effect of quinolone photoproducts on the productionof the inflammatory mediators and that of indomethacin on PGE₂level were also examined. Treatment with SPFX at 100 µMplus UVA irradiation markedly increased levels of PGE₂ and 6-keto-PGF₁but not that of LTB SPFX or LVFX alone at up to 100 µM,100 µM SPFX, or 100µM LVFX, or less plus UVA irradiation,or UVA-preirradiated quinolone up to 100µM had no effect.indomethacin even at 0.1 µM completely inhibited the PGE₂elevation induced by 100 µM SPFX with UVA. These resultssuggest that PGs released from dermal fibroblasts in the simultaneouspresence of quinolone and UVA could contribute in part to thedevelopment of skin inflammation in vivo.     

Radical prostatectomy and adjuvant endocrine therapy for prostate cancer with or without preoperative androgen deprivation: Five-year results

BACKGROUND: The effects of preoperative androgen deprivation on the outcomes of prostate cancer patients who received radical prostatectomy and subsequent adjuvant endocrine therapy have not yet been fully evaluated. METHODS: Patients with stage A(2), B or C prostate cancers were randomized to one of two groups: group I (n = 90), who received androgen deprivation (leuprolide and chlormadinone acetate) for 3 months followed by radical prostatectomy and subsequent adjuvant endocrine therapy (leuprolide alone), and group II (n = 86), who underwent the surgery followed by 3-month androgen deprivation (leuprolide and chlormadinone acetate) and subsequent adjuvant endocrine therapy (leuprolide alone). The effects of preoperative androgen deprivation on survival, clinical relapse (serum prostate specific antigen, PSA, above the normal level, local recurrence, or distant metastases), and PSA relapse (PSA above the detectable level) were evaluated at 5 years or later after treatment. RESULTS: There were no significant differences in overall, cause-specific, clinical relapse-free, or PSA relapse-free survival rates between the two groups. In a subanalysis, no prostate cancer deaths or clinical relapses were noted in 29 patients with organ-confined disease (OCD: negativity of capsular invasion, seminal vesicle invasion, surgical margins or nodal involvement). The odds ratio for OCD depending on group assignment was 2.44 (95% confidence interval, CI 1.04-5.72), for group I, demonstrating a higher probability of having OCD. This ratio was increased to 4.00 (95% CI 1.06-15.16) if the analysis was conducted in a subpopulation with prostate specific antigen levels less than 35.6 ng/mL and with clinical stage B or C cancers. CONCLUSION: Preoperative androgen deprivation has no demonstrable benefit in 5-year outcomes for patients undergoing radical prostatectomy and adjuvant endocrine therapy. However, it did increase the probability of OCD, which was associated with no clinical relapse during the follow-up. A longer observation is needed to clarify the exact extent of the benefits in terms of survival.     

Relationship between Hepatocyte Necrosis, Proliferation, and Initiation Induced by Diethylnitrosamine in the Male F344 Rat

Diethylnitrosamine (DEN) is commonly used as an initiator inrodent models of multistage carcinogenesis. Because the initiatingactivity of DEN has been attributed, in part, to its inductionof regenerative cell proliferation, the temporal and quantitativerelationships among necrosis, replication, and initiation werecharacterized in livers of male F344 rats subsequent to administrationof a single dose of 10 or 150 mg DEN/kg. Following a dose of150 mg DEN/kg body weight, maximal hepatocellular necrosis wasobserved 2 days postinjection and amounted to 9% of the hepaticvolume being necrotic by light microscopic criteria. Changesin serum levels of alanine and aspartate aminotransferases,indicators of hepatocellular necrosis, paralleled changes inthe necrotic volume fraction. Hepatocyte replication was estimatedusing nuclear labeling with bromodeoxyuridine (BrdU), whichwas constantly infused for 2 or 7 days by osmotic minipump.BrdU labeling was maximally increased at 4 days with 2-day infusion(26.1% in treated vs 0.5% in controls) and at 7 days with 7-dayinfusion (46% in treated vs 2% in controls). Initiation wasquantitated by enumeration of hepatocytes which stained positivefor placental glutathione-S-transferase (GST-P). Increased numbersof GST-P-positive hepatocytes were observed on Day 4 and increasedto a maximum of 109/cm² section area, or 0.077% of all hepatocytes.Thus, the temporal pattern changes following 150 mg DEN/kg bodywt are consistent with the attribution of regenerative cellproliferation contributing to the yield of initiated cells.A comparison of the peak BrdU (2-day) labeling index and thepeak GST-P staining frequency suggests a rate of initiationof roughly 10^–3-10^–4/cell division following 150mgDEN/kg body wt. In contrast, 10 mg/kg DEN did not cause necrosisat Day 2 or increase in BrdU labeling (7-day infusion, 3.1%);however, GST-P hepatocytes were slightly increased over control(1.7 vs 0.0 and 4.1 vs 0.3/cm² at 14 and 28 days, respectively).Thus, cell replication and yield of initiated (GST-P-positive)hepatocytes in rats receiving 10 mg DEN/kg body wt were bothapproximately 100-fold lower than those in rats receiving 150mg DEN/kg body wt. These results indicate the dependence ofthe frequency of GST-P-positive cells on hepatocyte replicationin initiation by DEN and provide crucial response data for quantitativemodeling of experimental hepatocarcinogenesis.     

Morphological Investigation of Cavity Formation in Articular Cartilage Induced by Oiloxacin in Rats

Morphological Investigation of Cavity Formation in ArticularCartilage Induced by Ofloxacin in Rats. Kato, M., andOnodera,T.( 1988).Fundam. Appl Toxwol. 11, 110–119. Ofloxacin,a quinolone antibacterial agent, induced blisters and/or erosionsin the articular cartilage of the humeral trochlea, femoralcondyle, and femoral head of immature rats. Histologically,cavity formation was seen in the middle zone of the articularcartilage. Changes were detected as early as 5 hr after a singleoral administration of 1000 or 3000 mg/kg. These changes werecharacterized by condensation, atrophy, and deformation of thenuclei of chondrocytes distributed in the middle zone. In suchnuclei, aggregation of heterochromatin was observed. Degeneratedcells with vacuolated and partially disintegrated cytoplasmswere also seen in this zone. These lesions were followed byedema of the matrix accompanied with markedly decreased stainabilitywith safranin-O, and a cavity was formed later by liquefactionof the cartilage. The changes were reversible, with reboundingoccurring even with continued treatment with ofloxacin. Theproliferation of chondrocytes around the lesion chiefly contributedto the repair. Ofloxacin had no adverse effects on the articularcartilage in rats when treatment was initiated at 8 weeks ofage or later.     

Imaging characteristics of papillary renal cell carcinoma by computed tomography scan and magnetic resonance imaging

AIM: To analyse the differences in the patterns between clear and papillary renal cell carcinomas using magnetic resonance imaging (MRI) and dual-phase helical computed tomography (CT). METHODS: We examined seven patients with papillary renal cell carcinoma, and six with clear cell carcinoma. The highest attenuation value of tumors in the corticomedullary phase (CMP) and the excretory phase (EP) was measured using the observer-defined region of interest (ROI). MRI consisted of T1-weighted and T2-weighted spin-echo imaging. RESULTS: All five tumors except for one with papillary renal cell carcinoma showed homogenous hypointensity, but all six tumors with clear cell carcinoma showed heterogeneous hyperintensity on their T2-weighted images. In the CMP, the mean CT numbers of the papillary renal cell carcinomas were significantly lower than those of the clear cell carcinomas. The mean enhancement of the papillary renal cell carcinomas in the CMP and the EP was significantly lower than that of the clear renal cell carcinomas. The mean CT numbers of the clear cell carcinomas in the CMP were markedly increased from those on the unenhanced CT; those in the EP were decreased gradually. But the mean CT numbers of the papillary renal cell carcinomas in the EP were still slightly more increased than those in the CMP. The enhancement patterns of the papillary renal cell carcinomas in the CMP and the EP were homogenous, but those of the clear cell carcinomas were heterogeneous. CONCLUSIONS: We can speculate the differential diagnosis from clear to papillary renal cell carcinoma using MRI and dual-phase helical CT.     

Adverse drug reactions of intravesical bacillus Calmette–Guérin instillation and risk factors of the development of adverse drug reactions in superficial cancer and carcinoma in situ of the bladder

BACKGROUND: We examined the incidence and severity of adverse drug reactions following intravesical bacillus Calmette-Guerin (BCG) instillation for superficial bladder cancer including carcinoma in situ. We investigated the relationship between adverse drug reactions and patient background to clarify risk factors for the development of adverse drug reactions. METHODS: A total of 123 patients who underwent intravesical BCG instillation for treatment and prophylaxis between April 1997 and June 2000 were included in this study. Adverse drug reactions were divided into local and systemic categories and the severity of reactions was classified according to the presence or absence of postponement or discontinuation of instillation, with or without treatment for the reaction itself. RESULTS: Of 123 patients, 95.9% showed adverse drug effects and 50.4% needed some sort of treatment. Discontinuation of instillation due to adverse drug reactions was observed in nine patients. Regarding the necessity of treatment for adverse drug effects, the purpose of instillation and BCG dose were independent significant factors on multivariate analysis. CONCLUSION: Although there was a high rate of adverse drug reactions after intravesical BCG instillation, the rate of discontinuation of instillation was not high and serious adverse reactions were rare. The scale of the present study was small, but these results suggest that BCG instillation was well tolerated. When instillation is being performed for the purpose of treatment, and the BCG dose is 80 mg, greater attention might be needed to monitor for the development of adverse drug effects.     

Stage specific follow-up strategy after cystectomy for carcinoma of the bladder

BACKGROUND: Follow-up strategies after cystectomy for carcinoma of the bladder should be determined according to the risk of recurrence, which is stage dependent. We aimed to develop follow-up protocol for monitoring patients with carcinoma of the bladder for tumor recurrence and diverted urinary tract complications after radical cystectomy. METHODS: The records of 351 patients with carcinoma of the bladder who underwent cystectomy between 1979 and 1999 were reviewed for dates and presenting symptoms of local and distant recurrences. The results of imaging studies and blood tests were also reviewed. Based on the division of patients into pathological stages of pT1 and lower, pT2, and pT3 and higher groups, we proposed a new follow-up schedule for carcinoma of the bladder. RESULTS: The risk of metastasis was related to the pathological stage of the primary tumor. Recurrence developed in 10 of 124 patients (8%) with pT1 or lower, 17 of 101 patients (17%) with pT2, and 55 of 101 patients (54%) with pT3 or higher disease at a median of 11 (range 6-186), 10 (1-40) and 7 (1-76) months, respectively. Recurrences in patients with pT3 or higher were found earlier and more frequently than those with pT2 or lower. Of 82 patients with metastases, 54 initially were symptomatic, and three of pT1 or lower, six of pT2, and 19 of pT3 or higher were asymptomatic. Based on these results we proposed a stage specific follow-up protocol. CONCLUSIONS: A stage-driven follow-up strategy for monitoring patients after radical cystectomy can reduce medical expenses while efficiently detecting recurrences and complications.     

Effect of Bile Duct Ligation and Unilateral Nephrectomy on Brain Concentration and Convulsant Potential of the Quinolone Antibacterial Agent Levofloxacin in Rats

To mimic the excretion route of the quinolone antibacterialagent levofloxacin (LVFX) in humans, we produced an excretion-limited(EL) model in male Sprague–Dawley rats by bile duct ligationand unilateral nephrectomy. We then examined the relationshipbetween brain levels of LVFX and its convulsant effects in controland EL animals. Serum concentrations of LVFX in EL animals (EL+ LVFX) were 2.38- and 1.59-fold and brain concentrations were1.33- and 1.19-fold those of the controls (control + LVFX) at30 min after a single intravenous injection of 10 and 100 mg/kgLVFX, respectively. Furthermore EL animals became more susceptibleto the convulsant effect of LVFX with a 1.28-fold decrease inconvulsion-inducing dose. In combination with oral pretreatmentwith 400 mg/kg 4-biphenylacetic acid (BPAA), convulsion-inducingdoses in the control (control + LVFX + BPAA) and EL (EL + LVFX+ BPAA) groups were markedly decreased by 2.25 and 9 times thatof the control + LVFX group. EL operation and BPAA pretreatmentslowed the elimination of LVFX in the serum and brain 4 hr laterin the following order: EL + LVFX + BPAA, control + LVFX + BPAA,EL + LVFX, and control + LVFX groups. This order reflects thatfor the convulsion-inducing doses. These results suggest thatEL rats may be a useful model for humans and that the convulsanteffect of LVFX with or without BPAA arises not only from theattainment of maximum brain concentration but also from delayeddisappearance from the brain.