Blinded and uniform causes of death verification in cancer screening: a major influence on the outcome of a prostate cancer screening trial?

BACKGROUND: To assess the agreement between the causes of death assigned by a blinded and uniform review panel of the Rotterdam section of the European Randomised Study of Screening for Prostate Cancer and the official vital statistics and to explore the possible effect of the use of either of these two sources on the outcome of the screening trial. METHODS: A total of 670 deaths amongst men with prostate cancer, reviewed by the causes of death committee (CODC) up to 31st December 2006 were included in this study. The kappa statistics with confidence intervals (CI), sensitivity and specificity of the official statistics were determined, with the CODC considered the gold standard. The rate ratio (RR) and 95% confidence intervals (95% CI) for prostate cancer mortality, official statistics relative to CODC, were calculated following the Mantel-Haenszel procedure. RESULTS: The overall concordance and the kappa between official statistics and the CODC were 90.6% and 0.76 (0.71-0.82), remaining comparable when only the CODC category definitely prostate cancer was applied, with the sensitivity of official statistics increasing from 88.3% to 91.3% and specificity hardly changing (91.3% and 90.5%). High specificity and lower sensitivity is observed in the screening arm, whilst the opposite was seen in the control arm in men aged 55-69 and 70-74 years at entry. Considerable lower false positive rate was seen for both age groups in the screening arm (3.9% and 4.7%) compared to the control arm (8.4% and 14.3%). A statistically significant excess of prostate cancer death was observed for the official statistics in the age group 70-74 years, 1.53 (1.07-2.19), whilst it was not significant for men aged 55-69 at entry, 1.06 (0.83-1.36). CONCLUSION: In the Rotterdam ERSPC section, official statistics tended to overreport prostate cancer as an underlying cause of death, particularly in the age group 70-plus in the control arm, which would overestimate the true effect in favour of screening.

Development of a non-invasive strategy to classify bladder outlet obstruction in male patients with LUTS.

To diagnose bladder outlet obstruction in male patients with lower urinary tract symptoms (LUTS), it is necessary to measure the bladder pressure via a transurethral (or suprapubic) catheter. This procedure incurs some risk of urinary tract infection and urethral trauma and is sometimes painful to the patient. We developed an external condom catheter to measure non-invasively the bladder pressure and developed a strategy to classify bladder outlet obstruction (BOO) based on this measurement. Seventy-five patients with a wide range of urological diagnoses underwent a pressure-flow study followed by a non-invasive study. We tested five different strategies to classify the patients using the provisional International Continence Society (ICS) method for definition of obstruction as the gold standard. Leakage of the external catheter occurred in eight (40%) of the first 20 tested patients. In the remaining 55 patients, only five (9%) of the measurements failed because of leakage. Of the 75 patients, 56 were successfully tested non-invasively. According to the ICS nomogram, the PFS showed that 22 of these patients were non-obstructed, 12 patients were equivocal, and 22 patients were obstructed. Ten of these 56 patients strained, and we found that the relatively high abdominal pressures in these patients were not reflected in the externally measured bladder pressure. Of the remaining 46 patients, 12 of 13 non-obstructed patients and 30 of 33 combined equivocal and obstructed patients could be correctly classified. We developed a simple, non-invasive classification strategy to identify BOO in those male patients who did not strain during voiding.

A mixture of cottonseed meal, soybean meal and animal byproduct mixture as a fish meal substitute: growth and tissue gossypol enantiomer in juvenile rainbow trout (Oncorhynchus mykiss).

Diets incorporating three different sources of extracted cottonseed meal (CM), soybean meal and an animal protein mixture were evaluated for juvenile rainbow trout. Fish averaging 0.96 g were divided into groups of 30; 3 groups per treatment, and each group was fed one of four diets for a 16-week period. Fish meal (FM) was replaced on a 25% protein basis by each of three different sources of CM from California (CA), Tennessee (TN), and Arkansas (AR), U.S.A. In the three CM-containing diets another 25% soybean meal protein and 50% animal protein mixture were also incorporated to completely replace FM protein. The results of growth rate and feed utilization showed that FM could be entirely replaced by a mixture of plant proteins (CM and soybean meal) and animal by-product proteins. Hematocrit levels were significantly lower in the group fed CM-containing diets than in the control. The findings suggest that CM can be used as a good protein source by the incorporation of at least 15% in diets (25% of fish meal protein replacement), and that the nutritive values of CM in juvenile trout can be different due to their different origin. Significantly higher concentrations of total gossypol were found in faeces of CM-TN (5.8 +/- 0.4 micromol/g) and CM-AR (5.6 +/- 0.6) groups than in that of CM-CA (3.7 +/- 0.4) group. It was documented that gossypol enantiomers, present in an equal proportion in diets, selectively accumulated in liver and bile, whereas equal proportions of (+)- and (-)-enantiomers were found in whole-body and faeces. Depending on CM source, fish can absorb approximately 35-50% of dietary gossypol, and the majority of the absorbed gossypol seemed to be excreted.

Reproductive efficiency and maternal-offspring transfer of gossypol in rainbow trout (Oncorhynchus mykiss) fed diets containing cottonseed meal.

In a preceding study, complete substitution of fish meal protein with cottonseed meal (CM) protein did not affect the survival or growth rate of adult rainbow trout over a 6-mo period. Gossypol, a naturally occurring compound in cottonseeds, has an antifertility effect in terrestrial animals, but information regarding salmonid fish is lacking. Female rainbow trout in this experiment were fed diets with either 0, 25, 50, 75, or 100% (diets 1 to 5) of the fish meal protein replaced with CM protein until first maturation and spawning to study long-term effects on growth and reproduction. Feeding diets containing CM over a total period of 10 mo did not result in differences in growth and mortality compared to the control group (P > 0.05). Increased CM incorporation levels resulted in decreased (P < 0.05) blood hemoglobin (10.6 +/- 1.3, 8.4 +/- 1.8, 7.3 +/- 1.1, 6.9 +/- 0.8, and 5.6 +/- 1.4 g/dL) and hematocrit (49.6 +/- 3.9, 38.5 +/- 9.3, 34.4 +/- 3.7, 34.8 +/- 4.9 and 28.0 +/- 6.8%) levels in diets 1 to 5, respectively. The CM incorporation level had no effect (P > 0.05) on the number of eggs produced per female but led to a reduction (P < 0.05) in egg weight. Eyed stage survival of embryos was low in all dietary groups and did not show differences (P > 0.05). However, an increasing CM incorporation level led to a linear increase (P < 0.05) in the number of females that produced no viable embryos (23.1, 37.5, 42.9, 60.0, and 71.4%). Gossypol in the diet was absorbed by the female trout and transferred to the eggs (0, 2.2 +/- 0.5, 6.7 +/- 1.6, 10.6 +/- 4.2, and 20.0 +/- 2.6 micrograms/g in diets 1 to 5, respectively). A high concentration of gossypol remained in the juveniles at the swim-up stage (endogenous yolk-absorbed) (0.6 +/- 0.3, 2.4 +/- 0.3, 3.4 +/- 0.0, and 4.7 +/- 1.0 micrograms/g, diets 2 to 5, respectively). The findings suggest that replacement of the dietary fish meal protein with CM protein has no effect on fish growth and mortality but may lead to a reduction in reproductive performance in female rainbow trout.

Gossypol isomers bind specifically to blood plasma proteins and spermatozoa of rainbow trout fed diets containing cottonseed meal.

We investigated the role of gossypol isomers binding to blood plasma, seminal plasma and spermatozoa to elucidate gossypol anti-fertility action in the teleost fish, rainbow trout (Oncorhynchus mykiss). Growth and hematological indicators of males were depressed when fish meal protein in diets was completely replaced with cottonseed meal. The cottonseed meal contained equal proportions of (-) (47.8+/-1.6%) and (+) gossypol isomers. Concentrations of spermatozoa were decreased with increasing proportions of gossypol in diets (from 0.22% to 0.95%); however, sperm motility and fertilizing ability were not affected. In contrast to mammals, steroid hormone concentrations were not suppressed in fish given diets with gradual increase of gossypol level. Gossypol concentrations were 100-fold higher in blood plasma than in seminal plasma, confirming a barrier in gossypol transfer between the general circulation and the testis. Spermatozoa accumulated predominantly (+) enantiomer (65-75%) with decreasing proportions as dietary gossypol concentrations increased. Spermatozoa bound most of the gossypol contained in the semen; however, this did not result in impairment of the sperm motility apparatus. Teleost fish sperm rely on ATP stores that accumulate during maturation as a source of energy during activation. In addition, the duration of sperm movement is short in these fish. As such, we hypothesize that the major action of gossypol on mammalian sperm, which is uncoupling of oxidative phosphorylation, does not impair the energy supply required for flagellar beating in fish spermatozoa.

Effects of diets containing gossypol on reproductive capacity of rainbow trout (Oncorhynchus mykiss).

We evaluated five practical diets in which 0%, 25%, 50%, 75%, and 100% (dietary treatments 1-5) of fish meal protein was replaced by solvent-extracted cottonseed meal protein. Adult rainbow trout (initial average weight 247 +/- 8 g) were fed the diets over a period of 131 days during which a general 2-fold body weight increase occurred. The total diet gossypol concentration (free and protein-bound) showed a gradual increase with increased cottonseed meal substitution. Blood samples were collected on Days 0, 64, 112, and 131 for hematological and steroid hormone determination in plasma of males and females. Hemoglobin content was significantly reduced in fish from treatment 5 (7.9 +/- 0.3 g/dl) in comparison to treatments 1-3 (10.3-10.9 g/dl). After 112 and 131 days of feeding, testis weights, concentrations of testosterone, and 11-ketotestosterone were elevated in fish from dietary treatments 2 and 3 in comparison to control and diets 4 and 5. On Day 71, sperm were collected from 6 fish per dietary treatment to assess sperm quality. No significant differences in sperm concentrations (7.2-9.8 x 10(9)/ml), motility (78-89%), and standardized (300 x 10(5) sperm/egg) fertilizing ability (18.9-22.6% hatched embryos) were found. Total gossypol concentrations in blood plasma differed significantly among treatments, and the levels were among the highest ever recorded in animals fed cottonseed-supplemented diets (2.9 +/- 0.2, 11.7 +/- 4.1, 21.7 +/- 1.4, and 29.9 +/- 3.9 microg/ml, for treatments 2-5, respectively). The major portion of gossypol in blood plasma was protein-bound (81-93%). This was in contrast to minute amounts of gossypol present in seminal plasma, mostly in free form (0.02-0.18 microg/ml), which indicates the presence of a barrier between general circulation and the testis with respect to gossypol distribution in lower vertebrates. Thus, the reproductive parameters of male rainbow trout examined in this study were not significantly affected by feeding cottonseed meal for 131 days.

Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group.

OBJECTIVE: The authors present demographic and surgical data from a randomized phase III trial, instituted by the EORTC Genitourinary Group in 1988, the aim of which was to assess whether complete lymph node dissection in conjunction with radical nephrectomy for renal cell cancer is more effective than radical nephrectomy alone. METHODS: Before surgery, the renal cell carcinoma was staged and judged to be nonmetastatic and resectable. The patients were randomized prior to surgery into those having radical nephrectomy combined with complete lymph node dissection or into those having radical nephrectomy alone. Postoperatively all patients were followed until progression of disease or death. RESULTS: Of the 772 randomized patients, 41 were not eligible. 383 had a complete lymph node dissection together with a radical nephrectomy. 389 had a radical nephrectomy alone. The complication rate did not differ significantly between the two groups. A complete lymph node dissection in 336 patients revealed absence of lymph node metastases in 325 of them. CONCLUSIONS: The present study shows that complete lymph node dissection does not add morbidity to the radical nephrectomy. After proper preoperative staging, the incidence of unsuspected lymph node metastases is low (3.3%).

Diagnosis and management of seminal vesicle cysts associated with ipsilateral renal agenesis: a pooled analysis of 52 cases.

OBJECTIVE: Seminal vesicle cysts combined with ipsilateral renal agenesis represent a rare urological anomaly. We searched the literature to review the clinical presentation, diagnosis and therapeutic treatment options of this anomaly. METHODS: A pooled analysis was performed of 52 cases of seminal vesicle cysts combined with ipsilateral renal agenesis, including our own observation. The evaluation included: patient age at diagnosis, race, laterality (R/L), presence of ureteral remnant in the cyst, presenting symptoms, diagnostic examinations, treatment and outcome. RESULTS: The mean age at diagnosis was 30.2 years. The majority presented in the 2nd, 3rd and 4th decade of their lives. Only 2 patients (4%) were of African origin, all others were Caucasians. The distribution R:L was 2:1. Ureteral remnants were present in 14 patients (27%). The most common symptoms were: dysuria (37%), frequency (33%), perineal pain (29%), epididymitis (27%), pain following ejaculation (21%) and scrotal pain (13%). Infertility was found in 9 patients (17%). The cyst was palpable by digital rectal examination in 79%. All patients underwent intravenous urography, and 88% underwent cystoscopy. Other frequently performed investigations are: ultrasonography (27%), CT scanning (27%), vasovesiculography (46%) and urethrocystography (23%). The final treatment was open surgery in 74%, aspiration in 6%, transurethral deroofing of the cyst in 6% and spontaneous rupture in 4%. In 6% no treatment was given and in 4% the treatment is unknown. All patients were free of symptoms after open exploration. The success rates after transurethral deroofing and aspiration were 75 and 30% respectively. CONCLUSION: Seminal vesicle cysts combined with ipsilateral renal agenesis are a rare urological anomaly, occurring in men in the 2nd to 4th decade of their life. They present with symptoms of bladder irritation and obstruction and with pain in the perineum and scrotum. Epididymitis is frequently found. The diagnostic work-up consists of a digital rectal examination, transrectal and abdominal ultrasonography, CT scan and a cystoscopy. Open surgery and transurethral deroofing of the cyst give excellent results (100 and 75% cure respectively). Aspiration of the cyst should only be used for diagnostic purposes.

Continuous of "pulse-and-withdraw" supply of ascorbic acid in the diet: a new approach to altering the bioavailability of ascorbic acid, using teleost fish as a scurvy-prone model.

In scurvy-prone animals ascorbic acid uptake is regulated by the number of intestinal "brush-border" carriers available for transport. The number of carriers is negatively affected by an increasing dietary ascorbic acid intake, thus limiting the maximum attainable uptake. We tested a new approach towards manipulating the accumulation of ascorbic acid in rainbow trout by repeatedly feeding a 10 day ascorbic acid allowance in a 1 or 3 day "pulse" followed by withdrawal, rather than spread out over the entire 10 day period. Pulse dosing led to initially increased mortalities compared to continuous dosing, but this was reversed after 55 days. Although individual weight and cumulative mortality were not significantly different after 88 days, total liver ascorbic acid levels were significantly higher in the 1-day pulse group (16.3 +/- 3.9 micrograms/g) than in the 3-day pulse (9.8 +/- 0.9 micrograms/g) or continuous (9.3 +/- 0.9 micrograms/g) groups. This led us to conclude that after an initial adaptation phase a feeding profile with intermittent ascorbic acid withdrawal results in a compensatory increase in uptake of ascorbic acid from the diet and/or a better conservation of the body pool of ascorbic acid, opening interesting new avenues for ascorbic acid dosing and therapy.

Reproductive success of female rainbow trout (Oncorhynchus mykiss) in response to graded dietary ascorbyl monophosphate levels.

Ascorbic acid is an essential nutrient in rainbow trout diets and has been shown to play an important role in fish reproduction. Recommended dietary levels are based on immature fish, and the specific requirements for brood stock are unknown. To establish the optimum dietary level for mature rainbow trout, six graded levels of ascorbyl-2-monophosphate were fed to groups of female fish over a period of 10 mo until spawning. Increasing dietary levels of ascorbyl monophosphate resulted in significantly increased ascorbic acid concentrations in liver, kidney, ovaries, and ovulated eggs. Liver and egg concentrations were saturable at 109.3 and 266.6 micrograms ascorbic acid/g tissue, respectively. Tissue saturation levels of 83.7% and 91.2%, respectively, were reached at the highest dietary level (870 mg ascorbyl monophosphate/kg diet) tested. Both fecundity and embryo survival increased significantly with dietary ascorbyl monophosphate levels. The results indicated that the present National Research Council recommended dietary level of 50 mg ascorbic acid/kg diet for rainbow trout is inadequate for brood stock fish. An amount 8 times higher is necessary to optimize tissue ascorbic acid levels and achieve maximum reproductive success.

The influence of age on treatment choice and survival in 735 patients with renal carcinoma.

OBJECTIVE: To determine whether age is related to treatment choice and survival in patients with renal carcinoma. PATIENTS AND METHODS: In this retrospective study 735 patients with renal carcinoma, diagnosed between 1982 and 1990 in one of the hospitals connected to the Rotterdam Cancer Registry, were evaluated with respect to treatment choice and survival. RESULTS: Nephrectomy was performed less often in elderly patients, both with and without distant metastases. The resection rate for patients aged 70 years and older was 63% against 82% for younger patients (P < 0.001). Crude 5-year survival rates for patients aged 20-59, 60-69 and 70+ were 54, 38 and 22% respectively. For patients with tumours restricted to the kidney (Robson stage 1), corrected survival rates were 80, 70 and 48% respectively. The overall post-operative mortality was 3.8% and was not related to age (P = 0.73). CONCLUSION: Treatment choice and outcome in patients with renal carcinoma were affected by age. As the proportion of patients aged 70 years and older, now 38%, will inevitably increase in the next decades, more attention is needed with respect to contra-indications for surgical treatment in the elderly.

Relationship between vitamin C and plasma concentrations of testosterone in female rainbow trout, Oncorhynchus mykiss.

Two-year old rainbow trout females were fed diets containing 0, 30, 110, 220, 440 and 870 mg kg(-1) ascorbyl-2-monophosphate Mg(+) salt (groups 1, 2, 3, 4, 5, and 6, respectively) from August until March. At the time of spawning (February-March) blood was sampled and the ovulating females were hand stripped. Estradiol (E2) and testosterone (T) concentrations in plasma, and ascorbic acid (AA) concentrations in plasma and eggs were determined. The mean plasma concentrations of T were higher in group 4, 5, or 6 than in group 2 or 3 (p < 0.05). Moreover, the average plasma concentration of T in fish fed the diets with AA level below National Research Council (NRC) recommendations (groups 1, 2 and 3) was significantly lower (p<0.01) than the average plasma concentration in fish fed diets with AA level above NRC recommendations (groups 4, 5, and 6). These data are consistent with the hypothesis that AA can influence production of steroids in female rainbow trout.

Deoxyribonucleic acid ploidy of core biopsies and metastatic lymph nodes of prostate cancer patients: impact on time to progression. The European Organization for Research and Treatment of Cancer Genitourinary Group.

We studied 98 patients with locally confined but lymph node positive prostatic cancer (1 stage T1, 29 stage T2, 55 stage T3 and 2 stage T4) who were not treated by radical prostatectomy. A retrospective analysis was done of deoxyribonucleic acid (DNA) ploidy of pretreatment core biopsies of the primary tumor and lymph node metastases. While DNA ploidy has been shown to be an important prognostic factor if applied to radical prostatectomy specimens, core biopsy specimens and nodal metastases have rarely been studied. Of the 98 patients 87 were evaluable for DNA ploidy: 45 (52%) had diploid, 13 (15%) had tetraploid and 29 (33%) had aneuploid tumors. The ploidy of the primary tumor and of the lymph node metastases correlated significantly with the rate of progression and interval to progression. Also, significant correlations were noted between the percentages of cells in the S phase or S plus G2 phases of the cell cycle and interval to progression. Most patients in this study are part of the European Organization for Research and Treatment of Cancer protocol 30846, a prospective randomized study of early versus delayed treatment in lymph node positive, otherwise locally confined prostate cancer. This study is ongoing. Early endocrine treatment was associated with a significantly longer interval to progression. In a Cox regression analysis of the prognostic factors involved in this study, early endocrine treatment was more important than ploidy or proliferation patterns. Stage (T category) and histopathological grade did not show a correlation with progression. Followup is still too short and the numbers of patients are too small for relevant subgroup analysis. DNA ploidy measurement by flow cytometry on archival (paraffin embedded) core biopsy and lymph node material is possible, and produces meaningful results in predicting the prognosis of prostatic cancer. Since this information can be made available before treatment decisions, its exact value in the management of locally confined prostate cancer can be determined.

Effects of estrogen deprivation on human benign prostatic hyperplasia.

Sex steroids are thought to play an essential role in the pathogenesis of human benign prostatic hyperplasia (BPH). Since recent studies in animal models and in men have shown that estrogens might be causally linked to the onset and maintenance of BPH, we examined the effect of 1-methyl-androsta-1,4-diene-3,17-dione (Atamestane), a newly developed aromatase inhibitor, in men with BPH. In an open multicenter study 49 men (mean age 70.1 years, range 55 to 84) with obstructive BPH were treated with atamestane (3 x 200 mg/day) for 3 months. Of the 49 patients 44 completed the treatment period; the other patients discontinued the study for reasons unrelated to treatment. With treatment BPH-related symptoms such as daytime voiding frequency, nycturia, peak flow and residual urine improved considerably; however, these parameters did not reach statistical significance. The mean prostatic volume decreased significantly from 74.2 +/- 31.7 to 64.0 +/- 31 ml (mean +/- SD). Serum estrogen levels decreased markedly during treatment. In addition intraprostatic estrogen concentration decreased with treatment as compared to estrogen levels in hyperplastic prostates from untreated patients. The following conclusions can be drawn from this study: first, estrogens appear to have an important supportive role in established BPH, and second, estrogen deprivation improved BPH-related symptoms and reduced significantly prostatic volume.

Penile sensitivity in men with premature ejaculation and erectile dysfunction.

Previous research indicates that penile sensitivity is typically lower in men with erectile dysfunction than in age-matched controls. On the assumption that sensitivity might be greater in men with short ejaculation latency (premature ejaculation), the present research investigated penile threshold (sensitivity) to vibrotactile stimulation in men with premature ejaculation, erectile dysfunction, or a combination of the two. Premature ejaculators showed thresholds commensurate with controls, while men with erectile dysfunction, or combined erectile dysfunction and premature ejaculation, showed significantly elevated thresholds. Although premature ejaculators did not show penile hypersensitivity, there was a significant correlation in this group between ejaculation latency and threshold. Overall, these findings argue against a primary role for penile sensitivity in ejaculation latency, and suggest that other somatic factors or cognitive factors may play the more critical role in premature ejaculation.

Surgical management of renal carcinoma with extensive involvement of the vena cava and right atrium.

Between 1988 and 1990, 8 patients with a renal tumour extending into the vena cava and with supradiaphragmatic extension were treated by an operative technique involving extracorporeal circulation and deep hypothermic circulatory arrest. In 4 patients the thrombus extended into the right atrium. Six patients appeared to have a renal carcinoma. Intra-operatively one patient's tumour proved to be a metastasis of a squamous cell carcinoma of the lung and another patient was found post-operatively to have a leiomyosarcoma of the vena cava. Two of these 6 patients died from metastases 6 weeks and 8 months post-operatively. Four patients are symptom-free, although 3 of them have liver or lung metastases 10, 20 and 37 months post-operatively. One has no evidence of disease 18 months post-operatively. The use of extracorporeal circulation and deep hypothermic circulatory arrest provides optimal surgical exposure and gives the patients a considerable complaint-free interval post-operatively. How often cure is also achieved is as yet unclear.

Mitomycin C and aminoglutethimide in the treatment of metastatic prostatic cancer: a phase II study.

In a phase II study, 24 patients with metastatic prostatic cancer were treated with mitomycin C 15 mg/m2 i.v. every 6 weeks, combined with aminoglutethimide 250 mg twice a day. A low dose of 37.5 mg cortisone acetate was supplied daily to compensate for adrenal cortical suppression. A partial response was demonstrated in 4 of 24 evaluable patients with bi-dimensionally measurable metastases. Stable disease occurred in 8 patients over a period of more than 6 months. Within the maximum cumulative dose limit of 2 mg/kg body weight mitomycin C, toxicity was observed in 21 cases, including 2 deaths due to treatment toxicity. The poor response rate and high toxicity suggest that the addition of aminoglutethimide does not enhance the effect of mitomycin C in these patients.