Salvage radiotherapy for prostate cancer recurrence after cryosurgical ablation.

OBJECTIVES: To retrospectively determine the outcome of patients treated with salvage three-dimensional conformal radiotherapy (RT) for prostate cancer recurrence after cryosurgical ablation of the prostate (CSAP). Biochemical control rates and morbidity were analyzed. METHODS: Between January 1990 and November 1999, a total of 49 patients initially treated with CSAP were later irradiated because of a rising prostate-specific antigen (PSA) level and/or a positive biopsy at Allegheny General Hospital. The clinical stage before cryosurgery was T1c in 7 patients; T2a in 7 patients; T2b in 10 patients; T3 in 17 patients; and T4 and/or N1 in 8 patients. The Gleason score was 6 or lower in 29 patients, 7 in 11 patients, and 8 or higher in 9 patients. The mean pre-CSAP PSA level was 15.7 ng/mL (range 2.4 to 45). One patient had a PSA level less than 4 ng/mL, 16 had a PSA level of 4 to 10 ng/mL, 21 had a PSA level of 10 to 20 ng/mL, and 11 had a PSA level greater than 20 ng/mL. Before the start of RT, a complete restaging workup was performed and was negative for distant metastatic disease in all 49 patients. The mean interval to recurrence after CSAP was 19 months (range 3 to 78). The mean RT dose to the planning target volume was 62.9 Gy (range 50.4 to 68.4). RESULTS: The mean pre-RT PSA level was 2.4 ng/mL (range 0.1 to 7.4). After RT, the mean nadir PSA level was 0.4 ng/mL (range 0 to 4.2). The mean time to PSA nadir was 5.8 months (range 1 to 15). In 42 patients, the PSA nadir was less than 1.0 ng/mL, in 5 patients the PSA nadir was greater than 1 ng/mL, and in 2 patients the PSA level remained stable. With a median follow-up time of 32 months (range 12 to 85), the overall biochemical control rate was 61%. The mean time to biochemical failure was 14.5 months (range 1 to 47). Of 30 patients with a pre-RT PSA level of 2.5 ng/mL or less, the disease of 22 (73%) was controlled compared with only 8 (42%) of 19 with a pre-RT PSA level greater than 2.5 ng/mL (P = 0.040). Biochemical control occurred in 18 (69%) of 26 patients with a dose of 64 Gy or greater compared with only 12 (52%) of 23 patients with a dose of less than 64 Gy (P = 0.024). The disease of 20 (70%) of 29 patients with a Gleason score of 6 or lower was controlled versus 10 (50%) of 20 patients with a Gleason score of 7 or greater (P = 0.064). Only 2 patients developed subacute morbidity (proctitis and a urethral stricture). All complications resolved with conservative measures. CONCLUSIONS: Salvage RT for prostate cancer recurrence after CSAP appears feasible. Our preliminary experience revealed that post-CSAP RT in patients with prostate cancer appears to effectively diminish the post-RT PSA level to a nadir of 1.0 ng/mL or less in most patients. The pre-RT PSA level and radiation dose may be important predictors of biochemical control in the salvage setting. RT as described was associated with minimal toxicity to the gastrointestinal/genitourinary systems. Additional prospective randomized studies are necessary to better assess the role of RT in the treatment of these patients.

Phase advance in moderately sleepy and alert normals.

Phase advanced sleep (by 4 hours) was studied in 28 healthy, normal men and women, aged 21-50 years, without nocturnal sleep or daytime sleepiness complaints. Eleven subjects (6 men and 5 women) with moderately short (< or = 10 minutes) average daily sleep latencies on the multiple sleep latency test (MSLT) were compared to 17 (11 men and 6 women) with relatively long (> or = 12 minutes) latencies. Nocturnal sleep on both a baseline and a shift night differed between the groups. The moderately "sleepy" group had shorter sleep latencies and less wakefulness during sleep than the moderately "alert" group. The phase advanced sleep schedule reduced sleep efficiency in both groups, but the moderately sleepy group showed a lessened effect of the shift. Additionally, sleep efficiency was reduced in the moderately sleepy group only during the first 2 hours of the sleep period, while sleep efficiency was uniformly disturbed in the moderately alert group throughout the night during the phase advance.

Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for post radiation recurrence of adenocarcinoma.

BACKGROUND: Surgical techniques utilizing the application of very low temperatures to malignant tissues have been used increasingly in recent years in the minimally invasive treatment of prostate cancer. An area of potential application appears to be in the management of radiation resistant prostate cancer. METHODS: This study represents a retrospective chart review of 33 patients undergoing cryosurgical ablation of the prostate (CSAP) according to a protocol designed by an institutional review board at a single institution for the treatment of radiation resistant prostate cancer. Radiation resistance was defined as a positive prostate needle biopsy and rising prostate specific antigen (PSA). Treatment effect was assessed by serial post treatment PSA determinations and extensive systematic post treatment prostate needle biopsies. RESULTS: Of the 33 patients analyzed, 24 converted to an all negative biopsy status after one CSAP treatment. Repeat treatment converted two additional patients to a biopsy negative status. CSAP appeared to lower PSA dramatically in most patients. One year after treatment, of 10 patients not on androgen deprivation therapy, 3 maintained a PSA of < 0.4 ng/mL and those patients with androgen deprivation therapy maintained a PSA of < 4.0 ng/mL. The most frequent complications included sloughing syndrome (15.4%) and incontinence (10.3%). CONCLUSIONS: CSAP appears to eliminate biopsy detectable prostate tumor effectively in the majority of cases in the salvage setting following radiation therapy. A significant discrepancy exists, however, between the biopsy "cure" rate and the biochemical "cure" rate, even in the short term. There is a suggestion that early detection of radiation failure may improve results of this salvage therapy.

Effects of theophylline on nocturnal sleep and daytime sleepiness/alertness.

To study the short-term effects of theophylline on sleep and wakefulness, 24 healthy men and women, aged 21 to 35 years, received each of three doses, 0, 3, and 6 mg/kg, of theophylline double-blind in a Latin Square design, administered to 12 subjects at 9 AM and to the other 12 at 11 PM. After the daytime administration, sleep latency was tested at 10 AM, 12 Noon, 2 PM, and 4 PM and divided attention and auditory vigilance performance were tested at 10:30 AM and 2:30 PM. After the nighttime administration, a standard 8-h polysomnogram was collected. On a separate day all subjects received a single 6-mg/kg dose at 9 AM and blood samples were drawn at 8:30 and 10:30 AM, 12:30 PM, 2:30 PM, and 4:30 PM. The serum theophylline levels for the 6-mg/kg dose peaked at 11.0 micrograms/mL and declined to 8.1 micrograms/mL by 4:30 PM. In the daytime administration, daytime mean sleep latency was increased by both doses and performance was improved by the high dose but not the low dose. In the nighttime administration, nocturnal sleep onset was delayed and total wake time was increased by the high dose but not the low dose. The low dose increased the amount of light stage 1 sleep without producing wakefulness.

Sedative, memory, and performance effects of hypnotics.

The sedative, amnestic, and performance disruptive effects of benzodiazepine (Bz) receptor selective and non-selective hypnotics were studied in 23 healthy, normal subjects, aged 26.8 +/- 1.0 years. Triazolam (0.25 and 0.50 mg), zolpidem (10 and 20 mg) and placebo were administered, double-blind, at bedtime in a repeated measures design. During an awakening 90 min later (at approximate peak concentration of each drug) a 30-min performance battery which included memory, vigilance, and psychomotor tasks was completed. Each drug and dose impaired memory (both immediate and delayed), vigilance, and psychomotor performance relative to placebo. Among active drugs impairment was greatest with zolpidem 20 mg, next triazolam 0.50 mg, then zolpidem 10 mg, and finally triazolam 0.25 mg. Next morning delayed recall was also impaired by all drugs and doses (i.e. anterograde amnesia). The amnestic and performance-disruptive effects paralleled the relative hypnotic effects of the drugs and doses. No receptor selectivity in these pharmacodynamic effects was observed.

Experimental sleep fragmentation.

Thirty-six healthy young men and women (age range 21-35 years) were studied in an experimental model of sleep fragmentation. On 2 nights sleep was disrupted by presenting tones to produce brief electroencephalogram (EEG) arousals (without shortening sleep time) and daytime function was assessed the following day with the Multiple Sleep Latency Test and a divided attention performance test. The fragmentation of sleep produced significant disruption of nocturnal sleep and reduced daytime alertness. Adaptation in EEG-defined arousals occurred from the 1st to the 2nd night of fragmentation. Threshold (measured indirectly) characteristics of EEG-defined arousals were somewhat different than those of previous studies requiring behavioral awakening. The percent of tone series producing arousal, number of tones necessary for arousal and duration of the arousal all reflected heightened thresholds in stage 3/4 and rapid eye movement (REM) sleep compared to stage 1 and stage 2 sleep. In the last 3 hours of sleep versus the first 3 hours, arousals occurred less frequently, required more tones to produce, resulted in shorter durations and in fewer sleep stage changes, except for REM sleep where the converse was the case.

Percutaneous transperineal cryosurgical ablation of the prostate for the primary treatment of clinical stage C adenocarcinoma of the prostate.

OBJECTIVES: To assess short-term response rate and local tissue destructive capabilities of cryosurgical ablation of the prostate (CSAP) in patients with clinical Stage C adenocarcinoma of the prostate. METHODS: A retrospective chart review of 62 patients (mean age, 66 years; range, 49 to 79 years) treated on an institutional review board approved protocol at Allegheny General Hospital between June 1990 and December 1993 was performed. Standard follow-up examination included serial prostate-specific antigens (PSAs), digital rectal examination, and extensive biopsies at 3 months after CSAP. RESULTS: Average hospital stay was 2 days and morbidity was minimal. Biopsy findings showed no residual detectable prostatic tumor in 79% of patients 3 months after 1 CSAP treatment and in 94.8% 3 months after 1 or 2 treatments. Mean/median 3-month postoperative PSAs for patients with negative biopsy findings were 0.59 +/- 1.66 and 0.10 ng/mL, respectively, compared with 14.0 +/- 12.1 and 8.90 ng/mL preoperatively. CONCLUSIONS: CSAP appears to produce controllable, reproducible local tissue destructive effects. Long-term (more than 5 years) crude and disease-free survival rates are not known for CSAP.

Long-term study of the sleep of insomnia patients with sleep state misperception and other insomnia patients.

OBJECTIVE: The objectives were 1) to investigate differences among patients with subjective insomnia (sleep state misperception), patients with objective findings of insomnia, and normal volunteers and 2) to assess the consistency of the sleep findings during a 2-month period. METHOD: Twenty-one subjects were studied. Subjects with sleep state misperception (N = 7) had insomnia complaints for more than 1 year, no objective sleep disturbance, and sleep efficiency of 90% or greater (on the diagnostic screening sleep recording), while subjectively estimating that sleep time was less than 6.5 hours. Subjects with objective insomnia (N = 7) met the same subjective criteria, but objectively sleep efficiency was 85% or less. Normal subjects (N = 7) had no insomnia complaints and objective sleep efficiency of 90% or greater. All subjects were recorded on 2 consecutive nights three times with a 3-week period between each pair of nights (6 standard all-night polysomnographic sessions of 8 hours). A subjective sleep questionnaire was administered after each sleep recording night. RESULTS: Sleep stage variables (percentages) were similar between the two insomnia groups, and both were different from the normal subjects. Sleep continuity variables were disturbed in the objective insomnia group, but they were similar in the sleep state misperception and normal groups. Both insomnia groups rated their sleep as inadequate on the questionnaires and differed from the normal subjects. The distinct sleep patterns of each of the three groups did not vary over the 6 nights of assessment. CONCLUSIONS: Sleep state misperception may be a prodromic or transitional state of sleep dysfunction between normal sleep and the sleep pattern of objective insomnia.

Comparative effects of pravastatin and lovastatin on nighttime sleep and daytime performance.

Pravastatin and lovastatin, two HMG-CoA reductase inhibitors with similar cholesterol-lowering effects, differ in their lipid solubility. The hydrophilic characteristics of pravastatin may explain why the drug has not been detected in cerebrospinal fluid. On the other hand, lovastatin, a lipophilic compound, has been detected in the cerebrospinal fluid. Previous reports have suggested that lovastatin administration may be associated with insomnia, which reflects an action in the central nervous system. The effects of the two drugs on nocturnal sleep and day-time performance in young, healthy men have been assessed in randomized, double-blind, placebo-controlled studies. Computer-based performance tests were administered on two consecutive days before drug administration and at the end of a 3-week active drug or placebo treatment period. Results from both sites were combined for analysis. Neither pravastatin nor lovastatin significantly affected nocturnal sleep or daytime sleepiness in this study population, but lovastatin significantly affected daytime performance. In subjects treated with lovastatin, the results showed that two measures of performance, divided attention (p less than 0.05) and vigilance (p less than 0.01), worsened significantly from baseline as did global performance (p less than 0.01). Performance was not affected in the pravastatin and placebo groups. These results provide preliminary evidence of an adverse effect of lovastatin on daytime performance.

Rebound insomnia and hypnotic self administration.

Twenty-one (three groups of seven), men and women, 25-50 years of age were studied to determine whether or not rebound insomnia would increase the likelihood of self administering a benzodiazepine (triazolam 0.25 mg) hypnotic. The groups compared were patients with insomnia and disturbed sleep, insomnia and normal sleep, and healthy normals. Rebound insomnia, by both subjective and polysomnographic assessment, was induced. The experience of rebound insomnia did not increase the likelihood of self administering a benzodiazepine hypnotic in any of the groups. There were clear group differences in pill self administration with normals rarely and insomnia patients frequently, but not differentially (placebo versus active drug) self administering pills.

Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation.

Rebound insomnia was studied in subjects, aged 25-50 years, with insomnia complaints and normal sleep, insomnia complaints and disturbed sleep, and normal sleep with no complaints (N = 21, n = 7 per group). Standard sleep recordings were collected on a baseline night and after abrupt discontinuation of 6 nights of 0.50 mg triazolam, tapered discontinuation (3 nights of 0.50 mg, 2 nights of 0.25 mg, and 1 night of 0.125 mg triazolam) and 6 nights of placebo. Significantly disturbed sleep on the discontinuation night compared to the baseline night was found. The relative degree of rebound insomnia was greater in the abrupt condition than in either the tapered or placebo conditions. The tapered condition reduced sleep time by half that of the abrupt condition which was twice the reduction found in the placebo condition. An overall (regardless of group or condition) difference in baseline versus discontinuation sleep was found, suggesting that pill discontinuation itself leads to sleep disturbance. Subjects did not differ in rebound insomnia as a function of pre-existing sleep disturbance.

Rebound insomnia: duration of use and individual differences.

This study assessed consistency, duration of use, and individual difference in rebound insomnia. Eleven healthy men, 20-30 years old, with normal sleep by both subjective and polysomnographic criteria, received each of four treatments in a double-blind Latin Square design (triazolam 0.50 mg for 1, 6, and 12 nights and placebo for 12 nights), followed by two placebo discontinuation nights. Triazolam increased sleep compared with placebo without differences in effects between the first and last nights of treatment. On discontinuation following active drug, sleep efficiency was reduced compared with placebo, but duration of administration did not alter the likelihood or intensity of rebound insomnia. Those subjects (5) showing poorer sleep on discontinuation from the 12-night treatment also had poorer sleep in the 1- and 6-night treatment. Subjects with rebound insomnia had poorer baseline sleep and a greater drug effect than did subjects without.

Enforced 24-hour recovery following sleep deprivation.

The pattern of recovery sleep after sleep deprivation was investigated in healthy young adults. Six subjects experienced three experimental conditions (0, 24, and 48 hr sleep deprivation) in a Latin Square design. The recovery period consisted of a 24-hr enforced time in bed during which subjects were polysomnographically recorded beginning at 0800. To assess the differential effects of the deprivation conditions, the total sleep time on the 24-hr recordings was submitted to a six (4-hr block) by three (deprivation condition) multivariate analysis of variance. Subjects slept more following the 24- and 48-hr conditions when compared to the 0-hr condition. Across conditions, subjects slept more during the first 4 hr when compared to the remaining five blocks. Importantly, there was a significant interaction of sleep deprivation by 4-hr block. In block 1 sleep was differentially recovered between each condition with more sleep being recorded following longer hours of deprivation. In block 2 subjects in the 24- and 48-hr conditions slept comparable amounts and significantly more than those in the 0-hr condition. In blocks 3 and 4 only the 48-hr condition exhibited significantly more sleep than the 0-hr condition. However, significantly less sleep was found in block 6 following the 48-hr condition. Overall, subjects recovered 72% and 42% of the total amount of sleep lost during the 24- and 48-hr conditions, respectively.

Subjective and polysomnographic characteristics of patients diagnosed with narcolepsy.

In order to better characterize the subjective and polysomnographic findings in patients with narcolepsy, a follow-up questionnaire was mailed to all patients diagnosed with the disorder at the Henry Ford Hospital Sleep Disorders and Research Center. The questionnaire inquired regarding the present, previous, and change in status for the constellation of narcolepsy symptoms. Memory problems, problems of daytime function, and nocturnal sleep disturbance were included among the questions related to the symptomatic constellation. By definition, all patients were symptomatic of daytime sleepiness and were diagnosed with narcolepsy only if there were two or more rapid eye movement (REM) onsets documented on the polysomnographic evaluation. A high percentage of patients reported nocturnal sleep disturbance, which was one of the symptoms with the latest reported onset. Retrospective comparison of questionnaire responses to the clinical polysomnography revealed significantly more sleep maintenance difficulties in the group of patients reporting this symptom on the questionnaire. Patients with disturbed nocturnal sleep reported taking more naps during the day, although the Multiple Sleep Latency Test (MSLT) failed to show differences in sleep latency. Interestingly, this group of patients was found to have a significantly higher number of sleep onset REM episodes on the MSLT. Finally, the findings are discussed as they compare to studies that required the presence of cataplexy as part of their inclusion criteria.

The dose effects of zolpidem on the sleep of healthy normals.

This study determined the dose effects of zolpidem in 12 healthy males with normal sleep patterns. Subjects spent 7 weeks, 3 consecutive nights per week, in the laboratory and had a 4-night washout between treatments. The first week was a screening and adaptation week. Then subjects received zolpidem (2.5, 5.0, 7.5, 10.0, or 20.0 mg) or placebo on the first two nights for each of the next 6 consecutive weeks. Treatments were organized in a Latin square design and administered in a double-blind fashion. On the third night of each treatment, subjects always received placebo. The 5.0 mg and larger doses of zolpidem significantly decreased latency to persistent sleep and wake before sleep. Sleep maintenance measures were not affected by zolpidem. The 7.5 mg and higher doses of zolpidem significantly increased total sleep time. The only significant sleep stage effect was a decrease in percent of rapid eye movement sleep at only the 20 mg dose. No consistent discontinuation effects were found. Zolpidem was hypnotically active at doses as low as 5.0 and 7.5 mg, and sleep stage effects occurred only at the 20 mg dose, thus separating the dose range of hypnotic and sleep stage effects.