Sleep disturbance and melatonin levels following traumatic brain injury.

OBJECTIVES: Sleep disturbances commonly follow traumatic brain injury (TBI) and contribute to ongoing disability. However, there are no conclusive findings regarding specific changes to sleep quality and sleep architecture measured using polysomnography. Possible causes of the sleep disturbances include disruption of circadian regulation of sleep-wakefulness, psychological distress, and a neuronal response to injury. We investigated sleep-wake disturbances and their underlying mechanisms in a TBI patient sample. METHODS: This was an observational study comparing 23 patients with TBI (429.7 +/- 287.6 days post injury) and 23 age- and gender-matched healthy volunteers on polysomnographic sleep measures, salivary dim light melatonin onset (DLMO) time, and self-reported sleep quality, anxiety, and depression. RESULTS: Patients with TBI reported higher anxiety and depressive symptoms and sleep disturbance than controls. Patients with TBI showed decreased sleep efficiency (SE) and increased wake after sleep onset (WASO). Although no significant group differences were found in sleep architecture, when anxiety and depression scores were controlled, patients with TBI showed higher amount of slow wave sleep. No differences in self-reported sleep timing or salivary DLMO time were found. However, patients with TBI showed significantly lower levels of evening melatonin production. Melatonin level was significantly correlated with REM sleep but not SE or WASO. CONCLUSIONS: Reduced evening melatonin production may indicate disruption to circadian regulation of melatonin synthesis. The results suggest that there are at least 2 factors contributing to sleep disturbances in patients with traumatic brain injury. We propose that elevated depression is associated with reduced sleep quality, and increased slow wave sleep is attributed to the effects of mechanical brain damage.

The effect of traumatic brain injury on the timing of sleep.

While there have been single case reports of the development of circadian rhythm sleep disorders, most commonly delayed sleep phase syndrome following traumatic brain injury (TBI), to our knowledge there have been no group investigations of changes to sleep timing in this population. The aim of the present study was to investigate sleep timing following TBI using the dim light melatonin onset (DLMO) as a marker of circadian phase and the Morningness-Eveningness Questionnaire (MEQ) as a measure of sleep-wake behavior. A sleep-wake diary was also completed. It was hypothesized that the timing of DLMO would be delayed and that there would be a greater tendency toward eveningness on the MEQ in a post-acute TBI group (n=10) compared to a gender and age matched control group. Participants were recruited at routine outpatient review appointments (TBI) and from the general population (control) as part of a larger study. They attended the sleep laboratory where questionnaires were completed, some retrospectively, and saliva melatonin samples were collected half-hourly according to a standard protocol. The results show that the TBI and control groups reported similar habitual sleep times and this was reflected on the MEQ. There was, however, significant variability in the TBI group's change from the pre-injury to the current MEQ score. The timing of melatonin onset was not different between the groups. While subtle changes (advances or delays) in this small sample may have cancelled each other out,. the present study does not provide conclusive objective evidence of shift in circadian timing of sleep following TBI. Furthermore, although participants did report sleep timing changes, it is concluded that the MEQ may not be suitable for use with this cognitively impaired clinical group.

Circadian locomotor activity rhythms of the diurnal Indian palm squirrel in constant light.

The parametric or tonic effects of light were studied in a recently established diurnal circadian model-the Indian palm squirrel, Funambulus pennanti. Sixteen squirrels (7 female, 9 male) were housed individually under varying constant light conditions (0.1 lux to 46 lux) with gross locomotor activity continuously monitored. Free-running period (tau), amplitude, mesor and day-to-day stability of the activity rhythm were determined using modified periodogram and iterative harmonic analyses, while the ratio of activity to rest time was estimated by eye-fit. The main findings were as follows: 1) tau did not vary between sexes or between light conditions, although a trend for tau to lengthen when light intensity was increased was noted; 2) amplitude and mesor did not show sex differences, but both sexes showed a decrease in amplitude and mesor when light intensity was decreased; 3) the stability of the activity rhythm was greater in males than in females, and a trend was observed for rhythm stability to decrease when light intensity was reduced. These descriptive data contribute to the growing literature on this diurnal species.

Effect of moderate alcohol upon obstructive sleep apnoea.

Moderate-to-large quantities of alcohol are known to aggravate severe obstructive sleep apnoea (OSA), however, the reported effects of moderate alcohol consumption upon mild-to-moderate OSA are inconsistent. Given the reported benefits of moderate alcohol consumption on cardiovascular mortality, recommendations regarding the management of patients with OSA are difficult to formulate. The aim of this study was to evaluate the effects of moderate alcohol on sleep and breathing in subjects with mild-to-moderate OSA. Twenty-one male volunteers, who snored habitually, underwent polysomnography with and without 0.5 g alcohol x kg body weight (BW)(-1) consumed 90 min prior to sleep time, in random order. The mean blood alcohol concentration (BAC) following alcohol at the time of lights out was 0.07 g x dL(-1). The distribution amongst the various sleep stages was not significantly altered by alcohol. The mean apnoea/hypopnoea index rose from 7.1+/-1.9 to 9.7+/-2.1 events x h(-1) (mean+/-SEM, p=0.017); however, there was no significant change in the minimum arterial oxygen saturation measured by pulse oximetry Sp,O2, apnoea length or snoring intensity. Mean sleep cardiac frequency rose significantly from 53.9+/-1.4 to 59.9+/-1.9 beats x min(-1) (P<0.001) and overnight urinary noradrenalin increased from 14.9+/-2.3 to 18.8+/-2.3 nmol x mmol creatinine(-1) (p=0.061) on the alcohol night compared to the nonalcohol night. To conclude, modest alcohol consumption, giving a mean blood alcohol concentration of 0.07 g x dL(-1), significantly increases both obstructive sleep apnoea frequency and mean sleep cardiac frequency.

Social contact synchronizes free-running activity rhythms of diurnal palm squirrels.

Social contact with conspecifics entrains rhythms of a number of species, although convincing demonstrations of the phenomenon in diurnal mammals are limited. The present study examined the question of whether social contact mutually synchronizes free-running locomotor activity rhythms of the diurnal Indian palm squirrel, Funambulus pennanti. Twelve male squirrels were housed individually, without visual contact, in two separate laboratories (six in each laboratory). The squirrels were initially held under opposing light-dark (LD) schedules (with an 11 h phase difference), and were then placed under constant bright light (LL). Squirrels from separate laboratories were paired together, and each pair was placed into a fresh cage on the day of the pairing. After 48 days of social contact, the squirrel pairs were separated, and returned to their original positions in the two laboratories in fresh cages. Free-running phase and period were assessed prior to and after the social contact for each squirrel. The phase difference in the free-running rhythms of pairs of squirrels was significantly decreased following social contact. Actogram records revealed strong evidence of social synchronization of free-running rhythms in four of the six pairs. For the remaining two pairs, the data were ambiguous. This study confirmed the findings in other species, that social cues are a potent zeitgeber for F. pennanti.

Entrainment of rat circadian rhythms by the melatonin agonist S-20098 requires intact suprachiasmatic nuclei but not the pineal.

S-20098 is a potent nonindolic melatonin agonist that has been shown to entrain free-running circadian rhythms. The current experiments examined the role of the suprachiasmatic nuclei (SCN) and of the pineal gland in the entrainment of circadian rhythms by S-20098. First, daily injections of S-20098 (1 and 10 mg/kg s.c.) were administered to SCN- and sham-lesioned rats. At both dose levels, circadian effects were noted in all sham-lesioned animals. Locomotor activity and body temperature rhythms in 3 of 5 sham-lesioned rats were entrained by the daily injections. In SCN-lesioned rats, S-20098 had no synchronizing or entraining effects at either dose level. These results show that S-20098 exerts its entraining effects on circadian rhythms via the circadian pacemaker located in the SCN. Second, the effects of daily injections of S-20098 (10 mg/kg s.c.) were examined in pinealectomized, sham-pinealectomized, and intact rats. All rats receiving S-20098, irrespective of surgical treatment, showed circadian changes. Rhythms in 81% of these animals entrained to daily administration of the compound, indicating that entrainment induced by S-20098 does not depend on an intact pineal. When injected with 10 mg/kg S-20098, 69% of rats, irrespective of surgical treatment, showed long-term modifications of free-running period that still were evident several weeks after administration ceased. If confirmed, this finding may have therapeutic implications in humans regarding the optimal mode and administration of S-20098 in a clinical setting.

Interactive effects of sleep deprivation, time of day, and driving experience on a driving task.

Performance decrements after more than 24 hours of sleep deprivation (SD) are not only a monotonic function of the duration of SD, but are the result of an interaction between SD and time of day. The major deteriorations in performance during SD are still evident throughout the night, as in the non-sleep-deprived state. Twelve experienced and 12 inexperienced drivers drove a driving simulator for 20 minutes at 0800, 1100, 1400, 1700, and 2000 hours on two testing days. One testing day was conducted after a normal night's sleep, and the other after one night of SD. Reaction time (RT) was also measured while driving. The standard deviation of both lateral position and speed were significantly higher during SD. Performance steadily improved across the day between 0800 and 2000 hours, and the absence of any sleep-by-time interactions suggests that the rhythm of driving performance across the day was similar after both normal sleep and SD. Inexperienced drivers had higher RTs than experienced drivers in both sleep-deprived and non-sleep-deprived conditions. These results have important implications for those involved in the transport industry.

Entrainment of activity rhythms to temperature cycles in diurnal palm squirrels.

Ambient temperature cycles entrain circadian rhythms of homeotherms. The phase that entrainment occurs at varies, particularly in diurnal species. We investigated whether ambient temperature cycles of 12 h warm (34 to 40 degrees C) and 12 h cool (24 to 28 degrees C) entrained locomotor activity rhythms of diurnal Indian palm squirrels (Funambulus pennanti) that were free-running in constant dim light (3.2 to 7.6 lux). Seven female squirrels were exposed to the temperature cycle for 21 days, after which a 5-h phase delay of the cycle was imposed. The cycle then continued for a further 50 days. Three of the seven squirrels showed entrainment to the temperature cycle. Of the three which entrained, one was warm-active and two were cool-active. Of the remaining squirrels, two showed entrainment or relative coordination of one component of the rhythm, and two did not show any entrainment. Positive and negative masking of activity by the warm and cool fractions were observed regardless of whether or not squirrels entrained. These results suggest that ambient temperature is an effective zeitgeber for F. pennanti. As has been reported for other diurnal species, interindividual differences exist in the phase of entrainment to temperature cycles.

Circadian entrainment and phase shifting in mammals with melatonin.

Circadian effects of exogenous melatonin, whereby daily administration induces entrainment or phase shifts, have been demonstrated in both nocturnal and diurnal mammals. In Long-Evans rats, as used in early studies, effects occur reliably when melatonin is administered late in the subjective day. A second period of sensitivity to melatonin, late in the subjective night, is evident in certain strains of mice and the diurnal Funambulus pennanti. This late night to early morning sensitive phase previously had been identified in human subjects. Different circadian responses to melatonin also may occur between rat strains. Circadian effects of melatonin in hamsters are diverse and vary with strain, developmental age, and method of administration. Characteristics of melatonin binding sites within the suprachiasmatic nuclei vary both between and within species, as do profiles of endogenous melatonin rhythms. These differences may explain the variations in circadian responses to melatonin.

Effects of daily melatonin administration on circadian activity rhythms in the diurnal Indian palm squirrel (Funambulus pennanti).

Exogenous melatonin induces phase shifts in circadian rhythms according to a phase response curve in nocturnal rodents, several nonmammalian diurnal species, and humans. Daily administration of melatonin entrains rhythms within a narrow circadian window of sensitivity in these species. Entrainment to exogenous melatonin has not previously been demonstrated in a (nonhuman) diurnal mammal. The authors examined the effects of daily melatonin administration (via food) in the diurnal Indian palm squirrel, Funambulus pennanti. The effects of melatonin or vehicle were examined at two times of day: zeitgeber time 0 (ZT 0: light onset time) and ZT 12 (dark onset time). In addition to melatonin- and vehicle-treated squirrels, there was a third group of squirrels that received no treatment. Squirrels were held initially under 12:12 light-dark (LD) cycles, and melatonin (1 mg/kg) or vehicle was administered in food (a raisin) at either ZT 0 or ZT 12 for a total of 17 days. On the third day of treatment, constant lighting (LL) was imposed. Treatment continued at the same ZTs for a further 14 days. The number of days before free-running commenced under constant conditions was assessed for squirrels in each treatment group. Results showed that regardless of the ZT of administration, the number of days before free-running commenced was significantly greater in melatonin-treated squirrels than in vehicle-treated and untreated squirrels, and there was no difference between vehicle-treated and untreated squirrels. Although there was not a significant difference in the number of days before free-running commenced between the two times of administration, the results showed a trend for greater sensitivity to melatonin at ZT 12. This study has therefore demonstrated that the palm squirrel circadian system is entrainable to melatonin at both times of day tested, ZTs 0 and 12. This finding is in contrast to previous melatonin entrainment studies in other species, where entrainment generally occurred at only one phase, around circadian times 10 to 12. Interspecies differences in response to melatonin were discussed.

Time of day variations in driving performance.

Numerous factors may contribute to the 24-hour pattern of automobile accidents. One factor may be a time of day variation in driving ability. In the present study, 11 male subjects operated a driving simulator for 30 minutes at six times of day. Subjects were instructed to maintain a stable position in the left-hand lane and to drive at a constant speed of 80 km/hour. In addition subjects performed a secondary reaction time task. Subjective mood was measured at the beginning and end of each session. Driving performance was measured in terms of the mean and standard deviation of lateral position and speed. The mean and standard deviation of speed varied significantly across the day for both curved and straight segments. Reaction time was also affected by time of day. Performance was more impaired at 0600 and 0200 hours, with improvements in driving performance between 1000 and 2200 hours and an early afternoon dip. These results suggest that driving performance is subject to diurnal variations. Of particular importance is the result that impairments in driving performance in the early afternoon are of a similar magnitude to those occurring in the late evening and early morning.

Combined modality therapy for cutaneous T-cell lymphoma.

BACKGROUND: Cutaneous T-cell lymphoma (CTCL) may respond to many therapies, but long-term disease-free survival is uncommon. Patients with advanced disease have a median survival of approximately 3 years. OBJECTIVE: Our purpose was to combine known effective agents sequentially to determine whether we could achieve remission in more patients or for longer duration. METHODS: Patients with mycosis fungoides (n = 23) or Sézary syndrome (n = 5) were treated with 4 months of recombinant interferon alfa together with isotretinoin, followed by total skin electron beam therapy alone (for stage I to II disease) or preceded by chemotherapy (for stage III to IV disease). Maintenance therapy consisted of interferon for 1 year and topical nitrogen mustard for 2 years. RESULTS: Twenty-eight patients were treated. The overall response rate (complete and partial remissions) was 82%. Although the median duration of remission was 5 months in patients with stage III to IV disease, two patients remain in complete remission at 39 + and 46 + months. In patients with stage I to II disease the median duration of remission has not been reached at a median follow-up of 18 months. Five patients, all with stage III to IV disease, have died. Overall, the regimen was well tolerated with one treatment-related death from neutropenic sepsis. CONCLUSION: Combined modality therapy may be effective for the treatment of CTCL with similar response rates to other current therapies.

The Vanderbilt Classification System in the evaluation of diabetic retinopathy patients treated with Alredase.

BACKGROUND: The Vanderbilt Classification System is a quantitative method of measuring features detected in diabetic retinopathy photographs. It does not require comparisons to preexisting standard photographs. This is the first report of the application of this system to a large-scale, multiple-medical-center drug trial. METHODS: This was a prospective, randomized, double-masked, placebo-controlled study that involved 74 medical centers. There were 3,679 out-patients followed for more that 4 years, with some observed for over 9 years. The Vanderbilt Classification System generated patient data for the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Diabetes Control and Complication Trial (DCCT) scales. The deterioration rate was one variable used to assess drug effect. A comprehensive Quality Assurance Program evaluated intergrader and intragrader reliability. RESULTS: Target values for reliability and reproducibility were met or exceeded on all measures of agreement between photo readers and over time. Kappa statistics were 0.610 or greater, with most weighted kappa values greater than 0.810. This represents "almost perfect agreement" and compares favorably with previous reports from the ETDRS and DCCT. CONCLUSION: Diabetic retinopathy can be evaluated in a reliable and reproducible manner with the VCS. The VCS is unique in that it produces a quantitative analysis of retinal lesions. Subtle variations that might be influenced by systemic medications can be measured accurately with this technique.

Risk classification for large cell lymphoma using lactate dehydrogenase, beta-2 microglobulin, and thymidine kinase.

We have previously proposed a staging system for large cell lymphoma using the two serum markers beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH). We recently tested this model in a different cohort of patients with large cell lymphoma and also examined the possible contribution of thymidine kinase (TK), a previously reported serologic prognostic factor. Using an inclusion criteria in the multivariate analysis for both forward and backward selection of p < 0.15, only LDH, B2M, and TK were significant independent prognostic factors for both time to treatment failure (TTF) and survival. Inclusion of TK in the serologic model resulted in three significantly different risk groups for both TTF and survival. Corresponding endpoints at three years were: 1) good risk (no markers elevated, n = 43): 78%, 91%; 2) intermediate risk (1 or 2 markers elevated, n = 47): 41%, 36%; 3) poor risk (3 markers elevated, n = 11): 0%, 0%. This analysis extends the observation of the independent prognostic significance of B2M and LDH. The addition of TK permits a more precise estimate of risk, contributing to the utility of a serological staging system for large cell lymphoma.

Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms.

The chronobiotic properties of melatonin are well documented. For example, following an 8-h phase advance of the light-dark cycle daily injections of melatonin administered at the pre-shift dark onset alter the direction of re-entrainment of rat activity rhythms. Using this 8-h phase advance paradigm, the effects of the melatonin agonist S-20098 (1 mg/kg and 3 mg/kg) on the rat circadian system were compared with those of melatonin. S-20098 altered the direction of re-entrainment in the same manner as melatonin. A study using lower doses of S-20098 showed that the effect on direction of re-entrainment was dose-dependent, with 100% of rats responding at a dose of 100 micrograms/kg. S-20098 may, therefore, have therapeutic potential as a chronobiotic in the treatment of circadian disorders in humans.

Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma.

PURPOSE: Fludarabine is an active agent for patients with low-grade lymphoma (LGL) but has mainly been used as a single agent. This trial was designed to define the maximum-tolerated dose (MTD) of a combination of fludarabine, mitoxantrone, and dexamethasone (FND), to identify the toxicities of these agents in combination, and to make preliminary observations about the efficacy of this combination. PATIENTS AND METHODS: Twenty-one patients with recurrent LGL or follicular large-cell lymphoma were treated, in cohorts of three, at stepwise escalating doses. Patients were required to have adequate marrow function and normal renal, hepatic, and cardiac function. RESULTS: The MTD of the combination was found to be as follows: fludarabine, 25 mg/m2/d (days 1 to 3); mitoxantrone, 10 mg/m2 (day 1); and dexamethasone, 20 mg/d (days 1 to 5). Each course was administered monthly, and up to eight courses were given. Dose-limiting toxicities were neutropenia and infections. Thrombocytopenia was modest. Nonhematologic toxicity was very modest. Responses were seen at every dose level. The overall response rate was 71%, with a 43% complete remission (CR) rate. The median duration of CR was 18 months (with follow-up duration from 13 to 28+ months). CONCLUSION: FND was well tolerated in this population. While our primary aim was to define the MTD, our preliminary observations on the efficacy of the regimen were favorable. The overall response rate was high, there was a high fraction of CRs, and our early impression is that these responses are durable.

Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family.

Four naturally occurring platelet-activating factor (PAF) analogs, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, 1-octadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine, stimulated human neutrophils (PMN) to mobilize Ca2+, degranulate, and produce superoxide anion. They were, respectively, 5-, 300-, 500-, and 4000-fold weaker than PAF in each assay; inhibited PMN-binding of [3H]PAF at concentrations paralleling their biological potencies; and showed sensitivity to the inhibitory effects of PAF antagonists. PAF and the analogs, moreover, desensitized PMN responses to each other but not to leukotriene B4 and actually increased (or primed) PMN responses to N-formyl-MET-LEU-PHE. Finally, 5-hydroxyeicosatetraenoate-enhanced PMN responses to PAF and the analogs without enhancing the actions of other stimuli. It stereospecifically raised each analog's potency by as much as 100-fold and converted a fifth natural analog, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine from inactive to a weak stimulator of PMN. PAF and its analogs thus represent a structurally diverse family of cell-derived phospholipids which can activate, prime, and desensitize neutrophils by using a common, apparently PAF receptor-dependent mechanism.

Limited effect of three types of daily stress on rat free-running locomotor rhythms.

The effects of three types of stress/arousal on rat free-running circadian locomotor rhythms in constant darkness were investigated over a 93-day treatment period. Rats were subjected to 30-min daily immobilisation stress or 30-min novelty or to brief handling (n = 10/group). Seven of the 30 rats exhibited some changes in circadian parameters. Three rats (two immobilised, one handling) showed entrainment, three rats (one from each group) showed a change in tau, and one rat (novelty) showed a phase advance. Thus, in total, 30% immobilisation, 20% percent novelty, and 20% handled rats showed circadian changes. These group changes paralleled changes in faecal boli and body weight, which were taken as indirect indices of the level of stress. Five of the seven changes took place when the end of the active phase (alpha), i.e., subjective dawn, coincided with the time of treatment and the other two when the onset of sigma, i.e., subjective dusk, coincided. Rat circadian locomotor rhythms appear much less susceptible to stress/arousal than those reported for hamsters.

Successful use of S20098 and melatonin in an animal model of delayed sleep-phase syndrome (DSPS).

In human delayed sleep-phase syndrome (DSPS), sleep onset and wake times occur far later than normal. In the population, DSPS may be an important contributor to complaints of sleep onset insomnia. We previously reported an animal model of DSPS in laboratory rats in which the onset of nocturnal activity is delayed by several hours [negative phase angle difference (PAD)]. The effect of melatonin 1 mg/kg SC and S20098 (Servier) 1 and 3 mg/kg on the negative PAD was investigated over 22 days of injections. In comparison to control injections of dimethylsulfoxide (DMSO), both melatonin and S20098 over approximately 9 days phase advanced the onset of activity toward the onset of darkness. At cessation of injections, activity onset delayed over approximately 11 days back toward, but as a group did not reach the original PAD. This effect of melatonin on the phase angle of entrained rats is consistent with its effects on delayed sleep in humans. It is likely, therefore, that S20098 may be of use to ameliorate DSPS in humans.

CHOP-Bleo plus interferon for stage IV low-grade lymphoma.

BACKGROUND: Alpha interferon (IFN) is an effective single agent for patients with low-grade lymphoma, but until 1982 had not been integrated with standard chemotherapy for these patients. Since relapse from complete remission (CR) is the rule for patients with advanced stage low-grade lymphoma, a maintenance IFN schedule was explored for patients in CR. PATIENTS AND METHODS: From 1982-1987, 127 patients with stage IV low-grade lymphoma were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) for 9-18 mo. (median 13 mo.), followed by interferon alfa-n-1 (Wellferon) maintenance therapy for 24 mo. for CRs. RESULTS: The overall response rate for the entire treatment program was 73% CR and 23% partial remission. The median follow up was 59 months. At 5 years, survival was 74%, failure-free survival (FFS) 47%, and FFS of CRs 60%. Compared to a group of 96 patients with similar pretreatment clinical features treated with CHOP-Bleo from 1972-1982, this represents a significant improvement for both overall FFS (p = 0.01) and FFS of CRs (P < 0.01). Toxicity from the IFN maintenance was generally acceptable, but even at the modest dose employed in this trial (3 x 10(6) U/m2 three times weekly), dose modification was required in more than 30% of patients, usually because of fatigue. CONCLUSIONS: The integration of IFN and conventional chemotherapy is feasible and effective. Maintenance IFN prolongs remission duration for patients with stage IV low-grade lymphoma.