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PubMed2005

Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.

BACKGROUND: Nitric oxide in exhaled air (FE(NO)) is a marker of eosinophilic airway inflammation. A study was undertaken to determine whether FE(NO) predicts asthma relapse in asymptomatic asthmatic children in whom inhaled corticosteroids are discontinued. METHODS: Forty children (21 boys) of mean age 12.2 years on a median dose of 400 mug budesonide or equivalent (range 100-400) were included. FE(NO) was measured before and 2, 4, 12, and 24 weeks after withdrawal of steroids. A relapse was defined as more than one exacerbation per month, or need for beta agonist treatment on 4 days per week for at least 2 weeks, or diurnal peak flow variability of >20%. FE(NO) measurements were performed online with an expiratory flow of 50 ml/s. RESULTS: Nine patients relapsed. Two and 4 weeks after withdrawal of steroids geometric mean FE(NO) in children who were about to relapse was higher than in those who did not relapse: 35.3 ppb v 15.7 ppb at 2 weeks (ratio 2.3; 95% CI 1.2 to 4.1; p = 0.01) and 40.8 ppb v 15.9 ppb at 4 weeks (ratio 2.6; 95% CI 1.3 to 5.1). An FE(NO) value of 49 ppb at 4 weeks after discontinuation of steroids had the best combination of sensitivity (71%) and specificity (93%) for asthma relapse. CONCLUSION: FE(NO) 2 and 4 weeks after discontinuation of steroids in asymptomatic asthmatic children may be an objective predictor of asthma relapse.

Administration, Inhalation↗

PubMed1999

Weight relapsers, maintainers, and controls: metabolic and behavioural differences.

The present investigation was undertaken to describe selected factors associated with the maintenance of body weight in three groups of women: relapsers (regained weight after losing weight), maintainers (maintained weight loss), and controls (weight stable). The following physiological variables were also assessed: resting energy expenditure (REE), serum glucose, insulin, leptin, triiodothyronine (T3), and body composition. As well, participants completed the interviewer-administered Weight Maintenance Questionnaire (WMQ). Overall, relapsers were older and heavier than maintainers and controls. As well, BMI, sum-of-four skinfolds, waist and arm circumference, serum leptin, and insulin levels were significantly greater for relapsers than for maintainers and controls. There were no differences between maintainers and controls in any of the parameters measured. Although relapsers revealed a history of weight cycling, the weight loss strategies and exercise habits of maintainers and relapsers did not differ. The data suggest that the higher body mass and fat mass in relapsers may explain the physiological differences between relapsers and maintainers.

Adipose Tissue↗

PubMed2004

TEL deletion analysis supports a novel view of relapse in childhood acute lymphoblastic leukemia.

PURPOSE: TEL (ETV6)-AML1 (RUNX1) chimeric gene fusions are frequent genetic abnormalities in childhood acute lymphoblastic leukemia (ALL). They often arise prenatally as early events or initiating events and are complemented by secondary postnatal genetic events of which deletion of the non-rearranged, second TEL allele is the most common. This consistent sequence of molecular pathogenesis facilitates an analysis of the clonal origins of relapse in this leukemia, which has some unusual clinical features. EXPERIMENTAL DESIGN: We compared the boundaries, by microsatellite mapping, of TEL deletions at relapse versus diagnosis in 15 informative patients. Moreover, we compared the relatedness of diagnostic and relapse clones using immunoglobulin and T-cell receptor genes rearrangements and clonotypic TEL-AML1 genomic fusion. RESULTS: Five patients retained the apparent same size TEL deletion, seven had larger deletions, and three had smaller deletions at relapse. In all of the cases evaluated, the clonal relatedness of diagnostic and relapse cells was confirmed by the retention of clonotypic TEL-AML1 genomic sequence and/or at least one identical immunoreceptor gene rearrangement. CONCLUSIONS: These data provide further evidence that TEL deletions are secondary to TEL-AML1 fusions in ALL. They are compatible with the novel idea that in at least some cases of childhood ALL, remission occurs with persistence of a preleukemic "fetal" clone, and subsequent relapse reflects the emergence of a new subclone from this reservoir after an independent "second hit," i.e., independent TEL deletion. To our knowledge, the study is the most extensive and comprehensive analysis of the relationship between diagnostic and relapse clones in childhood ALL presented thus far.

Artificial Gene Fusion↗

PubMed2002

Advances in the treatment of relapsed acute promyelocytic leukemia.

The presence of the characteristic fusion transcript gene, promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARalpha), provided hematologists with a rationale for the use of all-trans retinoic acid (ATRA) for differentiation therapy for acute promyelocytic leukemia (APL). Multiple studies have established that combination of ATRA and chemotherapy in newly diagnosed patients has increased the cure rate to 70% from 35% in patients treated with chemotherapy alone. However, still about 30% of the patients relapse and are often resistant to ATRA retreatment. Consequently, a number of novel agents that include several differentiation agents and monoclonal antibodies have been studied to provide improved outcomes for patients with APL who have relapsed. In particular, arsenic trioxide has shown great promise for the induction, consolidation, and maintenance of complete remission in relapsed patients with APL. The unique mechanisms of action by which arsenic trioxide exerts its effects are complementary to those of ATRA, potentially allowing for combination therapies with additive or even synergistic results. Within this context autologous or allogeneic bone marrow transplantations are also considered in second or subsequent relapse, especially after arsenic trioxide-induced complete remission in relapsing patients. Furthermore, molecular monitoring for the PML-RARalpha fusion protein permits prompt intervention for early molecular relapse of APL before clinical relapse, ultimately improving chances of prolonged remission.

Antineoplastic Agents↗

PubMed2003

Treatment of relapsed acute promyelocytic leukemia.

By all-trans retinoic acid (ATRA) and chemotherapy over 70% of patients with newly diagnosed acute promyelocytic leukemia (APL) may be cured; 20-30% of patients still relapse and require salvage therapy. For relapsed or refractory APL, a standard treatment has not yet been defined. However, several effective drugs and approaches have been described. Treatment options for relapsed APL include chemotherapy regimens used in the treatment of relapsed acute myeloid leukemia usually combined with ATRA or of other differentiating agents such as liposomal ATRA or synthetic retinoids. Presently, allogeneic peripheral stem cell or bone marrow transplantation is the treatment of choice for younger patients who have a histocompatible donor, as it gives the chance of cure in second or further relapse. For patients without a donor or for those who are not suitable for allogeneic transplantation, autologous stem cell or bone marrow transplantation may offer at least the possibility of a prolongation of remission, if the harvested cells are negative in the RT-PCR of PML/RAR alpha. Arsenic compounds have a high antileukemic effectiveness on APL cells. Arsenic trioxide has recently been approved for relapsed or refractory APL. With this drug, complete hematologic remission rates of 80-92% and long-lasting molecular remissions were achieved in relapsed patients. For patients who do not qualify for these treatment options, monoclonal anti-CD33 antibodies may represent further treatment options.

Antineoplastic Agents↗

PubMed2004

Gemtuzumab ozogamicin (Mylotarg) in children with refractory or relapsed acute myeloid leukemia.

BACKGROUND: Gemtuzumab ozogamicin (GO) is an immunoconjugate consisting of the CD33 antibody and calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. PATIENTS AND METHOD: We report 12 children with multiple relapsed or refractory AML receiving GO as compassionate use. 11 children had initially been treated according to the AML-BFM 93 or 98 protocol, 1 girl received relapse treatment (liposomal daunorubicin/FLAG) due to secondary AML. After relapse, 10 children received an intensive relapse therapy (AML-BFM 97 or international AML-Relapse Study 2001/01). 2 of them had been transplanted in first or second CR before GO therapy. RESULTS: 5 of 12 children responded to treatment with blast reduction to below 5%, but no child achieved CR after GO. Time until reoccurrence of blasts in almost all children with GO response was 3-8 months. In 5 children stem cell transplantation (SCT) was performed after GO therapy. 4 of them suffered from further progression of AML, 1 boy is in second remission with a follow-up of 8 months. 2 children had severe side effects. An anaphylactic reaction with severe hypotension was managed by catecholamine support and intensive care. In 1 girl, who relapsed after SCT in first remission, a veno-occlusive disease of the liver occurred, but could be treated successfully with defibrotide. CONCLUSION: GO therapy can induce blast reduction in children who have no further conventional treatment options. Frequency and severity of adverse events are limited, and therapy seems to be feasible for children with a sufficient general condition. Controlled studies are necessary to learn more about efficacy and side effects, especially implications for further therapy.

Acute Disease↗

PubMed2005

Virological and biochemical relapse after discontinuation of lamivudine monotherapy for chronic hepatitis B in Japan: comparison with breakthrough hepatitis during long-term treatment.

OBJECTIVE: Comparison of virological and biochemical relapse in patients with chronic hepatitis B, based on continuation or discontinuation of lamivudine monotherapy. METHODS: In Japanese genotype C-dominant hepatitis B patients, 25 patients who stopped treatment at normal levels of alanine transferase (ALT) were retrospectively compared with 75 patients who continued treatment. Both groups were matched for age, sex, and observation period after start of treatment. We investigated the relapse rates, and evaluated predictive factors for relapse and efficacy of retreatment of the discontinuous group. RESULTS: Virological and biochemical relapse occurred significantly earlier in the discontinuous than continuous group, and the peak levels and ratios of peak to pretreatment levels of serum bilirubin and ALT after relapse were not significantly different between the two groups. Multivariate analysis identified three independent factors at discontinuation of treatment associated with early biochemical relapse: HBeAg positivity, presence of liver cirrhosis, detection of basic core promoter mutant. Normalization of ALT levels with retreatment occurred in 62.5% of patients, but 2 HBeAg-positive patients retreated after the emergence of YMDD motif mutant developed severe relapse with hyperbilirubinemia. CONCLUSION: Our results in Japanese patients with genotype C-dominant hepatitis B suggest that discontinuation of lamivudine monotherapy, and retreatment after the emergence of YMDD mutant should be given attention.

Adult↗

PubMed2006

Social factors but not stress-coping styles predict relapse in detoxified alcoholics.

Alcohol-dependent patients face a substantial risk of relapse after detoxification. Though psychosocial stress and coping strategies are regarded as major contributing factors in returning to drinking, the direct effects of coping styles on relapse are not clear. In this treatment outcome study, a mixed gender sample of 130 detoxified and well-characterized alcohol-dependent patients (37 women) was followed up over a period of 12 months after 6 weeks of inpatient treatment. Patients had completed a comprehensive baseline assessment, including a stress coping questionnaire (SVF120). We hypothesized that these individual stress coping styles would contribute to treatment outcome. A logistic regression analysis was used to evaluate the impact of stress coping styles, as well as the effect of pretreatment drinking and social characteristics on relapse. Approximately half the patients (49%) relapsed within 1 year after treatment. In contrast to our hypothesis, stress coping styles did not predict relapse. However, significant predictors of relapse were social factors related to living situation (living alone), marital status (being separated from the spouse) and pretreatment frequency of alcohol intake. These findings suggest that a partnership is more relevant for the risk of relapse than stress coping styles.

Adult↗

PubMed1978

[Treatment of relapses in juvenile acute lymphoblastic leukemia].

Recurrence of childhood acute lymphoblastic leukemia occurs in about 30-50% and indicates irresistable progression of the disease. While systemic (= hematologic) relapse is due to drug resistance of leukemic cells, pharmacologic barriers may be responsible for local relapses as meningeal involvement, leukemic ophthalmopathy or testicular infiltration. L-asparginase seems to be an important component of drug combinations for re-induction therapy for systemic relapse. Following reinduction therapy modification of continuation therapy is necessary. Local relapses require local treatment, i.e. radiotherapy and e.g. intrathecal drug application. Local relapse is almost always followed by hematologic relapse. Therefore, intensification of systemic therapy is also recommended. Prevention of these relapses is much more important and probably more successful than treatment. Therefore, initial therapy should include preventive measures for pharmacologic sanctuaries.

Asparaginase↗

PubMed2004

A nested case-control study on treatment-related risk factors for early relapse of tuberculosis.

This nested case-control study aimed at evaluating treatment-related risk factors of relapse of tuberculosis under a service program of directly observed treatment. Out of 12,183 patients with pulmonary tuberculosis who completed treatment within 1 year, 113 relapsed within 30 months after commencement of therapy. The overall 30-month relapse rate was 0.9% (95% confidence interval [CI] 0.8-1.1%). On matching 113 cases with 226 control subjects in a conditional logistic model, thrice-weekly treatment increased the risk of relapse in comparison with daily treatment (odds ratio 3.92, 95% CI 1.78-8.63), whereas prolonging both intensive phase and overall treatment by 50% or more protected against relapse (odds ratio 0.24, 95% CI 0.08-0.70). When pretreatment culture was positive and cavitation was absent, the 30-month relapse rate for standard thrice-weekly regimen was 1.1% (95% CI 0.6-2.0%). The corresponding rates in the presence of cavitation were 7.8% (95% CI 4.0-14.6%) for standard thrice-weekly regimen; 3.3% (95% CI 1.9-5.5%) for standard daily regimen; 0.5% (95% CI 0.1-2.6%) for extended thrice-weekly regimen; and 0.4% (95% CI 0.1-0.9%) for extended daily regimen. Further studies are required to reduce the risk of relapse under program settings.

Adult↗

PubMed1992

Relapse after cognitive behavior therapy of depression: potential implications for longer courses of treatment.

OBJECTIVE: The authors studied the risk of relapse among depressed patients after cognitive behavior therapy in order to document the need and potential indications for longer-term models of treatment. METHOD: Forty-eight patients with major depression who responded during a 16-week course of cognitive behavior therapy entered a 1-year prospective follow-up study, as did two patients who received 20 weeks of therapy. Standardized, independent clinical assessments were completed 1, 3, 6, 9, and 12 months after treatment. Relapse was defined as, at minimum, a 2-week period in which the subject met the DSM-III-R criteria for major depression and had a Hamilton depression scale score of 15 or more. RESULTS: Sixteen patients (32%) relapsed during the 1-year follow-up. Correlates of relapse included a history of depressive episodes, higher levels of depressive symptoms and dysfunctional attitudes, slower response to therapy, and being unmarried. Patients who fully recovered during therapy (Hamilton depression score of 6 or less for 8 weeks or more) were at significantly lower risk for relapse than those who partially recovered (9% and 52%, respectively). Slower response to therapy, unmarried status, and high residual scores on the Dysfunctional Attitudes Scale were independently and additively related to increased risk of relapse. CONCLUSIONS: These findings provide further evidence of a relation between residual symptoms and relapse after cessation of active treatment. The authors strongly recommend that models of longer-term psychotherapy be developed for depressed patients who do not recover fully during time-limited cognitive behavior therapy.

Adult↗

PubMed1994

Noradrenergic activity and prediction of psychotic relapse following haloperidol withdrawal in schizophrenia.

OBJECTIVE: The purpose of this study was to develop a model based on the authors' previous studies to identify which neuroleptic-treated schizophrenic patients are at risk of early relapse following drug withdrawal. METHOD: Clinical and CSF monoamine-related variables obtained for 50 male haloperidol-treated, schizophrenic patients were used in a logistic regression model to identify those who relapsed (N = 24) within 6 weeks after placebo substitution and those who did not (N = 26). RESULTS: The oral dose of haloperidol, weight, CSF norepinephrine, 3-methoxy-4-hydroxyphenylglycol and chromogranin A-like immunoreactivity, and the anxiety and paranoia subscale ratings of the Brief Psychiatric Rating Scale produced a model that correctly predicted 18 relapsers and 21 nonrelapsers. By including the interactions of paranoia subscale by CSF norepinephrine and anxiety by CSF norepinephrine, the model correctly identified 20 relapsers and 23 nonrelapsers with a sensitivity and specificity of 83% and 88%, respectively. CONCLUSIONS: Increased noradrenergic activity during chronic dopamine blockade may be an episode marker and may predict relapse within 6 weeks following haloperidol withdrawal in schizophrenia. Effective relapse prediction models have important practical implications for the treatment of schizophrenia and the understanding of the psychotic relapse process.

Adult↗

PubMed1995

Relapse and impairment in bipolar disorder.

OBJECTIVE: The purpose of this study was to evaluate the outcome of bipolar disorder in the context of maintenance pharmacotherapy. METHOD: Eighty-two bipolar outpatients were followed prospectively for a mean of 4.3 years (minimum of 2 years); symptom rating and psychosocial outcome scales were used, and pharmacotherapy was rated on a 5-point scale. RESULTS: Despite continual maintenance treatment, survival analysis indicated a 5-year risk of relapse into mania or depression of 73%. Of those who relapsed, two-thirds had multiple relapses. Relapse could not be attributed to inadequate medication. Even for those who did not relapse, considerable affective morbidity was observed. A measure of cumulative affective morbidity appeared to be a more sensitive correlate of psychosocial functioning than was the number of relapses. Poor psychosocial outcome paralleled poor syndromal course. Poor psychosocial functioning, especially occupational disruption, predicted a shorter time to relapse. Depressions were most strongly related to social and family dysfunction. CONCLUSIONS: Even aggressive pharmacological maintenance treatment does not prevent relatively poor outcome in a significant number of bipolar patients.

Adaptation, Psychological↗

PubMed1997

Superiority of carbohydrate-deficient transferrin to gamma-glutamyltransferase in detecting relapse in alcoholism.

OBJECTIVE: The usefulness of carbohydrate-deficient transferrin is widely accepted in screening (male) population samples for heavy alcohol consumption, but its role in relapse detection is not convincingly established. The authors therefore compared the diagnostic value of carbohydrate-deficient transferrin with the commonly used gamma-glutamyltransferase in identifying relapsed alcoholics during outpatient aftercare. METHOD: The patients were 101 male alcoholics who entered a 6-month rehabilitation program after hospital detoxification. Drinking status was assessed by means of self- and collateral reports obtained during regular contacts with the rehabilitation team; relapse was defined as consumption of any alcohol. Visits occurred weekly during month 1, biweekly during month 2, and every 4 weeks during months 3-6. At every visit a blood sample was taken for measurement of carbohydrate-deficient transferrin and gamma-glutamyltransferase. RESULTS: The proportion of men who reported relapse was 25.6% per scheduled contact on average. Positive predictive values indicated that relapse was identified with a 76.2% probability by carbohydrate-deficient transferrin values above the upper normal limit, in contrast to a 32.9% chance with gamma-glutamyltransferase. Carbohydrate-deficient transferrin was especially useful in detecting early relapses during the initial rehabilitation phase, when gamma-glutamyltransferase values had not normalized. Because of the longer half-life of gamma-glutamyltransferase, it had some value with a 4-week monitoring schedule in detecting new drinking episodes in alcoholics whose previous results had been normal. CONCLUSIONS: Carbohydrate-deficient transferrin proved to be superior to gamma-glutamyltransferase in relapse detection in an outpatient care setting for alcoholics.

Adult↗

PubMed2001

Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: results of a 28-week double-blind, placebo-controlled study.

OBJECTIVE: The study examined the efficacy of sertraline, compared with placebo, in sustaining improvement and preventing relapse over 28 weeks in patients with posttraumatic stress disorder (PTSD) who had completed a 12-week double-blind, placebo-controlled acute treatment study and a subsequent 24-week open-label study of continuation treatment with sertraline. METHOD: Ninety-six patients were randomly assigned, in a double-blind design, to 28 weeks of maintenance treatment with sertraline (50-200 mg, N=46; 78% were women) or placebo (N=50; 62% were women). Measures used in biweekly assessments included the Clinician-Administered PTSD Scale, the Impact of Event Scale, and the Clinical Global Impression severity and improvement ratings. Kaplan-Meier analyses were used to estimate time to discontinuation from the study due to relapse, relapse or study discontinuation due to clinical deterioration, and acute exacerbation. RESULTS: Continued treatment with sertraline yielded lower PTSD relapse rates than placebo (5% versus 26%). Patients who received placebo were 6.4 times as likely to experience relapse as were patients who received sertraline. Kaplan-Meier analyses confirmed the protective effect of sertraline in significantly extending time in remission. The ability of sertraline to sustain improvement was comparable across the three core PTSD symptom clusters (reexperiencing/intrusion, avoidance/numbing, and hyperarousal). A regression analysis found early response during acute treatment to be associated with a more than 16-fold reduced risk of relapse after placebo substitution. Sertraline, at a mean endpoint dose of 137 mg, was well tolerated, with no sertraline-related adverse events observed at a rate of 10% or higher. CONCLUSIONS: The results provide evidence for the ability of sertraline both to sustain improvement in PTSD symptoms and to provide prophylactic protection against relapse.

Adult↗

PubMed2005

Postremission predictors of relapse in women with eating disorders.

OBJECTIVE: The authors sought to evaluate patterns and predictors of relapse among women with eating disorders. METHOD: Interviews were conducted biannually to annually to assess symptoms of eating disorders, axis I disorders, treatment, and psychosocial function on a weekly basis for women diagnosed with anorexia nervosa (N=136) or bulimia nervosa (N=110) and prospectively followed for 9 years. At the last follow-up, 229 (93%) of the subjects had been retained in the study group. RESULTS: Relapse occurred in 36% of the women with anorexia nervosa and 35% of the women with bulimia nervosa. Women with intake diagnoses of anorexia nervosa, restricting subtype, tended to develop bulimic symptoms during relapse, whereas women with intake diagnoses of anorexia nervosa, binge-purge subtype, or bulimia nervosa tended to return to bulimic patterns during relapse. Greater body image disturbance contributed to a risk of relapse in both eating disorders, and worse psychosocial function increased the risk of relapse in bulimia nervosa. CONCLUSIONS: These results may explain the long-term efficacy of interpersonal therapy for bulimia nervosa and suggest that focused body image work during relapse prevention may enhance long-term recovery from eating disorders.

Adaptation, Psychological↗

PubMedDate not supplied

Long-term relapses in breast cancer patients (estrogen receptor status).

To investigate the relation between estrogen receptor (ER) status and timing of relapse, we retrospectively studied two groups of patients (200 cases in each group) who underwent radical mastectomy and developed an early relapse (within 3 years of the surgery) or a long-term relapse (more than 8 years after surgery). One-hundred and eighty-two (91%) patients who developed a long-term relapse were ER-positive (ER+), whereas only 64% of patients who developed an early relapse were ER+ (P < 0.001), supporting the hypothesis that a long-term relapse is more frequently associated with an ER+ tumor. A review of the literature, which indicated that a long-term relapse arises more frequently in patients in whom a partial hormone control is maintained, seems to support this finding, albeit the presence of 18 ER-negative (ER-) cases in our study. However, this apparent contradictory observation could be explained by the fact that 12 of our patients were in premenopause and that ER-status could have been false ER- results due to the binding of endogenous estradiol to ER.

Breast Neoplasms↗

PubMed1998

In vitro cytokine profiles as indicators of relapse activity and clinical course in multiple sclerosis.

In vitro production of tumor necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and oligoclonal IgG (IgG OB) was evaluated in the aim to investigate their profile in correlation with multiple sclerosis (MS) clinical activity and clinical course. Whole blood stimulation with lipopolysaccharide or concanavalin A was performed in 61 patients presenting with relapsing-remitting, relapsing-progressive or chronic progressive MS; treatments received were: none, azathioprine (AZA), cyclosporin, cyclophosphamide, subcutaneous interferon-beta 1a (IFN-beta 1a) and corticosteroids (CST). The cinetics of cytokine production showed that (i) in the absence of treatment, TNF-alpha and IL-6 dropped respectively after and during the periods surrounding relapse, while IL-4 was increasing before and IL-10 after relapse; (ii) with AZA, TNF-alpha and IL-6 lowered before exacerbation, IL-4 prolonged high levels after and IL-10 before relapse; (iii) with IFN-beta 1a, IL-10 was already increasing before relapse, and TNF-alpha was higher after relapse. When cytokine levels were analysed independently from MS clinical activity, the use of AZA inhibited IgG OB and TNF-alpha synthesis (P = 0.002) but increased IL-4 (P = 0.0024), whereas IFN-beta 1a stimulated TNF-alpha and inhibited IgG OB and IL-4 production. CST inhibited TNF-alpha, IL-6, IL-4 and IgG OB synthesis. This study stresses both the weight of clinical parameters and of methodology used in results obtained in cytokine analysis in MS.

Biomarkers↗