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A gene expression signature for relapse of primary wilms tumors.

Anaplastic histology and metastasis are each associated with higher relapse and mortality rates in Wilms tumor patients. However, not all anaplastic tumors relapse and some nonanaplastic tumors relapse unexpectedly. To identify more accurate early prognostic indicators, we analyzed expression of 4,900 cancer-related genes in 26 primary Wilms tumors. This analysis revealed that expression of a set of four genes predicts future relapse of primary Wilms tumors with high accuracy, independent of anaplasia. Random permutation testing of this prognostic gene expression signature yielded P = 0.003. Real-time reverse transcription-PCR analysis of the four genes in an independent primary tumor set resulted in correct prediction of future relapse with an accuracy of 92%. One of the four genes in the prognostic signature, CCAAT/enhancer binding protein beta (C/EBPB), is expressed at higher levels in both primary relapsing tumors and metastatic tumors than in primary nonrelapsing tumors. Short interfering RNA-mediated down-regulation of C/EBPB expression in WiT49, a cell line derived from a metastatic Wilms tumor, resulted in spontaneous apoptosis. These findings suggest that C/EBPB is a critical survival factor for Wilms tumor cells and that its expression contributes to the prognosis of Wilms tumor patients.

CCAAT-Enhancer-Binding Protein-beta↗

Increased frequency of aberrations in the p53/MDM2/p14(ARF) pathway in neuroblastoma cell lines established at relapse.

p53 mutations have been reported in cell lines derived from relapsed neuroblastoma tumors. We hypothesize that functional inactivation of p53 by mutation or other mechanisms is common in relapsed neuroblastoma and can contribute to chemoresistance. Our aim was to determine the frequency of p53 mutations, p14(ARF) methylation, or deletion and MDM2 amplification in 23 neuroblastoma cell lines (6 derived at diagnosis and 17 derived at relapse). One cell line was p53 mutant (BE2c) and two cell lines were deleted for p14(ARF) (LAN-6 and SHEP). Two cell lines were methylated for p14(ARF) (GIMEN and PER-108), one of which had low levels of p14(ARF) mRNA expression which increased following demethylation with 5-aza-2/deoxycytidine treatment (GIMEN), and four cell lines were confirmed to be MDM2-amplified. All these cell lines were derived from neuroblastomas at relapse. Inactivation of the p53 pathway was observed in 9 out of 17 neuroblastoma cell lines (53%) established at relapse and in none of the cell lines established from pretreatment tumors. If these data are confirmed in neuroblastoma tumors, this suggests that p53-independent therapy and reactivation of inactive p53 approaches would be useful in the management of relapsed neuroblastoma.

Cell Line, Tumor↗

Methylenetetrahydrofolate reductase genotype affects risk of relapse after hematopoietic cell transplantation for chronic myelogenous leukemia.

PURPOSE: Methylenetetrahydrofolate reductase (MTHFR) directs intracellular folate toward homocysteine metabolism and away from nucleotide synthesis. Two common MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity. We evaluated the association of these polymorphisms with risk of relapse and bcr-abl mRNA transcript detection among 336 Caucasian patients who underwent allogeneic hematopoietic cell transplantation for chronic myelogenous leukemia. EXPERIMENTAL DESIGN: Data on the transplant course and folate-related exposures were abstracted from medical records. MTHFR C677T and A1298C genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Qualitative bcr-abl mRNA testing was conducted using a two-step reverse transcription-polymerase chain reaction assay. Cox regression analysis was used to assess the association between MTHFR genotypes and time to relapse and bcr-abl mRNA detection. RESULTS: A statistically significant decreased risk of relapse was observed in patients with the variant A1298C genotype [1298AC, hazard ratio (HR)=0.48 and 95% confidence interval (CI)=0.26-0.88; 1298CC, HR=0.28 and 95% CI=0.09-0.84; P-trend <0.01). For the joint C677T/A1298C genotype, variant genotypes were associated with a decreased risk of relapse when compared with the wild-type 677CC/1298AA genotype. This risk was lowest for the 677CC/1298CC genotype (HR, 0.23; 95% CI, 0.08-0.72). MTHFR genotypes were not associated with bcr-abl transcript detection. CONCLUSIONS: These findings suggest that individuals with the 677CC/1298AA genotype are at higher risk of relapse after hematopoietic cell transplantation and that the balance of intracellular folate metabolites available for nucleotide synthesis (regulated by the relative activity of the MTHFR enzyme) may affect the progression from bcr-abl positivity to clinical relapse.

Adolescent↗

Cyclooxygenase-2 expression in postmastectomy chest wall relapse.

PURPOSE: Cyclooxygenase-2 (COX-2) expression has been shown to be associated with radiation resistance, which theoretically could be overcome with the use of COX-2 inhibitors. The purpose of this study was to assess the prognostic significance and clinical correlations of COX-2 expression (COX) in a cohort of patients treated with radiation for postmastectomy chest wall relapse. EXPERIMENTAL DESIGN: Between 1975 and 1999, 113 patients were treated for isolated postmastectomy chest wall relapse. All patients were treated with biopsy and/or excision of the chest wall recurrence followed by radiation therapy. Median follow-up was 10 years. All clinical data, including demographics, pathology, staging, receptor status, HER-2/neu status, and adjuvant therapy, were entered into a computerized database. Paraffin-embedded chest wall recurrence specimens were retrieved from 42 patients, of which 38 were evaluated, created into a tissue microarray, stained by immunohistochemical methods for COX, and graded 0 to 3+. A score of 2 to 3+ was considered positive. RESULTS: Overall survival from original diagnosis for entire cohort was 44% at 10 years. Survival rate after chest wall recurrence was 28% at 10 years. The distant metastasis-free survival rate after chest wall recurrence was 40% at 10 years. Local-regional control of disease was achieved in 79% at 10 years after chest wall recurrence. COX was considered positive in 13 of 38 cases. COX was inversely correlated with estrogen receptor (P = 0.045) and progesterone receptor (P = 0.028), and positively correlated with HER-2/neu (P = 0.003). COX was also associated with a shorter time to postmastectomy chest wall relapse. The distant metastasis-free rate for COX-negative patients was 70% at 10 years, compared with 31% at 10 years for COX-2-positive patients (P = 0.029). COX positive had a poorer local-regional progression-free rate of 19% at 10 years, compared with 81% at 10 years for COX negative. This was of high statistical significance with a P value of 0.003. CONCLUSIONS: Outcome following radiation therapy for postmastectomy chest wall relapse is relatively poor. Positive COX correlated with other markers of poor outcome, including a shorter time to local relapse, negative estrogen receptor/progesterone receptor, and positive Her-2/neu status. Positive COX correlated with higher distant metastasis and lower local-regional control of disease. If confirmed with larger studies, these data have implications with respect to the concurrent use of COX-2 inhibitors and radiation for postmastectomy chest wall relapse.

Adult↗

An evaluation of the 'Coping with Depression Course' for relapse prevention with unipolar depressed patients.

BACKGROUND: Patients with treated episodes of depression are at high risk of relapse and recurrence. This study describes the clinical course of patients who had received cognitive-behavioral group intervention for relapse prevention. METHOD: Forty-four remitted unipolar depressed patients with recently treated episodes of illness participated in a 16-week group program, the 'Coping with Depression Course' (CWD). The majority of patients had suffered from multiple episodes of depression and nearly half of them were only partially remitted when they started the program. Assessments took place throughout the intervention and 17-23 months after the pretest. Descriptive analyses included proportions of reliable and clinically significant improvements, and cumulative relapse rates were estimated using survival analysis. RESULTS: At posttest, residual depression and dysfunctional attitudes had significantly decreased. Improvements were similar in patients with and those without parallel antidepressant medication. Two thirds of patients starting within a dysfunctional depression range showed a clinically significant improvement at the end of the intervention. The estimated cumulative relapse rates at 6, 12, 17, and 23 months after pretest were 13.6, 30.0, 37.0 and 44.9%. CONCLUSIONS: Participants appeared to be protected from relapse during active intervention, but a substantial proportion suffered relapses in the postintervention period. Further research into the CWD is needed within the framework of randomized controlled trials.

Cognitive Behavioral Therapy↗

Hypercalcaemia in relapsed medulloblastoma 8 years post-diagnosis; evidence to support PTHrP production by medulloblastoma cells.

BACKGROUND: A 19-year-old male presented with symptomatic hypercalcaemia as the first manifestation of relapsed metastatic medulloblastoma. Management at the time of the initial presentation 8 years earlier was with surgical excision and craniospinal radiotherapy. His biochemistry at the time of relapse and studies of medulloblastoma cell lines provide an insight into the pathogenesis of his hypercalcaemia. METHODS: Parathyroid hormone-related protein (PTHrP) was measured by immunoradiometric assay in blood, and in conditioned and control media from three medulloblastoma cell lines following 72 h growth. RESULTS: The histology at initial presentation (11 years of age) and at the time of relapse (with bone marrow infiltration and widespread bony metastases) demonstrated medulloblastoma. Ionised calcium concentrations at relapse were 2.89 mmol/l and serum PTHrP levels were increased at the same time (2.7 pmol/l; normal range: 0.7-1.8 pmol/l). There was evidence of PTHrP production by one cell line (MHH-MED-8A) while results for both other lines tested were below the limit of detection. CONCLUSIONS: Relapse 8 years after diagnosis is unusual in medulloblastoma and for this relapse to manifest as hypercalcaemia is also very uncommon. Our investigations suggest that the clinical picture was a reflection of PTHrP production by medulloblastoma cells.

Adolescent↗

Late relapses in acute promyelocytic leukaemia.

From January 1988 to December 1997, among 53 acute promyelocytic leukaemia patients in 1st complete remission (CR) after 5 years from diagnosis, we observed 5 late relapses (9.4%) after 60, 61, 71, 101 and 155 months from diagnosis; 3 of those late relapses (7.7%) occurred among 39 patients previously treated with all-trans-retinoic acid. An involvement of the mastoid occurred in 3/5 patients (60%), compared with 2/32 patients (6.3%) at an early relapse (p < 0.02). As to the treatment of the late relapse, 1 patient received all-trans-retinoic acid alone followed by allogeneic transplantation and 4 patients were treated according to the GIMEMA 0191 protocol. All patients achieved a 2nd CR and are still alive: 4 in the 2nd molecular CR after 6, 33, 34 and 115 months; 1 relapsed after 15 months and is now in the 3rd CR. In conclusion, a late relapse occurred in a sizeable fraction of acute promyelocytic leukaemia patients: the high rate of ear involvement might be explained considering the ear as a 'disease sanctuary'.

Adolescent↗

Handmirror cells and central nervous system relapse in childhood acute lymphoblastic leukaemia.

In 53 children with acute lymphoblastic leukaemia (ALL), initial handmirror cell (HMC) count among lymphoblasts was studied in relation to the occurrence of a relapse in the central nervous system (CNS), taking into account the white blood cell count (WBC) and the immunological phenotype. The children were followed for a period limited by (1) the first CNS relapse, (2) death or (3) the closing day of this study. The median follow-up period was 30 months, range 2-106 months. HMC counts were available in bone marrow smears of 41 children and in cytospins of 35 children. Cytospins proved to give more reliable and consistent results than bone marrow smears. In the 35 'cytospin' children no CNS relapses occurred in the group of 16 children with non-T-non-B-ALL and HMC counts above 10%. However, in the group of 10 children with non-T-non-B-ALL and HMC counts below 10%, and in the group of 9 children with T-ALL (HMC less than or equal to 11%), 6 and 5, respectively, got a CNS relapse. The CNS relapse-free period was not significantly different between these last two groups, whereas both groups did differ significantly from the group mentioned first (p less than 0.01). This was not found in bone marrow smears of 41 children, presumably because of the inaccurate counting results. A low initial HMC count in cytospins is associated with an increased risk for the occurrence of a CNS relapse in children with ALL. This prognostic factor seems to be independent of other prognostic signs such as immunological phenotype and high WBC.

Adolescent↗

[Premonitory blood count changes in the relapse of juvenile acute lymphatic leukemia].

Investigation was done in 80 children with acute lymphocytic leukemia (ALL) with respect to premonitory changes of peripheral blood cell counts before a hematologica relapse. 38 patients suffered from one or more relapses. Evaluation was done by t-test and Friedmann test. 9 weeks before a relapse there was a significant decrease in thrombocytes numbers demonstrable. Granulocytes numbers and monocytes numbers declined 6 and 3 weeks before the relapse, respectively. The lymphocytes counts had already increased 6 weeks before a relapse. The blood cell counts during intercurrent infections did not interfere with the typical pattern of blood cell counts before a relapse. Also the changes in blood cells found are different from those seen in untreated cases of ALL.

Blood Platelets↗

Relapse of Hodgkin's disease after ten years.

We report four cases of Hodgkin's disease (HD) relapsing after complete remission for over a 10-year period after the initial therapy. Three of the patients had mixed-cellularity subtypes as a primary histological diagnosis, and the rebiopsies demonstrated mixed cellularity in all very late relapse cases. Two patients were initially treated with radiotherapy, while in the other two advanced cases polychemotherapy was administered. All patients had advanced disease at the time of the very late relapses, though the relapse was not identifiable in the previously involved regions. By rescue therapy, all patients achieved a second complete remission. However, two patients relapsed again with one of them dying during relapse. The three remaining patients are still in complete remission. Our report demonstrates the necessity of prolonged follow-up of patients with HD.

Adult↗

Relapse after short-term drug therapy in neurotic outpatients.

A 6-month follow-up of 184 anxious depressed neurotic outpatients who reported improvement after controlled drug trials of several weeks duration revealed an astonishing relapse rate of 81% for anxious and 87% for depressed patients. Early as compared to late relapse was associated with more chronicity and less improvement at the end of the drug trial, while type of drug received did not affect relapse. Onset of relapse had no effect on help-seeking behavior. At time of follow-up, non-relapsed patients had lowest and untreated relapsed patients had highest symptom levels. It was concluded that short-term drug treatment alone does not represent sufficient therapy for chronic neurotic anxious or depressed outpatients.

Adult↗

L-dopa challenge and relapse in schizophrenia.

Neuroleptic administration has been shown to be superior to placebo in prolonging schizophrenic remission. However, individual patients are able to maintain long periods of remission in the absence of neuroleptic treatment, while others relapse soon after neuroleptic withdrawal. This study attempted to predict time to relapse in 28 schizophrenic patients withdrawn from neuroleptics and challenged with L-dopa for 7 days, then followed until relapse. Time to relapse correlated significantly with L-dopa-induced increase in BPRS score (p = .006). Five of six patients who responded to L-dopa relapsed within 4 weeks after L-dopa administration, while only four of 22 who did not respond relapsed in a comparable period.

Adult↗

Rate and prediction of relapse in bulimia nervosa.

OBJECTIVE: The purpose of this study was to provide an estimate of the rate of relapse in patients with bulimia nervosa and to attempt to identify indexes of functioning before or after treatment that predicted subsequent relapse. METHOD: The subjects were 48 female patients with bulimia nervosa who achieved symptom control while attending a specialized day hospital treatment program for eating disorders. The subjects were assessed before treatment, after treatment, and at a 2-year follow-up interview with respect to their eating symptoms and psychosocial functioning. RESULTS: A relapse rate of 31% was observed during the 2-year follow-up period, and the vast majority of relapses occurred within the first 6 months after treatment. The strongest predictors of relapse were younger age, higher vomiting frequency, and a higher score on the bulimia subscale of the 26-item Eating Attitudes Test before treatment and higher vomiting frequency and a higher score on the interpersonal distrust subscale of the Eating Disorder Inventory at the end of treatment. Measures of binge eating frequency, self-esteem, depression, and social adjustment were not significant predictors of relapse. CONCLUSIONS: Vomiting frequency, even at subthreshold levels, appears to be an important prognostic indicator and may be one of the best barometers of residual symptoms in these patients.

Adolescent↗

Expressed emotion, perceived criticism, and relapse in depression: a replication in an Egyptian community.

OBJECTIVE: The aims of this study were to determine the value of families' expressed emotion and patients' perception of family criticism in predicting relapse in Egyptian depressed patients and to evaluate transcultural differences in assessment of these measures. METHOD: The subjects were 32 consecutive depressed patients from psychiatric clinics in Cairo and Ismailia, Egypt, who fulfilled the DSM-III-R criteria for major depression or bipolar disorder. An Arabic version of the Camberwell Family Interview was administered to key relatives of the depressed patients. Rating of expressed emotion was performed blindly by a qualified rater to assess levels of criticism, hostility, emotional overinvolvement, warmth, and positive remarks. Patient perception of family criticism (perceived criticism) was also assessed. All patients were followed up for 9 months to assess relapse and compliance with treatment. RESULTS: The relation of family criticism to relapse was statistically significant. Although this result replicates previous findings, the criticism level that best differentiated relapsers and nonrelapsers was a score of 7, which is much higher than previously reported in Western studies. This relation was not observed for other expressed emotion components. Also, no association between perceived criticism and relapse was detected. CONCLUSIONS: Expressed emotion is a prognostic factor that should be assessed with consideration of the specific culture and intrafamilial patterns. The use of perceived criticism in the prediction of relapse in depression is questionable. There is a need for a simplified, less time-consuming assessment tool that takes cross-cultural differences and specificities into consideration.

Adolescent↗

Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials.

OBJECTIVE: The authors performed a systematic review and meta-analysis of studies of the potential of new-generation antipsychotic drugs to improve adherence and decrease relapse rates in patients with schizophrenia. METHOD: Randomized, controlled trials comparing new-generation antipsychotic drugs with placebo and/or conventional antipsychotics were identified. Data on relapse, general treatment failure, and dropout due to adverse events were extracted and combined in a meta-analysis. RESULTS: Because few trials were available for each individual drug, the effects of new-generation antipsychotic drugs as a group were analyzed. The analysis of six placebo comparisons, involving a total of 983 patients, clearly demonstrated that new-generation antipsychotic drugs are effective for relapse prevention. Eleven studies with a total of 2,032 patients provided comparative data on relapse/treatment failure for new-generation and conventional antipsychotics. The analysis revealed that rates of relapse and overall treatment failure were modestly but significantly lower with the newer drugs. Whether this advantage was partly mediated by improved adherence to treatment remains unclear. No significant superiority in terms of fewer dropouts due to adverse events was found for the newer drugs. Furthermore, a number of methodological problems were identified. CONCLUSIONS: Overall, the currently available data suggest that new-generation antipsychotics have the potential to reduce relapse rates. Methodological issues to be addressed in future trials include the choice of comparator, use of appropriate doses, application of clinically relevant relapse criteria, monitoring of adherence, and minimization of dropouts.

Antipsychotic Agents↗

Relapse of substance use disorder and its prevention among persons with co-occurring disorders.

This article summarizes the scientific literature on the relapse process, describes the basic principles of relapse prevention treatment, highlights the major empirical studies, and offers suggestions for future research and application, especially in terms of ongoing care for persons with co-occurring disorders. Relapse prevention treatments have a well-established efficacy and effectiveness for persons with substance use disorders. Key ingredients include reducing exposure to substances, fostering motivation for abstinence, self-monitoring, recognizing and coping with cravings and negative affect, identifying thought processes with relapse potential, and deploying, if necessary, a crisis plan. Relapse prevention approaches may be best suited for persons in the action of maintenance stages of treatment or recovery. Further research is needed to examine relapse prevention therapies as a key component to continuing care for persons with co-occurring substance use and psychiatric disorders.

Adaptation, Psychological↗

Successful long-term jejunostomy feedings in relapsing pancreatitis: a case report.

Relapsing pancreatitis is characterized by repeated episodes of acute inflammation of the pancreas, with either a localized or a systemic organic response that may progress to chronic pancreatitis. Enteral jejunal feedings have been shown to be effective in the management of acute pancreatitis, but long-term use of jejunal feedings as treatment of relapsing pancreatitis has not been reported. We describe the case of a young patient treated with long-term jejunal feedings to induce remission and prevent recurrence of acute relapsing pancreatitis. An 18-year-old Hispanic man had well-documented recurrent episodes of acute pancreatitis. Multiple studies were performed as part of the diagnostic workup of the patient's relapsing pancreatitis, including endoscopic ultrasound, endoscopic retrograde cholangiopancreatography with biliary sphincterotomy, and laparoscopic cholecystectomy. Despite medical therapy, endoscopic and surgical procedures, the patient continued having episodes of pancreatitis on a monthly basis, with over 13 distinct documented episodes of pancreatitis during a 15-month period. A jejunostomy tube was inserted surgically, and long-term jejunal feedings were instituted, with excellent control of the patient's symptoms. There was only 1 episode of pancreatitis in the ensuing 24 months associated with the resumption of oral feedings and a weight gain of 20 pounds during this time period. Chronic jejunal feedings seem to be an effective alternative for treatment and prevention of acute relapsing pancreatitis. To our knowledge, this is the first report of long-term enteral feedings in acute relapsing pancreatitis.

Adolescent↗

Salvage with radiotherapy of postsurgical relapses of endometrial cancer.

From January 1960 to June 1974, 71 patients with a postsurgical relapse of endometrial adenocarcinoma have been referred to the Radiology Institute of the University of Florence. Eleven patients showed hematogenous metastases; the remaining 60 cases showed locoregional relapses and were treated with radiotherapy. Forty-eight patients, whose relapse was localized to the pelvis, vagina, inguinal nodes or perineal scar, were treated with a radical aim (4,500-6,000 rad in 5-6 weeks); the treatment was palliative in 12 cases with abdominal extrapelvic relapse. The therapeutic response was not evaluated in 8 patients lost to follow-up shortly after the treatment. In the cases treated with a radical scope, a complete regression was attained in 22 of 43 (51%); a survival rate of 16 of 43 (37%) was attained at 5 years. In 9 cases treated with a palliative aim, only subjective remission was attained, and no patient was alive one year after the therapy. The most favorable therapeutic response was attained in the vaginal relapses (50% survivors at 5 years) and the cases with a late recurrence (more than 3 years) after the initial surgery. No definite correlation was found between the prognosis of the relapse and the histological grading of the primary tumor.

Adenocarcinoma↗