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Relapses among leprosy patients treated with multidrug therapy: experience in the leprosy control program of the All Africa Leprosy and Rehabilitation Training Center (ALERT) in Ethiopia; practical difficulties with diagnosing relapses; operational procedures and criteria for diagnosing relapses.

Multidrug therapy (MDT), according to the recommendations of a WHO Study Group of 1982, was introduced in the leprosy control program of the All African Leprosy and Rehabilitation Training Center (ALERT), Ethiopia, in January 1983. Paucibacillary (PB) patients are treated with 6 months of MDT. Multibacillary (MB) patients are treated with at least 2 years of MDT and until skin-smear negativity. An analysis was made of the relapses which had been diagnosed among self-reporting patients in four rural districts and Addis Ababa. Among 3065 PB patients, 34 relapses (1.1%) were diagnosed during an average period of 6.1 years after stopping MDT (range 2 1/2 to 7 1/2 years). Among 2379 MB patients, 24 relapses (1.0%) were diagnosed during an average period of 4.7 years after stopping MDT (range 2 1/2 to 6 years). The estimated relapse rate per 1000 patient-years after release from MDT was 2.1 for PB patients and 2.4 for MB patients. From the analysis of the clinical, bacteriological, and histopathological findings, it was concluded that there was strong positive evidence for the diagnosis for 16 of the 34 relapses in the PB patients and for 0 of the 24 relapses in the MB patients. The main cause for overdiagnosis of MB relapses was that too much reliance had been put on skin-smear results, without a careful comparison of the results with those from before, during, and at completion of MDT; the diagnosis was based on the finding of positive smears in one set of smears only; insufficient attention was given to finding solid-staining bacilli; and findings in biopsies, if these were examined, did not confirm the diagnosis. The main cause of overdiagnosis of PB relapses was that too much reliance was put on histological findings, while these are often inconclusive for differentiating between a relapse and late reversal reaction. Recommendations are made on how to limit overdiagnosis of relapses. Operational procedures and criteria for making the diagnosis under conditions where facilities for back-up histological and mouse foot pad investigations are not available are proposed.

Clofazimine

Radiotherapy for locoregional relapses of rectal carcinoma after initial radical surgery: definite but limited influence on relapse-free survival and survival.

A group of 95 patients, treated with irradiation for relapse after radical surgery as only initial treatment modality for a rectal carcinoma was studied. The term locoregional relapse relates to evidence of tumor recurrent in the pelvis or the perineal area. Seventy-six patients presented with locoregional relapse only, and 19 patients presented with locoregional relapse and concomitant distant metastases. All patients were irradiated at the site of locoregional relapse. Total dose of irradiation was resp. 44 Gy median (range 6-66 Gy) and 40 Gy median (range 6-50 Gy). In the group of patients with locoregional relapse only, recurrence-free survival and survival after radiotherapy were, respectively, 23% and 61% at 1 year, and 6% and 13% at 3 years. In the group of patients with concomitant distant metastases, survival after radiotherapy was even worse, 33% at one year, and nihil at 3 years. Recurrences after radiotherapy occurred early during follow-up with 75% of the recurrences being recorded during the first year of follow-up. Recurrent or persistent disease inside the irradiation volume was the most important clinical problem in both groups, being documented in, respectively, 43/76 and 7/19 (7/13 if six patients were excluded with a survival of less than 3 months from onset of therapy). In the group of patients with locoregional relapse only, using recurrence-free survival as the endpoint, dose of irradiation (p = 0.01) was a significant multivariate prognostic factor and using survival as the endpoint, dose of irradiation (p = 0.005) and grade of tumor differentiation (p = 0.002) were significant. Potentials of current radiotherapy regimes are limited. Therefore, maximal initial treatment is warranted. In the event of a relapse after initial radical surgery, one should opt for either more aggressive standard therapy, or either new combined modalities approaches should be studied.

Adenocarcinoma

Who will relapse? Symptoms of nicotine dependence predict long-term relapse after smoking cessation.

Results of a prospective examination (N = 618) of factors associated with smoking relapse are reported. At 1-year follow-up, a modified version of the Fagerstrom Tolerance Questionnaire (Dependence Index; DI) and a measure of craving entered the logistic model (odds ratio of 2.7 [p less than .001]). At Year 2, only the DI entered the model (odds ratio of 2.2 [p less than .001]). The ability of signal detection analysis (SDA) to produce clinically useful decision rules was also examined. At Year 1, SDA produced 1 subgroup with a 25% nonrelapse rate and another with a 9% nonrelapse rate (odds ratio of 3.4 [p less than .001]). At Year 2, SDA produced 1 subgroup with a nonrelapse rate of 19% and another with a nonrelapse rate of 7% (odds ratio of 3.0 [p less than .001]). The use of signal detection methods may help clinicians to identify those at greater or lesser risk of relapse.

Adult

Factors Impacting Overall Survival Post-Relapse in High-Risk Neuroblastoma: Children's Oncology Group Outcomes From 2000 to 2019.

PURPOSE: Prior studies of features impacting post-relapse survival in high-risk neuroblastoma (HRNB) evaluated patient cohorts that did not receive contemporary high-risk or relapse therapies. We describe overall survival (OS) after first progression or first relapse of HRNB in a modern cohort. METHODS: Patients with HRNB enrolled on COG ANBL00B1(NCT00904241) between 2000 and 2019, who had relapsed or progressive disease were eligible. Clinical and molecular risk factors at diagnosis, therapy era, clinical trial enrollment, and clinical features at relapse, including site of and time to relapse, were evaluated. OS post-relapse was compared between groups using log-rank tests and Cox models. RESULTS: Among 4253 eligible HRNB patients, 1616 had relapse or progression as a first event. Five-year OS post-relapse was 19.1&#xa0;&#xb1;&#xa0;1.1%. The risk group with the lowest post-relapse survival was observed in patients with INSS Stage 4 or 4S disease <&#xa0;18 months of age at diagnosis with MYCN amplified (MYCN-A) tumors. The other significant most unfavorable factors at diagnosis included diagnosis 2000-2004, tumor MYCN-A, 1p loss of heterozygosity (LOH), and elevated LDH or ferritin. Unfavorable factors at relapse included the time to relapse <&#xa0;36 months from diagnosis, and combined local and metastatic disease at relapse. Multivariable analysis indicated that those with tumors harboring 1p LOH, age &#x2264;&#xa0;5 years at diagnosis, or earlier treatment therapy era (2000-2004) had a higher risk of post-relapse death. CONCLUSIONS: While the 5-year OS rate was low in this cohort, there are subsets of patients with relapsed HRNB who demonstrate long-term survival. TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00904241.

Humans

Orthodontic relapse in subjects with varying degrees of anteroposterior and vertical dysplasia.

Fifty seemingly well-treated orthodontic cases were studied by means of pretreatment, posttreatment, and postretention dental casts, lateral cephalograms, and other orthodontic records. The sample was restricted to cases exhibiting anteroposterior and/or vertical dysplasia as revealed by pretreatment dental casts. The sample was divided into a stable group and a relapse group. Each group contained twenty-five cases. A double-blind design was used. The raw data were analyzed by the stepwise discriminant analysis and by the multivariate analysis of variance. On the basis of the results obtained from this study, the following conclusions can be drawn: 1. In seemingly well-treated orthodontic cases, relapse or stability can neither be predicted nor judged from one set of records alone. 2. Relapse or stability of an orthodontic case can be predicted by comparing the posttreatment variables with the pretreatment variables. 3. Relapse or stability of an orthodontic case can be judged by comparing the postretention variables to the posttreatment variables. 4. The PP-GoGn angle and the mandibular intercanine width are the two most important variables associated with orthodontic relapse. 5. Changing the PP-GoGn angle, either by treatment or by growth, was associated with relapse. In other words, changes in the PP-GoGn angle tended to be unstable. This suggests that decreasing the PP-GoGn angle should be avoided. 6. In both the stable and the relapse groups, the mandibular intercanine width decreased postretention. This decrease was associated more with the relapse group than with the stable group. 7. The mandibular intercanine width tended to relapse toward its original pretreatment value. This suggests that, at the end of active treatment, the mandibular intercanine width should be maintained as originally presented. 8. There was no significant interaction between orthodontic relapse (or stability) and Angle Class I and II cases. 9. There was no significant interaction between relapse (or stability), of an orthodontic case, and the sex of the patient. 10. There was no significant interaction between orthodontic relapse (or stability) and whether or not extraction was included as a part of the mechanotherapy. Thus, the pretreatment deep overbite is not necessarily a contraindication to extraction.

Analysis of Variance

Genomic and transcriptomic features of relapsed small cell lung cancer.

BACKGROUND: Relapsed small cell lung cancer is characterized by treatment resistance and poor outcomes. Genomic and transcriptomic alterations in relapsed SCLC have not been characterized well. We comprehensively profiled relapsed SCLC samples along with patient-matched treatment-naive samples, when available, using whole-exome (WES), whole-genome (WGS), and RNA-sequencing (RNA-seq) to describe the molecular landscape of relapsed SCLC. Our goal is to identify potential novel pathways for additional functional validation and eventually novel therapeutic options. METHODS: We analyzed 54 relapsed and 27 treatment-naive SCLC samples using WES (with 26 patient-matched paired samples). A subset of the samples was also analyzed by WGS (n=28) and RNA-seq (n=31). Differences in mutational signatures, gene expression, structural variants, splicing, and neoantigen profiles at diagnosis and relapse were investigated. RESULTS: Relapsed SCLC samples demonstrated mutation signatures characteristic of platinum and APOBEC mutagenesis. Furthermore, these samples were characterized by MYC, MYCL and MYCN amplifications. Both treatment-naive and relapsed SCLC samples showed high prevalence of mutation-associated neoantigens (median= 86 in treatment-naive and 90 in relapsed SCLC; p=0.8) and TP53 was the most frequently altered gene to result in a neoantigen (48% of analyzed samples). Potential mechanisms of immune evasion, including amplification of CD24, overexpression of IDO1, increased M2 macrophage presence, and upregulation of HLA-E were also observed in relapse samples. Differences in alternative splicing patterns were observed between treatment-naive and relapsed small cell samples. Retained intron events were significantly enriched in treatment-naive samples and affected genes involved in DNA repair, metabolism, and WNT and MYC pathways. CONCLUSIONS: This study highlights the genomic and transcriptomic features of relapsed SCLC. These samples were characterized by genomic instability, WNT and MYC dysregulation, and splicing aberrations. Additional studies targeting the splicing machinery, WNT signaling, and immune evasion pathways could identify novel therapeutic vulnerabilities in SCLC.

Journal Article

Relapse in Burkitt's lymphoma.

Of 109 patients with histologically confirmed Burkitt's lymphoma who completed a course of chemotherapy, 86 (79%) achieved complete remission. Forty-five (52%) of patients with initial complete remission relapsed with tumour over an observation period ranging from 2 years to over 5 years. Relapse was more common in patients who initially presented with abdominal or central nervous system (CNS) involvement than in patients who presented with localized facial tumours (p less than 0.01). Anatomical distribution of tumour on relapse differed from that at presentation. Facial bones were much less frequently involved on relapse; on the other hand, the CNS, cranial nerves, orbits and skin were frequent sites of disease on relapse. CNS involvement occurred in 42% (19/45) of patients at the first relapse and in 73% (11/15) of patients with multiple relapses. Prognosis in these patients was poor. Two relapse types were clinically identifiable. Early relapse (remission duration less than 12 weeks) was associated with frequent involvement of the CNS, drug resistance and a generally unfavourable outcome. Patients with late relapse (remission duration greater than 12 weeks) responded much better to secondary treatment. Possible pathogenic mechanisms underlying these two relapse types are discussed.

Abdominal Neoplasms

Long-term, low-dose prednisolone therapy in frequently relapsing nephrotic syndrome.

The efficacy of daily administration of a small dose of prednisolone was examined in 21 patients with corticosteroid-responsive, frequently relapsing nephrotic syndrome (FRNS). After induction of remission of a third or subsequent relapse with a 6-week course of prednisolone (standard therapy with prednisolone, STP), this drug was continued in a single daily dose of 0.25 mg/kg body weight (low-dose prednisolone, LDP) for 18 months. Relapses occurring during this period were treated with STP, following which LDP therapy was resumed. The historical controls comprised 14 patients with FRNS in whom relapses were treated with STP and who were observed over a minimum period of 30 months. The two groups were comparable for age at the onset of nephrotic syndrome and sex. Twenty patients completed LDP therapy, during which 12 had no relapse, 6 had infrequent and 2 frequent relapses (1 patient became steroid dependent and was taken off LDP). Twelve patients were followed for 12-42 months after stoppage of LDP; during this period 7 had no relapse, 4 had infrequent relapses and 1 showed steroid dependence. The number of relapses during LDP therapy (0.5/patient per year) was significantly less (P less than 0.001) than in the preceding 12 months (3.62/patient per year), and continued to remain low during the following 12 months (0.6/patient per year). Whereas the frequency of relapses in the LDP group was similar to that in the historical control group in the 1st year of comparison, it was significantly less during LDP therapy (0.5/patient per year versus 2.25/patient per year). No side effects were observed in patients on the LDP regimen, at the end of which the height percentiles improved in 6 patients and remained unchanged in 14. Our observations indicate that long-term therapy with a small daily dose of prednisolone can significantly reduce the number of relapses in patients with FRNS, and that the beneficial effect may continue even after its stoppage.

Child

Preventing relapse in the treatment of nicotine addiction: current issues and future directions.

Although smoking-cessation rates have continued to increase, the vast majority of smokers who quit eventually relapse. Between 1974 and 1985, over 1.3 million smokers quit during each of those years. However, 75% to 80% of those individuals resumed smoking within six months. This article describes the dynamic phenomenon of smoking relapse within the context of cyclical episodes of smoking and quitting during an individual's lifetime. Theories of the determinants of smoking relapse are reviewed and methods designed to prevent relapse are described. Smoking relapse is discussed in terms of three aspects of tobacco addiction: (1) biological-addiction mechanisms, (2) conditioning processes, and (3) cognitive-social learning factors. The major determinants of smoking relapse are reviewed, including nicotine withdrawal, stress, weight gain, social influences, conditioning factors, causal attributions, and environmental variables. A transtheoretical-developmental model is explored in the longitudinal investigation of the natural history of slips (lapses) and relapse episodes. Relapse prevention interventions are described that emphasize self-awareness, self-regulation, self-efficacy, affect regulation, social support, and lifestyle balance. Recent developments in pharmacological adjuncts to treatment are also examined. It is concluded that innovative relapse prevention methods need to be designed for hard-core smokers with histories of cessation failures, substance abuse and/or psychiatric impairment. These and other recommendations for future research on smoking relapse and relapse prevention are discussed.

Humans

Value of routine bone marrow examination for detection of bone marrow relapse in children with standard risk acute lymphoblastic leukemia.

The value of routine bone marrow examination (RBME) in children during and after treatment for standard risk acute lymphoblastic leukemia (SR-ALL) was investigated. The clinical symptoms and peripheral blood findings at the time of bone marrow relapse of 28 children were reviewed and compared with those of 28 matched controls in continuous complete remission. Five (45%) children with bone marrow relapse during maintenance therapy and six (35%) after cessation of cytostatic treatment were asymptomatic at the time of relapse. Signs indicative of relapse during treatment were lymphoblast cells in the peripheral blood, thrombocytopenia, hepatomegaly, anemia, or leukopenia in decreasing order of frequency. After cessation of treatment these signs were lymphoblasts in the peripheral blood, hepatomegaly, splenomegaly, thrombocytopenia, or leukocytosis. Except for one case with thrombocytopenia, no signs suspicious for relapse were found in the control groups. When each sign was evaluated separately only the presence of lymphoblasts in peripheral blood and hepatomegaly were significant symptoms for relapse after cessation of treatment. The mean percentage of lymphoblasts in the bone marrow at the time of relapse was significantly lower for patients with an unpredicted relapse (46.8%) than patients with clinical and/or laboratory evidence of relapse (79.5%). When lymphoblasts were present in the peripheral blood the percentage of lymphoblasts in the bone marrow was always more than 40%, both during and after cessation of treatment. These data suggest a relation between clinical and laboratory symptoms and progression of the disease. It is concluded that 46% of relapses are detected by RBME in the absence of clinical or laboratory symptoms. This early detection may have a positive prognostic influence with more effective treatment for relapsed ALL.

Adolescent