Breast cancer mortality is mainly due to distant recurrence of the disease arising from dormant tumor cells established by cancer therapies. Patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy. Although immunotherapy of breast cancer by means of anti-HER2 antibodies prolongs survival of breast cancer patients, disease recurrence remains a major challenge. On the other hand administration of human vaccines against infectious disease in a preventive setting or during latency/dormancy has been successful in offering a cure. Here, we sought to use adoptive immunotherapy (AIT) at the time of tumor dormancy in order to prevent progression of breast cancer. We used a low dose immunogenic chemotherapy by means of 5-FU, Adriamycin, and Cyclophosphamide (FAC) in order to stabilize tumor progression prior to AIT using autologous tumor-reactive lymphocytes. Low dose FAC established local tumor dormancy, inhibited distant tumor dormancy occurring long before distant metastasis, and induced predominate a Ki67- quiescent type of tumor dormancy, which is less susceptible to tumor immunoediting. Dormant tumor cells expressed the cell survival pathways, including the endothelin receptor/ligand (ETRA, ETRB and ET-1) and PD-L1, thereby protecting them from elimination by AIT. In addition, tumor-reactive CD8+ T cells also produced ET-1 as a survival ligand for ETRA positive tumor cells. A combination of AIT with the blockade of tumor cell survival pathways resulted in a significant improvement of AIT against tumor dormancy. We also showed that the inhibition Bcl-xL downstream of the tumor cell survival pathways is specifically effective against dormant tumor cells, suggesting a combination of AIT with small molecules inhibitors of Bcl-xL. Altogether, we showed that distant tumor dormancy is established long before distant recurrence of breast cancer, and that the expression of several tumor cell survival pathways in dormant cells protects them from immunotherapy. Our results suggest that immunotherapeutic targeting of tumor dormancy combined with the blockade of a common downstream cell survival pathway could prevent tumor progression and recurrence of the disease.

Le cancer du sein est le cancer le plus fréquent chez la femme et malgré une baisse de la mortalité ces dernières années, attribuable à une détection précoce et une meilleure prise en charge, il reste la première cause de mortalité par cancer et demeure donc un problème majeur de santé publique. La mortalité par cancer du sein s’avère être plus élevée dans le cas des cancers dits agressifs ou de mauvais pronostic tels que le cancer du sein de la femme jeune et le cancer du sein triple négatif (CSTN). Mes travaux de thèse portent sur ces deux types de cancer du sein avec comme objectifs l’étude des conséquences de la ménopause chimio-induite (MCI) chez les femmes jeunes atteintes d’un cancer du sein non métastatique d’une part et l’analyse des facteurs pronostiques de la rechute du cancer du sein triple négatif d’autre part. Le premier axe de ma thèse concerne l’étude clinique MENOCOR dont le but est d’évaluer chez les femmes jeunes atteintes d’un cancer du sein non métastatique l’impact de la MCI sur la qualité de vie (QdV). L’incidence de la MCI et l’étude des variations hormonales font également partie des objectifs secondaires. Dans le cadre de cette thèse, l’analyse intermédiaire, prévue dans le protocole, a été réalisée sur 59 patientes avec un recul de 18 mois post-chimiothérapie. Ces premiers résultats ont tendance à montrer une altération de la QdV évaluée par le QLQ-BR23 chez les patientes ménopausées vs les non ménopausées (p=0.17). A ce stade de l’essai, le QLQ-BR23 semble donc être plus adapté que le QLQ-C30 pour évaluer la QdV dans le contexte de cette étude. Nous avons également observé une prédiction possible de la MCI par le dosage de l’AMH initial et l’âge des patientes. Ainsi, ces résultats doivent être comparés à ceux de l’analyse finale et nous supposons qu’avec une puissance plus importante (effectif total prévu de 240 patientes et suivi de 30 mois post-traitement) les résultats concernant la QdV pourraient être significatifs.Le deuxième axe de ma thèse a consisté à la création d’une base de données sur le CSTN. Cette étude rétrospective s’inscrit dans la continuité des travaux réalisés au Centre Jean PERRIN et a pour but d’évaluer la dynamique et les facteurs prédictifs de la rechute du CSTN. Les analyses ont montré que l’atteinte ganglionnaire, la présence d’emboles et la taille tumorale sont les principaux facteurs pronostiques de la rechute. Les résultats présentés dans cette thèse confirment également l’hétérogénéité des CSTN avec l’existence d’une disparité des réponses à la CTNA (allant de la réponse complète à la chimiorésistance) et d’une diversité des rechutes (précoces (< 1 an), standards (1 à 5 ans) et tardives (> 5 ans)) soulignant la nécessité de poursuivre la recherche de nouveaux biomarqueurs pouvant prédire la réponse ou encore permettant de prévenir les rechutes afin d’améliorer la prise en charge des patientes. En conclusion, ces résultats permettent d’ouvrir de nombreuses perspectives de recherches. Nous prévoyons de comparer les résultats finaux de l’étude MENOCOR à ceux de l’analyse intermédiaire présentés dans cette thèse. A l’issu de l’essai, nous espérons avoir une meilleure compréhension de la MCI, de son impact sur la QdV et du rôle de l’AMH dans la prédiction de la ménopause. Concernant le CSTN, il est prévu de mener une autre étude rétrospective sur une cohorte plus large, avec cette fois-ci, l’analyse des paramètres hématologiques. En fonction des résultats, une étude prospective pourra être mise en place afin d’étudier le rôle du microenvironnement tumoral ainsi que des paramètres hématologiques et génétiques dans la rechute des CSTN. / Breast cancer is the most common cancer among women and despite a decline in mortality in recent years, due to early detection and better treatment management, it remains a major public health issue. Breast cancer mortality has been found to be higher in the case of aggressive or poor prognostic cancers such as breast cancer in young women and the triple negative subtype of breast cancer (TNBC).This PhD focuses on these two types of breast cancer and aims to study the consequences of chemotherapy-induced menopause (CIM) in young women with non metastatic breast cancer and evaluate the prognostic factors of TNBC relapse. One of the aspect of my PhD is based on the clinical study MENOCOR. The main objective of this study is to evaluate the impact of CIM on the quality of life (QoL) of young women with non metastatic breast cancer. The incidence of CIM and the study of hormonal variations are also a part of the secondary objectives. As a part of this PhD work, the interim analysis planned in the study protocol was conducted on 59 patients with a follow-up of 18 months post-chemotherapy. These first results tend to show a QoL decrease, evaluted by the QLQ-BR23, in menopausal women vs non menopausal women (p=0.17). At this stage of the trial, the QLQ-BR23 seems to be more appropriate than the QLQ-C30 to evaluate QoL. We also underline the possible prediction of CIM by the inital AMH level and age. Thus, these results should be compared to the final analysis and we expect that with a greater power (240 patients and a follow-up of 30 months post-chemotherapy) the QoL results will reach significance.The second axis consists of a database on TNBC. This retrospective study follows the work carried out in Jean PERRIN Cancer Center and aims to evaluate dynamics and pronostic factors of TNBC relapse. The analysis showed that the main pronostic factors are the node metastasis, the presence of emboli and the tumor size. The variability of response to chemotherapy (pCR to chemoresistance) and the diversity of relapses (early relapse (<1 year), standard relapse (1 to 5 years) and late relpase (> 5 years)) confirmed the heterogeneity of TNBC highlighting the need to continue the research of new biomarkers. In conclusion, these results open up many research perspectives. We plan to compare the final results of the MENOCOR study with those of the interim analysis presented in this PhD work. At the end of the study, we expect to have a better knowledge of CIM, its impact on QoL and the role of AMH in predicting menopause. Regarding the TNBC, it is planned to conduct another larger retrospective study focused in hematologic parameters evaluating the role of hematologic and genetic parameters. Depending on the results, a prospective study could be promoted in order to evaluate the role of tumoral micro-environment, and hematologic and genetic parameters in TNBC relapse.

制約場地偏好行為為研究藥物成癮的常用模式之一，對於其行為表現及再復發的神經機制，多巴胺系統佔有舉足輕重的地位。而大腦神經滋養因子(BDNF)與多巴胺系統密切相關，影響其神經元可塑性。故本研究以BDNF來作為目標分子，進行一系列的實驗探討制約場地偏好的神經機制。實驗一A以不同劑量安非他命建立制約場地偏好行為，並分析其BDNF mRNA的表現量。實驗結果顯示1 mg/kg安非他命能夠引發制約場地偏好行為，但是對於內側前額葉、紋狀體、依核、背側海馬迴、杏仁核等五個區塊的BDNF mRNA無顯著的影響效果。實驗一B再次確認實驗一A的結果，顯示俱有安非他命引發制約場地偏好行為的受試，其大腦五個區塊BDNF mRNA沒有顯著的變化。實驗二探測制約場地偏好行為再復發對於相同的五個區塊BDNF mRNA變化。結果發現0.75 mg/kg安非他命能誘發制約場地偏好再復發行為，並且能引發內側前額葉中BDNF mRNA的增加，但對其餘四個區塊則無明顯的影響效果。實驗三以單次注射安非他命探討對於BDNF mRNA是否有立即性的影響，結果顯示五個區塊皆無明顯的變化。實驗四以安非他命引發的行為致敏化反應為行為模式，偵測BDNF mRNA的表現情形。結果發現藥物制約配對組與單次注射安非他命組在活動量上無顯著的差異，顯示出無行為致敏化反應的發生。檢驗五個區塊BDNF mRNA的表現，亦沒有發現明顯的改變。綜合以上的實驗結果，本研究得到安非他命制約場地偏好再復發行為，會伴隨內側前額葉BDNF mRNA的增加。而單獨的安非他命引發制約場地偏好行為，並不會改變BDNF mRNA。這些結果顯示BDNF參與在較複雜的制約學習行為歷程，而不是在單獨的藥物注射或與環境配對的制約過程。 / Conditioned place preference (CPP) is widely used as an experimental behavioral model in the study of drug addiction and reward learning. Brain dopamine systems play an important role to drive the CPP performance and its relapse. Brain-derived neurotrophic factor (BDNF) is closely related to dopamine system that can promote neuron plasticity involved in certain types of behavior. Taking BDNF as the target molecule, this project conducted a series of experiments to delve into the neural mechanism of CPP. Different doses of amphetamine on the CPP behavior were assessed in Experiment 1A, and BDNF mRNA was tested after CPP test. The results show that 1 mg/kg amphetamine significantly induced CPP, but no significant effect on BDNF mRNA in any of five brain areas tested, including medial prefrontal cortex, striatum, nucleus accumbens, dorsal hippocampus and amygdala. The results of Experiment 1A was further confirmed by Experiment 1B, indicating no significant change on BDNF mRNA in five brain areas of rats with significant amphetamine-induced CPP. Experiment 2 examined the effects of CPP relapse and tested BDNF mRNA in the aforementioned five brain areas. The results show that 0.75 mg/kg amphetamine significantly induced CPP relapse and also increased BDNF mRNA level in medial prefrontal cortex. Such an increase of BDNF mRNA was not observed in any other four areas. Single acute injection of amphetamine was administered in Experiment 3 to delve into the possible immediate drug effect on BDNF mRNA. Its results show no significant change on five brain areas following this acute drug treatment. Experiment 4 used amphetamine-induced behavioral sensitization as a behavioral mode to determine the expression of BDNF mRNA. The results show no significant difference both for amphetamine-paired group and acute amphetamine group on locomotion, that indicated no behavioral sensitization formed in this test. There was no significant difference in the expression of BDNF mRNA in five brain areas. These results indicate that amphetamine-induced CPP relapse, but not CPP performance itself, is accompanied by the increase of BDNF mRNA level in medial prefrontal cortex. These findings indicate that BDNF is involved in place conditioning formed by psychostimulant drug when it is reinstated after extinction, rather than by a solitary drug injection or a relatively simple conditioning process by pairing drug with the environmental context.

Objectifs : La capacité en matière de prise de décisions des récidivistes de conduite avec capacités affaiblies (CCA) semble les distinguer des non-contrevenants, particulièrement dans des situations ambiguës à haut risque, telles que la CCA. Cette étude exploratoire vise à vérifier l’hypothèse selon laquelle les récidivistes de CCA (R) auraient une moins bonne capacité de prise de décisions et une plus faible réponse de conductibilité électrodermale par anticipation à la tâche Iowa Gambling Task (IGT) que les non-contrevenants (C). Méthode : Vingt-trois récidivistes et 24 non-contrevenants ont été recrutés. Leur âge moyen (± É.T.) était 44.17(10.03) et 37.29 (10.60) ans respectivement. Les participants devaient être âgés de 18 ans ou plus, et avoir eu deux condamnations pour CCA ou plus pour le groupe R, et zéro CCA et un permis de conduire pour le groupe C. Les participants ont effectué I’IGT, une tâche neurocognitive de prise de décisions comprenant 100 sélections de cartes divisées en cinq blocs pour les analyses. On a comparé la performance du groupe R versus le groupe C à l’aide d’une ANOVA à mesures répétées [2 (groupe) x 5 (blocs)]. On a évalué la performance durant les blocs 1 & 2 (décisions dans l’ambiguïté) et blocs 3-5 (décisions sous haut risque) en utilisant des tests t post-hoc. Finalement, on a mesuré leur réponse de conductibilité électrodermale (RCEA) durant l’IGT. Résultats : L’ANOVA à mesures répétées des blocs 1 à 5 a révélé un effet significatif de l’interaction groupe par bloc, F(1,45)=5.28, p=.03, état carré =.11. Les tests t post hoc ont révélé une différence significative entre les groupes pour la combinaison des blocs 3 à 5, t(45) = 3.38, p = .002. Un effet d’interaction significatif a été détecté pour la RCEA des récidivistes de CCA versus celle des non-contrevenants, F(8,160)=2.33, p=.02, état carré =.10. Conclusion : Les récidivistes de CCA performent moins bien que les non-contrevenants à l’IGT. Ils persistent à prendre des décisions basées sur le potentiel de gains immédiats et négligent donc les risques de pertes. Ceci suggère qu’ils ont des déficits en matière de prise de décision, ce qui, en tant que groupe, les différencie des non-contrevenants. Une difficulté en matière de prise de décisions pourrait expliquer en partie le comportement impulsif fréquemment associé au récidivisme de CCA. Finalement, puisque les analyses de RCEA manquaient de puissance statistique, il est possible que de plus grands échantillons puissent permettre d’observer des différences entre les groupes de participants dans l’analyse de RCEA. / Objectives: Poor decision making in ambiguous high-risk situations, such as driving while impaired (DWI) by alcohol, may differentiate DWI recidivists from non-offenders. In this study, we test the hypothesis that DWI recidivists (R) will exhibit poorer decision-making performance on the Iowa Gambling Task (IGT), and in line with the Somatic Marker Hypothesis, weaker anticipatory somatic activation (using skin conductance response as index) than non-offenders (C, comparison group). Methods: DWI recidivists and non-DWI control drivers were recruited, [R (n=23) and C (n=24), mean ages (± SD) 44.17(10.03) and 37.29 (10.60) years respectively]. Participant selection criteria included ≥ 18 years old and ≥2 DWI convictions for group R and 0 DWI convictions lifetime and a driver’s license for group C. The participants performed the IGT, a decision-making neurocognitive task containing 100 card selection trials that we divided into 5 blocks for analyses. A 2 (group) x 5 (blocks) repeated measures ANOVA was used to compare group R performance on the IGT versus group C, followed by post hoc independent t-tests on aggregated blocks 1-2 (decision under ambiguity) & 3-5 (decision under high risk) to identify the source of group X block significant interactions. Two 3 (group) x 5 (blocks) repeated measures ANOVAs (for good decks and for bad decks) were used to compare the aSCR of groups C and R. Results: ANOVA repeated measures on blocks 1 to 5 produced a significant effect of group by block interaction F(1,45)=5.28, p=.03, partial ƞ2 =.11. Post hoc t-tests on aggregated blocks 3 to 5 were statistically significant, t(45) = 3.38, p = .002. A significant group x block interaction effect was found for good decks aSCR, F(8,160)=2.33, p=.02, partial ƞ2 =.10 . Conclusion: DWI recidivists performed more poorly than controls on the IGT, persistently making decisions based on potential immediate gains and neglecting associated loss risks and long-term outcome. This suggests they have reduced neurocognitive decision-making capacities distinguishable from the general population. While DWI recidivists’ behaviour appears as impulsive, these results suggest that their behaviour pattern involves decision-making difficulties. Larger sample sizes may be needed to detect a between-group effect in the aSCR analyses, as they were considerably underpowered. / Thomas G. Brown, Ph.D., co-directeur de recherche

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

This study examines the link between the individual and social network, what social forces and social mechanisms involved in the interaction between individuals and groups and how we can explain and consider this relationship with the aim of understanding this connection. Through qualitative interviews, based on interviews of six active members in the organization Young KRIS (Young Criminal’s Return in the Society) examines the active social processes that the young members undergo, and motivates those who have been outside the expected conformed and regular society, to be included in the regular community and how this can be explained. The study shows that the organization through high availability, openness, knowledge of the needs of young people, good treatment, range of meaningful activities, has created a great venue for the young to develop and thus regain their place in the society. / Denna studie undersöker kopplingen mellan individ och sociala nätverk, det vill säga vilka sociala krafter och sociala mekanismer är verksamma i mötet mellan individen och gruppen, och hur man kan förklara och se på denna relation med målet att förstå denna koppling. Genom den kvalitativa metoden, baserad på intervjuer av sex medlemmar inom organisationen Unga KRIS, undersöker vi de verksamma sociala processer unga medlemmar genomgår och som motiverar dem som har befunnit sig utanför det förväntade, konforma och reguljära samhället, att komma att inkluderas i det reguljära samhället och hur detta kan förklaras. Studien visar att organisationen genom hög tillgänglighet, öppenhet, kunskap om ungdomarnas behov, gott bemötande och utbud av meningsfulla aktiviteter, har skapat en trygg arena för att unga medlemmarna ska kunna utvecklas och därmed återfinna sin plats i samhället.

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

[Truncated abstract] Childhood acute lymphoblastic leukaemia (ALL) accounts for the largest number of cases of childhood cancer (25-35%) and is the primary cause of cancer related morbidity. Today more than 76% of children with ALL are alive and disease free at 5 years. Approximately one in 900 individuals between the ages of 16 and 44 years is a survivor of childhood cancer. In contrast, those patients who relapse with childhood ALL currently have a 6-year event free survival of 20-30%. The short arm of chromosome 9p is mutated or deleted in many cancers including leukaemia. Aberrations of the INK4A/ARF and INK4B loci at the 9p21 band are linked to the development and progression of cancer. In murine cancer models there is evidence to suggest that mutations of Ink4a/Arf and p53 gene loci promote resistance to chemotherapeutic drugs known to trigger apoptosis. The initial aim of this project was to develop an accurate, reproducible method to detect deletions at the INK4A/ARF locus in patient bone marrow specimens. This technique was then applied to detect the incidence of deletions of this locus in childhood ALL specimens. The hypothesis developed was that deletion at the INK4A/ARF locus at diagnosis in childhood ALL is an independent prognostic marker and is involved in disease progression. A secondary aim of this study was to determine which deletions at the INK4A/ARF and INK4B loci are the most relevant in leukaemogenesis in childhood ALL. ... This study has shown that deletion of the INK4A/ARF locus is an independent prognostic indicator in childhood ALL. In addition, the frequency of deletion at the INK4A/ARF and INK4B loci is increased at relapse compared to diagnosis in childhood ALL. In the relapse study group, deletion of the p16INK4A gene at diagnosis was associated with a decreased median time to relapse compared to other genes analysed. Murine studies suggest that such deletions may result in an increased resistance to chemotherapy. If the findings from this study are confirmed in a larger cohort, it is expected that therapeutic interventions based on assessment of the p16INK4A gene in diagnostic childhood ALL specimens will be implemented to prevent relapse in standard risk patients and help to improve the outcome in high risk patients.

A descriptive survey to identify factors influencing relapse of psychiatric outpatients in the rural communities of the Eastern Cape was undertaken. A questionnaire was used to collect data from family caregivers who were relatives of psychiatric patients receiving their monthly medications from two rural clinics. Data were analysed using the Statistical Package for Social Sciences (SPSS) version 17. A total number of 92 family caregivers participated. Respondents reported side effects of psychotropic drugs, poor family role, poor referral system, lack of home visits, non-compliance and stigmatization as major factors contributing to relapse of psychiatric outpatients. Active involvement of caregivers in follow up care of their relatives is effective in fostering collaboration between the psychiatric hospitals and patients with the common goal of relapse avoidance. It is recommended that adequate provision of resources in conjunction with health education is effective in enhancing collaboration towards prevention of relapse in psychiatric patients. This would promote team work among patients, caregivers and health care providers. / Public Health / M.A. (Public Health)

INTRODUÇÃO: A poliquimioterapia (PQT-OMS) para tratamento da hanseníase resultou em drástica redução da sua prevalência, mas em limitado impacto na detecção de casos novos (CN), que se manteve estável em Santa Catarina, estado na fase de pós-eliminação. Casos com altos índices baciloscópicos apresentam risco de recidiva tardia e podem consistir em focos persistentes de transmissão da doença. OBJETIVOS: Avaliar a recidiva da doença em amostra de pacientes virchowianos regularmente tratados com PQT-OMS 24 doses; ensaios de resistência terapêutica em camundongos para os casos suspeitos; resposta imune específica (celular e humoral) e detecção do DNA do M. leprae nos casos-índices (CI) e seus contatos indradomiciliares (CID); e os achados frente aos indicadores epidemiológicos e operacionais de Santa Catarina. CASUÍSTICA E MÉTODOS: A partir da busca no Sistema de Informação de Agravos de Notificação (SINAN), foram selecionados 46 CI, tratados entre 1990-2000, e 187 CID, dos municípios de Itajaí e Joinville. A avaliação constituiu de: exames dermatoneurológico e anatomopatológico da pele; baciloscopia do esfregaço cutâneo; reação de Mitsuda; sorologia para glicolipídeo fenólico-I (IgM-anti-PGL-I); ensaios de resistência terapêutica em camundongos e de detecção do DNA bacilar no muco nasal por reação em cadeia da polimerase (PCR) para as seqüências repetitivas específicas RLEP-130 e RLEP-372. RESULTADOS: Entre os CI após alta por cura (m=11,2 ± 3 anos), a idade média (57,3±14,5 anos) foi superior (p<0,05) comparada aos CID, com predomínio de homens (p=0,001) e Mitsuda-negativos (78,6%). Em quatro casos (8,7%) considerados recidivados, o valor sérico médio (0,365) e as freqüências da positividade do anti-PGL-I e a da RLEP-130 (75%; p=0,03) foram consistentemente elevados, e os testes em camundongos, negativos. Dentre os 187 CID, 22 (11,8%) adoeceram (CIDd), a maioria (10 casos; 45,4%) foi diagnosticada entre 2 a 19 anos; 6 casos (27,3%), no mesmo período do seu respectivo CI; e 6 CN (3 dimorfo-tuberculóides e 3 tuberculóides) foram detectados durante a intervenção. Os CN evidenciaram elevada freqüência da positividade da RLEP-130 (50%) contrastante com a do anti-PGL-I (20%) e seu valor sérico médio (0,075) inferior. Entre os CI após a alta PQT-MB (>10 anos), houve inferioridade da freqüência da positividade (14,3%) e do valor sérico médio do anti-PGL-I (0,072), estabelecendo uma correlação negativa (p=0,038,r=-0,32) com o tempo decorrido. Valores similares da freqüência de positividade para RLEP-130 foram encontrados em: CI com alta por cura (26,7%), em períodos superiores (25%) a 10 anos de conclusão do tratamento e CID saudáveis (20,5%). A positividade para a RLEP-130 foi mais freqüente (p<0,001) comparada à da RLEP-372. CONCLUSÕES: A taxa de recidiva após PQT-MB 24 doses é baixa e prevalece alta percentagem de cura (91,3%). É racional considerar que o anti-PGL-I e a detecção do DNA bacilar por RLEP-130 devam ser analisados em conjunto com os demais achados clínicos e laboratoriais, ainda que nossos resultados possam ter diferenciado os grupos nas distintas condições: recidiva e alta por cura, e identificado doentes, contatos e famílias em risco. O seguimento e o monitoramento clínico e laboratorial por períodos prolongados incrementariam a detecção precoce de novos casos entre os comunicantes, desde que o intervalo para o diagnóstico foi longo para a maioria daqueles que adoeceram. Estas estratégias seriam potencialmente facilitadas em áreas com reduzida prevalência, e particularmente valiosas para a manutenção do controle na fase de pós-eliminação / Introduction: Multidrugtherapy (MDT-WHO) resulted in marked reduction of leprosy prevalence in Brazil, without impact on detection of new cases in Santa Catarina (SC) state in the post-elimination phase. Lepromatous cases with high bacilloscopic index have late relapse risk and can consist in the disease transmission focus. Objectives: The aim of this study was to evaluate the disease recurrence and microbiological resistance in lepromatous leprosy patients regularly treated with MDT-WHO/24 doses; specific immune response (cellular and humoral) and M. leprae DNA detection in index cases (IC) and their household contacts (HHC); and the findings face to the epidemiological and operational indicators of Santa Catarina state. Casuistic and methods: After consulting the Brazilian Information System of Notification (SINAN) database, 46 IC successfully diagnosed and treated between 1990 and 2000, and their 187 HHC from Joinville and Itajaí (SC) municipalities were selected. A dermatoneurological examination was performed, as well as the skin biopsies for histopathology and therapy resistance assay in mouse pads, skin smears for bacilloscopy, anti-PGL-I IgM serology, Mitsuda reaction, polymerase chain reaction for M. leprae DNA detection in nasal secretion based on 130bp and 372bp specific repetitive sequences (RLEP). Results: Cured IC (m=11.2±3 years) had mean age higher ((57.3±14.5 years old; p<0.05) than HHC, most of them were males (p=0.001) and Mitsuda negative (78.6%). In 4 relapsed cases (8.7%) the average anti-PGL-I serum levels (0.365), as well as frequency of positive antibody and RLEP-130 (75%; p=0.03) were consistently high and the mouse footpads assays resulted negative. Among 187 HHC, 22 (11.8%) became sick (sHHC), 10 cases (45.4%) were diagnosed between 2 and 19 years, being 6 cases (27.3%) in the same year of their IC; 6 new cases (3 borderline-tuberculoid and 3 tuberculoid) were detected during the study, with high RLEP-130 positive frequency (50%), as opposed to anti-PGL-I (20%) and low average serum levels (0.075). Among IC with more than 10 years of discharge, frequency of positive anti-PGL-I (14.3%) and average serum levels (0.072) were lower and had negative correlation (p=0.038, r= -0.32) with time after cure. Similar values of frequency of positivity for RLEP-130 were found: IC with discharge by cure (26.7%), when time interval was higher than 10 years (25%) and in healthy HHC (20.5%). RLEP-130 positivity was more frequent (p<0.001) than RLEP-372. Conclusions: Relapse rate after MDT-WHO 24 doses was low, with high cure rate (91.3%). Serology anti-PGL-I and M. leprae DNA detection by RLEP-130 must be analyzed together with other clinical and laboratory findings, though our results had differentiated groups in the following conditions: relapse and discharge by cure, patient identification, HHC and families at risk. Long term follow-up with laboratorial and clinical monitoring could lead to early detection of new cases among HHC, since the period between diagnoses was long for most sHHC. This strategy may be useful in areas with decreased prevalence, and of particular value for maintenance of disease control in the post-elimination phase