Objectif : La carcinose péritonéale (CP) d’origine appendiculaire est une pathologie rare avec un pauvre pronostic à long terme. Le but de cette étude fut d’évaluer une approche agressive utilisée dans notre institution au cours des cinq dernières années. Méthodes : Les données de tous les patients avec CP d’origine appendiculaire ont été recueillies et analysées de façon prospective. Le traitement consista en une cytoréduction chirurgicale complète de la CP suivie d’une chimiohyperthermie intrapéritonéale (CHIP) à l’oxaliplatine (460 mg/m2) dans 2 L/m2 de D5% à 43°C pendant 30 minutes. Résultats : De février 2003 à mars 2007, 38 patients eurent une laparotomie à visée curative. Vingt-trois patients reçurent la CHIP. Par contre, chez 10 patients, une cytoréduction complète fut impossible et pour 5 autres patients, la chirurgie de « second-look » s’est révélée négative ; ils ne reçurent donc pas de CHIP. Le suivi moyen fut de 23 mois. La survie globale à 3 ans fut de 100% pour le groupe « second-look » négatif, 86% pour le groupe CHIP et 29% pour les patients avec maladie non-résécable (p=0.0098). La survie sans maladie (SSM) à 3 ans fut de 49% pour les patients du groupe CHIP. Le grade histologique fut identifié comme facteur pronostique en regard de la SSM dans le groupe CHIP (p=0.011). Il y eut un décès post-opératoire. Le taux de complications chez les patients traités fut de 39%, incluant les abcès intra-abdominaux (22%), les hémorragies (18%) et les fuites anastomotiques (9%). Conclusion : Bien que ces résultats soient préliminaires, cette approche thérapeutique semble à la fois faisable et sécuritaire chez des patients sélectionnés. / Background: Peritoneal carcinomatosis (PC) arising from the appendix is a rare disease with a poor long-term prognosis. The aim of this study was to evaluate the results of an aggressive approach used at our institution over the last five years. Methods: Data from all patients with a PC arising from the appendix were prospectively collected and analyzed. Treatment consisted of complete surgical cytoreduction of the tumor followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (460 mg/m2) in 2 L/m2 of D5W at 43˚C during 30 minutes. Results: From February 2003 to March 2007, 38 patients with PC arising from the appendix underwent laparotomy with curative intent. Mean follow-up was 23 months. Twenty-three patients received HIPEC but 10 patients could not have complete cytoreductive surgery and received no HIPEC. Five patients with a negative second-look surgery also received no HIPEC. The 3-year overall survival (OS) was 100% for the negative second-look patients, 86% for the HIPEC patients, and 29% for the unresectable patients (p=0.0098). The 3-year disease-free survival (DFS) was 49% for the HIPEC patients. Histologic grade was a prognostic factor with regard to DFS for the HIPEC patients (p = 0.011). There was one postoperative mortality. The overall complication rate for treated patients was 39%, including intra-abdominal abscess (22%), hemorrhage (18%), and anastomotic leak (9%). Conclusions: Although these results are preliminary, this therapeutic approach seems both feasible and safe in selected patients.

Dor neuropática e neuropatia causadas pelo quimioterápico oxaliplatina são comuns e causam restrições às atividades funcionais e qualidade de vida. Muitos estudos têm quantificado e qualificado esses sintomas, porém raramente utilizando amostra expressiva e instrumentos validados e específicos para este fim. Neste estudo é proposta uma análise ampla, por instrumentos que quantificam e qualificam a dor e neuropatia relacionadas à oxaliplatina e suas características associadas. Objetivos: Identificar a prevalência de dor neuropática e neuropatia periférica em doentes com câncer colorretal recebendo tratamento com oxaliplatina durante os seis meses de tratamento quimioterápico e após seguimento (de 3 a 6 meses); avaliar, comparar e descrever as características da dor e neuropatia nesta população e avaliar seu impacto nas atividades de vida diária e qualidade de vida. Métodos: Foram incluídos 110 doentes (média 55,6 anos) com câncer colorretal durante o tratamento quimioterápico com oxaliplatina e seguidos por 3 a 6 meses após quimioterapia. Os doentes responderam ao questionário sócio-demográfico e a questionários específicos para dor e neuropatia antes da quimioterapia e bimestralmente por até seis meses durante a quimioterapia e em avaliação de seguimento realizada de 3 a 6 meses após o término da quimioterapia. Os instrumentos utilizados foram: Questionário de Qualidade de Vida da Organização Européia para Pesquisa e Tratamento do Câncer - C30 (EORTC QLQ-C30); Questionário de Dor McGill reduzido (QDMR), Inventário de Sintomas de Dor Neuropática (ISDN), Inventário Breve de Dor (BPI-Brief Pain Inventory) Questionário de Dor Neuropática 4 (DN4), Escala Hospitalar de Ansiedade e Depressão (HADS), Escore Total de Neuropatia (TNS - Total Neuropathy Score). Resultados: Em geral, a dor e neuropatia aumentaram durante o período de quimioterapia e diminuíram após fim do tratamento, permanecendo em níveis significativamente mais elevados após o fim do tratamento quimioterápico. A média de intensidade de dor (dor mais intensa) segundo o IBD foi 2,54 na V3 (após 4 meses de tratamento com oxaliplatina). A dor foi do tipo neuropática em 21,67% dos doentes ao fim da quimioterapia e em 10,00% após fim do seguimento. As médias segundo o ISDN foram 0,67 no basal, 18,67 na V2, 17,77 na V3, 17,44 após quimioterapia e 11,03 após seguimento. A característica da dor mais frequente foi em choque elétrico, enjoada e incômoda segundo o QDMR e segundo o ISDN foram choque elétrico, frio doloroso e dormência. A qualidade de vida sofreu impacto negativo. Conclusões: Dor neuropática foi prevalente após a quimioterapia e após seguimento e se associou com interferência negativa sobre as atividades diárias. Estes dados poderão auxiliar o desenvolvimento de tratamentos individualizados da neuropatia relacionada à oxaliplatina / Neuropathic pain and neuropathy caused by oxaliplatin chemotherapy are common and cause restrictions in activities of daily living and quality of life. Many studies have quantified and qualified these symptoms but only rarely used a comprehensive sample of patients and employed validated and specific instruments for pain assessment. In this study we proposed a comprehensive analysis by instruments that quantify and qualify the pain and neuropathy and its characteristics. Aim of Investigation: To identify the prevalence of neuropathic pain and peripheral neuropathy in patients with colorectal cancer receiving treatment with oxaliplatin during the six months of chemotherapeutic treatment and after follow-up (3 to 6 months); to evaluate, compare and describe pain and peripheral neuropathy characteristics in this population and evaluate their impact on activities of daily living. Methods:110 patients (mean 55.6 years) with colorectal cancer were included during the six months of chemotherapy with oxaliplatin and follow-up (3 to 6 months) after chemotherapeutic treatment. Patients answered socio-demographic questionnaires and specific assessment tools for pain and neuropathy evaluation at the baseline visit and every 2 months during chemotherapy and after follow-up (3-6 months). The instruments used were: The European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30); Reduced McGill Pain Questionnaire (MPQ), Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory (BPI) Neuropathic Pain Diagnostic Questionnaire (DN4), Hospital Anxiety and Depression Scale (HADS), Total Neuropathy Score (TNS), Results: In general, pain and neuropathy intensity increased during chemotherapy and decreased after the end of treatment (follow-up). The most severe pain according to the BPI was 2.54 in V3 (after 4 months treatment with oxaliplatin). Pain was neuropathic in 21.67% right after chemotherapy and in 10.00% after follow-up according to the DN4. The average sum of neuropathic pain symptoms according to the NPSI were 0.67 in V1, 18.67 in V2, 17.77 in V3, 17.44 after chemotherapy and 11.03 after follow-up. The most common characteristics of the pain was electric shocks, nauseating and fearful, according to MPQ and according to NPSI were electric shock, evoked by cold stimuli and tingling. Conclusions: Patients treated with oxaliplatin had significant pain and neuropathy that negatively interfeared with daily activities. These data may help tailor individualized treatment of chemotherapy related neuropathic pain

A avaliação sensitiva de pacientes tratados com oxaliplatina tem se tornado objeto de estudo, pelo fato deste medicamento causar como efeito colateral, uma neuropatia periférica com características sensitivas, imediatamente após início da infusão. Sintomas que causam restrições nas atividades de vida diárias e na qualidade de vida do paciente durante o tratamento. Para uma melhor compreensão do mecanismo das alterações sensitivas, atualmente tem se utilizado o teste quantitativo da sensibilidade (TQS), que através da mensuração quantitativa dos limiares de detecção aos estímulos quente, frio e de vibração, nos concede um perfil para melhor relacionar com as possibilidades de manejo ou tratamento. Neste estudo propomos uma análise da através do TQS e de instrumentos que quantificam e qualificam a neuropatia, a dor neuropática e suas características. Objetivos: Descrever de forma prospectiva as alterações de sensibilidade exteroceptiva somática causadas pelo uso da oxaliplatina em doentes com câncer colorretal. Métodos: Foram incluídos 110 doentes (média 55 anos) com câncer colorretal que realizaram tratamento antineoplásico com oxaliplatina por seis meses, e foram avaliados por mais seis após a quimioterapia. Os pacientes realizaram avaliação sensitiva com TQS e responderam questionário sócio demográfico e questionários específicos para dor e neuropatia na visita basal (VB), ao término da quimioterapia (VT) e novamente após 6 meses de seguimento (VS). Resultados: Os questionários de dor e neuropatia mostraram seu início e as suas características, na qual foi evidente a dor com características neuropáticas na visita término do tratamento em 21,7% dos participantes manifestada pela dormência, choque elétrico, alfinetadas e agulhadas e a sensibilidade ao frio. As principais alterações demonstradas pelo TQS foram: nos limiares de detecção mecânica; aumento dos limiares dolorosos térmicos; diminuição da hiperalgesia mecânica; diminuição do limiar de detecção vibratória na mão e aumento no pé. O TQS indicou alterações entre os participantes do estudo e o grupo de voluntários saudáveis em algum momento das avaliações. Conclusão: Os pacientes com câncer colorretal submetidos ao tratamento com oxaliplatina cursam com dor com características neuropáticas que interferem em suas atividades diárias. O TQS caracterizou as principais alterações relacionadas ao início do tratamento, término do tratamento e durante o seguimento. As comparações com voluntários saudáveis sugerem que a presença da neoplasia e outras comorbidades são capazes de causarem alterações no TQS / Sensory evaluation of patients treated with oxaliplatin has become an object of study, because this medication cause as a side effect, peripheral neuropathy with sensory characteristics, immediately after start of infusion. Symptoms that cause restrictions in daily activities and in the patient\'s quality of life during treatment. For a better understanding of the mechanism of sensory changes, currently it has used quantitative sensitivity testing (QST). That by the quantitative measurement of thresholds to warm stimuli, cold and vibration, gives us a profile to better relate to the possibilities of management or treatment. In this study we propose an analysis by QST and tools to quantify and qualify neuropathy, neuropathic pain and its features. Objectives: To describe prospectively the somatic exteroceptive sensitivity changes caused by the use of oxaliplatin in patients with colorectal cancer. Methods: We included 110 patients (mean 55 years) with colorectal cancer who underwent anticancer treatment with oxaliplatin for six months and were evaluated for six after chemotherapy. Patients underwent sensory evaluation with QST and answered sociodemographic questionnaire and specific questionnaires for pain and neuropathy at baseline, at the end of chemotherapy (visit six months) and again after 6 months of follow-up (visit twelve months). The instruments used were reduced McGill Pain Questionnaire (MPQ), Inventory symptoms of neuropathic pain (ISDN), Brief Pain Inventory (BPI-Brief Pain Inventory) Questionnaire neuropathic pain 4 (DN4), hospital scale of anxiety and depression (HADS). Results: The pain questionnaires and neuropathy showed its beginning and its characteristics, which was evident pain with neuropathic characteristics in the end visit of treatment in 21.7% of participants manifested by numbness, electric shock, pins and needles and sensitivity to cold. The main changes demonstrated by QST were in mechanical thresholds; painful increase in thermal thresholds; reduction in mechanical hyperalgesia; reduction of vibration detection limit for the hand and foot increases. The QST indicated changes between the study participants and the group of healthy volunteers at some point of the evaluations. Conclusion: Patients with colorectal cancer undergoing treatment with oxaliplatin occur with pain with neuropathic characteristics that interfere with their daily activities. QST characterized the major changes related to the start of treatment, end of treatment and during follow-up. Comparisons with healthy volunteers suggest that the presence of neoplasia and other comorbid conditions are capable of causing changes in the QST

Application of cytotoxic chemotherapy still remains the essential treatment strategy in advanced colorectal cancer. The intrinsic and acquired drug resistance represents one of the reasons that may even lead to failure of cancer therapy. The DNA damage response pathways have been shown to play an important role in the development of chemoresistance. There is sufficient evidence showing the high-frequency deregulated expression of many DNA repair genes across multiple cancer types. An example of such gene in colorectal cancer is MRE11, which encodes protein known as a sensor of DNA double-strand breaks. In year 2016, there was a substantial study published by our group at The Department of Molecular Biology of Cancer (IEM CAS, Prague), the study analysed the association of polymorphisms in predicted microRNA target sites of double-strand breaks (DSBs) repair genes, including MRE11, and clinical outcome and efficacy of chemotherapy in colorectal cancer. Our hypothesis, based on the mentioned study, is that specifically and exactly defined microRNAs with ability to regulate certain DNA repair proteins may not only affect the survival of colorectal cancer cells, but also the sensitivity to chemotherapy. In practical part of the submitted thesis we have identified miR-140 as a potential regulator of...

Objectif : La carcinose péritonéale (CP) d’origine appendiculaire est une pathologie rare avec un pauvre pronostic à long terme. Le but de cette étude fut d’évaluer une approche agressive utilisée dans notre institution au cours des cinq dernières années. Méthodes : Les données de tous les patients avec CP d’origine appendiculaire ont été recueillies et analysées de façon prospective. Le traitement consista en une cytoréduction chirurgicale complète de la CP suivie d’une chimiohyperthermie intrapéritonéale (CHIP) à l’oxaliplatine (460 mg/m2) dans 2 L/m2 de D5% à 43°C pendant 30 minutes. Résultats : De février 2003 à mars 2007, 38 patients eurent une laparotomie à visée curative. Vingt-trois patients reçurent la CHIP. Par contre, chez 10 patients, une cytoréduction complète fut impossible et pour 5 autres patients, la chirurgie de « second-look » s’est révélée négative ; ils ne reçurent donc pas de CHIP. Le suivi moyen fut de 23 mois. La survie globale à 3 ans fut de 100% pour le groupe « second-look » négatif, 86% pour le groupe CHIP et 29% pour les patients avec maladie non-résécable (p=0.0098). La survie sans maladie (SSM) à 3 ans fut de 49% pour les patients du groupe CHIP. Le grade histologique fut identifié comme facteur pronostique en regard de la SSM dans le groupe CHIP (p=0.011). Il y eut un décès post-opératoire. Le taux de complications chez les patients traités fut de 39%, incluant les abcès intra-abdominaux (22%), les hémorragies (18%) et les fuites anastomotiques (9%). Conclusion : Bien que ces résultats soient préliminaires, cette approche thérapeutique semble à la fois faisable et sécuritaire chez des patients sélectionnés. / Background: Peritoneal carcinomatosis (PC) arising from the appendix is a rare disease with a poor long-term prognosis. The aim of this study was to evaluate the results of an aggressive approach used at our institution over the last five years. Methods: Data from all patients with a PC arising from the appendix were prospectively collected and analyzed. Treatment consisted of complete surgical cytoreduction of the tumor followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin (460 mg/m2) in 2 L/m2 of D5W at 43˚C during 30 minutes. Results: From February 2003 to March 2007, 38 patients with PC arising from the appendix underwent laparotomy with curative intent. Mean follow-up was 23 months. Twenty-three patients received HIPEC but 10 patients could not have complete cytoreductive surgery and received no HIPEC. Five patients with a negative second-look surgery also received no HIPEC. The 3-year overall survival (OS) was 100% for the negative second-look patients, 86% for the HIPEC patients, and 29% for the unresectable patients (p=0.0098). The 3-year disease-free survival (DFS) was 49% for the HIPEC patients. Histologic grade was a prognostic factor with regard to DFS for the HIPEC patients (p = 0.011). There was one postoperative mortality. The overall complication rate for treated patients was 39%, including intra-abdominal abscess (22%), hemorrhage (18%), and anastomotic leak (9%). Conclusions: Although these results are preliminary, this therapeutic approach seems both feasible and safe in selected patients.

L’oxaliplatine, anticancéreux utilisé pour le traitement du cancer colorectal, est responsable d’une neurotoxicité périphérique dose-limitante affectant une grande majorité de patients. La neurotoxicité de l’oxaliplatine se présente sous deux formes : une forme immédiate, se traduisant par des paresthésies transitoires, et une forme retardée et cumulative, caractérisée par l’apparition d’une neuropathie périphérique douloureuse fortement invalidante. A l’heure actuelle, la prise en charge des douleurs neuropathiques est souvent incomplète, principalement à cause du manque de traitements efficaces et bien tolérés. Dans ce contexte, il existe un réel besoin d’innovation thérapeutique pour améliorer le traitement de ces neuropathies, nécessitant au préalable une meilleure compréhension de leur physiopathologie. La première partie de ce travail porte sur l’évaluation de l’effet d’une alimentation sans polyamines sur l’apparition et la chronicisation de la neurotoxicité de l’oxaliplatine chez le rat. En effet, en modulant positivement la sous-unité NR2B des récepteurs NMDA, les polyamines alimentaires pourraient faciliter la sensibilisation douloureuse. Un régime sans polyamines a permis de prévenir l’hypersensibilité thermique et mécanique induite par l’oxaliplatine. Bien que ces symptômes nociceptifs ne soient pas associés à une augmentation de l’expression de la sous-unité NR2B au niveau spinal, l’ifenprodil (antagoniste NR2B spécifique) permet d’en diminuer l’intensité de manière dose-dépendante. Enfin, une étude métabolomique réalisée par spectroscopie RMN du proton a montré que le régime sans polyamines permettait de réguler la neurotransmission excitatrice (glutamate) au niveau de la corne dorsale de la moelle épinière des animaux, expliquant ainsi son effet antalgique. Dans un deuxième temps, nous nous sommes intéressés aux mécanismes supraspinaux impliqués dans la neuropathie chronique induite par l’oxaliplatine, à l’aide d’une approche métabolomique par 1 H-RMN HRMAS. Cette étude a révélé d’importantes modifications métaboliques cérébrales chez les animaux traités par oxaliplatine, notamment une augmentation de la choline dans le cortex insulaire postérieur corrélée de manière significative aux seuils douloureux. Une analyse transcriptomique et pharmacologique a permis de mettre en évidence une implication de la neurotransmission cholinergique dans cette structure. Le ciblage pharmacologique de cette neurotransmission pourrait représenter une stratégie potentiellement intéressante pour le développement de nouveaux traitements antalgiques. L’ensemble de ces résultats expérimentaux a permis l’identification de nouvelles pistes pour la compréhension et le traitement des douleurs neuropathiques chimio-induites. Dans une perspective de recherche translationnelle, ces deux approches précliniques sont en cours de transposition dans des protocoles de recherche clinique. Un essai clinique de phase II (NEUROXAPOL, NCT01775449) a débuté afin de confirmer l’intérêt d’un régime appauvri en polyamines chez des patients recevant une chimiothérapie à base d’oxaliplatine. Une seconde étude clinique (INSULOX) est actuellement en cours de préparation au CHU de Clermont-Ferrand afin de mesurer par IRM les concentrations en choline dans l’insula de patients souffrant de douleurs neuropathiques induites par oxaliplatine. / Oxaliplatin, an anticancer drug used for the treatment of colorectal cancer, is responsible for a dose-limiting peripheral neurotoxicity in the majority of treated patients. This neurotoxicity appears with two components: a rapid-onset acute neurotoxicity manifesting as transient paresthesias and cold-induced dysesthesias; and a late-onset cumulative neurotoxicity characterized by the development of a painful chronic neuropathy. To date, the management of chemotherapy- induced neuropathic pain is still challenging because of the lack of effective treatments. In this context, a better understanding of the pathophysiological mechanisms underlying this neurotoxicity could lead to the identification of new therapeutic targets. Firstly, we aimed to assess the preventive effect of a polyamine deficient diet on the development of oxaliplatin-induced acute neurotoxicity. Exogenous polyamines, by positively modulating spinal NR2B-containing NMDA receptors, could facilitate pain sensitization. This study has shown that a polyamine deficient diet for 7 days totally prevented oxaliplatin-induced acute cold and mechanical hypersensitivity in rats. Although we observed no change in spinal NR2B expression or phosphorylation, intrathecal ifenprodil (a specific NR2B antagonist) reduced oxaliplatin-induced allodynia in a dose-dependent manner. Finally, proton NMR spectroscopy- based metabolomic analysis has revealed a regulation of spinal glutamate neurotransmission as the most likely mechanism underlying the preventive effect of the diet. Secondly, the metabolic variations associated with oxaliplatin-induced chronic neuropathy were assessed at the supraspinal level using a 1 H-NMR HRMAS-based metabolomic approach. Among the neurochemical changes evidenced in this study, we observed a significant increase in choline within the posterior insular cortex, significantly correlated with the mechanical pain thresholds. A transcriptomic and pharmacological approach have revealed an implication of cholinergic neurotransmission in this brain area. Targeting the cholinergic system using centrally active muscarinic agents could represent an interesting strategy for the treatment of oxaliplatin- induced neuropathic pain. These experimental results led to the identification of new molecular targets for the comprehension and the treatment of chemotherapy-associated painful neuropathy. In a translational approach, these preclinical data will be extended to the clinical setting. A phase II clinical trial (NEUROXAPOL, NCT01775449) is undergoing to confirm the therapeutic interest of a polyamine free diet in patients receiving oxaliplatin. A second clinical project (INSULOX) aiming at assessing the choline concentrations in the insula of patients suffering from oxaliplatin-induced neuropathy is in preparation.

A avaliação sensitiva de pacientes tratados com oxaliplatina tem se tornado objeto de estudo, pelo fato deste medicamento causar como efeito colateral, uma neuropatia periférica com características sensitivas, imediatamente após início da infusão. Sintomas que causam restrições nas atividades de vida diárias e na qualidade de vida do paciente durante o tratamento. Para uma melhor compreensão do mecanismo das alterações sensitivas, atualmente tem se utilizado o teste quantitativo da sensibilidade (TQS), que através da mensuração quantitativa dos limiares de detecção aos estímulos quente, frio e de vibração, nos concede um perfil para melhor relacionar com as possibilidades de manejo ou tratamento. Neste estudo propomos uma análise da através do TQS e de instrumentos que quantificam e qualificam a neuropatia, a dor neuropática e suas características. Objetivos: Descrever de forma prospectiva as alterações de sensibilidade exteroceptiva somática causadas pelo uso da oxaliplatina em doentes com câncer colorretal. Métodos: Foram incluídos 110 doentes (média 55 anos) com câncer colorretal que realizaram tratamento antineoplásico com oxaliplatina por seis meses, e foram avaliados por mais seis após a quimioterapia. Os pacientes realizaram avaliação sensitiva com TQS e responderam questionário sócio demográfico e questionários específicos para dor e neuropatia na visita basal (VB), ao término da quimioterapia (VT) e novamente após 6 meses de seguimento (VS). Resultados: Os questionários de dor e neuropatia mostraram seu início e as suas características, na qual foi evidente a dor com características neuropáticas na visita término do tratamento em 21,7% dos participantes manifestada pela dormência, choque elétrico, alfinetadas e agulhadas e a sensibilidade ao frio. As principais alterações demonstradas pelo TQS foram: nos limiares de detecção mecânica; aumento dos limiares dolorosos térmicos; diminuição da hiperalgesia mecânica; diminuição do limiar de detecção vibratória na mão e aumento no pé. O TQS indicou alterações entre os participantes do estudo e o grupo de voluntários saudáveis em algum momento das avaliações. Conclusão: Os pacientes com câncer colorretal submetidos ao tratamento com oxaliplatina cursam com dor com características neuropáticas que interferem em suas atividades diárias. O TQS caracterizou as principais alterações relacionadas ao início do tratamento, término do tratamento e durante o seguimento. As comparações com voluntários saudáveis sugerem que a presença da neoplasia e outras comorbidades são capazes de causarem alterações no TQS / Sensory evaluation of patients treated with oxaliplatin has become an object of study, because this medication cause as a side effect, peripheral neuropathy with sensory characteristics, immediately after start of infusion. Symptoms that cause restrictions in daily activities and in the patient\'s quality of life during treatment. For a better understanding of the mechanism of sensory changes, currently it has used quantitative sensitivity testing (QST). That by the quantitative measurement of thresholds to warm stimuli, cold and vibration, gives us a profile to better relate to the possibilities of management or treatment. In this study we propose an analysis by QST and tools to quantify and qualify neuropathy, neuropathic pain and its features. Objectives: To describe prospectively the somatic exteroceptive sensitivity changes caused by the use of oxaliplatin in patients with colorectal cancer. Methods: We included 110 patients (mean 55 years) with colorectal cancer who underwent anticancer treatment with oxaliplatin for six months and were evaluated for six after chemotherapy. Patients underwent sensory evaluation with QST and answered sociodemographic questionnaire and specific questionnaires for pain and neuropathy at baseline, at the end of chemotherapy (visit six months) and again after 6 months of follow-up (visit twelve months). The instruments used were reduced McGill Pain Questionnaire (MPQ), Inventory symptoms of neuropathic pain (ISDN), Brief Pain Inventory (BPI-Brief Pain Inventory) Questionnaire neuropathic pain 4 (DN4), hospital scale of anxiety and depression (HADS). Results: The pain questionnaires and neuropathy showed its beginning and its characteristics, which was evident pain with neuropathic characteristics in the end visit of treatment in 21.7% of participants manifested by numbness, electric shock, pins and needles and sensitivity to cold. The main changes demonstrated by QST were in mechanical thresholds; painful increase in thermal thresholds; reduction in mechanical hyperalgesia; reduction of vibration detection limit for the hand and foot increases. The QST indicated changes between the study participants and the group of healthy volunteers at some point of the evaluations. Conclusion: Patients with colorectal cancer undergoing treatment with oxaliplatin occur with pain with neuropathic characteristics that interfere with their daily activities. QST characterized the major changes related to the start of treatment, end of treatment and during follow-up. Comparisons with healthy volunteers suggest that the presence of neoplasia and other comorbid conditions are capable of causing changes in the QST

Dor neuropática e neuropatia causadas pelo quimioterápico oxaliplatina são comuns e causam restrições às atividades funcionais e qualidade de vida. Muitos estudos têm quantificado e qualificado esses sintomas, porém raramente utilizando amostra expressiva e instrumentos validados e específicos para este fim. Neste estudo é proposta uma análise ampla, por instrumentos que quantificam e qualificam a dor e neuropatia relacionadas à oxaliplatina e suas características associadas. Objetivos: Identificar a prevalência de dor neuropática e neuropatia periférica em doentes com câncer colorretal recebendo tratamento com oxaliplatina durante os seis meses de tratamento quimioterápico e após seguimento (de 3 a 6 meses); avaliar, comparar e descrever as características da dor e neuropatia nesta população e avaliar seu impacto nas atividades de vida diária e qualidade de vida. Métodos: Foram incluídos 110 doentes (média 55,6 anos) com câncer colorretal durante o tratamento quimioterápico com oxaliplatina e seguidos por 3 a 6 meses após quimioterapia. Os doentes responderam ao questionário sócio-demográfico e a questionários específicos para dor e neuropatia antes da quimioterapia e bimestralmente por até seis meses durante a quimioterapia e em avaliação de seguimento realizada de 3 a 6 meses após o término da quimioterapia. Os instrumentos utilizados foram: Questionário de Qualidade de Vida da Organização Européia para Pesquisa e Tratamento do Câncer - C30 (EORTC QLQ-C30); Questionário de Dor McGill reduzido (QDMR), Inventário de Sintomas de Dor Neuropática (ISDN), Inventário Breve de Dor (BPI-Brief Pain Inventory) Questionário de Dor Neuropática 4 (DN4), Escala Hospitalar de Ansiedade e Depressão (HADS), Escore Total de Neuropatia (TNS - Total Neuropathy Score). Resultados: Em geral, a dor e neuropatia aumentaram durante o período de quimioterapia e diminuíram após fim do tratamento, permanecendo em níveis significativamente mais elevados após o fim do tratamento quimioterápico. A média de intensidade de dor (dor mais intensa) segundo o IBD foi 2,54 na V3 (após 4 meses de tratamento com oxaliplatina). A dor foi do tipo neuropática em 21,67% dos doentes ao fim da quimioterapia e em 10,00% após fim do seguimento. As médias segundo o ISDN foram 0,67 no basal, 18,67 na V2, 17,77 na V3, 17,44 após quimioterapia e 11,03 após seguimento. A característica da dor mais frequente foi em choque elétrico, enjoada e incômoda segundo o QDMR e segundo o ISDN foram choque elétrico, frio doloroso e dormência. A qualidade de vida sofreu impacto negativo. Conclusões: Dor neuropática foi prevalente após a quimioterapia e após seguimento e se associou com interferência negativa sobre as atividades diárias. Estes dados poderão auxiliar o desenvolvimento de tratamentos individualizados da neuropatia relacionada à oxaliplatina / Neuropathic pain and neuropathy caused by oxaliplatin chemotherapy are common and cause restrictions in activities of daily living and quality of life. Many studies have quantified and qualified these symptoms but only rarely used a comprehensive sample of patients and employed validated and specific instruments for pain assessment. In this study we proposed a comprehensive analysis by instruments that quantify and qualify the pain and neuropathy and its characteristics. Aim of Investigation: To identify the prevalence of neuropathic pain and peripheral neuropathy in patients with colorectal cancer receiving treatment with oxaliplatin during the six months of chemotherapeutic treatment and after follow-up (3 to 6 months); to evaluate, compare and describe pain and peripheral neuropathy characteristics in this population and evaluate their impact on activities of daily living. Methods:110 patients (mean 55.6 years) with colorectal cancer were included during the six months of chemotherapy with oxaliplatin and follow-up (3 to 6 months) after chemotherapeutic treatment. Patients answered socio-demographic questionnaires and specific assessment tools for pain and neuropathy evaluation at the baseline visit and every 2 months during chemotherapy and after follow-up (3-6 months). The instruments used were: The European Organization for Research and Treatment of Cancer QLQ-C30 (EORTC QLQ-C30); Reduced McGill Pain Questionnaire (MPQ), Neuropathic Pain Symptom Inventory (NPSI), Brief Pain Inventory (BPI) Neuropathic Pain Diagnostic Questionnaire (DN4), Hospital Anxiety and Depression Scale (HADS), Total Neuropathy Score (TNS), Results: In general, pain and neuropathy intensity increased during chemotherapy and decreased after the end of treatment (follow-up). The most severe pain according to the BPI was 2.54 in V3 (after 4 months treatment with oxaliplatin). Pain was neuropathic in 21.67% right after chemotherapy and in 10.00% after follow-up according to the DN4. The average sum of neuropathic pain symptoms according to the NPSI were 0.67 in V1, 18.67 in V2, 17.77 in V3, 17.44 after chemotherapy and 11.03 after follow-up. The most common characteristics of the pain was electric shocks, nauseating and fearful, according to MPQ and according to NPSI were electric shock, evoked by cold stimuli and tingling. Conclusions: Patients treated with oxaliplatin had significant pain and neuropathy that negatively interfeared with daily activities. These data may help tailor individualized treatment of chemotherapy related neuropathic pain

[pt] A utilização de drogas à base de platina é o tratamento de primeira linha para diversos tipos de câncer. Pacientes tratados com estas drogas apresentam resultados melhores que os obtidos com outros regimes de quimioterapia para os mesmos tipos de malignidades. As principais limitações para a utilização destes compostos são os efeitos colaterais severos e a resistência dos tumores ao tratamento. A cisplatina foi a primeira droga dessa categoria a ser empregada. Desde o final dos anos 70 até hoje, esta droga vem sendo amplamente utilizada e com sucesso substancial. Acredita-se que o principal mecanismo de ação desta classe de medicamentos seja a ligação de dois sítios ativos da platina com o DNA das células tumorais, impedindo sua multiplicação e finalmente induzindo a apoptose, o que provoca a redução, e em alguns casos a eliminação, dos tumores. Entretanto, devido à complexidade dos mecanismos envolvidos, uma descrição clara da atuação intracelular destas drogas ainda não foi estabelecida. A combinação de técnicas de separação como eletroforese ou cromatografia líquida de alta performance com técnicas de espectrometria atômica tem se apresentado como uma poderosa alternativa para investigação de fenômenos biológicos que envolvem, de alguma maneira, espécies metálicas. A hifenação destas técnicas permite a separação e detecção em linha de biomoléculas contendo metais, possibilitando a obtenção de informações únicas sobre os processos biológicos. O presente trabalho apresenta o desenvolvimento de métodos analíticos utilizando eletroforese em gel de agarose (GE), cromatografia líquida de alta eficiência (HPLC) e espectrometria de massa com plasma indutivamente acoplado (ICP-MS) para a determinação de biomoléculas contendo platina em materiais biológicos. O principal objetivo do trabalho é fornecer ferramentas analíticas para o estudo dos mecanismos de ação de drogas à base de platina em humanos. Foram utilizados diversos materiais biológicos, como sangue, urina e culturas de células. A cromatografia líquida em fase reversa foi usada na determinação das drogas intactas e de seus produtos de hidrólise; a cromatografia de exclusão por tamanho foi empregada para a avaliação de proteínas presentes nas amostras enquanto a cromatografia de par iônico para separação de fragmentos de DNA. A detecção de platina nos eluatos por ICP-MS permitiu a obtenção de cromatogramas limpos apresentando claramente as moléculas contendo platina. A evidência da aplicabilidade dos métodos desenvolvidos foi avaliada com a prospecção de biomarcadores de eficiência do tratamento com cisplatina. Diversas linhagens celulares foram expostas a diferentes tratamentos com cisplatina e tiveram seus comportamentos avaliados. A determinação de adutos de DNA contendo platina apresentou-se como uma interessante perspectiva para a obtenção de um biomarcador de resistência ao tratamento com cisplatina. / [en] The use of platinum-based drugs is the first line treatment for many cancers. Patients treated with these drugs present better outcome when compared with other chemotherapy regimens for the same types of malignancies. The major limitations to the use of these drugs are the severe side effects and resistance tumors present to the treatment. Cisplatin was the first platinum-based drug to be approved for human use. Since the late 1970 s until today, this drug has been widely used with great success. It is believed that the major mechanism of action of these drugs is the binding of two active sites of platinum complexes with the DNA of the tumor cells, preventing their multiplication and finally inducing apoptosis, that leads to a reduction, and in some cases eliminating, tumors. However, due to the complexity of the mechanisms involved, a clear description of the intracellular action of these drugs has not been established. The combination of separation techniques such as electrophoresis or high performance liquid chromatography with atomic spectrometric techniques has emerged as a powerful alternative for investigation metal-related biological phenomena. The so called hyphenation of these techniques allows the separation and detection of biomolecules containing metals, making possible to obtain unique information about biological processes. This work presents the development of analytical methodologies using agarose gel electrophoresis (GE), high performance liquid chromatography (HPLC) and inductively coupled plasma with mass spectrometry (ICP-MS) for the determination of platinum-containing biomolecules in biological materials. The main objective of this work is to provide analytical tools for the study of the mechanisms of action of platinum-based drugs in humans. Various biological materials such as blood, urine and cell cultures were used. Reverse phase liquid chromatography was used for the determination of intact drugs and its hydrolysis products; size exclusion chromatography was used to assess the protein profile in samples while the ion-pair chromatography for separation of DNA fragments. The detection of platinum in the eluates by ICP-MS allowed the obtention of clean chromatograms clearly presenting the platinum-containing molecules. The evidence of the applicability of the developed methods was assessed with the search for biomarkers of efficacy of treatment with cisplatin. Several cell lines were exposed to different treatments of cisplatin and their behavior were evaluated. The determination of DNA adducts containing platinum presented an interesting approach for obtaining a marker of resistance to cisplatin treatment.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21306号 / 人健博第62号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 黒木 裕士, 教授 恒藤 暁, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM