A research report submitted to the Faculty of Medicine, University of the Witwatersrand, in partial fulfillment of the requirements for the Degree of Master of Medicine in the division of General Surgery. Johannesburg 2012 / Oesophageal cancer causes much morbidity and mortality in South Africa. This disease has a 5-year survival of less than 10% despite improvements in therapy. Most patients present with advanced disease and are suitable only for palliative care. Current standard of palliative care for patients with end-stage oesophageal cancer that present with dysphagia include brachytherapy and stenting. Brachytherapy improves survival and has a more stable quality of life in the long term when compared to stenting. Conversely stenting has a more acute relief of dysphagia. In South Africa many patients with malignant dysphagia face socio-economic constraints that cause delays in therapy, especially in patients from rural areas. Many prospective randomized trials of palliative treatment have been done in the developed world, not taking into account socio-economic constraints. We present a study from Tshepong Hospital (Klerksdorp, North West province), a secondary hospital in South Africa.

Introdução: A dissecção endoscópica submucosa (ESD) de neoplasias superficiais extensas de esôfago pode evoluir com altas taxas de estenose pós operatória, resultando em uma importante piora na qualidade de vida. Diversas terapias estão disponíveis para prevenir essa complicação. Entretanto, até o momento, nenhuma revisão sistemática e metanálise foram realizadas para avaliar esses resultados. Métodos: Uma revisão sistemática e metanálise foram realizadas utilizando as bases de dados eletrônicas Medline, Embase, Cochrane, LILACS, Scopus e CINAHL. Ensaios clínicos e estudos observacionais foram pesquisados de março de 2014 a fevereiro de 2015. Os termos pesquisados foram: endoscopy, ESD, esophageal stenosis, e esophageal stricture. Três estudos retrospectivos e quatro prospectivos (três randomizados) foram selecionados. Um total de 249 pacientes com diagnóstico de neoplasia superficial de esôfago, submetidos a ESD de pelo menos dois terços da circunferência do órgão foram incluídos. Foram selecionados estudos comparando diversas técnicas para prevenir a estenose de esôfago após extensa ESD. Resultados: Foram realizadas diferentes metanálises com ensaios clínicos randomizados (RCT), ensaios clínicos não randomizados (non- RCT) e uma análise global. Nos RCT (três estudos, n=85), a terapia preventiva diminuiu o risco de estenose (diferença de risco = - 0,36, IC 95% - 0,55 a - 0,18, p = 0,0001). Dois estudos (um randomizado e um não randomizado, n = 55) demonstraram que a terapia preventiva diminui o número médio de dilatações (diferença média = - 8,57, IC 95% - 13,88 a - 3,25, p < 0,002). Não houve diferenças significativas em três RCT em relação à taxa de complicações entre pacientes submetidos à terapia preventiva e aqueles não submetidos (diferença de risco = 0,002, IC 95% -0,09 a 0,14, p = 0,68). Conclusão: O uso da terapia preventiva após extensa ESD no esôfago, reduz o risco de estenose e o número de dilatações endoscópicas para resolução da estenose, sem aumentar o número de complicações / Background: Endoscopic submucosal dissection (ESD) of extensive superficial cancers of the esophagus may progress with high rates of postoperative stenosis, resulting in significant decrease in quality of life. Several therapies are performed to prevent this complication. However, they have not yet been compared in a systematic review. Methods: A systematic review of the literature and meta-analysis were performed using the Medline, Embase, Cochrane, LILACS, Scopus, and CINAHL databases. Clinical trials and observational studies were searched from March 2014 to February 2015. Search terms included: endoscopy, endoscopic submucosal dissection, esophageal stenosis, and esophageal stricture. Three retrospective and four prospective (3 randomized) cohort studies were selected. They involved 249 patients with superficial esophageal neoplasia who underwent ESD of at least two-thirds of the circumference. We grouped trials comparing different techniques to prevent esophageal stenosis post-ESD. Results: Were realized different meta-analyses on randomized clinical trials (RCT), non-RCT, and global analysis. In RCT (3 studies, n=85), preventive therapies decreased the risk of stenosis (risk difference = -0.36, 95% CI= -0.55 to -0.18, p = 0.0001). Two studies (1 randomized, 1 non-randomized, n = 55) showed that preventive therapies lowered the average number of endoscopy dilatations (mean difference = -8.57, 95% CI = -13.88 to -3.25, p < 0,002). There were no significant differences in the 3 RCT studies (n=85) with regards to complication rates between patients with preventive therapies and those without (risk difference = 0.02, 95% CI = -0.09 to 0.14, p = 0.68). Conclusion: The use of preventive therapies after extensive ESD of the esophagus reduces the risk of stenosis and the number of endoscopic dilatations for resolution of stenosis without increasing the number of complications

Introdução: A dissecção endoscópica submucosa (ESD) de neoplasias superficiais extensas de esôfago pode evoluir com altas taxas de estenose pós operatória, resultando em uma importante piora na qualidade de vida. Diversas terapias estão disponíveis para prevenir essa complicação. Entretanto, até o momento, nenhuma revisão sistemática e metanálise foram realizadas para avaliar esses resultados. Métodos: Uma revisão sistemática e metanálise foram realizadas utilizando as bases de dados eletrônicas Medline, Embase, Cochrane, LILACS, Scopus e CINAHL. Ensaios clínicos e estudos observacionais foram pesquisados de março de 2014 a fevereiro de 2015. Os termos pesquisados foram: endoscopy, ESD, esophageal stenosis, e esophageal stricture. Três estudos retrospectivos e quatro prospectivos (três randomizados) foram selecionados. Um total de 249 pacientes com diagnóstico de neoplasia superficial de esôfago, submetidos a ESD de pelo menos dois terços da circunferência do órgão foram incluídos. Foram selecionados estudos comparando diversas técnicas para prevenir a estenose de esôfago após extensa ESD. Resultados: Foram realizadas diferentes metanálises com ensaios clínicos randomizados (RCT), ensaios clínicos não randomizados (non- RCT) e uma análise global. Nos RCT (três estudos, n=85), a terapia preventiva diminuiu o risco de estenose (diferença de risco = - 0,36, IC 95% - 0,55 a - 0,18, p = 0,0001). Dois estudos (um randomizado e um não randomizado, n = 55) demonstraram que a terapia preventiva diminui o número médio de dilatações (diferença média = - 8,57, IC 95% - 13,88 a - 3,25, p < 0,002). Não houve diferenças significativas em três RCT em relação à taxa de complicações entre pacientes submetidos à terapia preventiva e aqueles não submetidos (diferença de risco = 0,002, IC 95% -0,09 a 0,14, p = 0,68). Conclusão: O uso da terapia preventiva após extensa ESD no esôfago, reduz o risco de estenose e o número de dilatações endoscópicas para resolução da estenose, sem aumentar o número de complicações / Background: Endoscopic submucosal dissection (ESD) of extensive superficial cancers of the esophagus may progress with high rates of postoperative stenosis, resulting in significant decrease in quality of life. Several therapies are performed to prevent this complication. However, they have not yet been compared in a systematic review. Methods: A systematic review of the literature and meta-analysis were performed using the Medline, Embase, Cochrane, LILACS, Scopus, and CINAHL databases. Clinical trials and observational studies were searched from March 2014 to February 2015. Search terms included: endoscopy, endoscopic submucosal dissection, esophageal stenosis, and esophageal stricture. Three retrospective and four prospective (3 randomized) cohort studies were selected. They involved 249 patients with superficial esophageal neoplasia who underwent ESD of at least two-thirds of the circumference. We grouped trials comparing different techniques to prevent esophageal stenosis post-ESD. Results: Were realized different meta-analyses on randomized clinical trials (RCT), non-RCT, and global analysis. In RCT (3 studies, n=85), preventive therapies decreased the risk of stenosis (risk difference = -0.36, 95% CI= -0.55 to -0.18, p = 0.0001). Two studies (1 randomized, 1 non-randomized, n = 55) showed that preventive therapies lowered the average number of endoscopy dilatations (mean difference = -8.57, 95% CI = -13.88 to -3.25, p < 0,002). There were no significant differences in the 3 RCT studies (n=85) with regards to complication rates between patients with preventive therapies and those without (risk difference = 0.02, 95% CI = -0.09 to 0.14, p = 0.68). Conclusion: The use of preventive therapies after extensive ESD of the esophagus reduces the risk of stenosis and the number of endoscopic dilatations for resolution of stenosis without increasing the number of complications

A Epidermólise Bolhosa (EB) é uma doença rara não-oncológica e crônica, caraterizada por uma desordem heterogênea da pele, com formação de bolhas e erosões na região cutâneo-mucosa em todo o corpo, em resposta à mínima tração ou trauma. Atualmente existem poucos estudos na área da Fonoaudiologia referentes à atuação com essa população e o objetivo do presente estudo é correlacionar os achados clínicos relacionados à biomecânica da deglutição e as manifestações de alterações em deglutição com a ocorrência de estenose esofágica em crianças diagnosticadas com Epidermólise Bolhosa. Método: Estudo observacional descritivo transversal prospectivo, realizado com pacientes diagnosticados com EB do tipo distrófica, idade entre 6 e 18 anos e encaminhados ao serviço de Fonoaudiologia de um hospital público pediátrico de referência, para avaliação e reabilitação. Os pacientes foram submetidos à avaliação clínica fonoaudiológica, que incluiu a avaliação motora oral e desempenho durante a mastigação e deglutição. Os dados encontrados foram relacionados à ocorrência de estenose esofágica. Resultados: A amostra do estudo foi composta por 54 pacientes, dos quais 28 apresentaram estenose esofágica. As variáveis que apresentaram significância estatística foram náuseas, engasgos e odinofagia. Também foi possível constatar que o risco de ocorrência de estenose em crianças com EB aumenta proporcionalmente de acordo com a idade, sem variação de acordo com gênero. Conclusão: Este estudo possibilitou uma análise da relação entre a sintomatologia e comprometimentos estruturais e funcionais que as crianças com a patologia referida apresentam / Epidermolysis Bullosa (EB) is a rare non-oncological and chronic disease, characterized by blistering and erosion in the cutaneous mucosal region throughout the human body. There are few studies in the area of Speech-Language Pathology devoted to the clinical care of the population with EB, and this study seeks to fill this gap. Its main objective was to correlate the clinical findings related to the biomechanics of swallowing with the occurrence of esophageal stenosis in children diagnosed with EB. Method: Prospective cross-sectional observational study performed with patients diagnosed with dystrophic type of EB, between 6 and 18 years, and referred to the speech and language pathology department of a public reference pediatric hospital for evaluation and rehabilitation. The patients were submitted to clinical speech-language evaluation, which included oral motor evaluation and performance of chewing and swallowing. The data found were related to the occurrence of esophageal stenosis. Results: The study sample consisted of 54 patients, of whom 28 had esophageal stenosis. The variables that presented statistical significance were nausea, gagging and odynophagia. It was also possible to verify that the risk of stenosis in children with EB increases proportionately according to age, regardless of gender. This study allowed an analysis of the correlation between the symptomatology and structural/ functional impairments of children with Dystrophic Epidermolysis Bullosa

Le développement récent de l’endoscopie interventionnelle digestive nous a conduit à prendre en charge deux types de pathologies préoccupantes. Il s’agit d’une part des fistules digestives souvent responsables d’une morbi-mortalité élevée et d’autre part des sténoses œsophagiennes après résection tumorale endoscopique étendue. Dans ces deux situations, des phénomènes inflammatoires chroniques conduisent soit à l’absence de fermeture de la fistule soit à une fibrose importante responsable de sténose de l’œsophage. La thérapie cellulaire a déjà été utilisée pour diminuer ces phénomènes inflammatoires et entrainer une cicatrisation. La thérapie tissulaire par cellules souches organisées en construction 3D représente un avantage important en permettant de cibler le site d’action par dépôt direct du feuillet cellularisé. Notre objectif était d’évaluer l’effet thérapeutique de ces nouveaux outils pour fermer les fistules digestives et pour prévenir la survenue des sténoses œsophagiennes. La première étape a consisté a évaluer l’efficacité du traitement par des cellules souches mésenchymateuses provenant de moelle osseuse humaine, marquées puis organisées en doubles feuillets, dans un modèle de fistule entéro-cutanée post-chirurgicale chez la souris nude. L’évaluation clinique et en imagerie (IRM et microscopie confocale) a montré une meilleure cicatrisation avec une augmentation de la microvascularisation et une accélération de la fermeture de la fistule chez les souris greffées. Les effets observés semblent liés à une augmentation précoce de la synthèse des facteurs de réparation (EGF et le VEGF) et des cytokines anti-inflammatoires (TGF-ß2 et IL-10). Après avoir développé un modèle inédit de fistule oeso-cutanée chez le porc grâce à la mise en place par voie endoscopique et chirurgicale de prothèses plastiques entre la lumière œsophagienne et la peau, nous avons évalué l’efficacité thérapeutique d’un gel contenant des vésicules extracellulaires issues de cellules souches isolées du tissu adipeux de porc. Ce gel injecté dans la fistule par voie endoscopique a permis la fermeture des fistules. Enfin, la troisième partie de notre travail a consisté à évaluer l’efficacité de la greffe allogénique de doubles feuillets de cellules souches mésenchymateuses pour prévenir la survenue des sténoses œsophagiennes dans un modèle porcin après dissection sous muqueuse étendue. Il existait une réduction significative du taux de sténose œsophagienne cicatricielle dans le groupe greffé avec une fibrose moins importante. En conclusion, l’effet paracrine antifibrosant des cellules souches mésenchymateuses organisées en feuillets est efficace à la fois pour fermer les fistules entéro-cutanées chez la souris et pour prévenir les sténoses œsophagiennes chez le porc. Un gel avec des vésicules extracellulaires issues des cellules souches a de la même façon un effet cicatrisant anti-inflammatoire permettant la fermeture des fistules œsophagiennes chez le porc. Ces résultats sont très encourageants et posent la question d’une évaluation future chez l’homme. / Recent developments in digestive interventional endoscopy lead us to manage two types of digestive disease. First, it is digestive fistulas associated in many cases with high morbi-mortality; and second is oesophageal stenosis after extended superficial endoscopic resection. In both situations, chronic inflammatory process resulted in delayed or no fistula healing for the first case or oesophageal stenosis due to fibrosis. Cellular therapy has proved to be successful in reducing the inflammatory process and to promote tissue healing. Tissue therapy with 3D construct stem cells represents a major advantage by allowing a direct adaptation on the right place. Our objective was to evaluate the therapeutic effect of new strategy to close the digestive fistula and to prevent oesophageal stenosis. First step was to evaluate the effect of labelled human bone marrow derived mesenchymal stem cells engraftment in the form of double cellsheet in a post-surgical fistula model in nude mice. Clinical and radiological (MRI and probe based confocal microscopy) evaluation showed a better fistula healing with higher microvascularization and a faster fistula closing in grafted mice. These effects appear to be related to an increase production of factors involved in tissue repair (EGF et le VEGF) and anti-inflammatory cytokines (TGF-ß2 et IL-10). We developed an unpublished eso-cutaneous fistula in a porcine model after plastic catheters placement by surgical and endoscopic way between the oesophageal lumen and the skin. We evaluated the therapeutic effect of a hydrogel with extracellular vesicles extracted from porcine adipose derived stem cells. The hydrogel with vesicles was injected into the fistula by endoscopy. Radiological and histological evaluation 15 days after injection showed a fistula tract closure in treated group.The third part of this work was to evaluate the effect of allograft of adipose derived stem cells 3D construct to prevent the stenosis after extended endoscopic submucosal dissection in a porcine model. There was a significant reduction of number and degree of stenosis with decrease fibrosis infiltration in the grafted group.In summary, thanks to their paracrine and antifibrotic effect, the mesenchymal stem cells organised as 3D construct allowed fistula closure in an entero-cutaneous model in mice and prevention of stenosis after extended oesophageal submucosal dissection in a porcine model. Moreover, endoscopic hydrogel and extracellular vesicles injection allowed oesophageal fistula healing in a porcine model. These promising results pose the challenge of future clinical studies.