Objetivos: A FCL é um novo padrão de doença intersticial pulmonar idiopática associado ao refluxo gastro-esofágico. Nós investigamos sua presença na ES com envolvimento pulmonar. Métodos: 28 pacientes com ES foram submetidos à biópsia pulmonar a céu aberto. As amostras foram classificadas conforme o novo consenso de classificação das pneumonias intersticiais idiopáticas e de acordo com os critérios do padrão FCL. Tomografia computadorizada de alta resolução (TCAR) de tórax, prova de função pulmonar (PFP), esofagograma de contraste e/ou endoscopia digestiva alta também foram realizadas. Resultados: Na ES, o padrão NSIP (67,8%) e a FCL (75%) foram os padrões mais freqüentemente encontrados e na maioria dos casos, eles co-existiam. Todos, exceto um paciente com FCL tinha a característica distribuição broncocêntrica das lesões, sendo mais extensa nos casos com FCL isolada (p=0,001). Da mesma forma, o conteúdo basofílico foi mais freqüente nos pacientes com FCL e completamente ausente no grupo NSIP (p<0,001). Na TCAR, a distribuição central do envolvimento pulmonar foi o achado mais prevalente nos pacientes com FCL isolada (57,14%) contrastando com a 10 predominância do padrão periférico nos outros grupos (p=0,02). Além disso, uma tendência quanto à distribuição segmentar na TCAR foi observada no grupo com FCL isolada (85,71%) e FCL+NSIP (71,43%), enquanto que 80% dos pacientes com NSIP tinham uma distribuição difusa das lesões pulmonares (p=0,08). Anormalidades esofágicas foram um achado quase universal. Conclusão: Está é a primeira descrição de fibrose centrilobular em pacientes com ES e envolvimento pulmonar. Este padrão tem características histológicas e tomográficas distintas e a identificação deste subgrupo de pacientes irá certamente contribuir para uma melhor abordagem terapêutica. / Objectives: CLF is a new histological pattern of idiopathic ILD associated to esophageal reflux. We have investigated its presence in SSc with lung involvement. Methods: 28 SSc patients were submitted to open lung biopsy. The specimens were classified according to the new consensus classification of idiopathic interstitial pneumonia and to the diagnostic criteria for CLF. High Resolution Computer Tomography (HRCT), Pulmonary Function Tests (PFT), contrast esophagogram and/or upper digestive endoscopy were also performed. Main Results: In SSc, the NSIP (67.8%) and the centrilobular (75%) patterns were the most frequent and in the majority of the cases, they co-existed. All, except one patient with CLF had the characteristic bronchocentric distribution and this lesion was more extensive in those with isolated CLF (p=0.01). Likewise, the basophilic content was more frequent in patients with CLF and completely absent in NSIP group (p<0.001). The central distribution of lung involvement on HRCT was the most prevalent finding in patients with isolated CLF (57.14%) contrasting with the predominant peripheral pattern in the other groups (p=0.02). Moreover, a trend towards a patchy distribution on HRCT was observed for CLF group (85.71%) and CLF+NSIP group (71.43%) whereas 80% of the NSIP group had diffuse distribution (p=0.08). Esophageal abnormalities were almost a universal finding. Conclusions: This is the first report of centrilobular fibrosis in SSc patients with lung involvement. This new pattern has distinct histological and tomographic features. The identification of this subgroup of patients will certainly contribute for a more appropriate therapeutic approach.

Pharmacodynamic processes and disease progression are increasingly characterized with pharmacometric models. However, modelling options for discrete-type responses remain limited, although these response variables are commonly encountered clinical endpoints. Types of data defined as discrete data are generally ordinal, e.g. symptom severity, count, i.e. event frequency, and time-to-event, i.e. event occurrence. Underlying assumptions accompanying discrete data models need investigation and possibly adaptations in order to expand their use. Moreover, because these models are highly non-linear, estimation with linearization-based maximum likelihood methods may be biased. The aim of this thesis was to explore pharmacometric methods and novel models for discrete data through (i) the investigation of benefits of treating discrete data with different modelling approaches, (ii) evaluations of the performance of several estimation methods for discrete models, and (iii) the development of novel models for the handling of complex discrete data recorded during (pre-)clinical studies. A simulation study indicated that approaches such as a truncated Poisson model and a logit-transformed continuous model were adequate for treating ordinal data ranked on a 0-10 scale. Features that handled serial correlation and underdispersion were developed for the models to subsequently fit real pain scores. The performance of nine estimation methods was studied for dose-response continuous models. Other types of serially correlated count models were studied for the analysis of overdispersed data represented by the number of epilepsy seizures per day. For these types of models, the commonly used Laplace estimation method presented a bias, whereas the adaptive Gaussian quadrature method did not. Count models were also compared to repeated time-to-event models when the exact time of gastroesophageal symptom occurrence was known. Two new model structures handling repeated time-to-categorical events, i.e. events with an ordinal severity aspect, were introduced. Laplace and two expectation-maximisation estimation methods were found to be performing well for frequent repeated time-to-event models. In conclusion, this thesis presents approaches, estimation methods, and diagnostics adapted for treating discrete data. Novel models and diagnostics were developed when lacking and applied to biological observations.

Made available in DSpace on 2015-07-22T20:49:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-09-30. Added 1 bitstream(s) on 2015-08-11T03:25:59Z : No. of bitstreams: 1 Publico-11859a.pdf: 1971801 bytes, checksum: dc22083567fcbecdefe8d1bc1ef866e9 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:59Z : No. of bitstreams: 2 Publico-11859a.pdf: 1971801 bytes, checksum: dc22083567fcbecdefe8d1bc1ef866e9 (MD5) Publico-11859b.pdf: 1464854 bytes, checksum: ed8fffe60a11710f362faadbbbf6b037 (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:59Z : No. of bitstreams: 3 Publico-11859a.pdf: 1971801 bytes, checksum: dc22083567fcbecdefe8d1bc1ef866e9 (MD5) Publico-11859b.pdf: 1464854 bytes, checksum: ed8fffe60a11710f362faadbbbf6b037 (MD5) Publico-11859c.pdf: 618900 bytes, checksum: ce78a0221e4d7c2792bf114602ddb45d (MD5). Added 1 bitstream(s) on 2015-08-11T03:25:59Z : No. of bitstreams: 4 Publico-11859a.pdf: 1971801 bytes, checksum: dc22083567fcbecdefe8d1bc1ef866e9 (MD5) Publico-11859b.pdf: 1464854 bytes, checksum: ed8fffe60a11710f362faadbbbf6b037 (MD5) Publico-11859c.pdf: 618900 bytes, checksum: ce78a0221e4d7c2792bf114602ddb45d (MD5) Publico-11859d.pdf: 1753706 bytes, checksum: 1aa5162c1f98a814fc5f261944e41f5a (MD5) / Desenho do estudo: Transversal, não experimental. Objetivos: Detectar e comparar as alterações funcionais esofágicas e da junção esôfago-gástrica em dois grupos de pacientes com lesão medular crônica, um no nível da inervação frênica e o outro em níveis torácicos superiores, e relacioná-las à contenção do refluxo gastroesofágico. Sumário e contexto: Em lesados medulares não há estudo manométrico esofágico associado à pHmetria. A estatística mundial revela que a prevalência de doença do refluxo gastroesofágico em lesados medulares é maior que a população geral, em torno de 22 a 27%. A "crura diafragmática" vem sendo reconhecida como importante barreira antirefluxo e, funcionalmente, deveria ser considerada como um músculo separado do diafragma costal, mas permanece a dúvida se essa diferença está relacionada com sua inervação. Métodos: O estudo é transversal em que participaram 29 pacientes com lesão medular completa, sendo 14 tetraplégicos (nível C4) e 15 paraplégicos (níveis T1 a T7). As alterações funcionais da junção esôfagogástrica, esôfago e diafragma foram avaliadas através da manometria esofágica e vídeo-fluoroscopia diafragmática; presença de refluxo gastroesofágico por dados subjetivos (pirose e regurgitação) e objetivos (dados pHmétricos e endoscópicos). Resultados: A prevalência da doença do refluxo gastroesofágico foi de 27,6%, sem diferença entre os grupos. Esta foi estatisticamente significante quando se comparou as médias da pressão da crura diafragmática (tetraplégico: 37,5&#61617;17,8; paraplégico: 26,6&#61617;7,2; p=0,048). Também teve significância em relação à prevalência de no mínimo um dos achados objetivos e/ou subjetivos de refluxo e/ou do peristaltismo esofágico (tetraplégico: 85,7%; paraplégico: 40%; p=0,011). Conclusões: A lesão medular no nível da inervação frênica não predispôs os tetraplégicos a um risco maior para desenvolver a doença do refluxo gastroesofágico. Paradoxalmente, a manometria mostrou uma contractilidade da crura diafragmática significantemente maior nos tetraplégicos. / Study design: Cross-sectional and non-experimental. Objective: To detect and compare functional abnormalities in the esophagus and esophagogastric junction in two groups with chronic spinal injuries, one with injuries at the phrenic innervation level and the other at upper thoracic levels, and to relate these to gastroesophageal reflux containment. Summary of background data: There are no studies on esophageal manometry with pH metering among spinal cord injury patients. Worldwide statistics reveal that the prevalence of gastroesophageal reflux disease among spinal cord injury patients is greater than among the general population, at around 22 to 27%. The "diaphragmatic crura" has been recognized as an important antireflux barrier and should functionally be considered to be a muscle separated from the costal diaphragm. However, doubts remain regarding whether this difference relates to its innervation. Methods: This was a cross-sectional study on 29 patients with complete spinal cord injuries: 14 quadriplegics (level C4) and 15 paraplegics (levels T1 to T7). Functional abnormalities of the esophagogastric junction, esophagus and diaphragm were investigated using esophageal manometry and diaphragmatic video fluoroscopy. Presence of gastroesophageal reflux was investigated subjectively (pyrosis and regurgitation) and objectively (pH metering and endoscopy). Results: The prevalence of gastroesophageal reflux disease was 27.6%, without difference between the groups. This became statistically significant when the mean diaphragmatic crura pressures were compared (quadriplegics: 37.5 &#61617; 17.8; paraplegics: 26.6 &#61617; 7.2; p=0.048). It was also significant in relation to the prevalence of at least one of the objective and/or subjective reflux findings and/or esophageal peristaltism (quadriplegics: 85.7%; paraplegics: 40%; p=0.011). Conclusions: Spinal injury at the level of the phrenic innervation did not predispose the quadriplegics towards greater risk of developing gastroesophageal reflux disease. Paradoxically, manometry showed significantly greater crura contractility among the quadriplegics. / TEDE / BV UNIFESP: Teses e dissertações

O objetivo foi evidenciar a presença do espaço intercelular dilatado do epitélio esofágico após a infusão de ácido clorídrico (HCl) à 0,1N comparando com a infusão de soro fisiológico (SF) em pacientes sem sintomas típicos da DRGE com mucosa esofágica normal e compará-los com os de sintomas típicos e esofagite erosiva. Foram entrevistados e realizaram o exame de endoscopia digestiva alta 60 pacientes destes, 29 foram incluídos no estudo sendo 18 com esôfago normal (9 foram infundidos SF e 9 HCl) e 11 com esofagite erosiva (6 foram infundidos SF e 5 HCl) e foram realizados 4 biópsias da mucosa esofágica (2 antes e 2 depois das infusões). Não foi encontrado diferença estatisticamente significante no espaço intercelular da mucosa esofágica dos pacientes com e sem esofagite erosiva com ácido clorídrico ou soro fisiológico não sendo um marcador da DRGE / The purpose was to prove the presence of extended intercellular space of the esophagic epithelium after chloridric acid infusion (HCI) to 0,1N comparing to the physiologic serum infusion (PS) in patients without typical symptoms of DGER with normal esophagic mucous membrane and compare them to ones with typical symptoms and erosive esophagitis. 60 patients were interviewed and took the high digestive endoscopy; 29 were included in the research, among them 18 with normal esophagus (9 were infused PS, and 9 HCI) and 11 with erosive esophagitis (6 were infused PS and 5 HCI); 4 biopsies of esophagic mucous membrane were made (2 before and 2 after infusions). It was not found any statistically meaningful difference in intercellular space of esophagic mucous membrane in patients with or without erosive esophagitis with chloridric acid or physiologic serum, and thus it is not a DGER

Objective: We aimed to assess the prognostic value of circulating tumor cells (CTC) in patients with advanced gastric and gastroesophageal adenocarcinomas. Methods: The presence of CTC was evaluated in 62 patients with advanced gastric and gastroesophageal adenocarcinomas before systemic therapy and at follow-up through immunomagnetic enrichment for mucin 1- and epithelial cell adhesion molecule (EpCAM)-positive cells, followed by real-time RT-PCR of the tumor-associated genes KRT19 , MUC1 , EPCAM , CEACAM5 and BIRC5 . Results: The patients were stratified into groups according to CTC detection (CTC negative: with all marker genes negative; CTC positive: with at least 1 of the marker genes positive). Patients who were CTC positive at baseline had a significantly shorter median progression-free survival (PFS; 3.5 months, 95% CI: 2.9–4.2) and overall survival (OS; 5.8 months, 95% CI: 4.5–7.0) than patients lacking CTC (PFS 10.7 months, 95% CI: 6.9–14.4, p < 0.001; OS 13.3 months, 95% CI: 8.0–18.6, p = 0.003). Alterations in the marker profile during the course of chemotherapy were not predictive of clinical outcome or response to therapy. Yet, a favorable clinical response depended significantly on CTC negativity (p = 0.03). Conclusion: Our data suggest that the presence of CTC is a major predictor of outcome in patients with gastric and gastroesophageal malignancies.