1,730 research outputs found
Multimodality treatment for esophageal squamous cell carcinoma
This thesis aims to optimize multimodality treatments for locally advanced esophageal squamous cell carcinoma (ESCC), specifically in East-Asia, recognizing that ESCC may differ in biology and response to treatment in different parts of the world. Part I of the thesis introduces the subtype ESCC and its characteristics from different geographical perspectives followed by an exposition of the differences between ESCC in eastern and western worlds. Part II optimizes trimodal therapy of ESCC in Taiwan, as a representative region of East-Asia. Finally, in Part III, the accuracy of liquid biopsies in identifying patients who may not need surgery after trimodal therapy is assessed.
PANCREATODUODENECTOMY FOR MALIGNANCY: FACTORS INFLUENCING SURGICAL AND ONCOLOGICAL OUTCOMES
Introduction:
Fit patients with a resectable pancreatic head adenocarcinoma (PDAC), ampullary adenocarcinoma (AA) or distal cholangiocarcinoma (CC) may be offered pancreatoduodenectomy (PD) with curative-intent. However, perioperative morbidity and cancer recurrence rates are high. This thesis aimed to explore the factors influencing PD outcomes. A focus was placed on nutrition, postoperative complications, and recurrence in AA patients. It is hoped the findings will guide patient selection/consenting and have implications for patient management.
Methods:
A retrospective cohort study of patients who underwent PD for histologically-confirmed malignancy was carried out (2012-2015). Twenty-nine centres from eight countries were involved. Data on the following were collected: preoperative comorbidities and investigations, neoadjuvant treatment, operative details, postoperative complications, histology, adjuvant treatment, cancer recurrence, palliative treatment, and overall survival (OS).
Results:
In total, 1484 patients were included; 885 (59.6%), 394 (26.5%) and 205 (13.8%) had PDAC, AA and CC, respectively. Overall morbidity, major morbidity (Clavien-Dindo grade 11 ≥III) and 90-day mortality rates were 53.4%, 16.9% and 3.8%, respectively. A high body mass index (BMI), an American Society of Anesthesiologists (ASA) grade >II and a classic Whipple approach all correlated with morbidity. Additionally, ASA grade >II patients were at increased risk of major morbidity and a raised BMI correlated with a greater risk of pancreatic leak. Almost half of the cohort received nutritional support (NS). Of these, 55.6% received parenteral nutrition (PN). In total, 19.6% of the patients who had an uneventful postoperative recovery received PN. Among the PDAC cohort, commencing adjuvant chemotherapy (AC) correlated with improved OS, and those who experienced major morbidity commenced AC less frequently. Among the AA cohort, 176 patients (44.7%) developed recurrence and the median time-to-recurrence was 14 months. Local only, local and distant, and distant only recurrence affected 34, 41 and 94 patients, respectively (site unknown: 7). A higher number of resected nodes, histological T stage >II, lymphatic invasion, perineural invasion (PNI), peripancreatic fat invasion (PPFI) and ≥1 positive resection margin all correlated with AA recurrence. Further, ≥1 positive margin, PPFI and PNI were associated with reduced time-to-recurrence.
Conclusions:
A considerable number of the patients that had an uneventful recovery received PN. Patients with a high BMI or ASA grade had worse perioperative outcomes. Those who experienced major morbidity commenced AC less frequently. Numerous histopathological predictors of AA recurrence and reduced time-to-recurrence were identified
Splenic nerve bundle stimulation in acute and chronic inflammation
Splenic neurovascular bundle stimulation holds potential to treat acute and chronic inflammatory conditions. In the first part of the thesis, the available literature on the interactions between the immune system and nervous system in the intestine is summarized. Then, it is shown that a specialized T-cell, that can produce the neurotransmitter acetylcholine, resides in the gut an plays a dual role in the development of experimental colitis in mice. Furthermore, electrical splenic neurovascular bundle stimulation ameliorated the outcomes of colitis in mice and reversed transcriptomic changes in the gut that were induced by colitis. The second part of the thesis focused on the translation of splenic neurovascular bundle stimulation to the human situation. It is shown that there are significant changes between murine and human innervation of the spleen. Using computed tomography (CT) images the course and the characteristics of the splenic artery were described. These data were used to develop a cuff electrode that could be used for electrical stimulation of the splenic neurovascular bundle in humans. Finally, it was demonstrated that splenic neurovascular bundle stimulation in humans was safe and feasible in a pilot study with patients that underwent esophagectomy
Contribution of Relatedness and Genetic Factors to the Clinical Picture of Coeliac Disease
Keliakia on yleinen autoimmuunisairaus, jossa tärkein altistava ympäristötekijä on ravinnon sisältämä gluteeni. Keliakiaa esiintyy maailmanlaajuisesti, mutta sen esiintyvyys Suomessa on erityisen korkea, vaikkakin laajalti alidiagnosoitu. Osasyy tälle on keliakian kirjava taudinkuva. Ruuansulatuskanavan oireet muodostivat pitkään keliakialle tyypillisen oirekuvan, mutta se on vähitellen korvautunut lievemmillä, usein ruuansulatuskanavan ulkopuolisilla oireilla. Nykyään keliakia voi ilmentyä myös täysin oireettomana. Oireiden lisäksi niiden puhkeamisessa, voimakkuudessa sekä kehittymisessä on paljon yksilöllisiä eroja. Myös keliakiapotilaiden vaste gluteenittomaan ruokavaliohoitoon vaihtelee. Syitä tai tekijöitä tämän potilaskohtaisesti vaihtelevan taudinkuvan taustalla ei kuitenkaan vielä tunneta.
Nykyisin moni keliaakikko on osannut aiemmin epäillä kohdallaan keliakiaa ja hakeutunut lääkäriin, koska sairaus on ollut tuttu keliakiaa sairastavien sukulaisten tai perheenjäsenten kautta. Nämä ns. familiaaliset keliaakikot ovat enemmistö, mutta keliakiaa esiintyy myös ns. sporadisesti, jolloin potilaalla ei ole tiedettyä sukutaustaa keliakialle. Tunnetuin keliakialle altistava perintötekijä on HLA-DQ2.5-haplotyyppi, mutta muidenkin, HLA-alueen ulkopuolisten, geenialueiden on todettu assosioituvan keliakiaan.
Tässä väitöskirjatutkimuksessa selvitettiin familiaalisen ja sporadisen keliakian eroavaisuuksia perintötekijöiden ja taudinkuvan suhteen. Lisäksi tutkittiin, onko HLA-DQ2.5-kuormalla (eli sillä, onko potilas HLA-DQ2.5-negatiivinen, - heterotsygootti vai -homotsygootti) ja HLA:n ulkopuolisilla geneettisillä varianteilla, mukaan lukien variantit kandidaattigeeneissä CCR9 ja CCL25, vaikutusta keliakian kliiniseen taudinkuvaan.
Tämän väitöskirjan tulokset paljastivat, että sporadinen keliakia omana erillisenä tautimuotonaan eroaa HLA-DQ-genotyypiltään familiaalisesta tautimuodosta, vaikka useita eroavaisuuksia kliinisen taudinkuvan suhteen ei löydettykään. Sporadisten potilaiden taudinkuva diagnoosihetkellä oli kuitenkin vakavampi ja yleinen terveydentila seurantahetkellä, gluteenittomalla dieetillä, huonompi kuin familiaalisilla potilailla. Tutkimukset myös osoittivat, että HLA-DQ2.5-negatiivisia potilaita leimasi HLA-DQ2.5-heterotsygootteja ja -homotsygootteja useammin klassinen oirekuva diagnoosihetkellä sekä pitkittyneet oireet seurantahetkellä. Nämä tutkimuslöydökset toivottavasti rohkaisevat lääkäreitä sekä muuta hoitohenkilökuntaa kiinnittämään erityistä huomiota edellä mainittuihin potilasryhmiin. Lisäksi väitöstutkimuksen geneettisten analyysien tulokset osoittivat neljän HLA-alueen ulkopuolisen variantin assosioituvan familiaaliseen keliakiaan. Näiden assosiaatioiden merkitys tulee kuitenkin vahvistaa jatkotutkimuksilla. HLA- DQ2.5-kuorman tai CCR9- ja CCL25-kandidaattigeenialueiden varianttien vaikutus keliakian taudinkuvaan oli tämän väitöskirjatutkimuksen perusteella vähäinen.Coeliac disease, a systemic autoimmune disorder induced by dietary gluten, is widespread globally, but in Finland even particularly prevalent although still heavily underdiagnosed. One reason contributing to this is the remarkably multifaceted clinical picture of coeliac disease. The originally typical gastrointestinal symptoms are currently being increasingly replaced by a milder presentation with extraintestinal symptoms and even totally asymptomatic presentation is no longer abnormal. Nevertheless, coeliac disease patients do not differ from each other only in terms of symptoms. There is a wide individual variation concerning the onset, severity and progression of symptoms as well as response to dietary treatment i.e., gluten-free diet (GFD). The reasons and contributary factors underlying this wide clinical heterogeneity remain obscure.
For many people nowadays, suspicion of coeliac disease is closely connected to known familial history of the disease. These familial cases are in the majority, but not every patient has affected relatives and such patients are considered sporadic. Where coeliac disease heredity is concerned, HLA-DQ2.5 is the best-known genetic component. However, numerous loci outside the HLA region have also been associated with the disease.
The studies presented in this dissertation focused in investigating whether there are genetic and/or phenotypic differences between familial and sporadic coeliac disease and whether the dose of HLA-DQ2.5 or the presence of genetic variants outside HLA region, including the ones within candidate genes CCR9 and CCL25, contributes to the clinical picture of the disease.
The findings of this dissertation managed to describe sporadic coeliac disease as an independent entity with a distinct HLA-DQ genotype even though not many significant phenotypic differences were observed between familial and sporadic coeliac disease. Nevertheless, the sporadic cases had more severe clinical phenotype at diagnosis as well as poorer overall health even after dietary treatment. Moreover, HLA-DQ2.5-negative coeliac disease patients were observed to present with classical phenotype at diagnosis as well as with persistent symptoms after dietary treatment more often than patients heterozygous or homozygous for high-risk HLA- DQ2.5. These findings will hopefully encourage physicians to pay special attention to both these patient groups. Four distinct non-HLA variants were associated with increased risk for familial coeliac disease, but the associations need to be confirmed in future studies. The contribution of HLA-DQ2.5 dose as well as non-HLA single nucleotide polymorphisms (SNPs) within CCR9 and CCL25 to the clinical picture of coeliac disease was found to be only modest
Effects of municipal smoke-free ordinances on secondhand smoke exposure in the Republic of Korea
ObjectiveTo reduce premature deaths due to secondhand smoke (SHS) exposure among non-smokers, the Republic of Korea (ROK) adopted changes to the National Health Promotion Act, which allowed local governments to enact municipal ordinances to strengthen their authority to designate smoke-free areas and levy penalty fines. In this study, we examined national trends in SHS exposure after the introduction of these municipal ordinances at the city level in 2010.MethodsWe used interrupted time series analysis to assess whether the trends of SHS exposure in the workplace and at home, and the primary cigarette smoking rate changed following the policy adjustment in the national legislation in ROK. Population-standardized data for selected variables were retrieved from a nationally representative survey dataset and used to study the policy action’s effectiveness.ResultsFollowing the change in the legislation, SHS exposure in the workplace reversed course from an increasing (18% per year) trend prior to the introduction of these smoke-free ordinances to a decreasing (−10% per year) trend after adoption and enforcement of these laws (β2 = 0.18, p-value = 0.07; β3 = −0.10, p-value = 0.02). SHS exposure at home (β2 = 0.10, p-value = 0.09; β3 = −0.03, p-value = 0.14) and the primary cigarette smoking rate (β2 = 0.03, p-value = 0.10; β3 = 0.008, p-value = 0.15) showed no significant changes in the sampled period. Although analyses stratified by sex showed that the allowance of municipal ordinances resulted in reduced SHS exposure in the workplace for both males and females, they did not affect the primary cigarette smoking rate as much, especially among females.ConclusionStrengthening the role of local governments by giving them the authority to enact and enforce penalties on SHS exposure violation helped ROK to reduce SHS exposure in the workplace. However, smoking behaviors and related activities seemed to shift to less restrictive areas such as on the streets and in apartment hallways, negating some of the effects due to these ordinances. Future studies should investigate how smoke-free policies beyond public places can further reduce the SHS exposure in ROK
Immune contexture monitoring in solid tumors focusing on Head and Neck Cancer
Forti evidenze dimostrano una stretta interazione tra il sistema immunitario e lo sviluppo biologico e la progressione clinica dei tumori solidi. L'effetto che il microambiente immunitario del tumore può avere sul comportamento clinico della malattia è indicato come "immunecontexture". Nonostante ciò, l'attuale gestione clinica dei pazienti affetti da cancro non tiene conto di alcuna caratteristica immunologica né per la stadiazione né per le scelte terapeutiche. Il tumore della testa e del collo (HNSCC) rappresenta il 7° tumore più comune al mondo ed è caratterizzato da una prognosi relativamente sfavorevole e dall'effetto negativo dei trattamenti sulla qualità della vita dei pazienti. Oltre alla chirurgia e alla radioterapia, sono disponibili pochi trattamenti sistemici, rappresentati principalmente dalla chemioterapia a base di platino-derivati o dal cetuximab. L'immunoterapia è una nuova strategia terapeutica ancora limitata al setting palliativo (malattia ricorrente non resecabile o metastatica). La ricerca di nuovi biomarcatori o possibili nuovi meccanismi target è molto rilevante quindi nel contesto clinico dell'HNSCC. In questa tesi ci si concentrerà sullo studio di tre possibili popolazioni immunitarie pro-tumorali studiate nell'HNSCC: i neutrofili tumore-associati (TAN), le cellule B intratumorali con fenotipo immunosoppressivo e i T-reg CD8+. Particolare attenzione è data all'applicazione di moderne tecniche biostatistiche e bioinformatiche per riassumere informazioni complesse derivate da variabili cliniche e immunologiche multiparametriche e per validare risultati derivati in situ, attraverso dati di espressione genica derivati da dataset pubblici. Infine, la seconda parte della tesi prenderà in considerazione progetti di ricerca clinica rilevanti, volti a migliorare l'oncologia di precisione nell'HNSCC, sviluppando modelli predittivi di sopravvivenza, confrontando procedure oncologiche alternative, validando nuovi classificatori o testando l'uso di nuovi protocolli clinici come l'uso dell'immunonutrizione.Strong evidences demonstrate a close interplay between the immune system and the biological development and clinical progression of solid tumors. The effect that the tumor immune microenvironment can have on the clinical behavior of the disease is referred as the immuno contexture. Nevertheless, the current clinical management of patients affected by cancer does not take into account any immunological features either for the staging or for the treatment choices. Head and Neck Cancer (HNSCC) represents the 7th most common cancer worldwide and it is characterized by a relatively poor prognosis and detrimental effect of treatments on the quality of life of patients. Beyond surgery and radiotherapy, few systemic treatments are available, mainly represented by platinum-based chemotherapy or cetuximab. Immunotherapy is a new therapeutical strategy still limited to the palliative setting (recurrent not resectable or metastatic disease). The search for new biomarkers or possible new targetable mechanisms is meaningful especially in the clinical setting of HNSCC. In this thesis a focus will be given on the study of three possible pro-tumoral immune populations studied in HNSCC: the tumor associated neutrophils (TAN), intratumoral B-cells with a immunosuppressive phenotype and the CD8+ T-regs. Biostatistical and bioinformatical techniques are applied to summarize complex information derived from multiparametric clinical and immunological variables and to validate in-situ derived findings through gene expression data of public available datasets. Lastly, the second part of the thesis will take into account relevant clinical research projects, aimed at improving the precision oncology in HNSCC developing survival prediction models, comparing alternative oncological procedures, validating new classifiers or testing the use of novel clinical protocols as the use of immunnutrition
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