Abstract Incidence trends of laryngeal cancer in Finland were analyzed, especially in relation to survival, in a patient series of 5766 patients diagnosed in 1956–1995 and identified from the Finnish Cancer Registry. The age-adjusted incidence rate decreased from 6.5 to 3.5 per 100 000 person-years in males and remained unchanged among females. Only minor improvement occurred in survival. In a hospital-based material from Northern Finland (353 patients with laryngeal squamocellular carcinoma, LSCC, diagnosed in 1976–1995), the incidence among males decreased only for supraglottic cancer, diminishing the supraglottic to glottic incidence ratio from 1.4:1 to 0.5:1. Evaluation of diagnostic delays and their impact on survival and risk of recurrence was undertaken in a sample of 66 LSCC patients. In only 38% of the patients was malignancy suspected at the initial visit to a physician; infection was the most common misdiagnosis (41%). Half of the first consultations resulted in referral, whereas 17% of the patients were neither referred nor controlled. The median patient delay was 2 months and median professional delay 3 months. The latter exceeded 12 months in 17% of the patients. The delays were not significantly related to any other clinical parameter, nor were they interrelated. Professional delay of 12 months or more resulted in increased relative hazard of death (HR = 4.74, p = 0.05), equalling the effect of advanced stage (stage IV). One-third of the patients developed a recurrence. In univariate analysis, professional delay of 12 months or more increased the risk of local (p = 0.019) and neck (p = 0.019) recurrence. In a multivariate model, professional delay of 12 months or more indicated an adjusted relative hazard ratio (HR) of 4.6 for local recurrence (p = 0.02) and 9.5 for neck recurrence (p = 0.015). Immunohistochemical factors p53, apoptosis, angiogenesis and proliferation were included in a multivariate model evaluating prognostic factors of LSCC in addition to clinical and sociodemographic factors. Advanced stage (stages III–IV) (relative hazard ratio of death (HR) 8.9, p = 0.01), supraglottic site (HR 5.6, p = 0.02) and high apoptotic index (≥ 0.3) (HR 11.1, p = 0.05) were the best indicators of impaired prognosis. Professional delay and enhanced apoptotic rate could be helpful in selecting LSCC patients for more aggressive primary treatment.

Abstract Traditional clinicopathological factors are not accurate enough to predict the behavior of head and neck squamous cell carcinoma (HNSCC). The most powerful indicator of prognosis is the stage of the disease. New prognostic markers have, however, been searched for in order to better identify patient groups in need of different treatments or follow-up. Gelatinases (MMP-2, -9) are endopeptidases associated with tumor invasion and angiogenesis, and their tissue inhibitors (TIMP-1, -2) are also linked to cancer cell invasion and metastasis formation. In some cancer types they are even prognostic and relate with a more aggressive clinical course of the disease. In the present work the expression and the clinical significance of tumor tissue and circulating immunoreactive proteins for MMP-2, -9, TIMP-1 and -2 were assessed in HNSCC. The study group included 74 patients with HNSCC and 44 healthy controls. The expression of immunoreactive proteins was examined in paraffin-embedded tumor sections by immunohistochemical staining using specific antibodies, and the pretreatment serum levels of those proteins were quantitatively measured by ELISA assay. Immunohistochemical overexpression of MMP-9 in tumor was for the first time found to predict the prognosis for shortened survival in HNSCC, the cause-specific survival rates being 45% and 92% and relapse-free survival being 42% and 79% in MMP-9 positive or negative cases, respectively. Additionally, tissue TIMP-1, MMP-2 and TIMP-2 positivity were all also linked with poorer survival of patients with HNSCC. However, these differences remained less distinct than with MMP-9. The expression of gelatinases and their inhibitors in tumor tissue was also an indicator for later lymph node or hematogenic relapses in HNSCC patients. Circulating MMP-9 and TIMP-1 levels were significantly higher in HNSCC patients than in healthy controls. Further, the cause-specific and relapse-free survival rates were lower among HNSCC patients with high MMP-9 and TIMP-1 serum levels compared to patients with low levels of circulating MMP-9 and TIMP-1. A significant correlation was shown between circulating MMP-9 and MMP-9 immunohistochemical staining in the corresponding tumors. No correlation was found between tissue or circulating levels of gelatinases or their inhibitors and the traditional clinical or histopathological factors, except for the association between tissue and circulating TIMP-1 and the size of the primary tumor. Taken together, these results suggest that tissue expression of gelatinases and their inhibitors as well as pretreatment circulating MMP-9 and TIMP-1 levels could be prognostic in estimation of the clinical course of HNSCC. The results indicate further studies are needed with larger patient materials.

Meningitis remains a frightening disease with a high morbidity and mortality in spite of optimal treatment. In South Africa in particular, the incidence of HIV-infected patents with meningitis has risen considerably during the past decade. The first part of this meningitis study evaluated prognostic indicators in meningitis. In 100 adult patients with meningitis it was found that the Glasgow Coma Scale (GCS) at admission was a good indicator of the ultimate prognosis of the patient, with a GCS value of > 12 associated with a good outcome in 88% of patients. A GCS value of < 8 predicted an unfortunate outcome in 88% of patients. A high CSF protein level was also associated with an unfortunate outcome but the statistical significance was not as marked as with the GCS value. Age, CSF-neutrophil count, and glucose levels were also evaluated as possible prognostic indicators but were not found to be statistically significant. The electroencephalograms of 12 patients with pneumococcal meningitis showed that a grade 4 dysfunction within 48 hours of admission indicated a poor outcome; CT brain scans of 26 patients with TB meningitis showed that an adverse outcome was seen particularly in patients with TB meningitis and infarcts while in 33 patients with bacterial meningitis no specific sign was found to indicate a bad prognosis - probably due to the small number of patients evaluated. Prognostic factors in cryptococcal meningitis were lastly evaluated retrospectively in 44 patients; age, CSF white cell count and CD 4 counts were not found to be associated with outcome, while a GCS value of ≤ 14 at admission was found in almost three quarters of patients with an eventual adverse outcome. The second part of the study evaluated the impact of HIV-infection on meningitis. Between 1994 and 1998, the HIV-epidemic caused a marked shift in the spectrum of meningitis towards chronic infections such as TB and cryptococcal meningitis, while the incidence of HIV-related cases with meningitis rose from 14% in 1994 to 5% in 1998. A comparison of clinical, CSF and pathological findings and outcomes in 20 HIV-positive and 17 HIV-negative patients with tuberculous meningitis showed that HIV-infection does not significantly alter clinical and CSF findings in TB meningitis in South Africa, but ventricular dilatation and infarcts occur more frequently in HIV-positive patients. Diagnostic aids in meningitis were assessed in the final part of this study. The polymerase chain reaction for TB was measured in the CSF of 10 patients with suspected tuberculous meningitis and disappointingly only positive in two patients in spite of positive CSF cultures for TB in an additional four patients. Lymphnode biopsies were performed on seven patients with intracranial tuberculosis. Excision biopsy of an enlarged Iymphnode showing caseating granulomas and/or acid-fast bacilli confirmed the diagnosis of TB within 48 hours of admission. Thus, Iymphnode biopsies may be an effective and practical aid in diagnosing intracranial TB. Adenosine deaminase (ADA) levels are often elevated in both tuberculous and bacterial meningitis. ADA iso-enzymes analysis in 26 patients however, showed that the ADA2 iso-enzyme was the major contributor to increased ADA activity in the CSF of patients with tuberculous meningitis and not with bacterial meningitis. The EEG was evaluated as diagnostic aid in 55 patients with meningitis to discriminate between viral and non-viral meningitis. Sensitivities of 70% and 80% of VEEG and QEEG's respectively were attained for the prediction of patients with non-viral meningitis, while the VEEG had a specificity of 100% for the prediction of viral meningitis. / Thesis (MD (Neurology))--University of Pretoria, 2005. / Neurology / unrestricted

Lors de son fonctionnement, une machine tournante est le lieu de nombreux échanges thermiques et de sources de chaleur. Dans la littérature, les roulements font l'objet d'une attention toute particulière. En effet par leur fonctionnement les roulements ont tendance à produire de la chaleur en raison des frottements entre les différents éléments. Ces frottements se traduisent par de la fatigue qui peut entrainer un arrachement de matière sur les bagues ou les éléments roulants donnant naissance à un écaillage. L'écaillage, à son tour, produit un choc répétitif qui représente une nouvelle source d'énergie thermique. Ce travail propose un modèle physique pour l'étude du chauffage thermique d'un roulement à billes sain et d’un roulement endommagé en fonctionnement. Celui-ci s’appuie sur une théorie nodale considérant d’abord l'échauffement du roulement par friction et aussi par l'apport de chaleur dû à l'apparition d'un écaillage. La résolution du bilan énergétique est obtenue par la méthode nodale où l'échauffement dû au frottement et la chaleur induite par le passage des billes sur le défaut est pris en compte. Le modèle thermique proposé est validé par une analyse thermique expérimentale. Les résultats obtenus montrent que la température augmente dans les éléments où le défaut est localisé avec l'augmentation de la vitesse de rotation. Les mêmes résultats sont obtenus pour l'influence de la charge radiale.Le pronostic de défaillance des roulements peut être considéré comme une solution efficace. La prédiction précise de la durée de vie résiduelle (RUL) des roulements est indispensable pour des opérations sûres et optimisées dans le temps. Une nouvelle méthode met l'accent sur l'analyse des relations comme les corrélations entre l'indicateur de santé (IH) et la température est proposée. Nous développons une solution pour l'ensemble de données sur les roulements dans différentes conditions de fonctionnement et de sévérité des défauts. La performance de la méthode proposée est vérifiée par quatre ensembles de données sur les roulements recueillis dans le cadre d'une installation expérimentale. Les résultats montrent que l'indicateur de santé obtient des valeurs de monotonie et de corrélation assez élevées et qu'il est bénéfique pour la prédiction de la durée de vie du roulement. / Many sources of heat can emanate from the operation of a rotating machine, and one of which is the friction among the different parts of the ball bearings. Over time, these frictions may lead to a tearing of matter of the rings or on the rolling elements that cause some type of degradation by flaking. Flaking, in turn, produces a repetitive shock as a new source of thermal energy. This work proposes a physical model for the study of the thermal heating of a ball bearing during operation. The resolution of the energy balance is achieved by the Nodal method where both the heating due to friction and the heat induced by the passage of the balls on defect are taken into account. The proposed thermal model is validated through an experimental thermal analysis. The obtained results show that the temperature increases in the position of defect ball ring with increasing rotational speed. The same results are obtained for the influence of radial load.Bearings failure prognostics, which aims to achieve an effective way to handle the increasing requirements for higher reliability and in the same time reduce unnecessary costs, has been an area of extensive research. The accurate prediction of bearings Remaining Useful Life (RUL) is indispensable for safe and lifetime-optimized operations. A new method focuses on analysing the relationships such as correlations between the HI and temperature is proposed. We develop a solution for the Connectiomics contest dataset of bearings under different operating conditions and severity of defects. The performance of the proposed method is verified by four bearing data sets collected from experimental setup. The results show that the health indicator obtains fairly high monotonicity and correlation values and it is beneficial to bearing life prediction.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background: Pulmonary tuberculosis is a highly prevalent disease in low-income countries; clinical prediction tools allow healthcare personnel to catalog patients with a higher risk of death in order to prioritize medical attention. Methodology: We conducted a literature search on prognostic models aimed to predict mortality in patients diagnosed with pulmonary tuberculosis. We included prospective and retrospective studies where prognostic models predicting mortality were either developed or validated in patients diagnosed with pulmonary tuberculosis. Three reviewers independently assessed the quality of the included studies using the PROBAST tool (Prediction model study Risk of Bias Assessment Tool). A narrative review of the characteristics of each model was conducted. Results: Six articles (n = 3553 patients) containing six prediction models were included in the review. Most studies (5 out of 6) were retrospective cohorts, only one study was a prospective case-control study. All the studies had a high risk of bias according to the PROBAST tool in the overall assessment. Regarding the applicability of the prediction models, three studies had a low concern of applicability, two high concern and one unclear concern. Five studies developed new prediction rules. In general, the presented models had a good discriminatory ability, with areas under the curve fluctuating between 0.65 up to 0.91. Conclusion: None of the prognostic models included in the review accurately predict mortality in patients with pulmonary tuberculosis, due to great heterogeneity in the population and a high risk of bias. / Revisión por pares

Reprinted from Cancer Biomarkers, 15(4), Nakashima et al., Urine CXCL1 as a biomarker for tumor detection and outcome prediction in bladder cancer, 357-364, Copyright (2015), with permission from IOS Press. / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19596号 / 医博第4103号 / 新制||医||1014(附属図書館) / 32632 / 京都大学大学院医学研究科医学専攻 / (主査)教授 椛島 健治, 教授 武田 俊一, 教授 川村 孝 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background and objectives: Coronary artery disease (CAD) is the leading cause of death among women both nationally and internationally. Despite increased knowledge regarding CAD in women, early diagnosis remains a difficult clinical task. A correlation between peripheral arterial disease (PAD) and CAD has been noted in previous research; however, these studies were either retrospective or did not focus on women. This research investigates the correlation of ankle brachial index (ABI), measurements used to diagnose PAD, and presence of CAD in women, in an effort to determine the predictive value of ABI specifically in women. Subjects and methods: A prospective correlation design was used to study women (n = 30) who were undergoing a diagnostic cardiac catheterization. Ankle brachial index readings were obtained prior to the catheterization procedure. Catheterization findings were grouped according to absence of CAD or presence of 1-vessel or multivessel CAD and coupled with each woman's ABI and recorded cardiovascular risk factors. Results: Peripheral arterial disease (based on ABI of <0.90 mm Hg) was found in 13.3% of the women. A significant correlation was found between ABI of less than 0.90 mm Hg and increasing age (t = -2.30, P =.029). Coronary artery disease was found in 82.1% of the women; more than half (57.1%) had multivessel disease. Absence of CAD was noted in 17.9%. Women with CAD were older than women without CAD (F = 3.86, P =.035). No significant differences were found between presence or absence of PAD based on ABI and diagnosis of no coronary disease or 1-vessel or multivessel coronary disease. Conclusions: This study failed to show the expected correlation between ABI of less than 0.90 mm Hg and CAD, but did show a significant correlation of age with presence of both PAD and CAD. Further research that focuses specifically on women is needed and should include a larger sample, additional unique cardiovascular risk factors, and innovative diagnostic tests to determine presence of CAD in women early in the disease process.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23808号 / 医博第4854号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 長尾 美紀, 教授 西浦 博, 教授 朝長 啓造 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Prognostic scores, and more specifically comorbidity scores, are important and widely used measures in the health care field and in health services research. A comorbidity is an existing disease an individual has in addition to a primary condition of interest, such as cancer. A comorbidity score is a summary score that can be created from these individual comorbidities for prognostic purposes, as well as for confounding adjustment. Despite their widespread use, the properties of and conditions under which comorbidity scores are valid dimension reduction tools in statistical models is largely unknown. This dissertation explores the use of summary comorbidity measures in statistical models. Three particular aspects are examined. First, it is shown that, under standard conditions, the predictive ability of these summary comorbidity measures remains as accurate as the individual comorbidities in regression models, which can include factors such as treatment variables and additional covariates. However, these results are only true when no interaction exists between the individual comorbidities and any additional covariate. The use of summary comorbidity measures in the presence of such interactions leads to biased results. Second, it is shown that these measures are also valid in the causal inference framework through confounding adjustment in estimating treatment effects. Lastly, we introduce a time dependent extension of summary comorbidity scores. This time dependent score can account for changes in patients' health over time and is shown to be a more accurate predictor of patient outcomes. A data example using breast cancer data from the SEER Medicare Database is used throughout this dissertation to illustrate the application of these results to the health care field. / Statistics

Glioblastoma is the most common and lethal malignant brain tumor with a survival rate of 14.6 months and a tumor recurrence rate of ninety percent. Two key causes for glioblastomas grim outcome derive from the lack of applicable prognostic markers and effective therapeutic targets. By employing a loss of function RNAi screen in glioblastoma cells we found a list of 20 kinases that can be considered glioblastoma survival kinases. These survival kinases which we term as survival kinase genes, (SKGs) were investigated to find prognostic markers as well as therapeutic targets for glioblastoma. Analyzing these survival kinases in The Cancer Genome Atlas patient database, we found that CDCP1, CDKL5, CSNK1𝜀, IRAK3, LATS2, PRKAA1, STK3, TBRG4, and ULK4 genes could be used as prognostic markers for glioblastoma with or without temozolomide chemotherapeutic treatment as a covariate. For the first time, we found that patients with increased levels of NEK9 and PIK3CB mRNA expression had a higher probability of recurrent tumors. We also discovered that expression of CDCP1, IGF2R, IRAK3, LATS2, PIK3CB, ULK4, or VRK1 in primary glioblastoma tumors was associated with tumor recurrence prognosis. To note, of these recurrent prognostic candidates, PIK3CB expression in recurrent tumor tissue had much higher expression compared to primary tissue. Further investigation in the PI3K pathway showed a strong correlation with recurrence rate, days to recurrence and survival emphasizing the role of PIK3CB in tumor recurrence in glioblastoma. In efforts to find effective therapeutic targets for glioblastoma we used SKGs as potential candidates. We chose the serine/threonine kinase, Casein Kinase 1 Epsilon (CSNK1𝜀) as a target for glioblastoma because multiple shRNAs targeted this gene in our loss of function screen and multiple commercially available inhibitors of this gene are available. Casein kinase 1 epsilon protein and mRNA expression were investigated using computational tools. It was revealed that CSNK1𝜀 expression has higher expression in glioblastoma than normal tissue. To further examine this gene we knocked down (KD) or inhibited CSNK1𝜀 in glioblastoma cells lines and noticed a significant increase in cell death without any significant effect on normal cell lines. KD and inhibition of CSNK1𝜀 in cancer stem cells, a culprit of tumor recurrence, also revealed limited self-renewal and proliferation in cancer stem cells and a significant decrease in cell survival without affecting normal stem cells. Further analysis of downstream effects of CSNK1𝜀 knockdown and inhibition indicate a significant increase in the protein expression of β-catenin (CTNNB1). We found that CSNK1𝜀 KD activated β-catenin, which increased GBM cell death, but can be rescued using CTNNB1 shRNA. Our survival kinase screen, computational analyses, patient database analyses and experimental methods contributed to the discovery of novel prognostic markers and therapeutic targets for glioblastoma. / Ph. D.