Investigation of small-cell lung cancer epidemiology in Sweden and analysis of clinical and tumor specific prognostic biomarkers

Small-cell lung cancer (SCLC) accounts for approximately 13% of all newly diagnosed lung cancer (LC) cases. This disease is correlated with heavy smoking. It is characterized by a rapid doubling time combined with a propensity to metastasize quickly and by neuroendocrine differentiation. In patients with locally advanced disease, the standard of care is concurrent radiation and platinum-doublet chemotherapy (PDCT). Patients with stage IV disease have also until recently been treated with PDCT. Even though a majority of SCLC cases initially responds to PDCT, almost all patients inevitably relapse. This thesis aims to deepen the knowledge of SCLC. Paper I was a population-based study, where we aimed to investigate the possible association between educational levels and overall death of Swedish SCLC patients. The patient population consisted of 4256 subjects. The key findings showed that educational level is an independent prognostic factor in Swedish men diagnosed with SCLC and among patients with Limited disease. In paper II, we performed a validation of the 8th TNM staging system on 706 SCLC cases and compared the system´s prognostic performance to the 6th and 7th TNM editions as well as to the older two-stage system that segmented patients as either having Limited Disease (LD) or Extensive Disease (ED). The study provided additional information supporting the robustness of the 8th TNM edition in prognostically categorizing SCLC and confirms its usefulness in clinical practice. In paper III, we conducted a real-world study on 545 consecutive cases during an eight-year period. The aim was to understand in depth the treatment patterns of SCLC patients from Karolinska University Hospital. Another goal was to examine the outcome of SCLC patients upon re-challenge with PDCT. The survival outcomes for LD and ED SCLC patients were poor, correlating with previous studies. The results also showed that SCLC patients with sensitive relapse after first line PDCT may benefit from re-challenge. In paper IV, the expression of multiple biomarkers, including Notch1, Hes1, Ascl1, and DLL3, were analysed in a selected cohort of 46 SCLC patients. The study, in part, focused on how the expression patterns differed based on patients’ resistance or sensitivity to PDCT. We evaluated the prevalence of expression of these four biomarkers in human samples using biopsies and studied the potential association with survival and benefit from 1st line PDCT. The study showed that Notch1 seems to be an independent prognostic factor in SCLC. Furthermore, a negative association between Notch1 and Ascl1 expression was observed. In summary, this thesis expands on the understanding of SCLC by analysing epidemiological trends, the impact of socioeconomic status, changes to classifying patients, and possible prognostic biomarkers

Are Health Problems in Adulthood linked to our Experiences in the Womb? An Epigenetic Approach

The origins of adult disease have been a prime topic for research, as deciphering causes can lead to strategies for preventions and cures. There has been recent intrigue focused on the environment in the womb. Records from England and Wales in 1911 show that those who suffered from cardiovascular disease were geographically correlated with regions high in infant mortality in the past, seventy years before the study. When looking into the cause of the neonatal death rates, low birth weight, poor maternal health, and high maternal death rates during childbirth were clearly associated. Barker inferred that there is much happening in the intrauterine environment that ultimately affects our quality of life. This research helps support the concept that rather than looking at childhood adversity and socioeconomic circumstances to help explain adult disease, we might need to reach further back (Barker,1990). Through epigenetic mechanisms, alterations to the physical expression of our DNA can take place without changing the sequences of the actual DNA. Epigenetics is what is responsible during fetal development for the differentiation of stem cells to specific cells by adding or subtracting methyl groups to silence or activate particular genes. When an egg and sperm unite all previous methylation patterns are stripped from the newly formed diploid. However, by the time it becomes a blastocyst, new patterns have already formed. It is during this crucial stage of development that new patterns and changes to our epigenome our founded and passed down (Powledge, 2009). The purpose of this paper is to determine if chronic health issues in adulthood have their roots in the environment and changes experienced by the fetus in the womb. Environmental exposures like nutrition, stress, and toxicants are evaluated and tested for their potential hand in setting the course for adult disease. Many studies show correlation between malnutrition and the development of metabolic diseases like obesity, type II diabetes, and even hypertension. Likewise, stress during gestation has been linked to anxiety, depression, and posttraumatic stress disorder (PTSD) in offspring. Toxicants like bisphenol-A are the likely culprit for genetically expressed abnormalities that range from cancers of the reproductive system to attention/deficit hyperactive disorder (ADHD) in exposed offspring. The “how” and the “why” are explored in this paper. If we can better understand the origins of adult disease then we are better equipped to defend our future generations against it. Furthermore, the notion that our DNA is not at fault for these outcomes, but rather epigenetic adjustments written on top of our DNA, provides hope that just as easily as it can be added on, we can take it off (Powledge, 2009)

TMS for OCD

Introduction: Obsessive compulsive disorder (OCD) is a common disabling condition, which greater than 40% of patients do not respond to the available treatment options. Imbalances in the cortical-striatal-thalamic-cortical circuits have proven to be useful psychosurgical treatment targets making this circuit disorder an optimal target for intervention with TMS. Methods: PubMed and clinicaltrials.gov were reviewed for sham-controlled therapeutic rTMS studies for OCD. Results: Eighteen relevant studies are presented in a narrative fashion along with relevant methodological details, and distinctions.Conclusions: High and low frequency stimulation to lateral prefrontal cortices does not appear to have consistent efficacy in the small studies done to date. Several small studies with non-blinded operators suggest that low frequency high intensity rTMS to the supplementary motor area with a figure-8 coil reduces OCD symptoms. A fully blinded multicenter center study is warranted to confirm this finding. A promising pilot study and a subsequent multicenter study of high frequency high intensity deep rTMS with the HAC/H7 coil to the bilateral prefrontal orbitofrontal and anterior cingulate cortices were completed with positive results. Many areas of uncertainty remain, such as the optimal state of the circuitry during stimulation and identifying a priori biomarkers for responders and non-responders to specific protocols

Algorithm Development for Intrafraction Radiotherapy Beam Edge Verification from Cherenkov Imaging.

Imaging of Cherenkov light emission from patient tissue during fractionated radiotherapy has been shown to be a possible way to visualize beam delivery in real time. If this tool is advanced as a delivery verification methodology, then a sequence of image processing steps must be established to maximize accurate recovery of beam edges. This was analyzed and developed here, focusing on the noise characteristics and representative images from both phantoms and patients undergoing whole breast radiotherapy. The processing included temporally integrating video data into a single, composite summary image at each control point. Each image stack was also median filtered for denoising and ultimately thresholded into a binary image, and morphologic small hole removal was used. These processed images were used for day-to-day comparison computation, and either the Dice coefficient or the mean distance to conformity values can be used to analyze them. Systematic position shifts of the phantom up to 5 mm approached the observed variation values of the patient data. This processing algorithm can be used to analyze the variations seen in patients being treated concurrently with daily Cherenkov imaging to quantify the day-to-day disparities in delivery as a quality audit system for position/beam verification