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- Baaz, Marcus, 1993
(författare)
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Nonlinear Mixed Effects Modeling of Combination Therapies in Oncology
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- It has been shown that simultaneous administration of two or more anticancer agents can have a beneficial effect on cancer patients. This type of treatment is called combination therapy and is nowadays commonly used in the fight against cancer. New anticancer drugs are constantly being developed and what drugs to proceed with to the next development phase can be challenging. This thesis introduces the reader to how mathematical modeling can be used to inform such decisions by modeling the relationship between, e.g., drug concentration and in vivo efficacy. Specifically, compartment models based on ordinary differential equations and the nonlinear mixed-effects (NLME) framework are examined. The thesis contains three papers in manuscript form. The first paper, "Model- Based Assessment of Combination Therapies – Ranking of Radiosensitizing Agents in Oncology" explores preclinical radiation treatment data, inter-study variability, and ranking of test compounds. The second paper is entitled "A Model-Based Approach for Translation in On- cology - From Xenografts to RECIST". Here the focus is on the translational potential of semi-mechanistic NLME models. Preclinical data is used to cali- brate three models, which are then translated using commonly used techniques, and used to predict the result of clinical studies. The third paper, "Probabilistic Analysis of Tumor Models to Support Early Clinical Trial Design", details how one can derive probabilistic expressions for the predicted proportion of patients in each RECIST category in a clinical study. These are used to develop a method for predicting the required sample size to show a certain significance level and test power, for newly developed drugs.
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| 2. |
- de Lazzari, Mattia, 1996
(författare)
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Practical Implementation of Quality Assurance Guidelines for Hyperthermia Therapy
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hyperthermia therapy (HT) has been proven to be a potent enhancer of chemotherapy and radiotherapy in numerous clinical trials. The effectiveness of HT is strictly dependent on the administered thermal dose, which, in turn, is dependent on the quality of the therapeutic heat applied to the patient. Quality Assurance (QA) protocols in HT exist to ensure that heating devices can consistently deliver controlled, reproducible, and high-quality treatments. The physical characterization of HT devices requires specific procedures and instrumentation as well as adequate tissue-mimicking phantoms to perform QA experimental procedures. However, the implementation of QA guidelines is hampered due to the unavailability of suitable phantom materials and limited equipment for the QA experimental evaluation. This work addresses these gaps by (i) proposing the design of tissue-mimicking materials for routine use in HT QA procedures and (ii) demonstrating the practical implementation of the latest QA guidelines for both superficial and deep HT. A novel fat-mimicking material was developed to mimic superficial fatty tissue. This fat phantom is based on an ethylcellulose stabilized glycerol in oil emulsion and is intended to be used in superficial HT QA procedures. Measured dielectric and thermal properties were consistent with fatty tissue properties, with an acceptable variability in most of the frequency range used in HT. This fat-mimicking material was then used in the experimental implementation of HT guidelines. The physical characterization of a superficial HT device (Lucite Cone Applicator, LCA) was conducted by assessing the quality metrics defined in the HT guidelines, demonstrating acceptable performance. These findings were further validated through computational studies. For deep HT, a comparative study engaged six HT centers across Europe to assess the performance of commonly used deep regional heating devices. Preliminary results in experimental phantoms showed a good performance in terms of device heating capability and steerability. This study provided practical insights into implementing QA guidelines involving phantom properties, experimental setup, temperature acquisition, and time constraints. We are positive this research will benefit the routine implementation of deep HT guidelines in a clinical setting.
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| 3. |
- Ek, Frida, 1993-
(författare)
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Quiescent cancer cells : Three-dimensional cell models for evaluation of new therapeutics
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Inadequate metabolic conditions in solid tumors lead to the formation of quiescent cancer cells that are suspended in a transient cell cycle arrest. When conditions change, quiescent cancer cells can re-enter the cell cycle and cause recurrence. Drug screening efforts have revealed mitochondrial oxidative phosphorylation as a unique metabolic dependency in quiescent cancer cells. The anthelmintic drug nitazoxanide is an inhibitor of oxidative phosphorylation and preferentially active against quiescent cancer cells in multicellular tumor spheroids. In this thesis, we employed current and developed new models of quiescent cancer cells and applied live cell imaging for improved preclinical evaluation of cancer drugs in hepatocellular and colorectal carcinoma cell lines. As part of this work, a new assay to measure mitochondrial membrane potential in three-dimensional cell models was developed, an application of the JC-1 assay, and we demonstrated that the preferential activity against quiescent cancer cells of nitazoxanide is shared by two kinase inhibitors: sorafenib and regorafenib. The sensitivity of quiescent cancer cells to nitazoxanide, sorafenib, and regorafenib correlated with the disruption of the mitochondrial membrane potential. Nitazoxanide and sorafenib, in combination, caused an additive decrease in viability, mitochondrial membrane potential, and colony regrowth capacity. Furthermore, we developed a quiescent hollow fiber assay and implemented an improved analysis using live cell imaging and adenosine triphosphate analysis. Hypoxia and cancer cell quiescence were enriched in hollow fiber macrocapsules over time, and the culture conditions affected nitazoxanide sensitivity. Additionally, we used basement membrane extract gel to support cell growth in hollow fiber macrocapsules and implanted macrocapsules in mice. We observed that the in vivo environment was favorable to cell growth. Through this characterization of the quiescent hollow fiber assay, we were able to outline important paths for future research.
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| 6. |
- Ghaderi Aram, Morteza, 1988
(författare)
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Antenna Design, Radiobiological Modelling, and Non-invasive Monitoring for Microwave Hyperthermia
- 2022
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The death toll of cancers is on the rise worldwide and surviving patients suffer significant side effects from conventional therapies. To reduce the level of toxicity in patients treated with the conventional treatment modalities, hyperthermia (HT) has been investigated as an adjuvant modality and shown to be a potent tumor cell sensitizer for radio- and chemotherapy. During the past couple of decades, several clinical radiofrequency HT systems, aka applicators, have been developed to heat tumors. Systems based on radiative applicators are the most widely used within the hyperthermic community. They consist of a conformal antenna array and need a beamforming method in order to focus EM energy on the tumor through constructive interference while sparing the healthy tissue from excessive heating. Therefore, a hyperthermia treatment planning (HTP) stage is required before each patient's first treatment session to optimize and control the EM power deposition as well as the resultant temperature distribution. Despite the vast amount of effort invested in HTP and the progress made in this regard during recent years, the clinical exploitation of HT is still hampered by technical limitations and patients can still experience discomfort during clinical trials. This, therefore, calls for a more efficient hardware design, better control of EM power deposition to minimize unwanted hotspots, and more accurate quantification and monitoring of the treatment outcome. Given these demands, the present report tries to address some of the above-mentioned challenges by proposing - A new antenna model customized for HT applications that surpasses previously proposed models from several points of view. - A hybrid beamforming method for faster convergence and a versatile, robust thermal solver for handling sophisticated scenarios. - A radiobiological model to quantify the outcome of a combined treatment modality of the Gamma Knife radiosurgery and HT. - A differential image reconstruction method to assess the feasibility of using the same system for both heating and microwave thermometry.
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| 8. |
- Karlsson, Katarina
(författare)
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Exploring symptom clusters in patients with lung cancer
- 2024
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis explored symptom clusters in patients with lung cancer before, during and after oncological treatment. A literature review and an interview study was used to explore the symptom cluster experience from the patients’ perspective. A large diversity of symptom cluster constellations were identified, in which fatigue was the most commonly occurring symptom, followed by dyspnea, pain, depression, cough and nutritional impact symptoms. Many symptom assessment instruments were identified, measuring mostly the intensity-dimension alone or in combination with timing. The results also stress that living with symptom clusters during treatment is more about survival than actually living. Patients’ symptom management strategies were shaped by impacting conditions such as knowledge and earlier experience of symptoms. Symptoms were often regarded as unavoidable by the patients and something to accept. How symptoms were recognized by health care professionals further added to the normalization of symptom clusters. Subsequently, patients would not always ask for support, and their quality of life was negatively affected. Holistic person-centered care including multi-dimensional symptom assessment is considered essential to ensure adequate symptom cluster management for patients with lung cancer.
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| 10. |
- Majedy, Motasam, 1983-
(författare)
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Evaluation of a melanoma screening framework based on depth resolved light scattering
- 2023
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Melanoma is one of the most aggressive types of skin cancer. When detected at an early-stage treatment is usually successful, however, outcomes are often poor when the disease is detected at an advanced stage. There has been considerable progress in our understanding of the molecular biology, genetics, and immunology of melanoma over the past decade. This has been accompanied by rapid advances in therapeutic strategies for patients with melanoma and an overall improvement in survival rates. However, in spite of these successes, new techniques, and strategies to facilitate early detection, and thus improvements of patient’s outcome is needed as mortality remains high. The work in this thesis aims to utilize a novel noninvasive spatial frequency domain spectroscopy (SFDS) based imaging approach to facilitate early detection on melanoma.
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