Diagnostics and treatment in bronchial carcinoid tumors

At the start of this thesis there were several unanswered questions with regard to optimal patient selection for different treatments of bronchial carcinoid. Also, there were unanswered questions with regard to classification of bronchial carcinoid on small histological samples and with regard to prognostic value of several new tissue biomarkers. The aim of this thesis was to further optimize patient selection for parenchyma sparing techniques, and to explore the potential value of biomarkers in the treatment of bronchial carcinoid. Part one (chapter 2-5) of this thesis describes the classification of bronchial carcinoid on small histological samples and the use of diagnostic and prognostic biomarkers. In Chapter 2 we analyze patient selection for endobronchial treatment and underscore the importance of radiological assessment of bronchial carcinoids. Differentiation between typical and atypical carcinoid according to the current WHO classification is accomplished by obtaining the mitotic count and the presence of necrosis. As outlined above, TC is defined as a neuroendocrine tumour with less than 2 mitoses per 2 mm2 and absence of necrosis, while AC is defined by 2-10 mitoses per 2 mm2 and/or the presence of (dot-like) necrosis. However, it is known that small biopsies have limited diagnostic value for the distinction between TC and AC. In Chapter 3 and Chapter 4 we analyzed biopsy-resection paired specimens of patients referred for treatment for bronchial carcinoid to measure accuracy of pretreatment biopsies and analyze the value of tumor biopsy size. Furthermore, we describe the reliability of different immunohistochemical markers on different biopsies and resection specimens, and assessed the impact of specimen size on the accuracy of the diagnosis. Because the current classification of TC and AC only partially reflects their metastatic potential, there is a need for more accurate prognostic biomarkers for bronchial carcinoids. In Chapter 5 we investigated a combination of morphological and novel immunohistochemical markers for predicting dissemination. Part two (chapter 6-8) focuses on therapeutic strategies and patient selection for EBT. In Chapter 6 we present the results of a systematic review of the available literature on the feasibility and outcome of endobronchial treatment compared to surgical resection. We studied several endpoints such as overall survival, disease free survival, recurrence rate, complications, quality of life, and healthcare costs. Where EBT can be curative for patients with small intraluminal carcinoid tumors, tumor debulking prior to surgery may potentially result in less lung parenchyma that has to be removed during surgery to achieve complete resection of the tumor. In addition, EBT may reduce the need for sleeve resection to achieve radical margins when bulky tumors are removed. It is in Chapter 7 that we investigated whether endobronchial therapy for bronchial carcinoid, if not curative, can reduce the extent of the surgical resection and whether EBT prior to surgery is associated with increased surgical morbidity. Several letters, in reply to comments from experts in the field of treatment for bronchial carcinoid tumors, regarding published studies by our group, are bundled in Chapter 8

Semi-high-throughput detection of Plasmodium falciparum and Plasmodium vivax oocysts in mosquitoes using bead-beating followed by circumsporozoite ELISA and quantitative PCR.

BACKGROUND: The malaria infection status of mosquitoes is commonly determined by microscopic detection of oocysts on the dissected mosquito midgut. This method is labour-intensive, does not allow processing of large numbers of mosquitoes and can be challenging in terms of objective classification of oocysts. Here, a semi-high-throughput bead-beating ELISA method is proposed for detection of the circumsporozoite protein (CSP) followed by confirmation by quantitative PCR (qPCR). METHODS: Cultured Plasmodium falciparum gametocytes were offered to Anopheles stephensi mosquitoes and examined by microscopy. After bead-beating, mosquito homogenate was examined by CSP-ELISA and 18S qPCR. As negative controls, mosquitoes that were offered a heat-inactivated gametocyte blood meal were used. The CSP-ELISA/qPCR methodology was applied to high and low-intensity infections of cultured P. falciparum gametocytes. A similar methodology optimized for P. vivax was used on mosquitoes that were offered blood from Ethiopian donors who were naturally infected with P. vivax. RESULTS: There was considerable variation in CSP-ELISA signal and qPCR values in mosquitoes with low oocyst intensities. There was a strong agreement mosquito positivity by CSP-ELISA and by qPCR in mosquitoes that fed on cultured P. falciparum material (agreement 96.9%; kappa = 0.97) and naturally infected P. vivax parasite carriers [agreement 92.4% (kappa = 0.83)]. CONCLUSIONS: The proposed bead-beating CSP-ELISA/qPCR methodology considerably increases throughput for the detection of mosquito infection. qPCR remains necessary to confirm infections in mosquitoes with low CSP-ELISA signal. This methodology may prove particularly useful for studies where very low mosquito infection prevalence is expected and study sites where experience with oocyst detection is limited

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model.

BACKGROUND: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. METHODS: In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes. Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. RESULTS: Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). CONCLUSIONS: The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. FUNDING: Funded by PATH Malaria Vaccine Initiative (MVI). CLINICAL TRIAL NUMBER: NCT02836002

Initial effects of structural complexity restoration treatments and deer browsing on ground-layer community composition and tree regeneration in northern hardwood forests

University of Minnesota M.S. thesis. March 2014. Major: Natural Resources Science and Management. Advisor: Anthony W. D'Amato. 1 computer file (PDF); ix, 120 pages, appendix A.As researchers realize the value of old-growth forests and their unique attributes and dynamics, managers have begun developing management regimes aimed at restoring old-growth characteristics in forests managed for wood products. However, changes in these forests since European settlement, especially increased population of white-tailed deer (Odocoileus virginianus Zimmerman) may have important implications for forest composition and regeneration. The objective of this research was to determine the initial (three- and four-year) effects of several old-growth structural restoration treatments and browsing by white-tailed deer on tree regeneration and understory community composition in northern hardwood forests in northern Wisconsin, USA. Community composition and tree regeneration were measured in stands with six different silvicultural treatments replicated across three large study areas (> 50 ha). Treatments consisted of a combination of two levels of coarse woody debris and three overstory gap treatments designed to emulate patterns of natural gap and mesoscale canopy disturbance: small gaps (10.7m diameter), large gaps (18.3 and 24.4m diameter), and a mesoscale wind disturbance treatment consisting of 0.4 and 1.2 ha shelterwoods. All treatments included multiple small deer exclosures to examine the impact of deer herbivory. Assessment of cover by herbaceous plants and seedlings indicated that overstory treatments had a larger effect on understory community composition than browsing by deer, whereas there was no effect of coarse wood levels. Species richness was highest in the small gap treatment and lowest in the control stands, possibly reflecting the increased dominance by a few ruderal and exotic species in treatments with increased canopy openness. Richness was also significantly lower inside exclosures than outside in some treatments, although browse-sensitive Trillium spp. were largely restricted to exclosures. Post-harvest seedling density increased with increasing overstory removal, with the mesoscale wind disturbance treatment containing the highest seedling density after three years. While browse protection generally did not have a significant effect on overall density of regeneration, several species, especially Betula alleghaniensis benefited from protection from deer browse. These initial results underscore the utility of natural disturbance-based treatments at increasing the complexity of second-growth communities and the importance of accounting for herbivory impacts on treatment responses

Non-linear elliptic systems involving measure data

We prove the existence of vectorvalued solutions for systems of the type −∂α(|∇u| p−2∂αu) = T in a bounded open set Ω, u = 0 on ∂Ω, where T is a given distribution acting on the space C∞o (Ω,IRN ) of testfunctions

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Background: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods: In a single centre, open-label randomised tr

Developing Digital Twins for Industrial Microgrids: The Ecofactorij Study Case

The concept of Digital Twin (DT) has emerged as a transformative approach in the digitalization of industrial systems. This study focuses on developing a DT for the Ecofactorij industrial microgrid, located in Apeldoorn, Netherlands. The Ecofactorij, with its diverse range of interconnected companies—including logistics, refrigeration, manufacturing, and offices—along with photovoltaic power plants, batteries, charging stations, and heat pumps, presents a complex and dynamic system. These entities are interconnected through a 12kV grid with a contracted capacity of 12MW and are monitored by a SCADA system called ManagedGrid. This project is financially supported by the MOOI Energy Control Bussinespark project and involves collaboration between Sparkling Projects, ManagedGrid, Scholt Energy, Saxion, and the University of Twente

UBO-register voor trusts en fondsen voor gemene rekening op komst

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A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model.

Background: Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods: In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes. Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Results: Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions: The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding: Funded by PATH Malaria Vaccine Initiative (MVI). Clinical trial number: NCT02836002