Features of esophageal cancer in the neoadjuvant setting

In patients with locally advanced esophageal cancer, standard treatment comprises neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. One-third of these patients has no residual tumor cells in the surgical resection specimen. An alternative strategy after nCRT might be active surveillance, which is currently investigated in the SANO trial. During active surveillance, surgery is performed only in case of proven residual tumor after nCRT, without distant dissemination. In that context, the goal of this thesis was to find tumor characteristics ("features") to distinguish patients with different treatment responses to nCRT and surgery.The main focus was on different image analysis techniques. Visual and complex analysis methods (using “radiomics”) of FDG PET/CT scans were shown inaccurate for tumor detection in the esophagus. The FDG PET/CT up to 12 weeks after nCRT cannot reliably distinguish residual tumor from radiation-induced esophagitis. The performance of another scan, the FDG PET/MRI, was found comparable to the FDG PET/CT. In contrast, serial FDG PET/CT scans up to one year after nCRT during active surveillance were found valuable to detect primary tumor regrowth.In the next part of the thesis, histopathological features were studied on pre-treatment biopsies and post-treatment resection specimens. A “fragmented pattern” in the resection specimen after nCRT, as opposed to a “shrinkage” pattern, was associated with higher risk of death and a higher risk of disease recurrence. Finally, acellular mucin pools, signet-ring cells and poorly cohesive cells in biopsies before nCRT were not correlated with histopathological response.<br/

Features of esophageal cancer in the neoadjuvant setting

In patients with locally advanced esophageal cancer, standard treatment comprises neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. One-third of these patients has no residual tumor cells in the surgical resection specimen. An alternative strategy after nCRT might be active surveillance, which is currently investigated in the SANO trial. During active surveillance, surgery is performed only in case of proven residual tumor after nCRT, without distant dissemination. In that context, the goal of this thesis was to find tumor characteristics ("features") to distinguish patients with different treatment responses to nCRT and surgery.The main focus was on different image analysis techniques. Visual and complex analysis methods (using “radiomics”) of FDG PET/CT scans were shown inaccurate for tumor detection in the esophagus. The FDG PET/CT up to 12 weeks after nCRT cannot reliably distinguish residual tumor from radiation-induced esophagitis. The performance of another scan, the FDG PET/MRI, was found comparable to the FDG PET/CT. In contrast, serial FDG PET/CT scans up to one year after nCRT during active surveillance were found valuable to detect primary tumor regrowth.In the next part of the thesis, histopathological features were studied on pre-treatment biopsies and post-treatment resection specimens. A “fragmented pattern” in the resection specimen after nCRT, as opposed to a “shrinkage” pattern, was associated with higher risk of death and a higher risk of disease recurrence. Finally, acellular mucin pools, signet-ring cells and poorly cohesive cells in biopsies before nCRT were not correlated with histopathological response.<br/

Umbilical Connect Techniques Improvement-Technology Study

The objective of this study was to develop concepts, specifications, designs, techniques, and procedures capable of significantly reducing the time required to connect and verify umbilicals for ground services to the space shuttle. The desired goal was to reduce the current time requirement of several shifts for the Saturn 5/Apollo to an elapsed time of less than one hour to connect and verify all of the space shuttle ground service umbilicals. The study was conducted in four phases: (1) literature and hardware examination, (2) concept development, (3) concept evaluation and tradeoff analysis, and (4) selected concept design. The final product of this study was a detail design of a rise-off disconnect panel prototype test specimen for a LO2/LH2 booster (or an external oxygen/hydrogen tank for an orbiter), a detail design of a swing-arm mounted preflight umbilical carrier prototype test specimen, and a part 1 specification for the umbilical connect and verification design for the vehicles as defined in the space shuttle program

A Model for cAMP-mediated cGMP Response in Dictyostelium discoideum

In Dictyostelium discoideum extracellular cyclic AMP (cAMP), as shown by previous studies, induces a transient accumulation of intracellular cyclic guanosine-5'-monophosphate (cGMP), which peaks at 10 s and recovers basal levels at 30 s after stimulation, even with persistent cAMP stimulation. Additional investigations have shown that the cAMP-mediated cGMP response is built up from surface cAMP receptor-mediated activation of guanylyl cyclase and hydrolysis of cGMP by phosphodiesterase. The regulation of these activities was measured in detail on a seconds time-scale, demonstrating complex adaptation of the receptor, allosteric activation of cGMP-phosphodiesterase by cGMP, and potent inhibition of guanylyl cyclase by Ca2+. In this paper we present a computer model that combines all experimental data on the cGMP response. The model is used to investigate the contribution of each structural and regulatory component in the final cGMP response. Four models for the activation and adaptation of the receptor are compared with experimental observations. Only one model describes the magnitude and kinetics of the response accurately. The effect of Ca2+ on the cGMP response is simulated by changing the Ca2+ concentrations outside the cell (Ca2+ influx) and in stores (IP3-mediated release) and changing phospholipase C activity. The simulations show that Ca2+ mainly determines the magnitude of the cGMP accumulation; simulations are in good agreement with experiments on the effect of Ca2+ in electropermeabilized cells. Finally, when cGMP-phosphodiesterase activity is deleted from the model, the simulated cGMP response is elevated and prolonged, which is in close agreement with the experimental observations in mutant stmF that lacks this enzyme activity. We conclude that the computer model provides a good description of the observed response, suggesting that the main structural and regulatory components have been identified