Pancreatic ductal adenocarcinoma : computed tomography for diagnosis, local staging and prediction of postoperative complications

Pancreatic ductal adenocarcinoma (PDAC) is a disease with a dismal prognosis, being the 4th leading cause of cancer deaths in Sweden and worldwide. The only potentially curative therapy is surgery. Unfortunately, by the time of diagnosis only 20% of patients have a resectable tumor and the overall 5-year survival rate does not exceed 5%. One of the main reasons for this is that some tumors are not detected, either because of small size or difficulty in delineation. Another reason is the underestimation or in some cases overestimation of the local tumor staging. These patients undergo an extensive but unnecessary operation or are withheld from potentially curative surgery, respectively. In some cases the patients develop serious postoperative complications, which can be predicted and perhaps avoided with proper preoperative planning. Technological advances in multidetector computed tomography (MDCT), combined with its wide availability, have made MDCT the modality of choice for PDAC imaging. The overall purpose of this thesis was to investigate the role of MDCT in patients with PDAC in terms of (i) tumor diagnosis, (ii) local staging assessment and (iii) prediction of postoperative complications. In Study I, we compared low-tube-voltage (80 kV) with normal-tube-voltage (120 kV) protocols regarding tumor detection by using a phantom that simulated the normal pancreatic parenchyma and hypovascular tumors. Our results showed that low tube-voltage significantly improves tumor detection. In Study II, we evaluated 30 MDCT examinations of the pancreas in patients with PDAC in the pancreatic head, obtained according to our institution’s standard protocol (120 kV and 0.75 g iodine (I)/kg body-weight). Based on our hospital’s classification system, we investigated the interobserver agreement among radiologists in local tumor staging assessment and the correlation of this assessment to the surgical outcome. Our results showed almost perfect agreement among radiologists as well as an increased risk for vascular involvement with more advanced preoperative staging. In Study III, we compared low-tube-voltage normal-iodine-load (80 kV and 0.75gI) with low-tube-voltage high-iodine-load (80 kV and 1gI) and with normal-tube-voltage normaliodine- load (120 kV and 0.75gI) protocols in 30 patients with PDAC, regarding tumor conspicuity and local vessel involvement. Our results showed that low tube-voltage and high iodine-load significantly improve tumor conspicuity. In Study IV, we correlated the pancreatic remnant volume (PRV) and pancreatic duct width (PDW) in 182 patients undergoing pancreaticoduodenectomy (PDE), to the risk for pancreatic leakage and fistula (PF) formation. Our results showed a significantly higher risk for PF in patients with high PRV and/or small PDW. In conclusion, a high-quality preoperative MDCT is a very useful tool in the evaluation of PDAC in terms of tumor diagnosis, staging and prediction of postoperative complications. The low-tube-voltage high-iodine-load technique has the potential to improve tumor diagnosis and local staging

Foxp3 Interacts With c-Rel to Mediate NF-κ\kappaB Repression

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-$\kappa$B (p65), Runx1 and ROR$\lambda$t, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells. Here we show that Foxp3 directly or as part of a multimeric complex engages with the NF-$\kappa$B component c-Rel. We demonstrate that the N-terminal region of Foxp3 is required for the binding of c-Rel, but not NFAT. Conversely, deletion of the forkhead domain causes a loss of interaction with NFAT, but not c-Rel. Our findings are of particular interest, as c-Rel is crucial for the induction of Foxp3 in regulatory T cells during thymic development, but has to be repressed in mature regulatory T cells to maintain their suppressive phenotype.Organismic and Evolutionary Biolog

Foxp3 interacts with c-Rel to mediate NF-κB repression.

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-κB (p65), Runx1 and RORγt, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells. Here we show that Foxp3 directly or as part of a multimeric complex engages with the NF-κB component c-Rel. We demonstrate that the N-terminal region of Foxp3 is required for the binding of c-Rel, but not NFAT. Conversely, deletion of the forkhead domain causes a loss of interaction with NFAT, but not c-Rel. Our findings are of particular interest, as c-Rel is crucial for the induction of Foxp3 in regulatory T cells during thymic development, but has to be repressed in mature regulatory T cells to maintain their suppressive phenotype

The role of contrast-enhanced computed tomography to detect renal stones

PURPOSE To investigate the detectability of renal stones in corticomedullary and nephrographic phases on contrast-enhanced computed tomography (CT). METHODS All consecutive patients between January 2012 and February 2016 undergoing CT of the kidneys according to our department's standard four-phase protocol and having at least one stone in the NC-phase (NCP) were included. Fifty patients with altogether 136 stones were eligible. Two radiologists in consensus evaluated the NCP from each examination and documented the number, location, and size of stones. Three abdominal radiologists blinded to the findings of the NCP reviewed independently the corticomedullary and nephrographic phases on two different occasions. They reported the number and location of stones in each kidney. For the inter-observer agreement the intra-class correlation coefficient (ICC) was estimated. The detection rate of renal stones was calculated for the three radiologists and compared between the two contrast-enhanced phases and the results were analyzed with concern to the size of the stones. RESULTS The ICC was 0.86. There was no statistically significant difference between corticomedullary and nephrographic phases (p = 0.94). The detection rate for stones measuring 3-5 mm was 82-88% and 98% for stones ≥ 6 mm. CONCLUSION The detectability of renal stones ≥ 6 mm on contrast-enhanced CT is extremely high. This means that stones with a higher risk of not passing spontaneously can be safely diagnosed

Low tube voltage CT for improved detection of pancreatic cancer: detection threshold for small, simulated lesions

Abstract Background Pancreatic ductal adenocarcinoma is associated with dismal prognosis. The detection of small pancreatic tumors which are still resectable is still a challenging problem. The aim of this study was to investigate the effect of decreasing the tube voltage from 120 to 80 kV on the detection of pancreatic tumors. Methods Three scanning protocols was used; one using the standard tube voltage (120 kV) and current (160 mA) and two using 80 kV but with different tube currents (500 and 675 mA) to achieve equivalent dose (15 mGy) and noise (15 HU) as that of the standard protocol. Tumors were simulated into collected CT phantom images. The attenuation in normal parenchyma at 120 kV was set at 130 HU, as measured previously in clinical examinations, and the tumor attenuation was assumed to differ 20 HU and was set at 110HU. By scanning and measuring of iodine solution with different concentrations the corresponding tumor and parenchyma attenuation at 80 kV was found to be 185 and 219 HU, respectively. To objectively evaluate the differences between the three protocols, a multi-reader multi-case receiver operating characteristic study was conducted, using three readers and 100 cases, each containing 0–3 lesions. Results The highest reader averaged figure-of-merit (FOM) was achieved for 80 kV and 675 mA (FOM = 0,850), and the lowest for 120 kV (FOM = 0,709). There was a significant difference between the three protocols (p t-test) shows that there was a significant difference between 120 and 80 kV, but not between the two levels of tube currents at 80 kV. Conclusion We conclude that when decreasing the tube voltage there is a significant improvement in tumor conspicuity.</p

Superparamagnetic iron oxide-labeled schwann cells and olfactory ensheathing cells can be traced in vivo by magnetic resonance imaging and retain functional properties after transplantation into the CNS

Schwann cell (SC) and olfactory ensheathing cell (OEC) transplantation has been shown experimentally to promote CNS axonal regeneration and remyelination. To advance this technique into a clinical setting it is important to be able to follow the fates of transplanted cells by noninvasive imaging. Previous studies, using complex modification processes to enable uptake of contrast agents, have shown that cells labeled in vitro with paramagnetic contrast agents transplanted into rodent CNS can be visualized using magnetic resonance imaging (MRI). Here we show that SCs and OECs efficiently internalize dextran-coated superparamagnetic iron oxide (SPIO) from the culture medium by fluid phase pinocytosis. After transplantation into focal areas of demyelination in adult rat spinal cord both transplanted SPIO-labeled SCs and OECs produce a signal reduction using T2-weighted MRI in anesthetized rats that persists for up to 4 weeks. Although signal reduction was discernable after transplantation of unlabelled cells, this is nevertheless distinguishable from that produced by transplanted labeled cells. The region of signal reduction in SPIO-labeled cell recipients correlates closely with areas of remyelination. Because the retention of functional integrity by labeled cells is paramount, we also show that SPIO-labeled SCs and OECs are able to myelinate normally after transplantation into focal areas of demyelination. These studies demonstrate the feasibility of noninvasive imaging of transplanted SCs and OECs and represent a significant step toward the clinical application of promising experimental approaches

Diffusion-weighted MR imaging of pancreatic cancer: A comparison of mono-exponential, bi-exponential and non-Gaussian kurtosis models

Objectives: To compare two Gaussian diffusion-weighted MRI (DWI) models including mono-exponential and bi-exponential, with the non-Gaussian kurtosis model in patients with pancreatic ductal adenocarcinoma. Materials and methods: After written informed consent, 15 consecutive patients with pancreatic ductal adenocarcinoma underwent free-breathing DWI (1.5T, b-values: 0, 50, 150, 200, 300, 600 and 1000 s/mm2). Mean values of DWI-derived metrics ADC, D, D*, f, K and DK were calculated from multiple regions of interest in all tumours and non-tumorous parenchyma and compared. Area under the curve was determined for all metrics. Results: Mean ADC and DK showed significant differences between tumours and non-tumorous parenchyma (both P < 0.001). Area under the curve for ADC, D, D*, f, K, and DK were 0.77, 0.52, 0.53, 0.62, 0.42, and 0.84, respectively. Conclusion: ADC and DK could differentiate tumours from non-tumorous parenchyma with the latter showing a higher diagnostic accuracy. Correction for kurtosis effects has the potential to increase the diagnostic accuracy of DWI in patients with pancreatic ductal adenocarcinoma. Keywords: Pancreas, Pancreatic ductal carcinoma, MRI, Diffusion-weighted MR