Routine contrast-enhanced CT is insufficient for TNM-staging of duodenal adenocarcinoma.

PURPOSE: Adequate TNM-staging is important to determine prognosis and treatment planning of duodenal adenocarcinoma. Although current guidelines advise contrast-enhanced CT (CECT) for staging of duodenal adenocarcinoma, literature about diagnostic tests is sparse. METHODS: In this retrospective single-center cohort study, we analyzed the real life performance of routine CECT for TNM-staging and the assessment of resectability of duodenal adenocarcinoma. Intraoperative findings and pathological staging served as reference standard for resectability, T-, and N-staging. Biopsies, 18FDG-PET-CT, and follow-up were used as the reference standard for M-staging. RESULTS: Fifty-two consecutive patients with duodenal adenocarcinoma were included, 26 patients underwent resection. Half of the tumors were isodense to normal duodenum on CECT. The tumor was initially missed in 7/52 patients (13%) on CECT. The correct T-stage was assigned with CECT in 14/26 patients (54%), N-stage in 11/26 (42%), and the M-stage in 42/52 (81%). T-stage was underestimated in (27%). The sensitivity for detecting lymph node metastases was only 24%, specificity was 78%. Seventeen percent of patients had indeterminate liver or lung lesions on CECT. Surgery with curative intent was started in 32 patients, but six patients (19%) could not be resected due to unexpected local invasion or metastases. CONCLUSION: Radiologists and clinicians have to be aware that routine CECT is insufficient for staging and determining resectability in patients with duodenal adenocarcinoma. CECT underestimates T-stage and N-stage, and M-stage is often unclear, resulting in futile surgery in 19% of patients. Alternative strategies are required to improve staging of duodenal adenocarcinoma. We propose to combine multiphase hypotonic duodenography CT with MRI.

Quantitative CT perfusion imaging in patients with pancreatic cancer: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Quantitative CT perfusion (CTP) can provide additional diagnostic information compared to the limited accuracy of the current standard, contrast-enhanced CT (CECT). This systematic review evaluates CTP for diagnosis, grading, and treatment assessment of PDAC. The secondary goal is to provide an overview of scan protocols and perfusion models used for CTP in PDAC. The search strategy combined synonyms for 'CTP' and 'PDAC.' Pubmed, Embase, and Web of Science were systematically searched from January 2000 to December 2020 for studies using CTP to evaluate PDAC. The risk of bias was assessed using QUADAS-2. 607 abstracts were screened, of which 29 were selected for full-text eligibility. 21 studies were included in the final analysis with a total of 760 patients. All studies comparing PDAC with non-tumorous parenchyma found significant CTP-based differences in blood flow (BF) and blood volume (BV). Two studies found significant differences between pathological grades. Two other studies showed that BF could predict neoadjuvant treatment response. A wide variety in kinetic models and acquisition protocol was found among included studies. Quantitative CTP shows a potential benefit in PDAC diagnosis and can serve as a tool for pathological grading and treatment assessment; however, clinical evidence is still limited. To improve clinical use, standardized acquisition and reconstruction parameters are necessary for interchangeability of the perfusion parameters.

Continuity of care experienced by patients in a multi-institutional pancreatic care network: a pilot study.

BACKGROUND: Over the past decades, health care services for pancreatic surgery were reorganized. Volume norms were applied with the result that only a limited number of expert centers perform pancreatic surgery. As a result of this centralization of pancreatic surgery, the patient journey of patients with pancreatic tumors has become multi-institutional. To illustrate, patients are referred to a center of expertise for pancreatic surgery whereas other parts of pancreatic care, such as chemotherapy, take place in local hospitals. This fragmentation of health care services could affect continuity of care (COC). The aim of this study was to assess COC perceived by patients in a pancreatic care network and investigate correlations with patient-and care-related characteristics. METHODS: This is a pilot study in which patients with (pre) malignant pancreatic tumors discussed in a multidisciplinary tumor board in a Dutch tertiary hospital were asked to participate. Patients were asked to fill out the Nijmegen Continuity of Care-questionnaire (NCQ) (5-point Likert scale). Additionally, their patient-and care-related data were retrieved from medical records. Correlations of NCQ score and patient-and care-related characteristics were calculated with Spearman's correlation coefficient. RESULTS: In total, 44 patients were included (92% response rate). Pancreatic cancer was the predominant diagnosis (32%). Forty percent received a repetition of diagnostic investigations in the tertiary hospital. Mean scores for personal continuity were 3.55 ± 0.74 for GP, 3.29 ± 0.91 for the specialist and 3.43 ± 0.65 for collaboration between GPs and specialists. Overall COC was scored with a mean 3.38 ± 0.72. No significant correlations were observed between NCQ score and certain patient-or care-related characteristics. CONCLUSION: Continuity of care perceived by patients with pancreatic tumors was scored as moderate. This outcome supports the need to improve continuity of care within multi-institutional pancreatic care networks.

Does perfusion computed tomography correlate to pathology in colorectal liver metastases?

INTRODUCTION: Targeted therapy against tumor angiogenesis is widely used in clinical practice for patients with colorectal liver metastases (CRLM). Possible predictive biomarkers for tumor angiogenesis, such as, microvessel density (MVD), hypoxia and cell proliferation, can be determined using immunohistochemical staining. However, patients ineligible for surgical treatment need to undergo invasive diagnostic interventions in order to determine these biomarkers. CT perfusion (CTP) is an emerging functional imaging technique, which can non-invasively determine vascular properties of solid tumors. The purpose of this study was to evaluate CTP with histological biomarkers in CRLM. MATERIAL AND METHODS: Patients with CRLM underwent CTP one day before liver surgery. CTP analysis was performed on the entire volume of the largest metastases in each patient. Dual-input maximum slope analysis was used and data concerning arterial flow (AF), portal flow (PF) and perfusion index (PI) were recorded. Immunohistochemical staining with CD34, M75/CA-IX and MIB-1 was performed on the rim in the midsection of the tumor to determine respectively MVD, hypoxia and cell proliferation. RESULTS: Twenty CRLM in 20 patients were studied. Mean size of the largest CRLM was 37 mm (95% CI 21-54 mm). Mean AF and PF were respectively 64 ml/min/100ml (95% CI 48-79) and 30 ml/min/100ml (95% CI 22-38). Mean PI was 68% (95% CI 62-73). No significant correlation was found between tumor growth patterns and CTP (p = 0.95). MVD did not significantly correlate to AF (r = 0.05; p = 0.84), PF (r = 0.17; p = 0.47) and PI (r = -0.12; p = 0.63). Cell proliferation also did not significantly correlate to AF (r = 0.07; p = 0.78), PF (r = -0.01; p = 0.95) and PI (r = 0.15; p = 0.52). Hypoxia did not significantly correlate to AF (r = -0.05; p = 0.83), however, significantly to PF (r = 0.51; p = 0.02) and a trend to negative correlation with PF (r = -0.43; p = 0.06). However, after controlling the false discovery rate, no significant correlation between CTP and used immunohistochemical biomarkers was found. CONCLUSION: In conclusion, this feasibility study found a trend to negative correlation between PI and hypoxia, CTP might therefore possibly evaluate this prognostic marker in CRLM non-invasively. However, CTP is not an appropriate technique for the assessment of microvessels or cell proliferation in CRLM.

Controlled mechanical ventilation to detect regional lymph node metastases in esophageal cancer using USPIO-enhanced MRI; comparison of image quality.

BACKGROUND: Artifacts caused by respiratory motion or ventilation-induced chest movements are a major problem for thoracic MRI, as they can obscure important anatomical structures such as lymph node metastases. We compared image quality of routine breathhold with intermittent apnea during controlled mechanical ventilation of patients under general anesthesia as the ideal situation without respiratory motion in the detection and characterization of regional lymph nodes in esophageal cancer. METHODS: In this prospective study, 10 patients treated for esophageal cancer underwent ultrasmall superparamagnetic iron oxide (USPIO) enhanced MRI scans. Before neoadjuvant therapy, MRI scans were acquired with a routine breathhold technique. After neoadjuvant therapy, patients were scanned under general anesthesia immediately prior to surgery with controlled mechanical ventilation. The image quality was compared using a Likert scale questionnaire based on visibility of anatomical structures and image artifacts. RESULTS: MRI with controlled mechanical ventilation and prolonged controlled apnea of 4 min was safe and feasible. All cardio-respiratory monitoring parameters remained stable during the apnea phases. Mediastinal and upper abdominal lymph nodes down to 2 mm in size could be visualized with all sequences. All image quality criteria, including visibility of thoracic structures and regional lymph nodes were scored higher using the controlled ventilation sequences compared to the routine breathhold phase. CONCLUSION: USPIO-enhanced MRI with controlled mechanical ventilation is superior to routine breathhold MRI in visualizing lymph nodes, which warrants new motion reduction techniques to use MRI for the detection of lymph node metastases in patients with esophageal cancer.

Diagnostic accuracy of contrast-enhanced diffusion-weighted MRI for liver metastases of pancreatic cancer: towards adequate staging and follow-up of pancreatic cancer - DIA-PANC study: study protocol for an international, multicenter, diagnostic trial.

BACKGROUND: At the time of surgery, approximately 10-20% of the patients with pancreatic cancer are considered unresectable because of unexpected liver metastasis, peritoneal carcinomatosis or locally advanced disease. This leads to futile surgical treatment with all the associated morbidity, mortality and costs. More than 50% of all liver metastases develop in the first six months postoperatively. These (subcentimeter) liver metastases are most likely already present at the time of diagnosis and have not been identified pre-operatively, due to the poor sensitivity of routine preoperative contrast-enhanced CT (CECT). METHODS: The DIA-PANC study is a prospective, international, multicenter, diagnostic cohort study investigating diffusion-weighted, contrast-enhanced MRI for the detection of liver metastases in patients with all stages of pancreatic cancer. Indeterminate or malignant liver lesions on MRI will be further investigated histopathologically. For patients with suspected liver lesions without histopathological proof, follow up imaging with paired CT and MRI at 3-, 6- and 12-months will serve as an alternative reference standard. DISCUSSION: The DIA-PANC trial is expected to report high-level evidence of the diagnostic accuracy of MRI for the detection of liver metastases, resulting in significant value for clinical decision making, guideline development and improved stratification for treatment strategies and future trials. Furthermore, DIA-PANC will contribute to our knowledge of liver metastases regarding incidence, imaging characteristics, their number and extent, and their change in time with or without treatment. It will enhance the worldwide implementation of MRI and consequently improve personalized treatment of patients with suspected pancreatic ductal adenocarcinoma. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03469726 . Registered on March 19th 2018 - Retrospectively registered.

[A male patient with postural syncope]. / Een man met houdingsafhankelijke syncope.

A 75-year-old male with a history of CABG and aortic aneurysm was seen in the emergency department. When he lay down, he suddenly became unresponsive. ECG, thoracic X-ray and blood tests ruled out common causes of syncope. An abdominal CT scan revealed a huge renal cyst, which was compressing the inferior vena cava.

Interactive 3D U-net for the segmentation of the pancreas in computed tomography scans.

The increasing incidence of pancreatic cancer will make it the second deadliest cancer in 2030. Imaging based early diagnosis and image guided treatment are emerging potential solutions. Artificial intelligence (AI) can help provide and improve widespread diagnostic expertise and accurate interventional image interpretation. Accurate segmentation of the pancreas is essential to create annotated data sets to train AI, and for computer assisted interventional guidance. Automated deep learning segmentation performance in pancreas computed tomography (CT) imaging is low due to poor grey value contrast and complex anatomy. A good solution seemed a recent interactive deep learning segmentation framework for brain CT that helped strongly improve initial automated segmentation with minimal user input. This method yielded no satisfactory results for pancreas CT, possibly due to a sub-optimal neural network architecture. We hypothesize that a state-of-the-art U-net neural network architecture is better because it can produce a better initial segmentation and is likely to be extended to work in a similar interactive approach. We implemented the existing interactive method, iFCN, and developed an interactive version of U-net method we call iUnet. The iUnet is fully trained to produce the best possible initial segmentation. In interactive mode it is additionally trained on a partial set of layers on user generated scribbles. We compare initial segmentation performance of iFCN and iUnet on a 100CT dataset using dice similarity coefficient analysis. Secondly, we assessed the performance gain in interactive use with three observers on segmentation quality and time. Average automated baseline performance was 78% (iUnet) versus 72% (FCN). Manual and semi-automatic segmentation performance was: 87% in 15 min. for manual, and 86% in 8 min. for iUNet. We conclude that iUnet provides a better baseline than iFCN and can reach expert manual performance significantly faster than manual segmentation in case of pancreas CT. Our novel iUnet architecture is modality and organ agnostic and can be a potential novel solution for semi-automatic medical imaging segmentation in general.

Postoperative surveillance of pancreatic cancer patients.

BACKGROUND: The aim of this study is to collect the best available evidence for diagnostic modalities, frequency, and duration of surveillance after resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: PDAC guidelines published after 2015 were collected. Furthermore, a systematic search of the literature on postoperative surveillance was performed in PubMed and Embase from 2000 to 2019. Articles comparing different diagnostic modalities and frequencies of postoperative surveillance in PDAC patients with regard to survival, quality of life, morbidity and cost-effectiveness were selected. RESULTS: The literature search resulted in 570 articles. A total of seven guidelines and twelve original clinical studies were eventually evaluated. PDAC guidelines increasingly recommend a combination of tumor marker testing and computed tomography (CT) imaging every three to six months during the first two years after resection. These guidelines are, however, based on expert opinion and other low-level evidence. Prospective studies comparing different surveillance strategies are lacking. According to recent studies, surveillance with tumor markers and imaging at regular intervals results in the detection of PDAC recurrence before the onset of symptoms and more frequent administration of further therapy, such as chemotherapy or radiotherapy. CONCLUSION: Current evidence for recurrence-focused surveillance after PDAC resection is limited and contradictory. Consequently, recommendations on surveillance are conflicting. To define the clinical merit of recurrence-focused surveillance, patients who are most likely to benefit from early detection and treatment of PDAC recurrence need to be identified. To this purpose, well-designed prospective studies are needed, accounting for both economical and psychosocial implications of surveillance.

Improving preoperative detection of synchronous liver metastases in pancreatic cancer with combined contrast-enhanced and diffusion-weighted MRI.

PURPOSE: To explore the value of gadolinium-enhanced MRI combined with diffusion-weighted MRI (Gd-enhanced MRI with DWI) in addition to contrast-enhanced CT (CECT) for detection of synchronous liver metastases for potentially resectable pancreatic cancer. METHODS: By means of a retrospective cohort study we included patients with potentially resectable pancreatic cancer on CECT, who underwent Gd-enhanced MRI with DWI between January 2012 and December 2016. A single observer evaluated MRI and CT and was blinded to imaging, pathology, and surgery reports. Liver lesions were scored in both modalities, using a 3-point scale: 1-benign, 2-indeterminate, 3- malignant (i.e., metastasis). The primary outcome parameters were the presence of liver metastases on Gd-enhanced MRI with DWI and the sensitivity of Gd-enhanced MRI with DWI for synchronous liver metastases. RESULTS: We included 66 patients (42 men, 24 women; median age 65 years, range 36-82 years). In 19 patients, liver metastases were present, which were confirmed by histopathology (n = 12), 18FDG-PET (n = 6), or surgical inspection (n = 1). Gd-enhanced MRI with DWI showed metastases in 16/19 patients (24%), which resulted in a sensitivity of 84% (95% CI 60-97%). Contrast-enhanced MRI showed 156 and DWI 397 metastases (p = 0.051), and 339 were particularly small (< 5 mm). CONCLUSIONS: In this study, Gd-enhanced MRI with DWI detected synchronous liver metastases in 24% of patients with potentially resectable pancreatic cancer on CECT with a sensitivity of 84%. Diffusion-weighted MRI showed a greater number of metastases than any other sequence, particularly small metastases (< 5 mm).

The diagnostic accuracy of CT and MRI for the detection of lymph node metastases in gallbladder cancer: A systematic review and meta-analysis.

BACKGROUND: Lymph node metastases (LNM) are an ominous prognostic factor in gallbladder cancer (GBC) and, when present, should preclude surgery. However, uncertainty remains regarding the optimal imaging modality for pre-operative detection of LNM and international guidelines vary in their recommendations. The purpose of this study was to systematically review the diagnostic accuracy of computed tomography (CT) versus magnetic resonance imaging (MRI) in the detection of LNM of GBC. METHODS: A literature search of studies published until November 2017 concerning the diagnostic accuracy of CT or MRI regarding the detection of LNM in GBC was performed. Data extraction and risk of bias assessment was performed independently by two reviewers. The sensitivity of CT and MRI in the detection of LNM was reviewed. Additionally, estimated summary sensitivity, specificity and diagnostic accuracy of MRI were calculated in a patient based meta-analysis. RESULTS: Nine studies including 292 patients were included for narrative synthesis and 5 studies including 158 patients were selected for meta-analysis. Sensitivity of CT ranged from 0.25 to 0.93. Estimated summary diagnostic accuracy parameters of MRI were as follows: sensitivity 0.75 (95% CI 0.6 - 0.85), specificity 0.83 (95% CI 0.74 - 0.90), LR + 4.52 (95% CI 2.55-6.48) and LR- 0.3 (95% CI 0.15 - 0.45). Small (<10 mm) LNM were most frequently undetected on pre-operative imaging. Due to a lack of data, no subgroup analysis comparing the diagnostic accuracy of CT versus MRI could be performed. CONCLUSION: The value of current imaging strategies for the pre-operative assessment of nodal status in GBC remains unclear, especially regarding the detection of small LNM. Additional research is warranted in order to establish uniformity in international guidelines, improve pre-operative nodal staging and to prevent futile surgery.

Glucocorticoid Receptor Signaling Impairs Protein Turnover Regulation in Hypoxia-Induced Muscle Atrophy in Male Mice.

Hypoxemia may contribute to muscle wasting in conditions such as chronic obstructive pulmonary disease. Muscle wasting develops when muscle proteolysis exceeds protein synthesis. Hypoxia induces skeletal muscle atrophy in mice, which can in part be attributed to reduced food intake. We hypothesized that hypoxia elevates circulating corticosterone concentrations by reduced food intake and enhances glucocorticoid receptor (GR) signaling in muscle, which causes elevated protein degradation signaling and dysregulates protein synthesis signaling during hypoxia-induced muscle atrophy. Muscle-specific GR knockout and control mice were subjected to normoxia, normobaric hypoxia (8% oxygen), or pair-feeding to the hypoxia group for 4 days. Plasma corticosterone and muscle GR signaling increased after hypoxia and pair-feeding. GR deficiency prevented muscle atrophy by pair-feeding but not by hypoxia. GR deficiency differentially affected activation of ubiquitin 26S-proteasome and autophagy proteolytic systems by pair-feeding and hypoxia. Reduced food intake suppressed mammalian target of rapamycin complex 1 (mTORC1) activity under normoxic but not hypoxic conditions, and this retained mTORC1 activity was mediated by GR. We conclude that GR signaling is required for muscle atrophy and increased expression of proteolysis-associated genes induced by decreased food intake under normoxic conditions. Under hypoxic conditions, muscle atrophy and elevated gene expression of the ubiquitin proteasomal system-associated E3 ligases Murf1 and Atrogin-1 are mostly independent of GR signaling. Furthermore, impaired inhibition of mTORC1 activity is GR-dependent in hypoxia-induced muscle atrophy.

A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.

OBJECTIVE: Endoscopic ultrasonography (EUS) and MRI are promising tests to detect precursors and early-stage pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs). It is unclear which screening technique is to be preferred. We aimed to compare the efficacy of EUS and MRI in their ability to detect clinically relevant lesions in HRI. DESIGN: Multicentre prospective study. The results of 139 asymptomatic HRI (>10-fold increased risk) undergoing first-time screening by EUS and MRI are described. Clinically relevant lesions were defined as solid lesions, main duct intraductal papillary mucinous neoplasms and cysts ≥10 mm. Results were compared in a blinded, independent fashion. RESULTS: Two solid lesions (mean size 9 mm) and nine cysts ≥10 mm (mean size 17 mm) were detected in nine HRI (6%). Both solid lesions were detected by EUS only and proved to be a stage I PDAC and a multifocal pancreatic intraepithelial neoplasia 2. Of the nine cysts ≥10 mm, six were detected by both imaging techniques and three were detected by MRI only. The agreement between EUS and MRI for the detection of clinically relevant lesions was 55%. Of these clinically relevant lesions detected by both techniques, there was a good agreement for location and size. CONCLUSIONS: EUS and/or MRI detected clinically relevant pancreatic lesions in 6% of HRI. Both imaging techniques were complementary rather than interchangeable: contrary to EUS, MRI was found to be very sensitive for the detection of cystic lesions of any size; MRI, however, might have some important limitations with regard to the timely detection of solid lesions.

Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress.

SIGNIFICANCE: Stroke, a leading cause of death and disability, poses a substantial burden for patients, relatives, and our healthcare systems. Only one drug is approved for treating stroke, and more than 30 contraindications exclude its use in 90% of all patients. Thus, new treatments are urgently needed. In this review, we discuss oxidative stress as a pathomechanism of poststroke neurodegeneration and the inhibition of its source, type 4 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX4), as a conceptual breakthrough in stroke therapy. RECENT ADVANCES: Among potential sources of reactive oxygen species (ROS), the NOXes stand out as the only enzyme family that is solely dedicated to forming ROS. In rodents, three cerebrovascular NOXes exist: the superoxide-forming NOX1 and 2 and the hydrogen peroxide-forming NOX4. Studies using NOX1 knockout mice gave conflicting results, which overall do not point to a role for this isoform. Several reports find NOX2 to be relevant in stroke, albeit to variable and moderate degrees. In our hands, NOX4 is, by far, the major source of oxidative stress and neurodegeneration on ischemic stroke. CRITICAL ISSUES: We critically discuss the tools that have been used to validate the roles of NOX in stroke. We also highlight the relevance of different animal models and the need for advanced quality control in preclinical stroke research. FUTURE DIRECTIONS: The development of isoform-specific NOX inhibitors presents a precious tool for further clarifying the role and drugability of NOX homologues. This could pave the avenue for the first clinically effective neuroprotectant applied poststroke, and even beyond this, stroke could provide a proof of principle for antioxidative stress therapy.

NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury.

Ischemia/reperfusion injury (IRI) is crucial in the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. Paradoxically, both the lack of oxygen during ischemia and the replenishment of oxygen during reperfusion can cause tissue injury. Clinical outcome is also determined by a third, post-reperfusion phase characterized by tissue remodeling and adaptation. Increased levels of reactive oxygen species (ROS) have been suggested to be key players in all three phases. As a second paradox, ROS seem to play a double-edged role in IRI, with both detrimental and beneficial effects. These Janus-faced effects of ROS may be linked to the different sources of ROS or to the different types of ROS that exist and may also depend on the phase of IRI. With respect to therapeutic implications, an untargeted application of antioxidants may not differentiate between detrimental and beneficial ROS, which might explain why this approach is clinically ineffective in lowering cardiovascular mortality. Under some conditions, antioxidants even appear to be harmful. In this review, we discuss recent breakthroughs regarding a more targeted and promising approach to therapeutically modulate ROS in IRI. We will focus on NADPH oxidases and their catalytic subunits, NOX, as they represent the only known enzyme family with the sole function to produce ROS. Similar to ROS, NADPH oxidases may play a dual role as different NOX isoforms may mediate detrimental or protective processes. Unraveling the precise sequence of events, i.e., determining which role the individual NOX isoforms play in the various phases of IRI, may provide the crucial molecular and mechanistic understanding to finally effectively target oxidative stress.

The NOX toolbox: validating the role of NADPH oxidases in physiology and disease.

Reactive oxygen species (ROS) are cellular signals but also disease triggers; their relative excess (oxidative stress) or shortage (reductive stress) compared to reducing equivalents are potentially deleterious. This may explain why antioxidants fail to combat diseases that correlate with oxidative stress. Instead, targeting of disease-relevant enzymatic ROS sources that leaves physiological ROS signaling unaffected may be more beneficial. NADPH oxidases are the only known enzyme family with the sole function to produce ROS. Of the catalytic NADPH oxidase subunits (NOX), NOX4 is the most widely distributed isoform. We provide here a critical review of the currently available experimental tools to assess the role of NOX and especially NOX4, i.e. knock-out mice, siRNAs, antibodies, and pharmacological inhibitors. We then focus on the characterization of the small molecule NADPH oxidase inhibitor, VAS2870, in vitro and in vivo, its specificity, selectivity, and possible mechanism of action. Finally, we discuss the validation of NOX4 as a potential therapeutic target for indications including stroke, heart failure, and fibrosis.

Role of fistulography in evaluating pancreatic fistula after pancreaticoduodenectomy.

OBJECTIVE: To evaluate the usefulness of fistulography as a diagnostic and management tool for clinically suspected pancreatic fistulas (PF) after pancreaticoduodenectomy (PD). METHODS: 84 consecutive fistulographies were performed for clinical suspicion of PF and retrospectively analysed. We radiologically defined two types of PF by means of fistulography, PF1 in the case of primary filling with contrast agent of the jejunal loop or stomach and PF2 in the case of secondary filling of the jejunal loop or stomach through a fistulous tract or a fluid collection. RESULTS: In 35/84 (41.7%) of the fistulograms, a PF1 was demonstrated owing to an instantaneous opacification of the intestinal lumen or the stomach, without evidence of a fistulous tract or fluid collection. In 49/84 (58.3%) fistulograms, a PF2 was demonstrated by the depiction of a fluid collection and/or a fistulous tract and a communication with the intestinal loop or the stomach anastomised with the pancreas. The mean healing time of a PF after PD was 2.7 days for PF1, and 9.8 days for PF2. CONCLUSION: Fistulography helps in the confirmation of clinically suspect PF, and can distinguish PF1 and PF2, thus decreasing post-operative morbidity significantly.

Correlation between radiological assessment of acute ankle fractures and syndesmotic injury on MRI.

OBJECTIVE: Owing to the shortcomings of clinical examination and radiographs, injury to the syndesmotic ligaments is often misdiagnosed. When there is no indication requiring that the fractured ankle be operated on, the syndesmosis is not tested intra-operatively, and rupture of this ligamentous complex may be missed. Subsequently the patient is not treated properly leading to chronic complaints such as instability, pain, and swelling. We evaluated three fracture classification methods and radiographic measurements with respect to syndesmotic injury. MATERIALS AND METHODS: Prospectively the radiographs of 51 consecutive ankle fractures were classified according to Weber, AO-Müller, and Lauge-Hansen. Both the fracture type and additional measurements of the tibiofibular clear space (TFCS), tibiofibular overlap (TFO), medial clear space (MCS), and superior clear space (SCS) were used to assess syndesmotic injury. MRI, as standard of reference, was performed to evaluate the integrity of the distal tibiofibular syndesmosis. The sensitivity and specificity for detection of syndesmotic injury with radiography were compared to MRI. RESULTS: The Weber and AO-Müller fracture classification system, in combination with additional measurements, detected syndesmotic injury with a sensitivity of 47% and a specificity of 100%, and Lauge-Hansen with both a sensitivity and a specificity of 92%. TFCS and TFO did not correlate with syndesmotic injury, and a widened MCS did not correlate with deltoid ligament injury. CONCLUSION: Syndesmotic injury as predicted by the Lauge-Hansen fracture classification correlated well with MRI findings. With MRI the extent of syndesmotic injury and therefore fracture stage can be assessed more accurately compared to radiographs.

Calcium scoring in unenhanced and enhanced CT data of the aorta-iliacal arteries: impact of image acquisition, reconstruction, and analysis parameter settings.

BACKGROUND: Several studies have been published on the matter of abdominal aortic and iliac calcifications and the association to clinical entities such as diabetes mellitus and renal failure. However, comparing of these studies is questionable since quantification methods for atherosclerosis differ. PURPOSE: To evaluate the effect of image acquisition settings, reconstruction parameters, and analysis methods on calcium quantification in the abdominal aorta. MATERIAL AND METHODS: Calcium scores were retrospectively determined on standardized abdominal CT scans of 15 patients. Two researchers obtained calcium scores with 10 different lower thresholds (LT) (130, 145, 160, 175, 200, 300, 400, 500, 600, 1000) in CT scans with and without contrast enhancement, with slice thicknesses (ST) varying between 2.0-5.0 mm for the non-contrast-enhanced series and between 1.0-5.0 mm for the contrast-enhanced series. In addition calcium scores obtained with two convolution kernels (B10f, B20f) were compared. Inter-observer variability was calculated. RESULTS: Calcium scoring at higher STs is overestimated compared to smaller STs and this effect was more pronounced with increasing calcium loads. Concerning the convolution kernel, scores obtained with kernel B10f were overestimated compared to kernel B20f. Increase of LT resulted in a decrease of the calcium score and scoring in contrast-enhanced series resulted in higher scores compared to non-contrast-enhanced series. These effects are more apparent in patients with higher calcium loads. Calcium scoring reproducibility with the reference standard is limited for the aorta-iliac trajectory, whereas scoring with the remaining settings is reproducible. CONCLUSION: Scores obtained with different settings cannot be compared. The inter-observer reproducibility was limited using the reference standard and practical difficulties were substantial. Scoring with higher LT, ST, and contrast enhancement is faster and has less practical difficulties.

Direct renin inhibition in a rat model of chronic allograft injury.

BACKGROUND: Blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers (ARBs) slow the progression of various chronic kidney diseases and chronic allograft dysfunction. RAS inhibition can be achieved also by directly blocking renin upstream from ACE. However, direct renin inhibition can have additional effects since formation of renoprotective Ang II breakdown products such as angiotensin (Ang) (1-7) that are produced by ACE2 are also inhibited. METHODS: Using a Fischer-to-Lewis renal transplantation model, the effect of the renin inhibitor aliskiren (10 mg/kg/day) was assessed on the development of chronic allograft dysfunction compared with vehicle treatment and Ang II receptor blockers candesartan. RESULTS: Aliskiren had no effect on renal function (proteinuria, creatinine clearance) or on renal morphological changes (glomerulosclerosis collagen deposition, myofibroblast accumulation and macrophage infiltration) compared with the vehicle- and candesartan-treated animals determined 24 weeks after transplantation. On the other hand, atrophy of tubular cells was significantly attenuated. Candesartan reduced both proteinuria and structural injury of the kidney. In aliskiren-treated animals reduced serum Ang II and Ang (1-7) levels were detected, whereas the level of urine angiotensinogen was unchanged. CONCLUSIONS: The renin inhibitor aliskiren does not slow the progression of chronic allograft dysfunction. We suggest that the lack of protection might be due to reduced formation of the protective Ang II breakdown products such as Ang (1-7) or due to unchanged intrarenal RAS activity demonstrated by urinary angiotensinogen levels.