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This study evaluated the relationship between apparent diffusion coefficient (ADC) values in pancreatic ductal adenocarcinoma (PDAC) and tumor grades based on WHO, Adsay, and Kalimuthu classifications, using whole-mount pancreatectomy specimens. If glandular formation plays a key role in the degree of diffusion restriction, diffusion-weighted imaging could facilitate non-invasive grading of PDAC. A freehand region of interest (ROI) was drawn along tumor borders on the preoperative ADC map in each tumor-containing slice. Resection specimens were retrospectively graded according to WHO, Adsay, and Kalimuthu classifications and correlated with overall survival and the 10th percentile of whole-volume ADC values. Findings from 40 patients (23 male, median age 67) showed no correlation between ADC p10 values and WHO differentiation ( p = 0.050), Adsay grade ( p = 0.955), or Kalimuthu patterns ( p = 0.117). There was no association between ADC p10 and overall survival ( p = 0.082) and other clinicopathological variables. Survival was significantly lower for poor tumor differentiation ( p = 0.046) and non-glandular Kalimuthu patterns ( p = 0.016) and there was a trend towards inferior survival for Adsay G3 ( p = 0.090) after correction for age, tumor location, and stage. Preoperative ADC measurements for determining PDAC aggressiveness had limited clinical utility, as there was no correlation with histological parameters or overall survival in resectable PDAC.

CT perfusion (CTP) analysis is difficult to implement in clinical practice. Therefore, we investigated a novel semi-automated CTP AI biomarker and applied it to identify vascular phenotypes of pancreatic ductal adenocarcinoma (PDAC) and evaluate their association with overall survival (OS)., Methods: From January 2018 to November 2022, 107 PDAC patients were prospectively included, who needed to undergo CTP and a diagnostic contrast-enhanced CT (CECT). We developed a semi-automated CTP AI biomarker, through a process that involved deformable image registration, a deep learning segmentation model of tumor and pancreas parenchyma volume, and a trilinear non-parametric CTP curve model to extract the enhancement slope and peak enhancement in segmented tumors and pancreas. The biomarker was validated in terms of its use to predict vascular phenotypes and their association with OS. A receiver operating characteristic (ROC) analysis with five-fold cross-validation was performed. OS was assessed with Kaplan-Meier curves. Differences between phenotypes were tested using the Mann-Whitney U test., Results: The final analysis included 92 patients, in whom 20 tumors (21%) were visually isovascular. The AI biomarker effectively discriminated tumor types, and isovascular tumors showed higher enhancement slopes (2.9 Hounsfield unit HU/s vs. 2.0 HU/s, p < 0.001) and peak enhancement (70 HU vs. 47 HU, p < 0.001); the AUC was 0.86. The AI biomarker's vascular phenotype significantly differed in OS ( p < 0.01)., Conclusions: The AI biomarker offers a promising tool for robust CTP analysis. In PDAC, it can distinguish vascular phenotypes with significant OS prognostication.

Background: We developed models for tumor segmentation to automate the assessment of total tumor volume (TTV) in patients with colorectal liver metastases (CRLM)., Methods: In this prospective cohort study, pre- and post-systemic treatment computed tomography (CT) scans of 259 patients with initially unresectable CRLM of the CAIRO5 trial (NCT02162563) were included. In total, 595 CT scans comprising 8,959 CRLM were divided into training (73%), validation (6.5%), and test sets (21%). Deep learning models were trained with ground truth segmentations of the liver and CRLM. TTV was calculated based on the CRLM segmentations. An external validation cohort was included, comprising 72 preoperative CT scans of patients with 112 resectable CRLM. Image segmentation evaluation metrics and intraclass correlation coefficient (ICC) were calculated., Results: In the test set (122 CT scans), the autosegmentation models showed a global Dice similarity coefficient (DSC) of 0.96 (liver) and 0.86 (CRLM). The corresponding median per-case DSC was 0.96 (interquartile range [IQR] 0.95-0.96) and 0.80 (IQR 0.67-0.87). For tumor segmentation, the intersection-over-union, precision, and recall were 0.75, 0.89, and 0.84, respectively. An excellent agreement was observed between the reference and automatically computed TTV for the test set (ICC 0.98) and external validation cohort (ICC 0.98). In the external validation, the global DSC was 0.82 and the median per-case DSC was 0.60 (IQR 0.29-0.76) for tumor segmentation., Conclusions: Deep learning autosegmentation models were able to segment the liver and CRLM automatically and accurately in patients with initially unresectable CRLM, enabling automatic TTV assessment in such patients., Relevance Statement: Automatic segmentation enables the assessment of total tumor volume in patients with colorectal liver metastases, with a high potential of decreasing radiologist's workload and increasing accuracy and consistency., Key Points: • Tumor response evaluation is time-consuming, manually performed, and ignores total tumor volume. • Automatic models can accurately segment tumors in patients with colorectal liver metastases. • Total tumor volume can be accurately calculated based on automatic segmentations., (© 2023. The Author(s).)

The preoperative prediction of resectability pancreatic ductal adenocarcinoma (PDAC) is challenging. This retrospective single-center study examined tumor and vessel radiomics to predict the resectability of PDAC in chemo-naïve patients. The tumor and adjacent arteries and veins were segmented in the portal-venous phase of contrast-enhanced CT scans, and radiomic features were extracted. Features were selected via stability and collinearity testing, and least absolute shrinkage and selection operator application (LASSO). Three models, using tumor features, vessel features, and a combination of both, were trained with the training set ( N = 86) to predict resectability. The results were validated with the test set ( N = 15) and compared to the multidisciplinary team's (MDT) performance. The vessel-features-only model performed best, with an AUC of 0.92 and sensitivity and specificity of 97% and 73%, respectively. Test set validation showed a sensitivity and specificity of 100% and 88%, respectively. The combined model was as good as the vessel model (AUC = 0.91), whereas the tumor model showed poor performance (AUC = 0.76). The MDT's prediction reached a sensitivity and specificity of 97% and 84% for the training set and 88% and 100% for the test set, respectively. Our clinician-independent vessel-based radiomics model can aid in predicting resectability and shows performance comparable to that of the MDT. With these encouraging results, improved, automated, and generalizable models can be developed that reduce workload and can be applied in non-expert hospitals.

Purpose To evaluate interobserver variability in the morphologic tumor response assessment of colorectal liver metastases (CRLM) managed with systemic therapy and to assess the relation of morphologic response with gene mutation status, targeted therapy, and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 measurements. Materials and Methods Participants with initially unresectable CRLM receiving different systemic therapy regimens from the randomized, controlled CAIRO5 trial (NCT02162563) were included in this prospective imaging study. Three radiologists independently assessed morphologic tumor response on baseline and first follow-up CT scans according to previously published criteria. Two additional radiologists evaluated disagreement cases. Interobserver agreement was calculated by using Fleiss κ. On the basis of the majority of individual radiologic assessments, the final morphologic tumor response was determined. Finally, the relation of morphologic tumor response and clinical prognostic parameters was assessed. Results In total, 153 participants (median age, 63 years [IQR, 56-71]; 101 men) with 306 CT scans comprising 2192 CRLM were included. Morphologic assessment performed by the three radiologists yielded 86 (56%) agreement cases and 67 (44%) disagreement cases (including four major disagreement cases). Overall interobserver agreement between the panel radiologists on morphology groups and morphologic response categories was moderate (κ = 0.53, 95% CI: 0.48, 0.58 and κ = 0.54, 95% CI: 0.47, 0.60). Optimal morphologic response was particularly observed in patients treated with bevacizumab ( P = .001) and in patients with RAS/BRAF mutation ( P = .04). No evidence of a relationship between RECIST 1.1 and morphologic response was found ( P = .61). Conclusion Morphologic tumor response assessment following systemic therapy in participants with CRLM demonstrated considerable interobserver variability. Keywords: Tumor Response, Observer Performance, CT, Liver, Metastases, Oncology, Abdomen/Gastrointestinal Clinical trial registration no. NCT02162563 Supplemental material is available for this article. © RSNA, 2022.

Background: In various cancer types, the first step towards extended metastatic disease is the presence of lymph node metastases. Imaging methods with sufficient diagnostic accuracy are required to personalize treatment. Lymph node metastases can be detected with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI), but this method needs validation. Here, a workflow is presented, which is designed to compare MRI-visible lymph nodes on a node-to-node basis with histopathology., Methods: In patients with prostate, rectal, periampullary, esophageal, and head-and-neck cancer, in vivo USPIO-enhanced MRI was performed to detect lymph nodes suspicious of harboring metastases. After lymphadenectomy, but before histopathological assessment, a 7 Tesla preclinical ex vivo MRI of the surgical specimen was performed, and in vivo MR images were radiologically matched to ex vivo MR images. Lymph nodes were annotated on the ex vivo MRI for an MR-guided pathological examination of the specimens., Results: Matching lymph nodes of ex vivo MRI to pathology was feasible in all cancer types. The annotated ex vivo MR images enabled a comparison between USPIO-enhanced in vivo MRI and histopathology, which allowed for analyses on a nodal, or at least on a nodal station, basis., Conclusions: A workflow was developed to validate in vivo USPIO-enhanced MRI with histopathology. Guiding the pathologist towards lymph nodes in the resection specimens during histopathological work-up allowed for the analysis at a nodal basis, or at least nodal station basis, of in vivo suspicious lymph nodes with corresponding histopathology, providing direct information for validation of in vivo USPIO-enhanced, MRI-detected lymph nodes.

Objectives: Compare total tumor volume (TTV) response after systemic treatment to Response Evaluation Criteria in Solid Tumors (RECIST1.1) and assess the prognostic value of TTV change and RECIST1.1 for recurrence-free survival (RFS) in patients with colorectal liver-only metastases (CRLM)., Background: RECIST1.1 provides unidimensional criteria to evaluate tumor response to systemic therapy. Those criteria are accepted worldwide but are limited by interobserver variability and ignore potentially valuable information about TTV., Methods: Patients with initially unresectable CRLM receiving systemic treatment from the randomized, controlled CAIRO5 trial (NCT02162563) were included. TTV response was assessed using software specifically developed together with SAS analytics. Baseline and follow-up computed tomography (CT) scans were used to calculate RECIST1.1 and TTV response to systemic therapy. Different thresholds (10%, 20%, 40%) were used to define response of TTV as no standard currently exists. RFS was assessed in a subgroup of patients with secondarily resectable CRLM after induction treatment., Results: A total of 420 CT scans comprising 7820 CRLM in 210 patients were evaluated. In 30% to 50% (depending on chosen TTV threshold) of patients, discordance was observed between RECIST1.1 and TTV change. A TTV decrease of >40% was observed in 47 (22%) patients who had stable disease according to RECIST1.1. In 118 patients with secondarily resectable CRLM, RFS was shorter for patients with less than 10% TTV decrease compared with patients with more than 10% TTV decrease ( P = 0.015), while RECIST1.1 was not prognostic ( P = 0.821)., Conclusions: TTV response assessment shows prognostic potential in the evaluation of systemic therapy response in patients with CRLM., Competing Interests: C.J.A.P. has an advisory role for Nordic Pharma. This funding is not related to the current research. The remaining authors declare no potential conflicts of interest. The CAIRO5 study is supported by unrestricted scientific grants from Roche and Amgen. The funders had no role in the design, conduct, and submission of the study, or in the decision to submit the manuscript for publication., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Endoscopic ultrasound (EUS) with fine needle aspiration (FNA) or biopsy (FNB) to diagnose lesions in the gastrointestinal tract is common. Demand for histology sampling to identify treatment-specific targets is increasing. Various core biopsy FNB needles to obtain tissue for histology are currently available, however, with variable (37-97%) histology yields. In this multicenter study, we evaluated performance, safety, and user experience of a novel device (the puncture biopsy forceps (PBF) needle). Twenty-four procedures with the PBF needle were performed in 24 patients with a suspected pancreatic lesion ( n = 10), subepithelial lesion ( n = 10), lymph node ( n = 3), or pararectal mass ( n = 1). In 20/24 (83%) procedures, the PBF needle yielded sufficient material for interpretation (sample adequacy). In 17/24 (71%), a correct diagnosis was made with the material from the PBF needle (diagnostic accuracy). All participating endoscopists experienced a learning curve. (Per)procedural technical issues occurred in four cases (17%), but there were no adverse events. The PBF needle is a safe and potentially useful device to obtain an EUS-guided biopsy specimen. As the design of the PBF needle is different to core biopsy FNB needles, specific training will likely further improve the performance of the PBF needle. Furthermore, the design of the needle needs further improvement to make it more robust in clinical practice.

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.

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., Competing Interests: The authors have declared that no competing interests exist.

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.

The exposure of oil paintings to organic solvents for varnish removal or to water for the removal of surface dirt can affect the chemical and physical properties of oil paint in an undesired way. Solvents can temporarily plasticise and swell the polymerised oil paint binding medium, enhancing both the thermal mobility and mechanical displacement of pigments embedded in this film. The enhancement of these microscopic motions can affect both the chemical and physical stability of the object as a whole. In order to minimise solvent exposure during cleaning, an analytical method that can quantitatively measure the microscopic motions induced by solvent uptake, is required first. In this study, we use Fourier Transform Laser Speckle Imaging (FT-LSI) and a newly developed portable FT-LSI setup as highly resolved motion detection instruments. We employ FT-LSI to probe pigment motion, with high spatiotemporal resolution, as a proxy for the destabilising effects of cleaning solvents. In this way, we can study solvent diffusion and evaporation rates and the total solvent retention time. In addition, qualitative spatial information on the spreading and homogeneity of the applied solvent is obtained. We study mobility in paint films caused by air humidity, spreading of solvents as a result of several cleaning methods and the protective capabilities of varnish. Our results show that FT-LSI is a powerful technique for the study of solvent penetration during oil paint cleaning and has a high potential for future use in the conservation studio.

Although the concentration of carboxylic acid (COOH) groups is crucial to understand oil paint chemistry, analytical challenges hindered COOH quantification in complex polymerised oil samples thus far. The concentration of COOH groups is important in understanding oil paint degradation because it drives the breakdown of reactive inorganic pigments to dissolve in the oil network and form metal carboxylates. The metal ions in such an ionomeric polymer network can exchange with saturated fatty acids to form crystalline metal soaps (metal complexes of saturated fatty acids), leading to serious problems in many paintings worldwide. We developed two methods based on ATR-FTIR spectroscopy to accurately estimate the COOH concentration in artificially aged oil paint models. Using tailored model systems composed of linseed oil, ZnO and inert filler pigments, these dried oil paints were found to contain one COOH group per triacylglycerol unit. Model systems based on a mixture of long chain alcohols showed that the calculated COOH concentration originates from side chain autoxidation at low relative humidity (RH). The influence of increasing RH and ZnO concentration on COOH formation was studied and high relative humidity conditions were shown to promote the formation of COOH groups. No significant ester hydrolysis was found under the conditions studied. Our results show the potential of quantitative analysis of oil paint model systems for aiding careful (re)evaluation of conservation strategies., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

The molecular structure around metal ions in polymer materials has puzzled researchers for decades. This question has acquired new relevance with the discovery that aged oil paint binders can adopt an ionomer structure when metal ions leached from pigments bind to carboxylate groups on the polymerized oil network. The characteristics of the metal-polymer structure are expected to have important consequences for the rate of oil paint degradation reactions such as metal soap formation and oil hydrolysis. Here, we use two-dimensional infrared (2D-IR) spectroscopy to demonstrate that zinc carboxylates formed in paint films containing zinc white pigment adopt either a coordination chain- or an oxo-type cluster structure. Moreover, it was found that the presence of water governs the relative concentration of these two types of zinc carboxylate coordination. The results pave the way for a molecular approach to paintings conservation and the application of 2D-IR spectroscopy to the study of polymer structure.

Purpose: Metabolic parameters are increasingly being used to characterize tumors. Motion artifacts due to patient respiration introduce uncertainties in quantification of metabolic parameters during positron emission tomography (PET) image acquisition. The present study investigates the impact of amplitude-based optimal respiratory gating (ORG) on quantification of PET-derived image features in patients with pancreatic ductal adenocarcinoma (PDAC), in correlation with overall survival (OS)., Methods: Sixty-nine patients with histologically proven primary PDAC underwent 2'-deoxy-2'-[ 18 F]fluoroglucose ([ 18 F]FDG) PET/CT imaging during diagnostic work-up. Standard image acquisition and reconstruction was performed in accordance with the EANM guidelines and ORG images were reconstructed with a duty cycle of 35%. PET-derived image features, including standard parameters, first- and second-order texture features, were calculated from the standard and corresponding ORG images, and correlation with OS was assessed., Results: ORG significantly impacts the quantification of nearly all features; values of single-voxel parameters (e.g., SUV max ) showed a wider range, volume-based parameters (e.g., SUV mean ) were reduced, and texture features were significantly changed. After correction for motion artifacts using ORG, some features that describe intra-tumoral heterogeneity were more strongly correlated to OS., Conclusions: Correction for respiratory motion artifacts using ORG impacts the quantification of metabolic parameters in PDAC lesions. The correlation of metabolic parameters with OS was significantly affected, in particular parameters that describe intra-tumor heterogeneity. Therefore, interpretation of single-voxel or average metabolic parameters in relation to clinical outcome should be done cautiously. Furthermore, ORG is a valuable tool to improve quantification of intra-tumoral heterogeneity in PDAC.

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.

Unlabelled: We have noted that bone lesions on CT respond differently from soft-tissue lesions to treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). We therefore compared the response of bone lesions with that of soft-tissue lesions to treatment with (177)Lu-octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors (NETs)., Methods: Forty-two patients with well-differentiated NETs who had bone metastases that were positive on [(111)In-DTPA(0)]octreotide somatostatin receptor scintigraphy (SRS) before treatment, and who had soft-tissue lesions, were studied. All patients had had a minimum of 1 follow-up CT scan. Lesions were scored on CT and bone lesions also on SRS before and after treatment. Tumor markers (chromogranin A and 5-hydroxyindoleacetic acid) before and after treatment were compared., Results: Because bone lesions were not visible on CT before treatment in 11 of 42 patients (26%), bone and soft-tissue lesions were evaluated in 31 patients. Whereas bone lesions increased in size, soft-tissue lesions decreased in size. The percentage change in bone and soft-tissue lesions was significantly different at all time points up to 12 mo of follow-up (P < 0.001). The intensity or number of bone lesions on SRS decreased after treatment in 19 of 23 patients (83%) in whom SRS after treatment was available. The tumor markers also decreased significantly after treatment. In 1 patient, bone lesions became visible on CT after treatment, mimicking progressive disease with "new" bone lesions, although there was an overall treatment response., Conclusion: In patients with NETs, the apparent increase in size of bone lesions or the appearance of new bone lesions on CT after treatment with (177)Lu-octreotate should be interpreted cautiously, as this finding may be therapy-related rather than indicative of tumor progression.

Background: The efficacy of anticancer therapy is usually evaluated by anatomical imaging. However, this method may be suboptimal for the evaluation of novel treatment modalities, such as targeted therapy. Theoretically, functional assessment of tumour response by diffusion weighted imaging (DWI) is an attractive tool for this purpose and may allow an early prediction of response. The optimal use of this method has still to be determined., Method: We reviewed the published literature on clinical DWI in the prediction of response to anticancer therapy, especially targeted therapy. Studies investigating the role of DWI in patients with cancer either for response prediction and/or response monitoring were selected for this analysis., Results: We identified 24 studies that met our criteria. Most studies showed a significant correlation between (changes in) apparent diffusion coefficient (ADC) values and treatment response. However, in different tumours and studies, both high and low pretreatment ADC were found to be associated with response rate. In the course of treatment, an increase in ADC was associated with response in most cases., Conclusion: The potential of DWI for (early) response monitoring of anticancer therapies has been demonstrated. However, validation is hampered by the lack of reproducibility and standardisation. We recommend that these issues should be properly addressed prior to further testing the clinical use of DWI in the assessment of treatments., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

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.

For decades, oxidative stress has been discussed as a key mechanism of endothelial dysfunction and cardiovascular disease. However, attempts to validate and exploit this hypothesis clinically by supplementing antioxidants have failed. Nevertheless, this does not disprove the oxidative stress hypothesis. As a certain degree of reactive oxygen species (ROS) formation appears to be physiological and beneficial. To reduce oxidative stress therapeutically, two alternative approaches are being developed. One is the repair of key signalling components that are compromised by oxidative stress. These include uncoupled endothelial nitric oxide (NO) synthase and oxidized/heme-free NO receptor soluble guanylate cyclase. A second approach is to identify and effectively inhibit the relevant source(s) of ROS in a given disease condition. A highly likely target in this context is the family of NADPH oxidases. Animal models, including NOX knockout mice and new pharmacological inhibitors of NADPH oxidases have opened up a new era of oxidative stress research and have paved the way for new cardiovascular therapies., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)

Background: The median laparotomy is frequently used by abdominal surgeons to gain rapid and wide access to the abdominal cavity with minimal damage to nerves, vascular structures and muscles of the abdominal wall. However, incisional hernia remains the most common complication after median laparotomy, with reported incidences varying between 2-20%. Recent clinical and experimental data showed a continuous suture technique with many small tissue bites in the aponeurosis only, is possibly more effective in the prevention of incisional hernia when compared to the common used large bite technique or mass closure., Methods/design: The STITCH trial is a double-blinded multicenter randomized controlled trial designed to compare a standardized large bite technique with a standardized small bites technique. The main objective is to compare both suture techniques for incidence of incisional hernia after one year. Secondary outcomes will include postoperative complications, direct costs, indirect costs and quality of life. A total of 576 patients will be randomized between a standardized small bites or large bites technique. At least 10 departments of general surgery and two departments of oncological gynaecology will participate in this trial. Both techniques have a standardized amount of stitches per cm wound length and suture length wound length ratio's are calculated in each patient. Follow up will be at 1 month for wound infection and 1 year for incisional hernia. Ultrasound examinations will be performed at both time points to measure the distance between the rectus muscles (at 3 points) and to objectify presence or absence of incisional hernia. Patients, investigators and radiologists will be blinded during follow up, although the surgeon can not be blinded during the surgical procedure., Conclusion: The STITCH trial will provide level 1b evidence to support the preference for either a continuous suture technique with many small tissue bites in the aponeurosis only or for the commonly used large bites technique.

A syndesmosis is defined as a fibrous joint in which two adjacent bones are linked by a strong membrane or ligaments.This definition also applies for the distal tibiofibular syndesmosis, which is a syndesmotic joint formed by two bones and four ligaments. The distal tibia and fibula form the osseous part of the syndesmosis and are linked by the distal anterior tibiofibular ligament, the distal posterior tibiofibular ligament, the transverse ligament and the interosseous ligament. Although the syndesmosis is a joint, in the literature the term syndesmotic injury is used to describe injury of the syndesmotic ligaments. In an estimated 1–11% of all ankle sprains, injury of the distal tibiofibular syndesmosis occurs. Forty percent of patients still have complaints of ankle instability 6 months after an ankle sprain. This could be due to widening of the ankle mortise as a result of increased length of the syndesmotic ligaments after acute ankle sprain. As widening of the ankle mortise by 1 mm decreases the contact area of the tibiotalar joint by 42%, this could lead to instability and hence early osteoarthritis of the tibiotalar joint. In fractures of the ankle, syndesmotic injury occurs in about 50% of type Weber B and in all of type Weber C fractures. However,in discussing syndesmotic injury, it seems the exact proximal and distal boundaries of the distal tibiofibular syndesmosis are not well defined. There is no clear statement in the Ashhurst and Bromer etiological, the Lauge-Hansen genetic or the Danis-Weber topographical fracture classification about the exact extent of the syndesmosis. This joint is also not clearly defined in anatomical textbooks, such as Lanz and Wachsmuth. Kelikian and Kelikian postulate that the distal tibiofibular joint begins at the level of origin of the tibiofibular ligaments from the tibia and ends where these ligaments insert into the fibular malleolus. As the syndesmosis of the ankle plays an important role in the stability of the talocrural joint, understanding of the exact anatomy of both the osseous and ligamentous structures is essential in interpreting plain radiographs, CT and MR images, in ankle arthroscopy and in therapeutic management. With this pictorial essay we try to fill the hiatus in anatomic knowledge and provide a detailed anatomic description of the syndesmotic bones with the incisura fibularis, the syndesmotic recess, synovial fold and tibiofibular contact zone and the four syndesmotic ligaments. Each section describes a separate syndesmotic structure, followed by its clinical relevance and discussion of remaining questions., (© 2010 The Authors. Journal of Anatomy © 2010 Anatomical Society of Great Britain and Ireland.)

Objective: Clinical studies have demonstrated the efficacy of oral and intravenous amiodarone therapy to prevent postoperative atrial fibrillation. However, because of significant extracardiac side effects, only high-risk patients are eligible for prophylactic amiodarone therapy. This study addressed the hypothesis that atrium-specific drug delivery through an amiodarone-eluting epicardial patch reduces vulnerability to atrial tachyarrhythmias, whereas ventricular and plasma drug concentrations are minimized., Methods: Right atrial epicardiums of goats were fitted with electrodes and a bilayered patch (poly[ethylene glycol]-based matrix and poly[lactide-co-caprolactone] backing layer) loaded with amiodarone (10 mg per patch, n = 10) or without drug (n = 6). Electrophysiologic parameters (atrial effective refractory period, conduction time, and rapid atrial response to burst pacing) and amiodarone levels in plasma and tissue were measured during 1 month's follow-up., Results: Epicardial application of amiodarone-eluting patches produced persistently higher drug concentrations in the right atrium than in the left atrium, ventricles, and extracardiac tissues by 2 to 4 orders of magnitude. Atrial effective refractory period and conduction time increased, whereas rapid atrial response inducibility decreased significantly (P < .05) during the 1-month follow-up compared with that seen in animals treated with drug-free patches. Amiodarone concentrations in plasma remained undetectably low (<10 ng/mL)., Conclusions: Atrium-specific drug delivery through an amiodarone-eluting patch produces therapeutic atrial drug concentrations, whereas ventricular and systemic drug levels are minimized. This study demonstrates that sustained targeted drug delivery to a specific heart chamber is feasible and might reduce the risk for ventricular and extracardiac adverse effects. Epicardial application of amiodarone-eluting patches is a promising strategy to prevent postoperative atrial fibrillation., (Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background & Aims: The prevalence of pancreatic cysts is not known, but asymptomatic pancreatic cysts are diagnosed with increasing frequency. We investigated the prevalence of pancreatic cysts in individuals who were screened by magnetic resonance imaging (MRI) as part of a preventive medical examination., Methods: Data from consecutive persons who underwent abdominal MRI (n = 2803; 1821 men; mean age, 51.1 +/- 10.8 y) at an institute of preventive medical care were included from a prospective database. All individuals had completed an application form including questions about possible abdominal complaints and prior surgery. MRI reports were reviewed for the presence of pancreatic cysts. Original image sets of all positive MRI reports and a representative sample of the negative series were re-assessed by a blinded, independent radiologist., Results: Pancreatic cysts were reported in 66 persons (2.4%; 95% confidence interval, 1.9-3.0); prevalence correlated with increasing age (P < .001). There was no difference in prevalence between sexes (P = .769). There was no correlation between abdominal complaints and the presence of pancreatic cysts (P = .542). Four cysts (6%) were larger than 2 cm and 3 (5%) were larger than 3 cm. Review of the original image sets by the independent radiologist did not significantly change these findings., Conclusions: The prevalence of pancreatic cysts in a large consecutive series of individuals who underwent an MRI at a preventive medical examination was 2.4%. Prevalence increased with age, but did not differ between sexes. Only a minority of cysts were larger than 2 cm., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Aldosterone plays a detrimental role in the pathology of chronic heart failure. An important mechanism resides in its ability to evoke extensive fibrosis in the heart. However, the locations of the aldosterone interaction sites responsible for triggering cardiac fibrosis are puzzling. Extra-cardiac aldosterone actions are known to contribute to cardiac fibrosis but whether local cardiac aldosterone actions are involved is unclear., Aims: This study aimed to investigate whether local aldosterone actions contribute to cardiac fibrosis in vivo., Methods: Saline treated male Wistar rats were intravenously (systemically) or intrapericardially (locally) infused for 8 weeks with 75 or 750 ng/h aldosterone to monitor end point left ventricular epicardial collagen levels (histology)., Results: Perivascular fibrosis was observed only at high dose aldosterone infusions and was not different for the administration routes. Regarding interstitial fibrosis however, clear differences between the administration routes were seen. Intrapericardial aldosterone infusions increased interstitial collagen levels 1.72x (P<0.05) at low dose, but -surprisingly- had no significant effect at high dose. In contrast, intravenous aldosterone had no significant effect at low dose but increased interstitial collagen 1.72x (P<0.05) at high dose., Conclusion: Our data suggest that local cardiac aldosterone actions contribute to the development of left ventricular interstitial fibrosis.

Reversal of cardiac fibrosis is a major determinant of the salutary effects of mineralocorticoid receptor antagonists in heart failure. Recently, R-fadrozole was coined as an aldosterone biosynthesis inhibitor, offering an appealing alternative to mineralocorticoid receptor antagonists to block aldosterone action. The present study aimed to evaluate the effects of R- and S-fadrozole on plasma aldosterone and urinary aldosterone excretion rate and to compare their effectiveness vs. the mineralocorticoid receptor antagonist potassium canrenoate to reverse established cardiac fibrosis. Male lean spontaneously hypertensive heart failure (SHHF) rats (40 wk) were treated for 8 wk by sc infusions of low (0.24 mg/kg.d) or high (1.2 mg/kg.d) doses of R- or S-fadrozole or by potassium canrenoate via drinking water (7.5 mg/kg.d). At the high dose, plasma aldosterone levels were decreased similarly by R- and S-fadrozole, whereas urinary aldosterone excretion rate was reduced only by S-fadrozole. In contrast, whereas at the high dose, R-fadrozole effectively reversed preexistent left ventricular interstitial fibrosis by 50% (vs. 42% for canrenoate), S-fadrozole was devoid of an antifibrotic effect. The low doses of the fadrozole enantiomers did not change cardiac fibrosis or plasma aldosterone but similarly reduced urinary aldosterone excretion rate. In conclusion, R-fadrozole may possess considerable therapeutic merit because of its potent antifibrotic actions in the heart. However, the observed discordance between the aldosterone-lowering and antifibrotic effects of the fadrozole enantiomers raises some doubt about the mechanism by which R-fadrozole diminishes cardiac collagen and about the generality of the concept of lowering aldosterone levels to treat the diseased heart.

Case reports of conjoined twins ("Siamese twins") in wild mammals are scarce. Most published reports of conjoined twins in mammals concern cases in man and domestic mammals. This article describes a case of cephalopagus conjoined twins in a leopard cat (Prionailurus bengalensis) collected on the island of Sumatra, Indonesia, in the period 1873-76. A review of known cases of conjoined twinning in wild mammals is given.

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11beta-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1.

Targeting drugs to the heart by intrapericardial (i.p.c.) delivery may be a promising strategy to obtain higher drug efficiencies with lesser side effects. We examined whether i.p.c. delivery of sotalol and atenolol in rats offers advantages over intravenous (i.v.) application. Following sustained IPC infusion of sotalol or atenolol, pericardial fluid levels exceeded plasma levels 97 and 134 times respectively (P < 0.01) resulting in 3.8 and 4.7 times higher overall left ventricular tissue drug levels (P < 0.05). In a second experiment, the effects of the i.p.c. or i.v. beta-blocker infusions on nitroprusside-induced tachycardia were studied in conscious rats. For both drugs, i.p.c. infusion of 0.03 mg/kg.h produced similar antitachycardiac effects as the 1 mg/kg.h i.v. dose. In a third set of studies, dP/dt max challenged by dobutamine infusion was assessed to study ventricular contractile function after i.v. and i.p.c. sotalol in anesthetized rats. i.p.c. sotalol infusion attenuated the dobutamine response curve to a greater extent than i.v. (P < 0.01). In conclusion, i.p.c. infusion of sotalol and atenolol results in high cardiac tissue concentrations with low systemic drug levels. Similar antitachycardiac effects can be obtained at a 10- to 30-fold lower dose compared with i.v. delivery. Also, depression of ventricular contractility is acquired at a substantially lower i.p.c. sotalol dose. Thus, beta-blocking properties of sotalol and atenolol can be greatly enhanced by applying them i.p.c.

1. To explain the large differences in (the stereoselectivity of) the clearances of the enantiomers of warfarin and acenocoumarol (4'-nitrowarfarin) their human liver microsomal metabolism has been studied and enzyme kinetic parameters determined. The effects of cimetidine, propafenone, sulphaphenazole, and omeprazole on their metabolism has been investigated. 2. The 4-hydroxycoumarins follow similar metabolic routes and are mainly hydroxylated at the 6- and 7-position (accounting for 63 to 99% of the metabolic clearances). 3. Due to the lower Km values of R- and S-acenocoumarol and higher Vmax values of S-acenocoumarol, the overall metabolic clearances of R/S acenocoumarol exceed those of R/S warfarin 6 and 66 times respectively. 4. The metabolism of both compounds is stereoselective for the S-enantiomers, which is 10 times more pronounced in the case of acenocoumarol. 5. Except for the 7-hydroxylation of the R-enantiomers (r = 0.90; P < 0.025), the 6- and 7-hydroxylation rates of R/S warfarin do not correlate with those of R/S acenocoumarol. 6. Sulphaphenazole competitively inhibits the 7- and in some samples partly (up to 50%) the 6-hydroxylation of S-warfarin as well as the 7-hydroxylation of R- and S-acenocoumarol and the 6-hydroxylation of S-acenocoumarol (Kis ranging from 0.5-1.3 microM). 7. Omeprazole partly (40-80%) inhibits the 6- and 7-hydroxylation of R-warfarin (Ki = 99 and 117 microM) and of R- (Ki = 219 and 7.2 microM) and S-acenocoumarol (Ki = 6.1 and 7.7 microM) but not S-warfarin in a competitive manner. 8. Differences in the partial (up to 40%) inhibition of the metabolism of the enantiomers of the 4-hydroxycoumarins were also observed for the relatively weak inhibitors, propafenone and cimetidine.9. The results suggest that the coumarin ring hydroxylations of both compounds are catalysed by different combinations of P450 isozymes. The 7-hydroxylation of R/S acenocoumarol and the 6-hydroxylation of S-acenocoumarol are at least partly conducted by (a) P450 isozyme(s) of the 2C subfamily different from P450 2C9 (the main S-warfarin 7- and 6-hydroxylase).