The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture.

The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14+ DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system.

Adrenal insufficiency is a contraindication for omalizumab therapy in mast cell activation disease: risk for serum sickness.

Omalizumab is an effective therapeutic humanized murine IgE antibody in many cases of primary systemic mast cell activation disease (MCAD). The present study should enable the clinician to recognize when treatment of MCAD with omalizumab is contraindicated because of the potential risk of severe serum sickness and to report our successful therapeutic strategy for such adverse event (AE). Our clinical observations, a review of the literature including the event reports in the FDA AE Reporting System, the European Medicines Agency Eudra-Vigilance databases (preferred search terms: omalizumab, Xolair®, and serum sickness) and information from the manufacturer's Novartis database were used. Omalizumab therapy may be more likely to cause serum sickness than previously thought. In patients with regular adrenal function, serum sickness can occur after 3 to 10 days which resolves after the antigen and circulating immune complexes are cleared. If the symptoms do not resolve within a week, injection of 20 to 40 mg of prednisolone on two consecutive days could be given. However, in MCAD patients whose adrenal cortical function is completely suppressed by exogenous glucocorticoid therapy, there is a high risk that serum sickness will be masked by the MCAD and evolve in a severe form with pronounced damage of organs and tissues, potentially leading to death. Therefore, before the application of the first omalizumab dose, it is important to ensure that the function of the adrenal cortex is not significantly limited so that any occurring type III allergy can be self-limiting.

Adjustment for time-invariant and time-varying confounders in 'unexplained residuals' models for longitudinal data within a causal framework and associated challenges.

'Unexplained residuals' models have been used within lifecourse epidemiology to model an exposure measured longitudinally at several time points in relation to a distal outcome. It has been claimed that these models have several advantages, including: the ability to estimate multiple total causal effects in a single model, and additional insight into the effect on the outcome of greater-than-expected increases in the exposure compared to traditional regression methods. We evaluate these properties and prove mathematically how adjustment for confounding variables must be made within this modelling framework. Importantly, we explicitly place unexplained residual models in a causal framework using directed acyclic graphs. This allows for theoretical justification of appropriate confounder adjustment and provides a framework for extending our results to more complex scenarios than those examined in this paper. We also discuss several interpretational issues relating to unexplained residual models within a causal framework. We argue that unexplained residual models offer no additional insights compared to traditional regression methods, and, in fact, are more challenging to implement; moreover, they artificially reduce estimated standard errors. Consequently, we conclude that unexplained residual models, if used, must be implemented with great care.

Blood and Cerebrospinal Fluid α-Tocopherol and Selenium Concentrations in Neonatal Foals with Neuroaxonal Dystrophy.

BACKGROUND: Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on α-tocopherol (α-TP)-deficient diet. OBJECTIVE: Intramuscular α-TP and selenium (Se) administration at 4 days of age would have no significant effect on serum or cerebrospinal fluid (CSF) α-TP in healthy foals. Serum and CSF α-TP, but not Se, would be significantly decreased in NAD/EDM-affected foals during first year of life. ANIMALS: Fourteen Quarter horse foals; 10 healthy foals supplemented with 0.02 mL/kg injectable α-TP and Se (n = 5) or saline (n = 5) at 4 days of age and 4 unsupplemented NAD/EDM-affected foals. METHODS: Complete neurologic examinations were performed, blood and CSF were collected before (4 days of age) and after supplementation at 10, 30, 60, 120, 180, 240, and 360 days of age. Additional blood collections occurred at 90, 150, 210, and 300 days. At 540 days, NAD/EDM-affected foals and 1 unsupplemented healthy foal were euthanized and necropsies performed. RESULTS: Significant decreases in blood, CSF α-TP and Se found in the first year of life in all foals, with most significant changes in serum α-TP from 4-150 days. Dam α-TP and Se significantly influenced blood concentrations in foals. Injection of α-TP and Se did not significantly increase CSF Se, blood or CSF α-TP in healthy foals. NAD/EDM-affected foals had significantly lower CSF α-TP through 120 days. CONCLUSIONS AND CLINICAL IMPORTANCE: Injection of α-TP and Se at 4 days of age does not significantly increase blood or CSF α-TP. Despite all 14 foals remaining deficient in α-TP, only the 4 genetically predisposed foals developed NAD/EDM.

Lymphatic Interventions for Treatment of Chylothorax.

PURPOSE: To determine effectiveness of lymphatic interventional procedures for treatment of chylothorax. MATERIAL AND METHODS: Analysis of interventions performed from 2001 to 2014. RESULTS: In 21 patients with therapy resistant chylothorax a lymphatic radiological intervention was attempted, which could be performed in 19 cases: 17 thoracic duct embolizations (15 transabdominal, one transzervical and one retrograde transvenous procedure), 2 percutaneous destructions of lymphatic vessels, one CT-guided injection of ethanol next to a duplicated thoracic duct. Fourteen of seventeen (82.3 %) of the technically successful embolizations lead to clinical cure. This encluded three patients with prior unsuccessful surgical thoracic duct ligation. Also the injection of ethanol was clinically effective. Complications were a bile peritonitis requiring operation, and one clinical deterioration of unknown cause. CONCLUSION: Interventional lymphatic procedures allow for effective treatment in many cases of chylothorax, and should be considered early during treatment. KEY POINTS: • Thoracic duct embolization is an effective treatment method for chylothorax. • If embolization is impossible, percutaneous lymphatic destruction or injection of sclerosants/tissue adhesive next to the thoracic duct may be tried.

[Our moral ancestors: determining adjustment sets in causal diagrams with ease]. / Die moralischen Vorfahren: Adjustierungsmengen in Kausaldiagrammen schnell und einfach berechnen.

This article is concerned with the application of causal diagrams (also called DAGs) to the following 2 tasks, which are often faced in epidemiology: (1) a posteriori verification of the adjustment performed in an empirical study; (2) a priori identification of appropriate covariate sets for adjustment during study design. Causal diagram theory provides several methods for solving both of these tasks. However, some of these methods are computationally highly demanding, and thus cannot be carried out by hand and even pose problems for fast modern computers. In order to ease everyday work with causal diagrams, we discuss here the most efficient method known to date for performing the stated tasks. This method is based on the so-called "ancestor moral graph" construction by Lauritzen et al. and enables epidemiologists to solve at ease even large causal diagrams with dozens of variables and associations. Moreover, the presented method is well-suited for implementation in computer software, like it has been done in the DAG program and its graphical counterpart DAGitty.

Caecal intussusceptions in horses: a New Zealand perspective.

OBJECTIVE: To establish the prevalence of intussusceptions involving the caecum in a population of horses admitted to a university hospital for colic. DESIGN: Retrospective clinical study METHODS: Medical records of all horses admitted to the Massey University Veterinary Teaching Hospital between 1991 and 2004 were examined for information of those horses diagnosed with an intussusception involving the caecum. RESULTS: A total of 135 horses were admitted for colic surgery during the study period and 61 horses had a diagnosis of ileocaecal (37), caecocaecal (5) or caecocolic intussusception (19) made either at surgery or necropsy. Of the horses with ileocaecal intussusception, 32 had an incomplete hand-sewn ileocaecostomy without reduction and 29 survived to discharge. All the horses with caecocaecal intussusceptions were diagnosed preoperatively via rectal examination and/or transabdominal ultrasound: 2 were euthanased at surgery and 3 survived to discharge. In the 19 horses with caecocolic intussusceptions, manually reduction at surgery was performed in 6 and 5 of them survived to discharge. A typhlectomy was performed via a colotomy in 6 horses, 3 of which survived to discharge. CONCLUSIONS: The high prevalence of intussusceptions involving the caecum seen at this referral centre may indicate a higher prevalence in New Zealand than is reported elsewhere in the world. CLINICAL RELEVANCE: Intussusceptions involving the caecum should be considered as a differential diagnosis in horses presenting with chronic low-grade colic. Transabdominal ultrasound is useful for identifying caecocaecal and caecocolic intussusceptions. Hand-sewn side-to-side incomplete ileocaecostomy is a quick, effective and safe method of surgical treatment of ileocaecal intussusceptions.

Surgical management and outcome of a type-III Salter-Harris fracture of the frontal plane of the distal radial physis in a foal.

CASE HISTORY: A 4-week-old Thoroughbred filly presented with lameness of acute, severe onset of the left foreleg (LF) of 3 days' duration. CLINICAL FINDINGS: Diffuse swelling was present around the distal radius and carpus of the LF. Carpal varus that could be reduced manually was present. Radiographs revealed an intra- articular frontal-plane fracture in the distal radial epiphysis, which continued cranially through the distal radial physis (DRP). The lateral aspect of the DRP was wider than expected. Latero-medial carpal instability was resolved by placement of a lag screw from the dorsal midline through the epiphysis across the fracture. The DRP closed prematurely, resulting in a non-reducible carpal varus deformity, which was partially corrected surgically, and reduced the length of the limb. DIAGNOSIS: Frontal-plane Salter-Harris type-III DRP fracture and varus deformity due to physeal injury. CLINICAL RELEVANCE: Frontal-plane Salter-Harris type- III fractures do not appear to have been previously reported in horses and may be associated with a poor prognosis for athletic activity.

Prostate cancer tissue is masked by bicalutamide: a case report.

Prostate cancer is the most common malignant tumor in men. Recently, a slightly decreased frequency of margin positivity following neoadjuvant bicalutamide treatment due to tumor shrinkage was reported. Trials investigating other anti-androgens in the past also reported lower frequencies of surgical margin positivity, but patients outcome has not improved. In this case, local recurrence was confirmed by needle biopsy in a patient five years following radical prostatectomy for prostate adenocarcinoma. After therapy with 50 mg bicalutamide for a month, the tumour was resected. Despite of detailed histological work-up and immunohistochemistry cancer suspicious lesions were not found. We think that bicalutamide may be capable of masking prostate cancer cells.

Renal agenesis in an alpaca cria.

A 4-day-old alpaca cria presented for inappetence that responded to symptomatic treatment. The cria re-presented with acute signs of inappetence and azotaemia. The azotaemia persisted despite intravenous fluid therapy. There was no right kidney on ultrasound and there appeared to be perirenal oedema around the left kidney. A diagnosis of right renal agenesis and acute renal failure of the left kidney was made. The cria failed to improve and was euthanased. Necropsy examination confirmed right renal agenesis and agenesis of the right ureter and right renal artery. A section of left kidney submitted for histological examination revealed diffuse, acute, marked tubular degeneration and nephrosis. The cause of the renal failure in the left kidney was not determined.

Aggressive angiomyxoma of the prostate mimicking benign prostatic hyperplasia.

Aggressive angiomyxoma (AAM) is a locally invasive soft tissue tumor with a high risk of local recurrence but without metastatic spread. The mesenchymal tumor is relatively site-specific and has a peak incidence in females in their 2nd or 4th decade. Only few cases in males have been reported in the literature. We describe what we think is the first case of an aggressive angiomyxoma arising in the prostate presenting with classical symptoms of benign prostatic hyperplasia.

[Diagnostic imaging of vascular leiomyosarcomas]. / Bildgebende Diagnostik von vaskulären Leiomyosarkomen.

Primary vascular leiomyosarcomas are very rare tumors, with the venous variety most often arising from the inferior caval vein and the arterial variety from the pulmonary artery. The tumors show either an exclusive intra- or extravascular pattern or a mixed growth pattern. The clinical symptoms depend on tumor location, with intraluminal tumors of the inferior caval vein causing edema or a Budd-Chiari syndrome. Leiomyosarcomas of the pulmonary artery can mimic chronic central or recurrent peripheral pulmonary embolism. Contrast enhanced spiral CT with multiplanar reconstruction is the diagnostic method of choice when a vascular leiomyosarcoma is suspected. MRI with MR-angiography can be added. If a tumor of undetermined origin shows a broad contact with a vessel and/or an intraluminal component, possible primary vascular leiomyosarcoma should be included in the differential diagnosis.

Limitations and pitfalls of Couinaud's segmentation of the liver in transaxial Imaging.

The segmental anatomy of the human liver has become a matter of increasing interest to the radiologist, especially in view of the need for an accurate preoperative localization of focal hepatic lesions. In this review article first an overview of the different classical concepts for delineating segmental and subsegmental anatomy on US, transaxial CT, and MR images is given. Essentially, these procedures are based on Couinaud's concept of three vertical planes that divide the liver into four segments and of a transverse scissura that further subdivides the segments into two subsegments each. In a second part, the limitations of these methods are delineated and discussed with the conclusion that if exact preoperative localization of hepatic lesions is needed, tumor must be located relative to the avascular planes between the different portal territories.

[MRI in cavernous transformation of the portal vein: secondary biliary abnormalities and portoportal collaterals]. / MRT bei kavernöser Transformation der Pfortader - Sekundäre Gallengangsveränderungen und portoportale Kollateralen.

PURPOSE: Evaluation of portoportal collateral vessels and associated biliary abnormalities in patients with cavernous transformation of the portal vein by MRI. MATERIAL AND METHODS: Review of 34 MRI examinations performed on patients with angiographically or MR-angiographically proven cavernous transformation. The analysis included the pattern of the portoportal collateral circulation and the abnormalities of the biliary system, such as wall thickening, stenosis, dilations and irregularities of the extra-and intrahepatic bile ducts. RESULTS: 23 (67.6%) of 34 patients with cavernous transformation had paracholedochal portoportal collateral vessels, with 22 (64.7%) showing visible luminal channels. Epicholedochal venous collaterals could be observed in 8 (23.5%) patients. 24 (70.5%) of 34 patients demonstrated biliary abnormalities due to portoportal collaterals, leading to stenosis with dilatation of the proximal bile ducts in 8 (23.5%) patients. The ductal walls were irregular in 7 (20.5%) patients, and thickened in 11 (32.3%). The gallbladder wall was thickened in 4 (12.9%) patients. CONCLUSION: Portoportal collaterals in patients with cavernous transformation of the portal vein can be identified by MRI. These collaterals frequently alter the biliary system, which must be considered in differential diagnosis of biliary abnormalities observed in the presence of portoportal collaterals.

Hemodynamic effects of propranolol and nitrates in cirrhotics with transjugular intrahepatic portosystemic stent-shunt.

BACKGROUND: The combination of tailored TIPS with vasoactive drugs might allow reduction of the rate of subsequent shunt-related sequelae. METHODS: We studied cirrhotic patients 8 weeks (median) after TIPS insertion (8-10 mm) for variceal bleeding. Nitrate (0.1 mg/kg) and propranolol (0.15 mg/kg) alone or combined (same dosages) were infused (I h) sequentially at 1-h intervals (n = 17). Similarly, propranolol was randomly compared to placebo (NaCl, n = 14). We measured mean arterial pressure (MAP, mmHg), heart rate (HR) and portal pressure gradient (PPG: portal minus central venous pressure) prior to and after drugs. RESULTS: Propranolol reduced PPG (mean +/- s, mmHg) significantly (14.8 +/- 3.7 versus 12.1 +/- 3.7; -21% +/- 10%; P < 0.001), while nitrates alone (14.3 +/- 3.4 versus 13.7 +/- 3.4; -11% +/- 3%; P=0.06) or nitrates plus propranolol (12.9 +/- 4 versus 12.4 +/- 4; -7% +/- 8%; P=0.2) induced only minor additive effects on portal pressure. However, nitrate reduced MAP (P < 0.001) and increased HR (P < 0.01), whereas propranolol reduced only HR (P < 0.001) with unchanged MAP, and the combination decreased MAP (P < 0.001). Compared to placebo (no effect), propranolol decreased PPG (14.4 +/- 5.6 versus 11.1 +/- 5.5; -23% +/- 11%; P < 0.001) and HR (P < 0.001). Overall, most patients (92%) responded to propranolol and 54% showed a marked PPG decrease (>20%). CONCLUSIONS: Propranolol significantly reduced portal pressure in cirrhotic patients after TIPS, whereas nitrates induced only minor benefit. TIPS-treated patients might therefore profit from additive propranolol therapy allowing limited shunts to be applied initially and/or to reduce the need for TIPS revisions in the case of shunt-dysfunction during follow-up.

FDG-PET findings of vertebral compression fractures in osteoporosis: preliminary results.

The aim of this study was to evaluate FDG-PET findings in patients with osteoporosis or preclinical osteoporosis and acute vertebral compression fractures in order to determine whether FDG-PET has a value for distinction of pathological from osteoporotic vertebral fractures. 17 patients with a spontaneous compression fracture of the spine were evaluated by bone scanning with Tc-99m HDP, positron emission tomography with fluorine-18 deoxyglucose (FDG-PET) and magnetic resonance imaging (MRI). Osteoporosis had been established in all cases by X-ray and osteodensitometry. PET and bone scan images were scored independently from 0 (no pathological uptake) to 4 (definitive pathological uptake) by two blinded nuclear medicine physicians. The results of the blinded scoring were compared to MRI findings which served as gold standard. In 13 out of 17 patients, MRI demonstrated a vertebral fracture generating from osteoporosis. In 12 of these 13 cases, PET scans were scored with 0 or 1 and categorized as true negative. Standard uptake values (SUV) ranged between 1.1 and 2.4. In one of the 13 patients, PET was interpreted false positive with an uptake score of 3 (SUV = 2.9). Of the 17 patients, MRI revealed a pathological fracture caused by spondylodiscitis in three patients and by plasmacytoma in one patient. In these patients, all PET scans were highly positive with a score of 3 and 4 and SUV values between 3.8 to 9.8. The bone scans of all 17 patients were positive with scores of 3 or 4 but a differentiation between osteoporotic and pathological fractures was not possible. Our preliminary results indicate that acute vertebral fractures that originated from osteoporosis or preclinical osteoporosis tend to have no pathologically increased FDG uptake. Since a high FDG uptake is characteristic for malignant and inflammatory processes, use of FDG-PET may have potential value for differentiation between osteoporotic and pathological vertebral fractures.

[Visceral artery aneurysms]. / Das Viszeralarterienaneurysma.

The purpose of this article is to review the etiology, clinical presentation and treatment options of visceral artery aneurysms (VAA) on the basis of our experiences. Visceral artery aneurysms are uncommon lesions with a frequency of 0,1-0,2 % in autopsy statistics. In fact many visceral artery aneurysms still present first with a rupture (22 %) and despite emergency laparotomies the mortality rate is about 8,5 %. The course of disease often is disastrous due to rupture of the aneurysms or thromboembolic complications, emphasizing the importance to be aware of this differential diagnosis of abdominal pain. This article covers 9 patients with VAA. 3 patients each revealed an a. lienalis aneurysm and a. gastrica aneurysm, resp. In the other 3 patients an aneurysm of the a. gastroepiploica, the a. pancreatico-duodenalis and the a. mesenterica superior resp. was proven. In 8 of 9 patients a surgical therapy of the VAA took place. Only 2 patients (22 %) were interventionally treated. 1 patient deceased due to postoperative hemorrhage. Both the surgical and the radiological intervention therapy are available for treatment of the VAA. The decision on the choice of the therapeutic procedure should be made on an individual basis.