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Objective Stereotactic body radiotherapy (SBRT) is a noninvasive treatment option for lymph node metastases (LNM). Magnetic resonance (MR)-guidance offers superior tissue contrast and enables treatment of targets in close vicinity to radiosensitive organs at risk (OAR). However, literature on MR-guided SBRT of LNM is scarce with no report on outcome parameters. Materials and methods We report a subgroup analysis of a prospective observational study comprising patients with LNM. Patients received MR-guided SBRT at our MRIdian Linac (ViewRay Inc., Mountain View, CA, USA) between January 2019 and February 2020. Local control (LC), progression-free survival (PFS) and overall survival (OS) analysis were performed using the Kaplan–Meier method with log rank test to test for significance (p Results Twenty-nine patients (72.4% with prostate cancer; 51.7% with no distant metastases) received MR-guided SBRT for in total 39 LNM. Median dose was 27 Gy in three fractions, prescribed to the 80% isodose. At 1‑year, estimated LC, PFS and OS were 92.6, 67.4 and 100.0%. Compared to baseline, six patients (20.7%) developed new grade I toxicities (mainly fatigue). One grade II toxicity occurred (fatigue), with no adverse event grade ≥III. Overall treatment experience was rated particularly positive, while the technically required low room temperature still represents the greatest obstacle in the pursuit of the ideal patient acceptance. Conclusion MR-guided SBRT of LNM was demonstrated to be a well-accepted treatment modality with excellent preliminary results. Future studies should evaluate the clinical superiority to conventional SBRT.

BACKGROUND: Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using (68)Ga-labelled FAP-Inhibitors ((68)Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent). PATIENTS AND METHODS: Patients underwent contrast enhanced staging CT (ceCT) and magnetic resonance imaging (ceMRI) before (68)Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150–250 MBq of (68)Ga-labelled FAPI tracers. SUV(max) and SUV(mean) values of ACCs and healthy organs were obtained using a 60% of maximum i so-contour. FAP and alpha smooth muscle actin (a-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without (68)Ga FAPI-PET/CT). Staging and radiotherapy planning based on (68)Ga-FAPI-PET/CT versus ceCT/MRI alone were compared. RESULTS: We observed elevated tracer uptake in all ACCs. lmmunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, (68)Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, (68)Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI. CONCLUSION: (68)Ga-FAPI-PET/CT is a promising imaging modality for ACC. Increasing the accuracy of staging exams and radiotherapy planning volumes, as compared conventional to CT and MRI.

We tested the hypothesis that the maternal supply of essential fatty acids (EFA), especially α-linolenic acid, and conjugated linoleic acid (CLA), affects glucose metabolism, the endocrine regulation of energy metabolism and growth, and the intestinal development of neonatal calves. We studied calves from dams that received an abomasal infusion of 76 g/d coconut oil (CTRL; n = 9), 78 g/d linseed oil and 4 g/d safflower oil (EFA; n = 9), 38 g/d Lutalin (BASF SE) containing 27% cis-9,trans-11 and trans-10,cis-12 CLA (CLA; n = 9), or a combination of EFA and CLA (EFA+CLA; n = 11) during the last 63 d of gestation and early lactation. Calves received colostrum and transition milk from their own dam for the first 5 d of life. Insulin-like growth factor (IGF)-I, leptin, and adiponectin concentrations were measured in milk. Blood samples were taken before first colostrum intake, 24 h after birth, and from d 3 to 5 of life before morning feeding to measure metabolic and endocrine traits in plasma. On d 3 of life, energy expenditure was evaluated by a bolus injection of NaH13CO3 and determination of CO2 appearance rate. On d 4, additional blood samples were taken to evaluate glucose first-pass uptake and 13CO2 enrichment after [13C6]-glucose feeding and intravenous [6,6-2H2]-glucose bolus injection, as well as postprandial changes in glucose, nonesterified fatty acids (NEFA), insulin, and glucagon. On d 5, calves were killed 2 h after feeding and samples of small intestinal mucosa were taken for histomorphometric measurements. The concentrations of IGF-I, adiponectin, and leptin in milk decreased during early lactation in all groups, and the concentrations of leptin in first colostrum was higher in EFA than in CTRL cows. Plasma glucose concentration before first colostrum intake was higher in EFA calves than in non-EFA calves and was lower in CLA calves than in non-CLA calves. Plasma IGF-I concentration was higher on d 1 before colostrum intake in EFA calves than in EFA+CLA calves and indicated an overall CLA effect, with lower plasma IGF-I in CLA than in non-CLA calves. Postprandial NEFA concentration was lowest in EFA and CLA calves. The postprandial rise in plasma insulin was higher in EFA than in non-EFA calves. Plasma adiponectin concentration increased from d 1 to d 2 in all groups and was higher on d 3 in CLA than in non-CLA calves. Plasma leptin concentration was higher on d 4 and 5 in EFA than in non-EFA calves. Maternal fatty acid treatment did not affect energy expenditure and first-pass glucose uptake, but glucose uptake on d 4 was faster in EFA than in non-EFA calves. Crypt depth was lower, and the ratio of villus height to crypt depth was higher in the ilea of CLA than non-CLA calves. Elevated plasma glucose and IGF-I in EFA calves immediately after birth may indicate an improved energetic status in calves when dams are supplemented with EFA. Maternal EFA and CLA supplementation influenced postprandial metabolic changes and affected factors related to the neonatal insulin response.

Pancreatic ductal carcinoma (PDAC) is a highly lethal cancer, and early detection and accurate staging are critical to prolonging survival. PDAC typically has a prominent stroma including cancer-associated fibroblasts that express fibroblast activation protein (FAP). FAP is a new target molecule for PET imaging of various tumors. In this retrospective study, we describe the clinical impact of PET/CT imaging using 68Ga-labeled FAP-inhibitors (68Ga-FAPI PET/CT) in 19 patients with PDAC (7 primary, 12 progressive/recurrent). Methods: All patients underwent contrast-enhanced CT (ceCT) for TNM staging before 68Ga-FAPI PET/CT imaging. PET scans were acquired 60 min after administration of 150–250 MBq of 68Ga-labeled FAP-specific tracers. To characterize 68Ga-FAPI uptake over time, additional scans after 10 or 180 min were acquired in 6 patients. SUVmax and SUVmean values of PDAC manifestations and healthy organs were analyzed. The tumor burden according to 68Ga-FAPI PET/CT was compared with TNM staging based on ceCT and changes in oncologic management were recorded. Results: Compared with ceCT, 68Ga-FAPI PET/CT results led to changes in TNM staging in 10 of 19 patients. Eight of 12 patients with recurrent/progressive disease were upstaged, 1 was downstaged, and 3 had no change. In newly diagnosed PDAC, 1 of 7 patients was upstaged, and the staging of 6 patients did not change. Changes in oncologic management occurred in 7 patients. Markedly elevated uptake of 68Ga-FAPI in PDAC manifestations after 1 h was seen in most cases. Differentiation from pancreatitis based on static imaging 1 h after injection was challenging. With respect to imaging after multiple time points, PDAC and pancreatitis showed a trend for differential uptake kinetics. Conclusion:68Ga-FAPI PET/CT led to restaging in half of the patients with PDAC and most patients with recurrent disease compared with standard of care imaging. The clinical value of 68Ga-FAPI PET/CT should be further investigated.

Background Radiotherapy is known to improve local tumor control in locally advanced pancreatic cancer (LAPC), although there is a lack of convincing data on a potential overall survival benefit of chemoradiotherapy over chemotherapy alone. To improve efficacy of radiotherapy, new approaches need to be evolved. Carbon ion radiotherapy is supposed to be more effective than photon radiotherapy due to a higher relative biological effectiveness (RBE) and due to a steep dose-gradient making dose delivery highly conformal. Methods The present Phase II PACK-study investigates carbon ion radiotherapy as definitive treatment in LAPC as well as in locally recurrent pancreatic cancer. A total irradiation dose of 48 Gy (RBE) will be delivered in twelve fractions. Concurrent chemotherapy is accepted, if indicated. The primary endpoint is the overall survival rate after 12 months. Secondary endpoints are progression free survival, safety, quality of life and impact on tumor markers CA 19–9 and CEA. A total of twenty-five patients are planned for recruitment over 2 years. Discussion Recently, Japanese researches could show promising results in a Phase I/II-study evaluating chemoradiotherapy of carbon ion radiotherapy and gemcitabine in LAPC. The present prospective PACK-study investigates the efficacy of carbon ion radiotherapy in pancreatic cancer at Heidelberg Ion Beam Therapy Center (HIT) in Germany. Trial registration The trial is registered at ClinicalTrials.gov: NCT04194268 (Retrospectively registered on December, 11th 2019).

OBJECTIVES Survival of patients with locally advanced pancreatic cancer (LAPC) is improved when neoadjuvant chemoradiation enables subsequent surgical resection. Here, the authors assess changes in vessel involvement as a possible indicator of resectability. METHODS Pancreatic gross tumor and all major abdominal vessels were contoured for 49 patients with unresectable LAPC before and after neoadjuvant chemoradiation. Changes were compared by paired t tests. Tumor-vessel relationships were automatically quantified using Medical Imaging Interaction Toolkit and examined for correlation with resectability and outcome. RESULTS Tumor volumes were significantly reduced by chemoradiation (41 to 33 mL, P

Purpose Cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein (FAP) have been associated with the aggressive nature of head and neck cancers (HNCs). These tumours grow diffusely, leading to extremely challenging differentiation between tumour and healthy tissue. This analysis aims to introduce a novel approach of tumour detection, contouring and targeted radiotherapy of HNCs using visualisation of CAFs: PET-CT with 68Ga-radiolabeled inhibitors of FAP (FAPI). Methods FAPI PET-CT was performed without complications prior to radiotherapy in addition to contrast enhanced CT (CE-CT) and MRI on 14 patients with HNC. First, for tissue biodistribution analysis, volumes of interest were defined to quantify SUVmean and SUVmax in tumour and healthy parenchyma. Secondly, using four thresholds of three-, five-, seven- and tenfold increase of FAPI enhancement in the tumour as compared with normal tissue, four different gross tumour volumes (FAPI-GTV) were created automatically. These were compared with GTVs created conventionally with CE-CT and MRI (CT-GTV). Results The biodistribution analysis revealed high FAPI avidity within tumorous lesions (e.g. primary tumours, SUVmax 14.62 ± 4.44; SUVmean 7.41 ± 2.39). In contrast, low background uptake was measured in healthy tissues of the head and neck region (e.g. salivary glands: SUVmax 1.76 ± 0.31; SUVmean 1.23 ± 0.28). Considering radiation planning, CT-GTV was of 27.3 ml, whereas contouring with FAPI resulted in significantly different GTVs of 67.7 ml (FAPI × 3, p = 0.0134), 22.1 ml (FAPI × 5, p = 0.0419), 7.6 ml (FAPI × 7, p = 0.0001) and 2.3 ml (FAPI × 10, p = 0.0001). Taking these significant disparities between the GTVs into consideration, we merged FAPI-GTVs with CT-GTVs. This resulted in median volumes, that were, as compared to CT-GTVs, significantly larger with FAPI × 3 (54.7 ml, + 200.5% relative increase, p = 0.0005) and FAPI × 5 (15.0 ml, + 54.9%, p = 0.0122). Furthermore, FAPI-GTVs were not covered by CE-CT-based planning target volumes (CT-PTVs) in several cases. Conclusion We present first evidence of diagnostic and therapeutic potential of FAPI ligands in head and neck cancer. Larger studies with histopathological correlation are required to validate our findings.

Feeding management of the postnatal and preweaning calf has an important impact on calf growth and development during this critical period and affects the health and well-being of the calves. After birth, an immediate and sufficient colostrum supply is a prerequisite for successful calf rearing. Colostrum provides high amounts of nutrient as well as non-nutrient factors that promote the immune system and intestinal maturation of the calf. The maturation and function of the neonatal intestine enable the calf to digest and absorb the nutrients provided by colostrum and milk. Therefore, colostrum intake supports the start of anabolic processes in several tissues, stimulating postnatal body growth and organ development. After the colostrum feeding period, an intensive milk feeding protocol, that is, at least 20% of BW milk intake/day, is required to realise the calf potential for growth and organ development during the preweaning period. Insufficient milk intake delays postnatal growth and may have detrimental effects on organ development, for example, the intestine and the mammary gland. The somatotropic axis as the main postnatal endocrine regulatory system for body growth is stimulated by the intake of high amounts of colostrum and milk and indicates the promotion of anabolic metabolism in calves. The development of the forestomach is an important issue during the preweaning period in calves, and forestomach maturation is best achieved by solid feed intake. Unfortunately, intensive milk-feeding programmes compromise solid feed intake during the first weeks of life. In the more natural situation for beef calves, when milk and solid feed intake occurs at the same time, calves benefit from the high milk intake as evidenced by enhanced body growth and organ maturation without impaired forestomach development during weaning. To realise an intensive milk-feeding programme, it is recommended that the weaning process should not start too early and that solid feed intake should be at a high extent despite intensive milk feeding. A feeding concept based on intensive milk feeding prevents hunger and abnormal behaviour of the calves and fits the principles of animal welfare during preweaning calf rearing. Studies on milk performance in dairy cows indicate that feeding management during early calf rearing influences lifetime performance. Therefore, an intensive milk-feeding programme affects immediate as well as long-term performance, probably by programming metabolic pathways during the preweaning period.

Mycotoxin contaminated feed has been associated with colic of horses caused by intestinal disorders. Whether such disease conditions alter the intestinal toxin metabolism and transfer across a compromised mucosal barrier is unknown. A screening approach was used to relate blood residue levels of DON, ZEN and their metabolites to the status of the horses (sick vs. healthy). A total of 55 clinically healthy horses from 6 different farms with varying feeding background served as control for sick horses (N = 102) hospitalized due to colic. ZEN, alpha-zearalenol (ZEL), beta-ZEL and DON were detectable in peripheral blood as indicators for the inner exposure with significant farm effects for alpha- and beta-ZEL. However, the levels in sick horses were similar to all farms. Moreover, the proportion of beta-ZEL of all detected ZEN metabolites as an indicator for the degree of metabolism of ZEN was not different for sick horses but differed amongst the control farms. Although the incidence of DON in blood was generally low and not significantly different amongst healthy and sick horses, the positive samples were nearly exclusively found in sick horses suggesting either a higher toxin transfer, an association of DON with the development of colic or a different feeding background.

Simple Summary Fatty acids play an important role in the regulation of inflammation and oxidative stress. The birth and the neonatal period are characterized by a high risk of inflammation and an increased production of reactive oxygen species in the calf. The present study deals with the effects of a different maternal fatty acid supply including the supplementation of saturated fatty acids by coconut oil, essential fatty acids, conjugated linoleic acid or a combination of essential fatty acids and conjugated linoleic acid on the immunological and oxidative as well as anti-oxidative status of neonatal calves. Maternal essential fatty acid as well as conjugated linoleic acid supply affected the inflammatory response and the oxidative and anti-oxidative status of the neonatal offspring. Essential fatty acids might have beneficial effects on the prevention of dysregulated inflammation after birth and reduced the plasma bilirubin concentrations in this period. Conjugated linoleic acid and saturated fatty acids might increase the inflammatory response. Similarly, plasma bilirubin increased, which in part might serve as a protector against oxidative stress in the early phase after birth. Abstract Fatty acids are known for their regulatory role in inflammation and oxidative stress. The present study investigated 38 calves born from dams, abomasally supplemented with coconut oil, essential fatty acids (EFA), conjugated linoleic acid (CLA) or EFA + CLA, according to immunological traits and the oxidative and anti-oxidative status for the first 5 days of life. On day 2 of life, plasma total bilirubin, cholesterol, interleukin 1-β and ferric ion reducing anti-oxygen power (FRAP) were lower in calves with than without maternal EFA supplementation, and FRAP additionally on day 4. On day 3, the concentrations of reactive oxygen metabolites were higher in calves with than without maternal EFA supplementation and additionally on day 5 together of retinol. Total leucocyte counts were decreased in the EFA group compared to the CLA group on day 5. Lymphocyte proportions decreased from day 1 to 5 only in the EFA + CLA group. On day 2, plasma total protein was higher in CLA and EFA + CLA than in EFA calves. Similarly, CLA calves had higher interleukin 1-β concentrations compared to EFA + CLA calves. FRAP was decreased by CLA on day 4. Overall, the maternal fatty acid supply affected the inflammatory response and the oxidative and anti-oxidative status of the neonatal offspring.

PurposeEffective treatment strategies for unresectable locally advanced pancreatic cancer (LAPC) patients are eagerly warranted. Recently, convincing oncological outcomes were demonstrated by carbon ion radiotherapy. Nevertheless, there is a lack of evidence for this modern radiation technique due to the limited number of carbon ion facilities worldwide. Here, we analyze feasibility and efficacy of carbon ion radiotherapy in the management of LAPC at Heidelberg Ion Beam Therapy Center (HIT).MethodsBetween 2015 and 2020, 21 LAPC patients were irradiated with carbon ions with a total dose of 48 Gy (RBE) in single doses of 4 Gy (RBE). Three patients (14%) were treated with concomitant chemotherapy with gemcitabine 300 mg/m2 body surface weekly. Toxicity rates were extracted from the charts. Overall survival, progression free survival, local control, and locoregional control were evaluated using Kaplan–Meier estimates.ResultsOne patient developed ascites CTCAE grade III during radiotherapy, which was related to a later histologically confirmed metachronous peritoneal carcinomatosis. No further higher-graded toxicity could be observed. The most common symptoms were nausea and abdominal pain. After a median estimated follow-up time of 19.1 months, the median progression free survival was 3.7 months, and the median overall survival was 11.9 months. The estimated 1-year local control and locoregional control rates were 89 and 84%, respectively.ConclusionCarbon ion radiotherapy of LAPC patients is safely feasible. Local tumor control rates were high. Nevertheless, compared to historical data, an overall survival improvement could not be observed. This could be explained by the poor prognosis of the selected underlying patients that mostly did not respond to prior chemotherapy as well as the early and frequent emergence of distant metastases that demonstrate the necessity of additional chemotherapy in further studies.

Background The objective of this investigation is to evaluate the outcomes and toxicity of carbon-ion re-irradiation (CIR) in patients with rare head and neck cancers (HNC). There is a paucity of data regarding treatment approaches in this patient cohort, which we aim to address in this work. Methods Thirty-two (n = 32) consecutive patients with uncommon HNC treated between 2010 and 2017 were retrospectively analyzed in terms of clinical outcomes, patterns of failure, and toxicity. Results Mucoepidermoid carcinoma (MEC) was the most common histology (22%). Patients received a median cumulative dose equivalent in 2 Gy fractions (EQD2) after CIR of 128.6 Gy (range, 105.8–146.5 Gy). The local and distant control rates 1 year after CIR were 66 and 72%. No serious acute or late toxicity (≥ grade 3) after CIR was observed. Conclusions CIR may represent an effective and safe treatment alternative to palliative systemic therapies in these rare indications.

The present study investigated clinical and immunological modulations due to intramuscular injection of Escherichia coli LPS in 49-wk-old laying hens over 48 h post injection (p.i.). LPS induced characteristic sickness behavior but no significant body temperature alterations ( P > 0.05). During experimental period decreases in blood albumin, calcium, phosphorus and tryptophan concentrations, hyperglycemia, increased plasma nitrite concentrations, leucopenia, decreased thrombocyte counts, lymphopenia, heterophilia and an increased heterophilic granulocyte/lymphocyte (H/L) ratio were observed after LPS administration. Time-dependent effects were shown on T and B cell subsets in caecal tonsils (CT) and on splenic CD3+/CD4+/CD8+ proportions, on IL-1β and -10 and inducible NO synthase mRNA expression in peripheral blood lymphocytes (PBL), liver, spleen and CT, and on the mRNA expression of the TLR4 in PBL, liver and spleen p.i. ( P

Simple Summary We demonstrate how manual target definition based on contrast-enhanced computed tomography is highly unreliable and inconsistent. In a second step, we used a novel positron emission tomography tracer, FAPI (68Ga-labeled fibroblast activation protein inhibitor) for target volume definition. FAPI-PET/CT contains biologic information as it visualizes cancer associated fibroblasts. The pioneering use of FAPI PET/CT in radiation treatment planning improved target definition in locally recurrent pancreatic cancer. Abstract (1) Background: A new radioactive positron emission tomography (PET) tracer uses inhibitors of fibroblast activation protein (FAPI) to visualize FAP-expressing cancer associated fibroblasts. Significant FAPI-uptake has recently been demonstrated in pancreatic cancer patients. Target volume delineation for radiation therapy still relies on often less precise conventional computed tomography (CT) imaging, especially in locally recurrent pancreatic cancer patients. The need for improvement in precise tumor detection and delineation led us to innovatively use the novel FAPI-PET/CT for radiation treatment planning. (2) Methods: Gross tumor volumes (GTVs) of seven locally recurrent pancreatic cancer cases were contoured by six radiation oncologists. In addition, FAPI-PET/CT was used to automatically delineate tumors. The interobserver variability in target definition was analyzed and FAPI-based automatic GTVs were compared to the manually defined GTVs. (3) Results: Target definition differed significantly between different radiation oncologists with mean dice similarity coefficients (DSCs) between 0.55 and 0.65. There was no significant difference between the volumes of automatic FAPI-GTVs based on the threshold of 2.0 and most of the manually contoured GTVs by radiation oncologists. (4) Conclusion: Due to its high tumor to background contrast, FAPI-PET/CT seems to be a superior imaging modality compared to the current gold standard contrast-enhanced CT in pancreatic cancer. For the first time, we demonstrate how FAPI-PET/CT could facilitate target definition and increases consistency in radiation oncology in pancreatic cancer.

Scientific reports 11(1), 14859 (1-9) (2021). doi:10.1038/s41598-021-94260-y, It is qualitatively well known that kinetics related to nucleation and growth can shift apparent phase boundaries from their equilibrium value. In this work, we have measured this effect in Bi using time-resolved X-ray diffraction with unprecedented 0.25 ms time resolution, accurately determining phase transition pressures at compression rates spanning five orders of magnitude (10$^{–2}$–10$^3$ GPa/s) using the dynamic diamond anvil cell. An over-pressurization of the Bi-III/Bi-V phase boundary is observed at fast compression rates for different sample types and stress states, and the largest over-pressurization that is observed is ΔP = 2.5 GPa. The work presented here paves the way for future studies of transition kinetics at previously inaccessible compression rates., Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Purpose Data on management of locally recurrent pancreatic cancer (LRPC) after primary resection are limited. Recently, surprisingly high overall survival rates were reported after irradiation with carbon ions. Here, we report on our clinical experience using carbon ion radiotherapy as definitive treatment in LRPC at the Heidelberg Ion-Beam Therapy Center (HIT). Methods Between 2015 and 2019, we treated 13 patients with LRPC with carbon ions with a median total dose of 48 Gy (RBE) in 12 fractions using an active raster-scanning technique at a rotating gantry. No concomitant chemotherapy was administered. Overall survival, local control, and toxicity rates were evaluated 18 months after the last patient finished radiotherapy. Results With a median follow-up time of 9.5 months, one patient is still alive (8%). Median OS was 12.7 months. Ten patients (77%) developed distant metastases. Additionally, one local recurrence (8%) and two regional tumor recurrences (15%) were observed. The estimated 1‑year local control and locoregional control rates were 87.5% and 75%, respectively. During radiotherapy, we registered one gastrointestinal bleeding CTCAE grade III (8%) due to gastritis. The bleeding was sufficiently managed with conservative therapy. No further higher-grade acute or late toxicities were observed. Conclusion We demonstrate high local control rates in a rare cohort of LRPC patients treated with carbon ion radiotherapy. The observed median overall survival rate was not improved compared to historical in-house data using photon radiotherapy. This is likely due to a high rate of distant tumor progression, highlighting the necessity of additional chemotherapy.

Objective: Stereotactic radiosurgery (SRS) is an established treatment for brain metastases in the management of metastasized melanoma. The increasing use of checkpoint inhibitors in melanoma therapy leads to combined treatment schemes consisting of immunotherapy and SRS that need to be evaluated regarding safety and feasibility. Methods: We retrospectively analyzed 36 patients suffering from cerebral metastasized melanoma. Between November 2011 and May 2016, altogether 66 brain metastases were treated with single-fraction SRS (18–20 Gy prescribed to the 80% isodose) in combination with a checkpoint inhibitor (ipilimumab: 82%, pembrolizumab: 14% or nivolumab: 4%), administered within 3 months before or after SRS. Toxicity was evaluated with focus on the incidence of central nervous system (CNS) radiation necrosis (CRN). Overall survival (OS), freedom from local progression (FFLP), freedom from central nervous system radiation necrosis (FFCRN), and freedom from distant intracranial progression (FFDIP) were analyzed using the Kaplan-Meier method. Results: The median follow-up was 25 months (range: 2–115 months). Two patients (6%) presented with cerebral edema CTCAE °III and another two patients (6%) presented with one-sided muscle weakness CTCAE °III after SRS. One of these four symptomatic cases correlated with an observed CRN, the other three symptomatic cases were related to local tumor progression (n = 2) or related to the performance of additional whole brain radiotherapy (WBRT). No further CTCAE °III or °IV toxicity was seen. During follow-up, seven of the growing contrast-enhanced lesions were resected, revealing two cases of CRN and five cases of local tumor progression. Altogether, the observed CRN rate of the irradiated metastases was 6–17% at the time of analysis, ranging due to the radiologically challenging differentiation between CRN and local tumor progression. The observed ranges of the 1- and 2-years FFLP rates were 82–85% and 73–80%, respectively. The median FFDIP was 6.1 months, the median OS was 22.2 months. Conclusion: In the presented cohort, the combination of SRS and checkpoint inhibitors in the management of cerebral metastasized melanoma was safe and effective. Compared to historic data on SRS only, the observed CRN rate was acceptable. To gain resilient data on the incidence of CRN after combined treatment schemes, prospective trials are needed.

Background We assessed the quantitative changes in muscle mass and strength during 2 weeks of hospitalization in immobile and mobile acutely ill hospitalized older adults. Methods Forty-one patients (82.4 ± 6.6 years, 73.0% females) participated in this prospective longitudinal observational study. Mobility status was defined according to walking ability as described in the Barthel-Index. Functional status, including handgrip strength and isometric knee-extension strength, and mid-thigh magnetic resonance imaging (MRI) measurements of cross-sectional area (CSA) were conducted on admission and at discharge. Results Twenty-two participants (54%) were immobile and 19 (46%) mobile. In all, 54.0 and 12.0% were at risk of malnutrition and malnourished, respectively. The median time between baseline and follow-up for MRI scans were 13 days in mobile and immobile participants (P = 0.072). Mid-thigh muscle and subcutaneous fat CSA significantly decreased by 3.9cm2 (5.0%, P = 0.002) and 5.3cm2 (5.7%, P = 0.036) during hospitalization whereas intermuscular fat remained unchanged in immobile subjects. No significant changes were observed in mobile patients. In a regression analysis, mobility was the major independent risk factor for changes in mid-thigh muscle CSA as a percentage of initial muscle area (P = 0.022) whereas other variables such as age (P = 0.584), BMI (P = 0.879), nutritional status (P = 0.835) and inflammation (P = 0.291) were not associated with muscle mass changes. There was a significant decrease in isometric knee extension strength (P = 0.002) and no change in handgrip strength (P = 0.167) in immobile patients whereas both parameters increased significantly over time in mobile patients (P = 0.048 and P = 0.012, respectively). Conclusions Two weeks of disease-related immobilization result in a significant loss of thigh muscle mass and muscle strength in older patients with impaired mobility. Concomitantly, there was a significant reduction of subcutaneous adipose tissue in immobile older hospitalized patients whereas no changes were observed in intermuscular fat among these patients. These data highlight the importance of mobility support in maintaining muscle mass and function in older hospitalized patients.

Pelleted feed is associated with improved broiler performance but also with a higher incidence of proventricular dilatation and ascites. The present study aimed to investigate influences of expanded and pelleted (ExP) or finely ground and pelleted feeds (FgP) containing either 6% rapeseed expeller (RSE) or 12% RSE on these adverse effects by studying performance, visceral organ, and immunological traits in 36 broilers. ExP reduced daily feed intake compared to FgP when feeding a 6% RSE diet (P < 0.05) but did not affect the daily feed intake when feeding a 12% RSE diet, which was also reflected in the body weight gain. There were no significant differences in the size of proventriculus and gizzard between feeding groups but significant diet-by-technical feed treatment interactions in case of proventricular and gizzard weights and the proventricular length (P < 0.05). Proventriculi and gizzards were heavier in birds fed 6%ExP than proventriculi or gizzards of animals from all other groups except for birds of the group 12%FgP. A total of three animals (1 from 6%ExP, 1 from 6%FgP, and 1 from 12%ExP) developed ascites during the study. Pooled LsMeans of peripheral blood leucocyte proportions of CD3+/CD4−/CD8− cells were increased in birds fed FgP compared to birds fed ExP (P = 0.048). Pooled LsMeans of CD3+/CD4+/CD8+ T cell subsets in jejunal lamina propria were higher in birds fed 12% RSE compared to birds fed 6% RSE (P = 0.024). Concluding, technical feed treatment or diet did not inhibit adverse effects of pelleting on gizzard and proventricular development. Morphometric alterations of proventriculus and gizzard might modify the local immune system of the distal digestive tract and promote the development of ascites; however, further studies are required to confirm this hypothesis since in the present study only three birds developed ascites.

Sufficient maternal supply of essential fatty acids (EFA) to neonatal calves is critical for calf development. In the modern dairy cow, EFA supply has shifted from α-linolenic acid (ALA) to linoleic acid (LA) due to the replacement of pasture feeding by corn silage-based diets. As a consequence of reduced pasture feeding, conjugated linoleic acid (CLA) provision by rumen biohydrogenation was also reduced. The present study investigated the fatty acid (FA) status and performance of neonatal calves descended from dams receiving corn silage-based diets and random supplementation of either 76 g/d coconut oil (CTRL; n = 9), 78 g/d linseed oil and 4 g/d safflower oil (EFA; n-6/n-3 FA ratio = 1:3; n = 9), 38 g/d Lutalin (BASF SE, Ludwigshafen, Germany) providing 27% cis-9,trans-11 and trans-10,cis-12 CLA, respectively (CLA; n = 9), or a combination of EFA and CLA (EFA+CLA; n = 11) in the last 9 wk before parturition and following lactation. The experimental period comprised the first 5 d of life, during which calves received colostrum and transition milk from their own dam. The nutrient compositions of colostrum and transition milk were analyzed. Plasma samples were taken after birth and before first colostrum intake and on d 5 of life for FA analyses of the total plasma fat and lipid fractions. Maternal EFA and CLA supplementation partly affected colostrum and transition milk composition but did not change the body weights of calves. Most EFA in calves were found in the phospholipid (PL) and cholesterol ester (CE) fractions of the plasma fat. Maternal EFA supplementation increased the percentage of ALA in all lipid fractions of EFA and EFA+CLA compared with CTRL and CLA calves on d 1 and 5, and the increase was much greater on d 5 than on d 1. The LA concentration increased from d 1 to 5 in the plasma fat and lipid fractions of all groups. The concentrations of docosapentaenoic acid, docosahexaenoic acid, and arachidonic acid in plasma fat were higher on d 1 than on d 5, and the percentage of n-3 metabolites was mainly increased in PL if dams received EFA. The percentage of cis-9,trans-11 CLA was higher in the plasma fat of EFA+CLA than CTRL calves after birth. By d 5, the percentages of both CLA isomers increased, leading to higher proportions in plasma fat of CLA and EFA+CLA than in CTRL and EFA calves. Elevated cis-9,trans-11 CLA enrichment was observed on d 5 in PL, CE, and triglycerides of CLA-treated calves, whereas trans-10,cis-12 CLA could not be detected in individual plasma fractions. These results suggest that an altered maternal EFA and CLA supply can reach the calf via the placenta and particularly via the intake of colostrum and transition milk, whereas the n-3 and n-6 FA metabolites partly indicated a greater transfer via the placenta. Furthermore, the nutrient supply via colostrum and transition milk might be partly modulated by an altered maternal EFA and CLA supply but without consequences on calf performance during the first 5 d of life.

Background Reductions in tumor movement allow for more precise and accurate radiotherapy with decreased dose delivery to adjacent normal tissue that is crucial in stereotactic body radiotherapy (SBRT). Deep inspiration breath-hold (DIBH) is an established approach to mitigate respiratory motion during radiotherapy. We assessed the feasibility of combining modern optical surface-guided radiotherapy (SGRT) and image-guided radiotherapy (IGRT) to ensure and monitor reproducibility of DIBH and to ensure accurate tumor localization for SBRT as an imaging-guided precision medicine. Methods We defined a new workflow for delivering SBRT in DIBH for lung and liver tumors incorporating SGRT and IGRT with cone beam computed tomography (CBCT) twice per treatment fraction. Daily position corrections were analyzed and for every patient two points retrospectively characterized: an anatomically stable landmark (predominately Schmorl's nodes or spinal enostosis) and a respiratory-dependent landmark (predominately surgical clips or branching vessel). The spatial distance of these points was compared for each CBCT and used as surrogate for intra- and interfractional variability. Differences between the lung and liver targets were assessed using the Welch t-test. Finally, the planning target volumes were compared to those of free-breathing plans, prepared as a precautionary measure in case of technical or patient-related problems with DIBH. Results Ten patients were treated with SBRT according this workflow (7 liver, 3 lung). Planning target volumes could be reduced significantly from an average of 148 ml in free breathing to 110 ml utilizing DIBH (p < 0.001, paired t-test). After SGRT-based patient set-up, subsequent IGRT in DIBH yielded significantly higher mean corrections for liver targets compared to lung targets (9 mm vs. 5 mm, p = 0.017). Analysis of spatial distance between the fixed and moveable landmarks confirmed higher interfractional variability (interquartile range (IQR) 6.8 mm) than intrafractional variability (IQR 2.8 mm). In contrast, lung target variability was low, indicating a better correlation of patients' surface to lung targets (intrafractional IQR 2.5 mm and interfractional IQR 1.7 mm). Conclusion SBRT in DIBH utilizing SGRT and IGRT is feasible and results in significantly lower irradiated volumes. Nevertheless, IGRT is of paramount importance given that interfractional variability was high, particularly for liver tumors.

Very little is known about the effect of malnutrition on short-term changes of body composition, particularly muscle, among older hospitalized patients. We sought to investigate the association of malnutrition as assessed by the Global Leadership Initiative on Malnutrition (GLIM) criteria with changes of thigh muscle mass and muscle strength among older patients during hospitalization. Forty-one patients (age range 66&ndash, 97 years, 73% female) participated in this prospective longitudinal observational study. Nutritional status was evaluated using the GLIM criteria on admission and at discharge. Functional status and mid-thigh magnetic resonance imaging (MRI) measurements of cross-sectional area (CSA) were conducted on admission and before discharge. In all, 17% were malnourished and 83% had no malnutrition. Mean mid-thigh muscle CSA declined by 7.0 cm2 (&minus, 9%) in malnourished patients during hospitalization (p = 0.008) and remained unchanged among non-malnourished patients (&minus, 1%, p = 0.390). Mean mid-thigh CSA of subcutaneous and intermuscular fat did not change significantly during hospitalization in both groups. Malnourished subjects lost 10% of handgrip strength (&minus, 1.8 kg) and 12% of knee extension strength (&minus, 1.5 kg) during hospitalization. However, the magnitude of both changes did not differ between groups. In a stepwise multiple regression analysis, malnutrition and changes in body weight during hospitalization were the major independent risk factors for the reduction of muscle CSA. Malnutrition according to the GLIM criteria was significantly and independently associated with acute muscle wasting in frail older patients during 2-week hospitalization.

Mustafa Syed,1–3 Jakob Liermann,1–3 Vivek Verma,4 Denise Bernhardt,1,2 Nina Bougatf,1,3 Angela Paul,1,2 Stefan Rieken,1–3 Jürgen Debus,1–3,5 Sebastian Adeberg1,2,5 1Heidelberg Institute of Radiation Oncology, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; 2Department of Radiation Oncology, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany; 3Heidelberg Ion-Beam Therapy Center (HIT), Im Neuenheimer Feld 450, 69120 Heidelberg, Germany; 4Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA; 5Clinical Cooperation Unit Radiation Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany Purpose: It is hypothesized that multifocal glioblastoma (mGBM) is associated with worse prognosis compared to unifocal disease (uGBM). This study aims to investigate the differences in survival rates and progression patterns of patients between these two groups after radiation therapy. Patients and methods: We retrospectively analyzed 265 patients with primary GBM undergoing radiation therapy at the Department of Radiation Oncology, University Hospital Heidelberg, Germany, between 2004 and 2013. Of these, 202 (76%) were uGBMs and 63 (24%) were mGBMs. First, progression-free survival (PFS) and overall survival (OS) between groups were compared using the Kaplan–Meier method. Second, univariate and multivariate Cox proportional hazards regression was applied to discern prognostic and predictive factors with PFS and OS in the cohorts. Third, recurrence patterns of uGBMs and mGBMs were assessed on follow-up MRIs and compared using the chi-squared test. Results: As compared to patients with uGBM, patients with mGBM experienced significantly worse median OS (11.5 vs 14.8 months, P=0.032). Overall, 195 (73.0%) patients experienced tumor progression: 153 (75.7%) patients with uGBM and 46 (73.0%) patients with mGBM. There were no significant differences in PFS between the respective groups (6.5 vs 6.6 months,P=0.750). Of note, concomitant temozolomide treatment was associated with an OS benefit in both uGBM and mGBM by about five months (P=0.006 and P

Tumour necrosis factor (TNF) signalling is mediated via two receptors, TNF-receptor 1 (TNFR1) and TNF-receptor 2 (TNFR2), which work antithetically to balance CNS immune responses involved in autoimmune diseases such as multiple sclerosis. To determine the therapeutic potential of selectively inhibiting TNFR1 in mice with experimental autoimmune encephalomyelitis, we used chimeric human/mouse TNFR1 knock-in mice allowing the evaluation of antagonistic anti-human TNFR1 antibody efficacy. Treatment of mice after onset of disease with ATROSAB resulted in a robust amelioration of disease severity, correlating with reduced central nervous system immune cell infiltration. Long-term efficacy of treatment was achieved by treatment with the parental mouse anti-human TNFR1 antibody, H398, and extended by subsequent re-treatment of mice following relapse. Our data support the hypothesis that anti-TNFR1 therapy restricts immune cell infiltration across the blood-brain barrier through the down-regulation of TNF-induced adhesion molecules, rather than altering immune cell composition or activity. Collectively, we demonstrate the potential for anti-human TNFR1 therapies to effectively modulate immune responses in autoimmune disease.

Effects of energy supply and nicotinic acid (NA) supplementation on the phagocytic activity of polymorphonuclear leukocytes (PMN) and peripheral blood mononuclear cells (PBMC), and on ROS production in PMN of periparturient cows differing in parity were examined. 29 pluriparous and 18 primiparous cows were allocated to four different feeding groups from 42days prepartum until 100days postpartum. They were fed either a ration with a low concentrate proportion of 30% (LC) or a high concentrate proportion of 60% (HC). After parturition all animals received 30% concentrate which was increased to 50% either within 16 (LC) or within 24days (HC). The different concentrate feeding strategies aimed at triggering differences in postpartum lipolysis. Half of the animals per group were supplemented with 24g per day of NA from 42days prepartum until 24days postpartum. All investigated parameters varied significantly over time compared to parturition (p

PURPOSE/OBJECTIVE(S) Adenoid cystic carcinomas (ACCs) are rare epithelial tumors mostly situated in the head and neck region and characterized by infiltrative growth. The tumor stroma of ACCs includes cancer-associated fibroblasts (CAFs) expressing Fibroblast Activation Protein (FAP), a new target for positron emission tomography (PET) imaging. Here we describe the value of PET/ computed tomography (PET/CT) imaging using 68Ga-labelled FAP-Inhibitors (68Ga-FAPI-PET/CT) and their clinical potential for staging and radiotherapy planning in 12 ACC patients (7 primary, 5 recurrent). MATERIALS/METHODS Patients underwent contrast enhanced CT (ceCT) and magnetic resonance imaging (ceMRI) before 68Ga-FAPI - PET/CT. PET-scans were acquired 10, 60 and 180 minutes after administration of 150-250 MBq of 68Ga-labelled FAPI tracers. SUVmax and SUVmean values of ACCs and healthy organs were obtained using a 60% of maximum iso-contour. FAP and alpha smooth muscle actin (α-SMA) immunohistochemistry was performed in 13 cases (3 with and 10 without 68Ga FAPI-PET/CT). Staging and radiotherapy planning based on 68Ga-FAPI-PET/CT versus ceCT/MRI alone were compared. RESULTS We observed elevated tracer uptake in all ACCs. Immunohistochemistry showed FAP-expressing CAFs in the tumor. Compared to conventional staging, 68Ga-FAPI-PET/CT led to upstaging in 2/12 patients and to detection of additional metastases in 3 patients, thus in total 42% of patients had their staging altered. Moreover, 68Ga-FAPI PET improved the accuracy of target volume delineation for radiotherapy, as compared to CT and MRI. CONCLUSION 68Ga-FAPI-PET/CT is a promising imaging modality for ACC, providing additional information for staging and leading to altered radiotherapy planning compared to CT and MRI.

The aim of this study was to investigate the influence of a new type of milking system on the behaviour of cows during milking by comparing a conventional milking system (CON) with an individual quarter milking system (MUL), MultiLactor®. Sixty-eight dairy cows were observed during their milking times (32 cows in CON, 36 cows in MUL) using video recordings to analyse their behavioural traits. The udder preparation duration, milking duration and milk yield were also evaluated. No significant differences were found between the CON and the MUL regarding cows’ head posture (P=0.38), body posture (P=0.85), number of steps (P=0.08) and number of kicks (P=0.56). However, the milk yield was lower (P=0.02), just as the udder preparation duration (P

Resumo O objetivo do estudo foi analisar como as crises econômicas afetam a saúde infantil a nível global e entre subgrupos de países com diferentes níveis de renda. Foram utilizados dados do Banco Mundial e da OMS para 127 países entre os anos de 1995 e 2014. Foi utilizado um modelo de efeitos fixos, avaliando o efeito da mudança em indicadores macroeconômicos (PIB per capita, taxa de desemprego e de inflação, e taxa de desconforto) na taxa de mortalidade neonatal, infantil, e de menores de cinco anos. Adicionalmente, avaliou-se a modificação do efeito da associação de acordo com a renda dos países e também a influência do gasto público em saúde nessa relação. As evidências mostraram que piores indicadores econômicos (menor PIB per capita e maiores inflação, taxa de desemprego e taxa de desconforto) estão associados com maiores taxas de mortalidade infantil. Nas subamostras por estrato de renda, observa-se a mesma relação, porém com efeitos de maior magnitude entre os países de renda baixa e média. Verificou-se ainda que um maior percentual nos gastos públicos em saúde ameniza os efeitos dos indicadores econômicos nas taxas de mortalidade infantil. Desta forma, é necessário aumentar a atenção aos efeitos nocivos das crises macroeconômicas para garantir melhorias na saúde infantil. Abstract The aim of the study was to analyze how economic crises affect child health globally and between subgroups of countries with different levels of income. Data from the World Bank and the World Health Organization were used for 127 countries between 1995 and 2014. A fixed effects model was used, evaluating the effect of the change on macroeconomic indicators (GDP per capita, unemployment and inflation rates and misery index) in neonatal, infant and under-five mortality rates. Moreover, we evaluated whether there was a change in the association effect according to the income of the countries and also analyzed the role of public health expenditure in this association. Evidence has shown that worse economic indicators (lower GDP per capita, higher inflation, unemployment rates and misery index) are associated with higher child mortality rates. In the subsamples by income strata, the same association is observed, but with effects of greater magnitude for low- and middle-income countries. We also verified that a higher percentage in public health expenditures alleviates the effects of economic indicators on child mortality rates. Thus, more attention needs to be paid to the harmful effects of the macroeconomic crises to ensure improvements in child health.

Colostrum provides high amounts of nutritive and non-nutritive substrates, which are essential for calf nutrition and passive immunization. Colostral growth factors and hormones have beneficial effects on postnatal maturation and may affect substrate utilization and energy expenditure in neonatal calves. We tested the hypothesis that energy metabolism and its endocrine regulation differ during the first 10 d of life in calves fed either colostrum or a milk-based formula with a similar nutrient composition to colostrum, but largely depleted of bioactive substances, for the first 2 d postnatum. Male Holstein calves (n = 18) were fed either pooled colostrum (COL; n = 9) or a milk-based formula (FOR; n = 9) for the first 2 d of life. From d 3 on, all calves received same milk replacer. On d 2 and 7 of life, calves were placed in a respiration chamber for indirect calorimetric measurements to calculate heat production, fat (FOX) and carbohydrate oxidation (COX), as well as respiratory quotient. Blood was sampled on d 1 before first colostrum intake and on d 2, 3, 7, 8, 9, and 10 before morning feeding, to measure plasma concentrations of immunoglobulins, metabolites, and hormones. Additional postprandial blood samples were taken on d 1 and 9 at 30, 60, 120, 240, and 420 min after milk feeding. Liver samples were collected on d 10 of life to determine gene expression related to energy metabolism. Formula-fed calves showed lower plasma concentrations of total protein, immunoglobulins, haptoglobin, leptin, adiponectin, and insulin-like growth factor (IGF) binding protein (IGFBP)-4 during the whole study but temporarily higher plasma concentrations of urea, insulin, glucagon, triglyceride, and cholesterol on the first day after feeding, compared with concentrations in COL. The temporary increase in glucagon, triglyceride, and cholesterol on d 1 reversed on d 2 or 3, showing higher concentrations in COL than in FOR calves. In FOR, IGF-I, IGFBP-2, and IGFBP-3 were lower on d 3 than in COL. Interestingly, FOR calves had higher heat production during respiratory measurements on d 2 and higher body temperature on d 2, 3, and 5 than those of COL. The hepatic mRNA abundance of cytosolic phosphoenolpyruvate carboxykinase was higher in FOR than in COL. Our results indicate that first milk feeding after birth influenced whole-body energy expenditure but not FOX and COX in neonatal calves, and the absorption of colostral leptin and adiponectin might affect insulin sensitivity on d 1 of life.

Fascioliasis is a food-borne anthropozoonotic disease caused by Fasciola hepatica that affects multiple hosts, including humans. We herein report the first case of human fascioliasis in the state of Santa Catarina, Brazil. A 57-year-old female patient complaining of abdominal pain was admitted to the hospital for a clinical investigation. The diagnosis of F. hepatica was confirmed by ultrasound and indirect enzyme-linked immunosorbent assay. Authorities of the Northern coast of Santa Catarina were notified to investigate other cases and risk factors for contamination. The disease is also prevalent in cattle, which could pose as a potential route for infection.

The removal of impassable dams can affect stream fish communities in many ways, including allowing previously separated anadromous and resident life history types to intermingle. Recolonization of steelhead Oncorhynchus mykiss (anadromous Rainbow Trout) into areas that were previously occupied solely by resident conspecifics presents a challenge for monitoring because (1) staging or spawning adults may be difficult to directly observe; and (2) the offspring of the two life history forms are indistinguishable during early life. We evaluated the utility of using redd attributes, fry (age-0) size, and fry density to distinguish the presence of steelhead and Rainbow Trout in the Elwha River, Washington. Redd area and substrate size differed between forms: steelhead redds were significantly larger and had a greater median substrate particle size than Rainbow Trout redds. Fry density was significantly higher in steelhead spawning reaches than in Rainbow Trout reaches during both survey years (2010 and 2...

Anthracosis often results in mediastinal nodal enlargement. The aim of this comparative study was to evaluate if it is possible to differentiate endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) proven anthracotic lymph nodes from malignant lymph node enlargement by means of multislice computed tomography (MSCT).We compared the MSCT findings of 89 enlarged lymph nodes due to anthracosis with 54 malignant lymph nodes (non-small cell lung cancer 75.9%, small cell lung cancer 18.5%, and non-Hodgkin lymphoma 5.6%). The lymph nodes were assessed for density (calcification, fat, and necrosis), shape (oval, round), contrast enhancement, and contour (sharp, ill-defined).Malignant lymph nodes showed significantly greater axis diameters (P0.001). Both anthracotic and malignant nodes were most often oval (86.5% of all malignant nodes vs. 81.5% of all anthracotic nodes, P = 0.420) and showed confluence in a remarkable percentage (28.1% vs. 42.6%, P = 0.075). Anthracotic nodes showed calcifications more often (18% vs. 0%, P0.001). Malignant lymph nodes showed a significantly greater short and long axis diameter (P0.001), and they had a higher frequency of ill-defined contours (27.8% vs. 2.2%, P0.001) and contrast enhancement (27.8% vs. 5.6%, P0.001). Nodal necrosis, which appeared in one third of the malignant nodes, was not observed in anthracosis (35.2% vs. 0%, P0.001). Confluence of enlarged lymph nodes was seen in malignant lymph nodes (42.6%), as well as in lymph node enlargement due to anthracosis (28.1%, P = 0.075).Our results show that there are significant differences in MSCT findings of malignant enlarged lymph nodes and benign lymph node enlargement due to anthracosis.

The aim of this study was to identify factors predisposing to lung infarction in patients with pulmonary embolism (PE).We performed a retrospective analysis on 154 patients with the final diagnosis of PE being examined between January 2009 and December 2012 by means of a Toshiba Aquilion 64 CT scanner. The severity of clinical symptoms was defined by means of a clinical index with 4 classes. The pulmonary clot load was quantified using a modified severity index of PE as proposed by Miller. We correlated several potential predictors of pulmonary infarction such as demographic data, pulmonary clot burden, distance of total vascular obstruction and pleura, the presence of cardiac congestion, signs of chronic bronchitis or emphysema with the occurrence of pulmonary infarction.Computed tomography revealed 78 areas of pulmonary infarction in 45/154 (29.2 %) patients. The presence of infarction was significantly higher in the right lung than in the left lung (p 0.001). We found no correlation between pulmonary infarction and the presence of accompanying malignant diseases (r = -0.069), signs of chronic bronchitis (r = -0.109), cardiac congestion (r = -0.076), the quantified clot burden score (r = 0.176), and the severity of symptoms (r = -0.024). Only a very weak negative correlation between the presence of infarction and age (r = -0.199) was seen. However, we could demonstrate a moderate negative correlation between the distance of total vascular occlusion and the occurrence of infarction (r = -0.504).Neither cardiac congestion nor the degree of pulmonary vascular obstruction are main factors predisposing to pulmonary infarction in patients with PE. It seems that a peripheral total vascular obstruction more often results in infarction than even massive central clot burden.

Connective tissue growth factor (CTGF/CCN2), a member of the CCN superfamily of secreted cysteine-rich glycoproteins, is a central mediator of tissue remodeling and fibrosis. CTGF is suggested to be an important down-stream effector of transforming growth factor-beta (TGF-β) signaling and has therefore reached considerable pathophysiological relevance because of its involvement in the pathogenesis of fibrotic diseases, atherosclerosis, skin scarring, and other conditions with excess production of connective tissue. In a search for inhibitors of inducible CTGF expression from fungi, two new macrocyclic lactones, namely 4-dechloro-14-deoxy-oxacyclododecindione (1) and 14-deoxy-oxacylododecindione, (2) along with the previously described congener oxacyclododecindione (3) were isolated from fermentations of the imperfect fungus Exserohilum rostratum. The structure of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy and mass spectrometry. Compounds 1 and 2 turned out to inhibit TGF-β induced CTGF promoter activity in transiently transfected HepG2 cells in a dose-dependent manner with IC50 values of 1.8 μM and 336 nM, respectively, and also antagonized TGF-β induced cellular effects including CTGF mRNA levels, CTGF protein expression and tube formation.