Prognostic impact of gross tumor volume during radical radiochemotherapy of locally advanced non-small cell lung cancer-results from the NCT03055715 multicenter cohort study of the Young DEGRO Trial Group.

BACKGROUND: In radical radiochemotherapy (RCT) of inoperable non-small-cell lung cancer (NSCLC) typical prognostic factors include T- and N-stage, while there are still conflicting data on the prognostic relevance of gross tumor volume (GTV) and particularly its changes during RCT. The NCT03055715 study of the Young DEGRO working group of the German Society of Radiation Oncology (DEGRO) evaluated the prognostic impact of GTV and its changes during RCT. METHODS: A total of 21 university centers for radiation oncology from five different European countries (Germany, Switzerland, Spain, Belgium, and Austria) participated in the study which evaluated n = 347 patients with confirmed (biopsy) inoperable NSCLC in UICC stage III A/B who received radical curative-intent RCT between 2010 and 2013. Patient and disease data were collected anonymously via electronic case report forms and entered into the multi-institutional RadPlanBio platform for central data analysis. GTV before RCT (initial planning CT, GTV1) and at 40-50 Gy (re-planning CT for radiation boost, GTV2) was delineated. Absolute GTV before/during RCT and relative GTV changes were correlated with overall survival as the primary endpoint. Hazard ratios (HR) of survival analysis were estimated by means of adjusted Cox regression models. RESULTS: GTV1 was found to have a mean of 154.4 ml (95%CI: 1.5-877) and GTV2 of 106.2 ml (95% CI: 0.5-589.5), resulting in an estimated reduction of 48.2 ml (p < 0.001). Median overall survival (OS) was 18.8 months with a median of 22.1, 20.9, and 12.6 months for patients with high, intermediate, and low GTV before RT. Considering all patients, in one survival model of overall mortality, GTV2 (2.75 (1.12-6.75, p = 0.03) was found to be a stronger survival predictor than GTV1 (1.34 (0.9-2, p > 0.05). In patients with available data on both GTV1 and GTV2, absolute GTV1 before RT was not significantly associated with survival (HR 0-69, 0.32-1.49, p > 0.05) but GTV2 significantly predicted OS in a model adjusted for age, T stage, and chemotherapy, with an HR of 3.7 (1.01-13.53, p = 0.04) per 300 ml. The absolute decrease from GTV1 to GTV2 was correlated to survival, where every decrease by 50 ml reduced the HR by 0.8 (CI 0.64-0.99, p = 0.04). There was no evidence for a survival effect of the relative change between GTV1 and GTV2. CONCLUSION: Our results indicate that independently of T stage, the re-planning GTV during RCT is a significant and superior survival predictor compared to baseline GTV before RT. Patients with a high absolute (rather than relative) change in GTV during RT show a superior survival outcome after RCT.

Lack of renewal effect in extinction of naturally acquired conditioned eyeblink responses, but possible dependency on physical context.

Context dependency of extinction is well known and has extensively been studied in fear conditioning, but has rarely been assessed in eyeblink conditioning. One way to demonstrate context dependency of extinction is the renewal effect. ABA paradigms are most commonly used to show the renewal effect of extinguished learned fear: if acquisition takes place in context A, and extinction takes place in context B (extinction phase), learned responses will recover in subsequent extinction trials presented in context A (renewal phase). The renewal effect of the visual threat eyeblink response (VTER), a conditioned eyeblink response, which is naturally acquired in early infancy, was examined in a total of 48 young and healthy participants with two experiments using an ABA paradigm. Twenty paired trials were performed in context A (baseline trials), followed by 50 extinction trials in context B (extinction phase) and 50 extinction trials in context A (renewal phase). In 24 participants, contexts A and B were two different rooms, and in the other 24 participants, two different background colors (orange and blue) and noises were used. To rule out spontaneous recovery, an AAA design was used for comparison. There were significant effects of extinction in both experiments. No significant renewal effects were observed. In experiment 2, however, extinction was significantly less using orange background during extinction compared to the blue background. The present findings suggest that extinction of conditioned eyeblinks depends on the physical context. Findings add to the animal literature that context can play a role in the acquisition of classically conditioned eyeblink responses. Future studies, however, need to be performed to confirm the present findings. Lack of renewal effect may be explained by the highly overlearned character of the VTER.

Age effects in storage and extinction of a naturally acquired conditioned eyeblink response.

Acquisition of conditioned eyeblink responses is known to decline with age, and age-related decline has been related to a reduction of cerebellar size and function. The aim of the present study was to investigate age-related effects on storage-related processes and extinction of visual threat eyeblink responses (VTERs), conditioned responses which are naturally acquired in early childhood. Storage and extinction of VTERs were tested in 34 healthy participants with an age range from 21 to 74 years (mean age 41.6±16.3 years). High-resolution structural magnetic resonance images (MRI) were acquired in all subjects. Conventional volumetric measures and voxel-based morphometry (VBM) were performed at the level of the cerebellum. Storage and extinction of VTERs showed a significant age-dependent decline. Likewise, cerebellar volume decreased with age. Storage, but not extinction showed a significant positive correlation with age-dependent reduction of total cerebellar volume. VBM analysis showed that gray matter volume in circumscribed areas of intermediate lobules VI, and Crus I and II bilaterally were positively correlated with VTER storage (p<0.05, FWE corrected). Considering extinction, no significant correlations with gray matter cerebellar volume were observed. The present findings show that reduction of storage of learned eyeblink responses with age is explained at least in part by age-dependent decline of cerebellar function. Future studies need to be performed to better understand which brain areas contribute to age-dependent reduction of extinction.

Sensitivity and specificity of intrapartum computerised FIGO criteria for cardiotocography and fetal scalp pH during labour: multicentre, observational study.

OBJECTIVE: To identify sensitivity and specificity of computerised cardiotocography (CTG) analysis for fetal acidosis during delivery. DESIGN: Retrospective observational study. SETTING: Tertiary referral labour ward, Technical University München (TUM) and University Witten/Herdecke (UWH). POPULATION: All deliveries, which had at least one fetal scalp pH measurement and electronically saved CTG traces, between 2000 and 2002 (TUM) and between 2004 and 2005 (UWH). METHOD: Correlation analysis of fetal scalp pH values and computerised International Federation of Obstetrics and Gynecology (FIGO) classification using 'CTG Online' program of digitally saved CTG traces. MAIN OUTCOME MEASURES: Fetal scalp pH values, FIGO parameter (baseline, variability, acceleration and deceleration) using computerised analysis. RESULTS: Both collectives showed a high sensitivity (95.0%) for computerised FIGO classification 'suspect' and 'pathological', together with a low specificity (21.8%) for fetal acidosis. The most sensitive single FIGO parameter was deceleration. Very low sensitivity (<50%) was shown for the parameters variability and acceleration. CONCLUSIONS: Computerised CTG analysis is highly sensitive for fetal acidosis and can be used as an objective adjunctive criterion during delivery. Further CTG data are needed to adjust and optimise each FIGO parameter and increase sensitivity and specificity.

Treatment of biliary obstruction in selected patients by endoscopic ultrasonography (EUS)-guided transluminal biliary drainage.

BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiopancreatography (ERCP)-guided implantation of a biliary endoprosthesis or stent is the gold standard treatment for biliary obstructions. When the papilla cannot be traversed because there is pyloric or duodenal stenosis, or the catheter cannot be introduced, or because of previous gastrointestinal surgery (Billroth II gastric resection, Whipple procedure, gastrectomy with Roux-en-Y reconstruction), the alternative treatment is considered to be percutaneous transhepatic cholangiography and drainage (PTCD). The aim of the study was to investigate the further alternative of endoscopic ultrasound (EUS)-guided transgastric or transjejunal biliary drainage where PTCD failed or was declined, and particularly, the feasibility and outcome of this option. PATIENTS AND METHODS: Over 3 years all appropriate consecutive patients (as defined above) were enrolled in this prospective, observational, single-center, case series study, and patient and intervention data were recorded. Feasibility was characterized by success rate (regression of cholestasis), and outcomes by complication rate, mortality, and follow-up findings. RESULTS: Between November 2002 and December 2005, eight patients (in 10 interventions) underwent this new biliary drainage procedure. The routes were transesophageal (n = 1), transgastric (n = 4), and transjejunal (n = 3, including a rendezvous technique with ERCP [n = 1]). The indications were cholestasis, arising from recurrent tumor growth (n = 5, 62.5%), that included gastric carcinoma after previous gastrectomy (n = 4) and a periampullary carcinoma after previous Whipple procedure (n = 1); arising from Klatskin tumor (n = 2, 25%); and from benign stenosis of a hepaticojejunostomy (n = 1, 12.5%). Five patients (62.5%) received a metal stent, and three (37.5%) had a plastic prosthesis (8.5-Fr double-pigtail). The technical success rate was 90% (9/10) and the clinical success rate was 88.9% (8/9). There was only one case of cholangitis (12.5%) and slight postinterventional pain, but no severe complications such as bleeding or perforation, and no mortality. During follow-up (range 4 weeks to 3 years) re-interventions were needed in two patients (20%) because of increasing cholestasis; these resulted in technical success and clinical improvement. CONCLUSION: EUS-guided transgastric or transjejunal biliary drainage is a reasonable, feasible and encouraging treatment option in selected patients as indicated, with a low peri-interventional risk. It broadens the therapeutic spectrum but still needs further evaluation and follow-up investigation.

A new variant of Glanzmann's thrombasthenia with defective activation-dependent fibrinogen binding and altered expression of epitopes for several monoclonal antibodies against GP IIb-IIIa.

In a family, a moderate bleeding disorder in two patients has been specified as Glanzmann's thrombasthenia because of characteristic defects in platelet function. Analysis of platelet membrane glycoproteins revealed about a 50% decrease in the amount of GP IIb-IIIa complex (α(11b)ß(3) integrin), which appeared normal with respect to electrophoretic mobility, apparent M, and isoelectric behaviour of GP IIb and GP IIIa. Content of platelet fibrinogen (Fg) was normal. [(125)I]Fg binding to ADP-stimulated platelets was strongly reduced but K(d) values indicated a much higher affinity of the residual receptors for both [(125)I]Fg and RGD peptide. Fg bound to the isolated complex as detected by crossed immunoelectrophoresis and there was substantial expression of endogenous Fg on the surface of washed thrombin-stimulated platelets. RGD-peptide induced increased binding of conformation-specific monoclonal antibodies (Mabs) LIBS 1 and PMI-1. Flow cytometric analysis revealed defective binding of nine Mabs, among them two out of three tested antibodies specific for GP IIIa (C 17, AP 5). Results indicate a genetic variant of GP IIb-IIIa complex with the structural abnormality possibly related to defective conformational change upon activation.

Chronic childhood spinal muscular atrophy in Germany (West-Thüringen)--an epidemiological study.

This study presents the most extensive epidemiological data on chronic forms of spinal muscular atrophy in childhood (CSMA) in West-Thüringen in Germany. The incidence of CSMA was calculated to be 1 in 9,420 live births. The prevalence was 1.624 in 100,000 of the general population (as of 31 December 1980).

Maps, routes, and the hippocampus: a neural network approach.

This study describes hippocampal participation in maze navigation in terms of a real-time, biologically plausible neural network. The system is composed of (1) a goal-seeking mechanism, (2) a cognitive map system, and (3) a route system. The goal-seeking mechanism displays exploratory behavior until either the goal is found or a sufficiently strong prediction of the goal is generated. The cognitive map is a topological map that stores associations between places and views of accessible places, and between places and reward. The route system establishes associations between cues and reward. Both systems compete with each other to establish associations with the reward, with the cognitive system generally overshadowing the route system. In agreement with previous models, it is assumed that the hippocampus modulates the storage of cognitive maps in cortical areas and mediates the competition between cognitive maps and route systems. After hippocampal lesions, animals navigate through mazes making use of the route system. Computer simulations show that the network effectively describes latent learning, detour behavior, and place learning in normal and hippocampal- and cortical-lesioned animals.

Epidemiological data on Werdnig-Hoffmann disease in Germany (West-Thüringen).

This study contains the largest body of epidemiological data on Werdnig-Hoffmann disease (acute infantile spinal muscular atrophy; ASMA) in West-Thüringen in Germany. The incidence of ASMA was calculated to be 1 in 10,202 live births. The prevalence was 1 in 595,362 of the general population (as of 31 December 1987). The study gives an unexpectedly high incidence rate confirming the suggestion that ASMA in Central and Eastern Europe might be more frequent than in Western Europe. However, we consider that this high incidence rate in West-Thüringen is a result of the almost complete ascertainment made possible because of the well-organised and centralised health system existing in Thüringen over the last few decades.

Fluorine-substituted corticosteroids: synthesis and evaluation as potential receptor-based imaging agents for positron emission tomography of the brain.

We have prepared eight fluorine-substituted corticosteroids representing ligands selective for Type I and Type II corticosteroid receptor subtypes as potential imaging agents for corticosteroid receptor-containing regions of the brain. Receptor binding affinity assays show that fluorine substitution for hydroxyl or hydrogen in these steroids generally results in some reduction in affinity, with the result that the absolute affinity of these fluorine-substituted ligands for receptor is less than that typical for steroid hormones that show receptor-based, target selective uptake in vivo. Five of these compounds were prepared in fluorine-18 labeled form by a simple sulfonate ester displacement reaction, and their tissue distribution was studied in the adrenalectomized rat. There is no selective accumulation nor selective retention of the Type I selective corticosteroids (18F-RU 26752, 21-[18F]fluoroprogesterone, 21-[18F]fluoro-11 beta-hydroxyprogesterone) in either the brain, or other target tissues (pituitary, kidney, liver). The Type II selective corticosteroids (18F-RU 28362, 18F-triamcinolone acetonide) show uptake into the hippocampus which can be partially blocked by a competing ligand; in target tissues outside the brain, the blocking is more complete. All of the 18F-labeled compounds show considerable defluorination, evident as high bone activity levels. These results, coupled with earlier findings in the literature, suggest that radiolabeled corticosteroid receptor ligands with both greater metabolic stability and higher receptor binding affinity and selectivity are needed for imaging corticosteroid receptors in the hippocampus.

Purposive behavior and cognitive mapping: a neural network model.

This study presents a real-time, biologically plausible neural network approach to purposive behavior and cognitive mapping. The system is composed of (a) an action system, consisting of a goal-seeking neural mechanism controlled by a motivational system; and (b) a cognitive system, involving a neural cognitive map. The goal-seeking mechanism displays exploratory behavior until either (a) the goal is found or (b) an adequate prediction of the goal is generated. The cognitive map built by the network is a topological map, i.e., it represents only the adjacency, but not distances or directions, between places. The network has recurrent and non-recurrent properties that allow the reading of the cognitive map without modifying it. Two types of predictions are introduced: fast-time and real-time predictions. Fast-time predictions are produced in advance of what occurs in real time, when the information stored in the cognitive map is used to predict the remote future. Real-time predictions are generated simultaneously with the occurrence of environmental events, when the information stored in the cognitive map is being updated. Computer simulations show that the network successfully describes latent learning and detour behavior in rats. In addition, simulations demonstrate that the network can be applied to problem-solving paradigms such as the Tower of Hanoi puzzle.

11 beta-methoxy-, 11 beta-ethyl- and 17 alpha-ethynyl-substituted 16 alpha-fluoroestradiols: receptor-based imaging agents with enhanced uptake efficiency and selectivity.

We have prepared three analogues of 16 alpha-fluoroestradiol (FES) substituted either with an 11 beta-methoxy group (1, 11 beta-MeO-FES), an 11 beta-ethyl group (2, 11 beta-Et-FES), or a 17 alpha-ethynyl group (3, 17 alpha-ethynyl-FES). These substituents all lower the binding of FES to the serum proteins alphafetoprotein and sex steroid binding protein, but their effect on estrogen receptor binding varies: Receptor binding is increased by the 11 beta-ethyl and 17 alpha-ethynyl groups, but decreased by the 11 beta-methoxy group. These substituents also have a parallel effect on the lipophilicity, and hence the nonspecific binding estimated for these compounds. All three compounds were prepared in fluorine-18 labeled form, at effective specific activities of 90-1600 Ci/mmol, by fluoride ion displacement reactions as done previously with FES. Tissue distribution studies in immature rats show high uptake selectivity by target tissue (uterus) and effective competition by an excess of unlabeled estradiol. Percent injected dose per gram values (% ID/g) at 1 h are 6% for 11 beta-MeO-FES and 11-13% for 11 beta-Et-FES and 17 alpha-ethynyl-FES (FES itself has a % ID/g of 9%). Uptake selectivity in terms of uterus to blood or muscle ratios at 1 h is highest for 11 beta-MeO-FES and 17 alpha-ethynyl-FES (43-149). Metabolic consumption studies show that most activity in uterus is unmetabolized and in blood is rapidly and nearly completely metabolized. In muscle, FES and the substituted estrogens show intermediate levels of metabolic consumption; in some cases activity in muscle extracts is nearly unmetabolized. Thus, the substituents on FES cause major alterations in receptor and nonreceptor binding affinity, uptake efficiency and selectivity, and extent of metabolism. It is not readily clear, however, whether the alterations in uptake efficiency and selectivity are the result of differences in receptor or nonreceptor binding or lipophilicity, or altered patterns of metabolism. Nevertheless, these compounds should be useful in providing a spectrum of uptake properties that could be used for imaging different estrogen-receptor-containing structures.