Search

Summary Background Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. Methods This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered ( NCT01254630 and EudraCT 2010-023156-89). Findings Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI −1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI −17·8 to 41·3). Interpretation The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Funding Merck & Co, Inc.

Background: Leukaemia in pregnancy is a rare complication demanding a multidisciplinary approach and careful management to handle potential complications and cope with ethical dilemmas. Patient and Methods: We report on a patient with acute myeloid leukaemia (AML) relapse in 22 weeks of gestation who received chemotherapy with cytarabine and mitoxantrone, as well as fludarabine, cytarabine, idarubicin, and gemtuzumabozogamicin. We describe findings on regular ultrasound examinations and successful management of complications. Results: The foetus developed signs of anthracyclineinduced cardiomyopathy, transient cerebral ventriculomegaly, anaemia, and intrauterine growth restriction. The child was delivered by Caesarean section at 33 + 1 weeks of gestation. The newborn showed no congenital malformations. Conclusion: This case report confirms that chemotherapy for treatment of AML can be applied in the second trimester of pregnancy under close and careful maternal and foetal monitoring.

In this study we present the first results of the investigation of polymer-coated titanium implants implanted in the proximal tibia and distal femora of New Zealand white rabbits. The results of DEXA scans, micro-CT, and histological analysis showed an increase of osseointegration. We suggest that controlled release kinetics after coupling of these polymers with BMP-2 can additionally increase osseointegration.

A magnetic video tape can be used to record the polarization of light from each minimum resolvable area of an extended astronomical source. The raster scan of a television camera is recorded on a video tape. The rotation index of a polarizer is recorded on the magnetic-tape audio channel. Raw data input to a computer is provided by the digitized output from the recorded magnetic tape. For each minimum resolvable area of the extended light source, the computer printout shows the intensity and the percentage and direction of polarization. The solar corona during an eclipse is one example of a suitable subject.

The expedition of the Harvard College Observatory, the Smithsonian Astrophysical Observatory, and the National Geographic Society to Miahuatlan, Mexico, to observe the total solar eclipse of 7 March 1970, is described. Instrumentation included a coronal spectrograph, television cameras recording on videotape, telescopes for photography of coronal polarization, and cameras for direct photography. Photographs and preliminary microphotometer tracings are included.

The glass transition temperature T g of polymers is identified by terahertz time-domain spectroscopy (TDS). The thermo-quasi-optic coefficient noticeably changes in the region of the glass transition. THz TDS can thus serve as a non-destructive and non-contact technique for polymer analysis.

Decreasing the temperature leads to a blue shift of the B 1u lattice mode in different types of polyethylene, which can be observed using terahertz time-domain spectroscopy. Moreover, the frequency shift reveals the glass transition of high-density polyethylene due to the semi-crystalline nature in this polymer. In addition, morphological factors on the B 1u lattice mode of LDPE, LLDPE, and HDPE are discussed.

In this report, the Commission recommends approaches to national authorities for their definition of the scope of radiological protection control measures through regulations, by using its principles of justification and optimisation. The report provides advice for deciding the radiation exposure situations that should be covered by the relevant regulations because their regulatory control can be justified, and, conversely, those that may be considered for exclusion from the regulations because their regulatory control is deemed to be unamenable and unjustified. It also provides advice on the situations resulting from regulated circumstances but which may be considered by regulators for exemption from complying with specific requirements because the application of these requirements is unwarranted and exemption is the optimum option. Thus, the report describes exclusion criteria for defining the scope of radiological protection regulations, exemption criteria for planned exposure situations, and the application of these concepts in emergency exposure situations and in existing exposure situations. The report also addresses specific exposure situations such as exposure to low-energy or low-intensity adventitious radiation, cosmic radiation, naturally occurring radioactive materials, radon, commodities, and low-level radioactive waste. The quantitative criteria in the report are intended only as generic suggestions to regulators for defining the regulatory scope, in the understanding that the definitive boundaries for establishing the situations that can be or need to be regulated will depend on national approaches.

We report on a lasting remission from multimodal treatment in a patient with hepatic metastasized breast cancer. After surgical removal of a singular hepatic metastasis, the patient underwent leukapheresis of peripheral blood mononuclear cell (PBMCs). For induction chemotherapy, the patient received 2 cycles of epirubicin and paclitaxel (ET). After 1 cycle of epirubicin and ifosfamide (El), peripheral blood stem cells were harvested. After a final cycle of ET, the patient underwent high-dose chemotherapy (HDCT; thiotepa 600 mg/m 2 / melphalan 180 mg/m 2 ) and autologous stem cell transplantation. Once reconstitution was achieved, PBMCs were reinfused followed by i.v. application of a trifunctional antibody (TrAb) with specificities anti-EpCAM x anti-CD3. TrAbs are able to simultaneously bind tumor cells, T cells, and additionally FcyR type I and III + accessory cells via their Fc region. Side-effects during treatment were hematotoxicity, mucositis and gastrointestinal toxicity. TrAb treatment resulted in intermittent fever, chills, elevated liver enzymes, systemic inflammatory response syndrome and pulmonary leakage. With a follow-up period of more than 8 years the patient is still in remission (96+ months). This case suggests the feasibility and efficacy of combining surgery, standard and HDCT, and subsequent immunotherapy in metastatic breast cancer. Further investigation of this approach is indicated in a subgroup of patients with oligometastatic breast cancer.

In this study we present the first results of the investigation of polymer-coated titanium implants implanted in the proximal tibia and distal femora of New Zealand white rabbits. The results of DEXA scans, micro-CT, and histological analysis showed an increase of osseointegration. We suggest that controlled release kinetics after coupling of these polymers with BMP-2 can additionally increase osseointegration.

This pilot study analyzed the efficacy and toxicity of high-dose chemotherapy (HDCT), autologous stem-cell transplantation (ASCT) and subsequent immunotherapy with T-cell reinfusion and trifunctional antibodies (trAbs) in chemotherapy-sensitive patients with metastatic breast cancer (MBC).After leukapheresis and cryopreservation of T-cells, patients received 2 cycles of induction chemotherapy ET (epirubicin/paclitaxel) and 1 cycle of El (epirubicin/ifosfamide), followed by G-CSF and stem-cell harvest. After a final cycle of ET, responders (CR/PR) underwent HDCT (thiotepa 600 mg/m2/melphalan 140-180 mg/m2) and ASCT. Once reconstitution was achieved, T-cells were reinfused, followed by application of trifunctional antibodies with specificities anti-EpCAM X anti-CD3 and anti-Her2/neu X anti-CD3.Thirty-three patients were recruited into the study and 19, who had responded to initial chemotherapy, underwent HDCT and ASCT (4 CR, 15 PR, OR = 57.6%; 95% CI: 40-75%). Two early deaths were observed (1 toxic, 1 early progression). T-cell reinfusion and trAbs were given to 17 patients. TrAbs treatment resulted in intermittent fever, chills and elevated liver enzymes, which were seen in all patients. The median overall survival was 27.7 months (range: 5.9-82.6+). Patients who received 3 trAbs doses showed a trend towards an improved overall survival (47.2 vs. 22.4 months, p = 0.08 log rank).This pilot study has shown the feasibility of combining HDCT with immunotherapy in MBC. Further investigation of this approach is indicated.

Objective: Disorders of steroid hormone metabolism might be related to the etiology of focal nodular hyperplasia of the liver (FNH), a benign tumor, especially prevalent in women. The cytochrome P450 1AI (CYP1A1) enzyme is implicated in the bioactivation of multiple precarcinogens as well as in the metabolism of steroids. Genetic polymorphisms of CYP1A1 have been associated with altered catalytic activity in the hydroxylation of sex hormones and this may account for interindividual variability in exposure to hormone-mediated cell proliferation signals and reactive steroid metabolites. In the study at hand, we aimed to evaluate a possible association between CYP1A1*1, *2A, *2B, and *4 alleles and FNH. Method: Genotyping of 26 affected female patients of Caucasian origin was carried out using PCR/RFLP. Results: Allele frequencies for the CYP1A1 variants *2A, *2B and *4 in 26 female patients with FNH were 0.058, 0.019 and 0.058, respectively. Crude odds ratios for the individual alleles were 0.75 (95% Cl 0.23 - 2.44), 0.72 (95% CI 0.10 - 5.34) and 1.96 (95% CI 0.59 - 6.50), respectively. There were no significant differences between these values and corresponding allele frequencies obtained in a large German sample of unaffected Caucasian women. Conclusion: The present data do not suggest a relevant association between CYP1A1 polymorphisms and focal nodular hyperplasia of the liver in female Caucasians.

Selenium and the selenium-dependent glutathione peroxidase (GSH-Px) were measured in healthy and diabetic children from Germany and Hungary. Hyperglycemia and hyperlipidemia are present in diabetes mellitus and they are associated with increased lipid peroxidation. The selenium content of erythrocytes, whole blood and plasma, as well as of plasma glutathione peroxidase activity, were found to be low in the healthy Hungarian children compared to the healthy Germans. Both groups of diabetics had significantly higher blood selenium (1.05 +/- 0.14 versus 0.86 +/- 0.1 mumol/L in Hungarians, 1.34 +/- 0.21 versus 1.12 +/- 0.22 mumol/L in Germans) and higher plasma selenium (0.89 +/- 0.15 versus 0.68 +/- 0.01 mumol/L in Hungarians and 1.01 +/- 0.2 versus 0.88 +/- 0.19 mumol/L in Germans) than the healthy children of the same countries. In all diabetic children the plasma glutathione peroxidase activity and triglycerides were higher and the plasma HDL-cholesterols (HDLC = high density lipoprotein-cholesterol) lower than those in healthy controls. The patients showed linear correlations between blood glucose and plasma glutathione peroxidase activity, as well as in erythrocyte glutathione peroxidase activity with triglycerides (TG) and an inverse correlation with HDL-cholesterol. Plasma selenium correlated only in healthy children with triglycerides, cholesterol and HDL-cholesterol. Irrespective of the geographical region diabetics had a higher selenium status than healthy children. In addition, we found correlations between selenium and lipoproteins in the reference group. The mode of glycation, oxidative procedures and the selenium binding to lipoproteins could explain the different associations in the healthy and diabetic children.

2529 Background: Peritoneal carcinomatosis (PC) from GI-tract cancer is associated with prognosis of 3–6 months. Since chemotherapy and surgical procedures showed only limited efficacy, there is no standard therapy recommended. The trifunctional antibody (trAb) catumaxomab (anti-EpCAM x anti-CD3, removab) represents a new class of intact antibodies, which are able to re-direct T-lymphocytes to tumor cells and to induce active anti tumor immunity by activating FcγRI/III+ APC/DC by their intact Fc region. In a phase I/II trial, intraperitoneal application of catumaxomab was investigated in patients with PC due to GI-tract cancer. Methods: 17 patients (mean age 55 years; 7 gastric-ca, 9 colon-ca, 1 CUP) were included after diagnosis of EpCAM+ PC. Treatment consisted of 4 escalating doses of catumaxomab within 10 days by i.p. application. MTD was defined separately for the 1st, 2nd, 3rd and 4th infusion according to a dynamic escalation schedule. Anti-tumor efficacy was evaluated by immunohistochemical analys...

A low Se intake in dietetically treated patients with phenylketonuria (PKU) or maple syrup urine disease (MSUD) leads to a marked reduction of the platelet glutathione peroxidase activity (GSHPx). The mean value amounted to 2.0 U/10(11) platelets with t-butyl hydroperoxidase (t-BOOH) (2.2 U/10(11) with H2O2) in patients and 5.8 U/10(11) with t-BOOH (5.4 U/10(11) with H2O2) in the control children. After Se supplementation with yeast rich in Se (dose: 135 micrograms Se/m2) the GSHPx activities rapidly increased. They reached a plateau after 2-3 weeks and remained there during the following 15-20 weeks of supplementation. After the cessation of supplementation there was a slow decrease, the values reached a low plateau after 24 weeks. In addition platelet glutathione S-transferase (GSHTf) was estimated with 1-chloro-2,4-dinitrobenzene. No significant difference between the values in healthy and dietetically treated patients in a low or normal Se state was observed. GSHTf did not exhibit peroxidase activity and did not show a compensatory increase when Se dependent GSHPx activity was low. The patients do not reveal clinical signs of disturbed platelet function. GSHPx may act in platelets via lipoxygenase on the prostaglandin pathway. The physiologic consequence of altered arachidonate metabolism, when GSHPx is deficient in platelets, remains to be elucidated.

Three exogenous pyrogens (Escherichia coli lipopolysaccharide, synthetic double-stranded ribonucleic acid. Newcastle disease virus) were compared with respect to their mechanisms of fever induction in rabbits. All inducers stimulated the production of an endogenous pyrogen demonstrated in the blood as well as prostaglandins of the E group, and of cyclic adenosine 3',5'-monophosphate in the cerebrospinal fluid. The concentrations of these compounds were elevated approximately twofold as compared to the controls. Independently of the mode of induction, the fever reaction could be prevented by pretreatment with 5 mg of cycloheximide per kg, although the three fever mediators were induced as in febrile animals. Consequently, at least one additional fever mediator that is sensitive to a 30 to 50% inhibition of protein synthesis by cycloheximide has to be postulated. The comparable reactions of the rabbits after administration of different pyrogens argues for a similar fever mechanism. In contrast to fever induction there was no stimulation of endogenous pyrogen, prostaglandins of the E group, and cyclic adenosine 3',5'-monophosphate in hyperthermia as a consequence of exposure of the animals to exogenous overheating. Furthermore, hyperthermia could not be prevented by cycloheximide.

Splanchnic arterio-hepatic venous differences for a variety of substrates associated with carbohydrate and lipid metabolism were determined simultaneously with hepatic blood flow in five patients after 3 days of starvation. Despite the relative predominance of circulating beta-hydroxybutyrate, the splanchnic productions of both beta-hydroxybutyrate and acetoacetate were approximately equal, totaling 115 g/24 h. This rate of hepatic ketogenesis was as great as that noted previously after 5-6 wk of starvation. Since the degree of hyperketonemia was about threefold greater after 5-6 wk of starvation, it seems likely that the rate of ketone-body removal by peripheral tissues is as important in the development of the increased ketone-body concentrations observed after prolonged starvation as increased hepatic ketone-body production rate. Splanchnic glucose release in this study was 123 g/24 h, which was less than that noted previously after an overnight fast, but was considerably more than that noted during prolonged starvation. Hepatic gluconeogenesis was estimated to be 99 g/24 h, calculated as the sum of lactate, pyruvate, glycerol, and amino acid uptake. This was greater than that observed either after an overnight fast or after prolonged starvation. In addition, a direct relationship between the processes of hepatic ketogenesis and gluconeogenesis was observed.

A method of the interpretation of gravity data is theoretically developed from models with interfaces of periodical structure. The basic equations are discussed for a single layer, whose lower boundary has a continuous cosine-wave form. With the help of the principle of superposition the formula for the m -layer case is derived and tested on model data. The method described may readily be extended to more general forms of gravity-anomaly structures.

Pretreatment with cycloheximide prevents virus-induced fever in rabbits. Compared to the febrile control animals, CH-pretreated afebrile animals exhibit similar concentrations of endogenous pyrogen in the blood and of prostaglandins of the E-group and adenosine 3′, 5′-cyclic monophosphate in the cerebrospinal fluid. The fever response seems to involve one or several additional so far unknown mediators which are sensitive to cycloheximide.

SUMMARY - The propagation of seismic waves in inelastic media is investigated.The relation between stress and strain tensor is of the form7 OV; + Ptj = U' Ekk Sij + z V + A £kk Sii + z (" EiiTehe velocity of propagation and the extinction both of compressional andshear-waves are calculated. The exitation of the waves is assumed to be purelyharmonic and acting at a line of the surface.

Selon les instructions reçues de la part du Secrétaire Général de l’UAI, l’esprit général du présent “Draft Report” de la Commission 17 “La Lune” ne doit plus représenter, comme par le passé, un résumé des travaux effectués dans la discipline au cours des trois dernières années. Son rôle sera de donner un aperçu général sur les aspects et les tendances des recherches sur la Lune, la contribution présente et future de la Commission 17 du l’UAI dans son développement, ainsi que les coopérations dont elle est l’objet ou devrait l’être dans l’avenir.

Torsional magneto-mechanical oscillations of finite amplitude in an idealized non-uniformly rotating star that possesses a poloidal magnetic field are governed, in a first approximation, by a pair of linear wave equations. The approximation is valid if the rotational energy and the magnetic energy are small compared with the gravitational energy. Making various assumptions about the form of the poloidal field, we derive numerical estimates for the period of the fundamental mode (table 1), and discuss the results as they relate to the problem of solar variability.

1. Classical Physics and the Classical Metaphysic. Modem physics, which had its beginnings in the inclined-plane experiments of Galileo, deals with the measurable aspects of the world about us. The laws and definitions of classical physics are, at least superficially, differential equations in which each variable represents the result of a particular kind of measurement. These variables are usually called physical quantites. Starting from a few general laws and definitions we can derive formally further relations between the physical quantities and their rates of change in space and time. If the original definitions are self-consistent and the original laws accurate, the relations we derive from them should enable us to predict what the numerical result of a certain measurement will be whenever certain other measurements have yielded specified numerical results. Classical physics met with striking success from the very start. People started to measure the "right" quantities-quantities between which they were able to formulate simple and general relations. The laws of conservation of energy and momentum go all the way back to Galileo, though not in the general form we use them today. As people found new things to measure and learned to measure more precisely, they discovered increasingly general relationships between the results of their measurements. The success of this procedure called for an explanation. The immediate and "obvious" explanation has been part of our thought since the days of Newton. When we make a measurement on a physical system, we measure a physical quantity. Physical quantities exist in nature, independent of man and his measurements. They are related to each other by laws of nature, which are differential equations in the physical quantities. We discover these laws by making measurements. Time is a physical quantity, and laws of nature that involve the time are causal laws. They enable us to express in principle every physical quantity as a function of the time. Later in this section we shall formulate these familiar ideas more explicitly. For brevity we refer to the point of view they express as "the classical metaphysic." The classical metaphysic is a convenient and self-consistent way of viewing the body of classical physics. It is not by itself a metaphysical system, but in one form or another it has formed a part of most metaphysical systems since Descartes. More important, the classical metaphysic is a part of our everyday thought, so much so that the ideas it embodies have taken on an intuitive character. In recent times people have developed a new kind of physics, quantum mechanics. The new physics has succeeded in providing a simple and general framework for the quantitative description of atomic events, comparable to the framework that classical physics provided for the description of macroscopic experience. But, in the process, many of the "intuitive" ideas of the classical metaphysic have had to be abandoned. In viewing quantum mechanics we can no longer apply concepts like "causality" and "quantities in nature" in the sense of the classical metaphysic. 303