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Idiopathic pulmonary fibrosis (IPF) is a severe form of pulmonary fibrosis. IPF is a fatal disease with no cure and is challenging to diagnose. Unfortunately, due to the elusive etiology of IPF and a late diagnosis, there are no cures for IPF. Two FDA-approved drugs for IPF, nintedanib and pirfenidone, slow the progression of the disease, yet fail to cure or reverse it. Furthermore, most animal models have been unable to completely recapitulate the physiology of human IPF, resulting in the failure of many drug candidates in preclinical studies. In the last few decades, the development of new IPF drugs focused on changes at the cellular level, as it was believed that the cells were the main players in IPF development and progression. However, recent studies have shed light on the critical role of the extracellular matrix (ECM) in IPF development, where the ECM communicates with cells and initiates a positive feedback loop to promote fibrotic processes. Stemming from this shift in the understanding of fibrosis, there is a need to develop in vitro model systems that mimic the human lung microenvironment to better understand how biochemical and biomechanical cues drive fibrotic processes in IPF. However, current in vitro cell culture platforms, which may include substrates with different stiffness or natural hydrogels, have shortcomings in recapitulating the complexity of fibrosis. This review aims to draw a roadmap for developing advanced in vitro pulmonary fibrosis models, which can be leveraged to understand better different mechanisms involved in IPF and develop drug candidates with improved efficacy. We begin with a brief overview defining pulmonary fibrosis and highlight the importance of ECM components in the disease progression. We focus on fibroblasts and myofibroblasts in the context of ECM biology and fibrotic processes, as most conventional advanced in vitro models of pulmonary fibrosis use these cell types. We transition to discussing the parameters of the 3D microenvironment that are relevant in pulmonary fibrosis progression. Finally, the review ends by summarizing the state of the art in the field and future directions.

Background Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILAs are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of FVC and diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation Guidance for identifying clinically relevant ILA, with subsequent referral and follow-up, was established. These results lay the foundation for developing practical guidance on managing patients with ILA.

Integration of mechanical cues in conventional 2D or 3D cell culture platforms is an important consideration for in vivo and ex vivo models of lung health and disease. Available commercial and published custom-made devices are frequently limited in breadth of applications, scalability, and customization. Herein we present a technical report on an open-source, cell and tissue (CaT) stretcher, with modularity for different in vitro and ex vivo systems, that includes the following features: 1) Programmability for modeling different breathing patterns, 2) scalability to support low to high-throughput experimentation, and 3) modularity for submerged cell culture, organ-on-chips, hydrogels, and live tissues. The strategy for connecting the experimental cell or tissue samples to the stretching device were designed to ensure that traditional biomedical outcome measurements including, but not limited to microscopy, soluble mediator measurement, and gene and protein expression remained possible. Lastly, to increase the uptake of the device within the community, the system was built with economically feasible and available components. To accommodate diverse in vitro and ex vivo model systems we developed a variety of chips made of compliant polydimethylsiloxane (PDMS) and optimized coating strategies to increase cell adherence and viability during stretch. The CaT stretcher was validated for studying mechanotransduction pathways in lung cells and tissues, with an increase in alpha smooth muscle actin protein following stretch for 24 h observed in independent submerged monolayer, 3D hydrogel, and live lung tissue experiments. We anticipate that the open-source CaT stretcher design will increase accessibility to studies of the dynamic lung microenvironment through direct implementation by other research groups or custom iterations on our designs.

Background: Electronic Health Records (EHR) can help create patient ownership of information, enhance patient-centered collaborative advising, and increase advice utilization through increases in t...

The study found that encountering new information in an online chat rather than information that participants already knew and were familiar with was more likely to reduce support for the view that...

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG (P TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1–70.7; P ≤ 0.0001) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.

A common problem during floods along the lower Mississippi River is the formation of sand boils on the landward sides of levees. If the hydrostatic pressure in the pervious substratum landward of a levee becomes greater than the submerged weight of the topstratum, the uplift pressure may cause heaving and rupture at weak spots with a resulting concentration of seepage flow in the form of sand boils. This, in turn, can lead to piping and instability of the levees during critical high-water periods. The disposition of pervious versus impervious floodplain deposits beneath the levee and the angle at which such bodies are crossed by the overlying levees are controlling factors in the localization of sand boils. Thus recognition of alluvial landforms forming the riverbanks, the types of soils association with them, and their detailed mapping in plan and profile are important factors in levee design. Corrective design involves: (a) detailed delineation of the surface and subsurface geology (b) careful selection of borrow pits to avoid stripping critically thin topstratum deposits, and (c) the use of riverside of landside berms of blankets and/or the installation of relief wells.

Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 × hips, 9 × knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable.

In a test of how information mentioned in a group discussion affects post-discussion attitude polarization, participants stated their opinion about Donald Trump and read nine pieces of information about him that either reflected positively (three pieces) or negatively (six pieces) on his character. The participants then participated in an online chat in which the majority had a negative opinion of Trump. The online chat involved confederate group members who either discussed only new, unshared information the participant had not read before discussion or shared information the participant had just read. The experiment reported herein tested persuasive arguments theory (PAT) against structuration theory by comparing how group discussion of either shared or novel, unshared information affects attitude polarization. The data failed to support PAT’s premise that unshared arguments are more persuasive than shared arguments and contribute to polarization. Only minority members in the shared chat conditi...

The prognosis in children with refractory or relapsed (r/r) T-cell acute lymphoblastic leukaemia (T-ALL) or lymphoblastic lymphoma (T-LBL) is poor. Nelarabine (Ara-G) has successfully been used as salvage therapy in these children, but has been associated with significant, even fatal, neurotoxicities. We retrospectively analysed 52 patients with r/r T-ALL/T-LBL aged ≤19 years who were treated with Ara-G alone (n = 25) or in combination with cyclophosphamide and etoposide (n = 27). The majority of patients (45/52) received 1-2 cycles of Ara-G. Seventeen patients (32·7%) had refractory disease, 28 (53·8%) were in first relapse and 7 (13·5%) were in second relapse. A response to Ara-G was achieved in 20 patients and 15 (28·8%) were in remission at last follow-up. Twelve patients (23·1%) had neurotoxic adverse effects (neuro-AE) of any grade, of whom 7 (13·5%) developed neurotoxicity ≥ grade III. The most frequent neuro-AEs were peripheral motor neuropathy (19·2%), peripheral sensory neuropathy (11·5%) and seizures (9·6%). Three patients died of central neuro-AE after 1-2 cycles of combination therapy. Patients with neurotoxicity were significantly older (median 15·17 years) than those without (10·34 years, P = 0·017). No differences were observed between mono- and combination therapy concerning outcome and neuro-AE. The incidence of neuro-AE was not associated with concurrent intrathecal therapy or prior central nervous system irradiation.

Osteonecrosis (ON) is a debilitating side effect of anti-leukemic treatment. Thus far, the role of leukemic infiltration (LI) of bone is unclear. The first 30 children aged ≥10 years, who were enrolled in the ongoing OPAL trial and had MRI studies at diagnosis and at 6 months, were analyzed. MRI revealed extensive LIs in 24 (80%) patients. The signal abnormalities changed back to a physiological signal in 29 out of 30 children at 6 months. Of the 24 children with LIs at diagnosis, 3 (12.5%) developed ON ≥ II, whereas 4 (66.7%) patients without LIs subsequently developed ON ≥ II (p = .016). No differences between children initially presenting with/without LIs were observed concerning age, pubertal stage, white blood count, immunophenotype, and clinical presentation. Initial radiological LI of bone and, thus, single MRI at diagnosis cannot identify children at high risk of developing radiological ON at 6 months into treatment.

Using the linguistic software Linguistic Inquiry Word Count, we analyzed transcripts of group discussions of whether the words “under God” should be in the Pledge of Allegiance. We hypothesized that members with an extreme opinion would use less complex language and more you pronouns than other members. Furthermore, extreme members would have less influence when they used you pronouns or more complex language consistent with the illusion of understanding. Extreme members were more confident and perceived themselves as more knowledgeable, but they did not use less complex language than other members. When extreme members did use complex language, they were less influential. Extreme members used more you pronouns and use of you pronouns reduced their influence in the group. Groups containing at least one extreme member had a much lower level of complexity in their discourse than groups without extreme members. Results are situated within research in integrative complexity, illusion of understanding, and attitude extremity.

Effective use of available information is a problem that plagues group decision-making tasks. Groups heavily favor shared information, or information that is known to all group members, which can lead to incorrect decisions and selection of inferior alternatives. However, groups may be less prone to overlooking unshared information if they are focused to value uniqueness and novel input from group members. The present research demonstrates that groups that value uniqueness, or a separatist orientation, correctly solved a hidden profile task more often than groups with a synchronous orientation, or groups that value similarity. Separatist groups repeated more unshared information than synchronous overall. Separatists also repeated more shared information than synchronous groups. Further, groups with a correct minority member also repeated more unshared information than groups with either a majority correct or no correct members. Results are discussed in terms of group focus and biases that affect the discussion of information.

Protein composition at the plasma membrane is tightly regulated, with rapid protein internalization and selective targeting to the cell surface occurring in response to environmental changes. For example, ion channels are dynamically relocalized to or from the plasma membrane in response to physiological alterations, allowing cells and organisms to maintain osmotic and salt homeostasis. To identify additional factors that regulate the selective trafficking of a specific ion channel, we used a yeast model for a mammalian potassium channel, the K(+) inward rectifying channel Kir2.1. Kir2.1 maintains potassium homeostasis in heart muscle cells, and Kir2.1 defects lead to human disease. By examining the ability of Kir2.1 to rescue the growth of yeast cells lacking endogenous potassium channels, we discovered that specific α-arrestins regulate Kir2.1 localization. Specifically, we found that the Ldb19/Art1, Aly1/Art6, and Aly2/Art3 α-arrestin adaptor proteins promote Kir2.1 trafficking to the cell surface, increase Kir2.1 activity at the plasma membrane, and raise intracellular potassium levels. To better quantify the intracellular and cell-surface populations of Kir2.1, we created fluorogen-activating protein fusions and for the first time used this technique to measure the cell-surface residency of a plasma membrane protein in yeast. Our experiments revealed that two α-arrestin effectors also control Kir2.1 localization. In particular, both the Rsp5 ubiquitin ligase and the protein phosphatase calcineurin facilitated the α-arrestin–mediated trafficking of Kir2.1. Together, our findings implicate α-arrestins in regulating an additional class of plasma membrane proteins and establish a new tool for dissecting the trafficking itinerary of any membrane protein in yeast.

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

The cure rates in pediatric oncology have been substantially improved due to standardized treatment strategies and centralization of therapy. Close clinical and hematological monitoring is mandatory for patients between periods of chemotherapy for early detection and treatment of therapy-related complications such as infections. This results in frequent and time-consuming outpatient examinations for the patient and family at the oncological center in order to evaluate clinical condition and hematological findings. In widespread regions such as the Weser-Ems area in northwest Lower Saxony, Germany, the long distances between patients' home and the oncological center lead to higher risks and impairment of quality of life (QoL) for the patients and their families. Accordingly, in 2001 pediatric hospitals and practices, patient care services and patients' support groups in Weser-Ems founded a network (Verbund PadOnko Weser-Ems). The "Verbund PadOnko" aims at coordinated, high-quality regional outpatient patient treatment in order to reduce risks of long-distance transports to reach the oncological center. Since 2005 a newly established mobile care team realized 1 443 home visits covering a total of 150 300 km. Since 2007 the network has been funded by health insurance organisations. Internal and external benchmarking was performed showing that the rate of short term inpatient treatments were reduced. Treatment quality was assured and the QoL of the patients and their families was improved through the work of the network. The "Verbund PadOnko Weser-Ems" network represents a promising prototype model for the regional coordination of outpatient treatment and care of patients with rare diseases in wide spread areas.

This study describes new yeast expression systems for each subunit of the heterotrimeric epithelial sodium channel (ENaC). We found that a significant amount of each subunit resides in the ER and is destroyed via ERAD. We also found that the chaperone requirements for ENaC subunit degradation were unlike any other ERAD substrate examined., The epithelial sodium channel (ENaC) is composed of a single copy of an α-, β-, and γ-subunit and plays an essential role in water and salt balance. Because ENaC assembles inefficiently after its insertion into the ER, a substantial percentage of each subunit is targeted for ER-associated degradation (ERAD). To define how the ENaC subunits are selected for degradation, we developed novel yeast expression systems for each ENaC subunit. Data from this analysis suggested that ENaC subunits display folding defects in more than one compartment and that subunit turnover might require a unique group of factors. Consistent with this hypothesis, yeast lacking the lumenal Hsp40s, Jem1 and Scj1, exhibited defects in ENaC degradation, whereas BiP function was dispensable. We also discovered that Jem1 and Scj1 assist in ENaC ubiquitination, and overexpression of ERdj3 and ERdj4, two lumenal mammalian Hsp40s, increased the proteasome-mediated degradation of ENaC in vertebrate cells. Our data indicate that Hsp40s can act independently of Hsp70 to select substrates for ERAD.

Kraniopharyngeome sind dysontogenetische Mittellinienfehlbildungen mit Raum forderndem Charakter. 30–50% der Falle werden im Kindes- und Jugendalter manifest und reprasentieren damit 5–10% aller intrakraniellen Tumoren im Kindesalter. Der Versuch einer kompletten Resektion unter Wahrung der optischen und hypothalamisch-hypophysaren Funktion stellt die Therapie der ersten Wahl bei gunstiger Lokalisation dar. Bei ungunstiger Lokalisation ist diese Therapieoption gegen eine begrenzte Resektion mit anschliesender Strahlentherapie abzuwagen. Bei insgesamt hoher Uberlebensrate wird die Lebensqualitat der Patienten durch ophthalmologische, neuropsychiatrische und endokrine Spatfolgen beeintrachtigt. Der Adipositas infolge hypothalamischer Essstorungen kommt hierbei besondere Bedeutung zu. In einer multizentrischen Querschnittuntersuchung (n=138) zeigte die Lebensqualitat keine signifikante Abhangigkeit vom intendierten oder realisierten neurochirurgischen Resektionsgrad. Im Rahmen einer multizentrischen Beobachtungsstudie (Kraniopharyngeom 2000; www.kraniopharyngeom.com) wird der Einfluss unterschiedlicher Therapiestrategien auf die Uberlebensrate und die Lebensqualitat von Kindern und Jugendlichen mit Kraniopharyngeom prospektiv untersucht. Aufgrund der hohen Meldebereitschaft der beteiligten Zentren ist zu hoffen, dass auch in Zukunft die Vollstandigkeit der Erfassung deutlich verbessert wird.

Background Infections are a major cause of morbidity and mortality in childhood acute lymphoblastic leukemia (ALL) and only limited information is available on infectious complications. Patients and Methods We investigated infectious complications in 293 children during different treatment phases of the multicenter protocol COALL-06-97. We also evaluated whether therapy reduction in prognostically good risk patients receiving either the low risk or high risk treatment arm would lead to fewer infectious complications. Results Thirty of 293 patients had no infections; 263 patients had 682 infectious complications (median 2, range 1–9), five of them lethal. Two thirds of the infections occurred during periods of neutropenia. The most frequent infectious episodes were fever of unknown origin (FUO): 483/682 (70.8%), microbiologically documented infections (MDI): 100/682 (14.6%), (61 gram-positive, 36 gram-negative, 3 fungal isolates), and clinically documented infections (CDI): 99/682 (14.5%). With standard reinduction, 44% low risk and 57% high risk patients had infections versus 26% low risk and 38% high risk patients with reduced reinduction therapy (P

In HIT Endo data on therapy and prognosis of 306 patients with childhood craniopharyngioma (CP) were analyzed. The 5 years-overall survival rate was 94 +/- 4 % in irradiated patients and 93 +/- 5 % in non-irradiated patients. Aims of the prospective study KRANIOPHARYNGEOM 2000 were to collect data on the incidence and time course of relapses after complete surgery and tumour progressions after incomplete resection. Furthermore, the impact of irradiation therapy (XRT) on tumour relapse and recurrence rates was analyzed. Since 2001 ninety-eight patients with CP were recruited at a median age at diagnosis of 9.9 years ranging from 1.8 to 18.0 years. Complete resection was achieved in 44 %, incomplete resection in 54 %. XRT was performed in 24 of 98 CP patients; in 10 early after incomplete resection, in 14 of 24 after progression of residual tumour or relapse, in 3 of 14 after second surgery of relapse. XRT was performed at a median age of 12.0 years ranging from 5.0 to 18.9 years and in median after an interval of 9 months after first diagnosis. The analysis of event-free survival rates (EFS) in patients with CP showed a high rate of early events in terms of tumour progression after incomplete resection (3y-EFS: 0.22 +/- 0.09) and relapses after complete resection (3y-EFS: 0.60 +/- 0.10) during the first three years of follow-up. A high rate of early events (1y-EFS: 0.78 +/- 0.10; 2y-EFS: 0.57 +/- 0.15) was also found for patients after XRT (3 cystic progressions, 3 progressions of solid tumour; in 24 patients after XRT). We conclude that tumour progression and relapse are frequent and early events even in irradiated patients. Monitoring of cerebral imaging and clinical status is recommended in follow-up of patients with childhood CP. In order to analyze the appropriate time point of XRT after incomplete resection, QoL, EFS and overall survival in patients (age > or = 5 years) will be analyzed in KRANIOPHARYNGEOM 2007 after stratified randomization of the time point of irradiation after incomplete resection (early irradiation versus irradiation at progression of residual tumour).

Data on the light output response of BC-505 liquid scintillator to neutrons ranging in energy from 0.5 to 12 MeV have been fitted with the parameterization of Chou using the GEANT4 toolkit to simulate the response of the scintillators. Excellent agreement is obtained with the parameters kB = 0.0061 ± 0.0003 g cm - 2 MeV - 1 and C = ( 1.0 ± 0.1 ) × 10 - 5 g 2 cm - 4 MeV - 2 .

We analyzed the impact of tumour localization and histology on functional capacity (FC) and body mass index (BMI) in children with sellar masses. FC was evaluated using the ability scale Fertigkeitenskala Munster–Heidelberg in 403 children and adolescents with sellar masses (276 craniopharyngioma, 14 germinoma, 21 optic/chiasmatic glioma, 40 hypothalamic glioma, 13 cysts of Rathke’s cleft and 39 other sellar masses). Besides tumour localization, the influence of gender, irradiation and age at diagnosis and at evaluation on FC and BMI was analyzed. General linear models with explanatory influential variables were built. In multivariate analysis, only age at diagnosis (p

Digital mammography is rapidly gaining acceptance across the US. The technology is more expensive than film screen mammography, but it presents significant opportunities for positively changing the delivery paradigm—if it is properly implemented. Implementation is, however, not simply a matter of exchanging film screen mammography units for digital acquisition units. Digital mammography, by contrast, must be viewed as a system that, in its ultimate iteration, integrates mammography both with other breast imaging modalities and with the supporting infrastructure that is critical to the entire process of mammography delivery. To realize the full potential of digital mammography, it is necessary to approach implementation in a strategic, as opposed to a tactical, manner. The strategic “driver” is the electronic format of the digital image. With this final electronic link, all information concerning the patient has the potential to be transferred and presented electronically, and the physical file, which has long controlled workflow in the breast center, can be relegated to historical memory. Such a transformational change requires a strategic approach that focuses on what is possible , rather than what is simple . It begins with infrastructure, and it leaves the choice of acquisition technology until last. This article will develop the strategic process for those considering implementation of digital mammography, and also provide a framework for reengineering existing digital programs to provide strategic integration of the various elements of the delivery system.

Craniopharyngiomas are rare dysontogenetic malformations. As the survival rate after craniopharyngioma diagnosed during childhood and adolescence is high, prognosis and quality of life (QoL) in survivors mainly depend on adverse late effects such as hypopituitarism and obesity. Appropriate laboratory diagnostics of endocrine deficiencies and sufficient hormonal substitution have significant impact on prognosis and QoL. In order to evaluate and standardize diagnostic and therapeutical strategies in childhood craniopharyngioma the prospective multicenter surveillance study KRANIOPHARYNGEOM 2000 was initiated for patients diagnosed with craniopharyngioma during childhood and adolescence. We are reporting on current strategies for laboratory diagnostics and endocrine substitution in patients with childhood craniopharyngioma recruited in KRANIOPHARYNGEOM 2000.

The pursuit of excellence in the breast care delivery process involves a program of integration, innovation, and imitation designed to yield sustained quality and economic improvement. Many stand-alone breast centers in the United States have adopted this approach and have become financially successful while delivering very high quality care. This article reviews basic economic principles governing breast care as a business enterprise. It then provides recommendations for the development of world-class breast centers that can also deliver financially responsible care.

The overall survival rate of patients with craniopharyngioma, an embryogenic malformation, is high (0.92 +/- 0.03). However, there is considerable morbidity and impaired quality of life, even when the tumor can be completely resected. Aim of our study was to analyze risk factors for severe obesity (body mass index [BMI] > or = 7 SD) and the prognosis of severely obese survivors of childhood craniopharyngioma recruited in our cross-sectional study on 183 patients (HIT-ENDO) and in the prospective study KRANIOPHARYNGEOM 2000. Severe obesity (BMI > or = 7 SD) was present in 16 % of patients and associated with higher tumor volume (p < 0.05), more frequent neurosurgical interventions (p < 0.05) and a higher rate of hypothalamic involvement (p < 0.001). Self-assessed functional capacity (FMH) was lower (p < 0.001) in severely obese survivors (FMH: median 33, range: 4-64) when compared with normal weight patients (FMH: 50; 1-95). Overall survival (20 years) was lower (p = 0.034) in patients with severe obesity in comparison to patients with moderate obesity and normal weight. Cardiovascular morbidity and mortality was high in severely obese patients. Between 10/01 and 03/04 fifty-seven patients (27 female/30 male) were recruited in KRANIOPHARYNGEOM 2000 (www.kraniopharyngeom.com). The impact of tumor localization (3.2 % intrasellar, 22.6 % suprasellar, 74.2 % combined intra/suprasellar; 51.6 % hypothalamic involvement) and treatment (26 complete resections, 22 partial resections followed by irradiation in one case; primary irradiation after biopsy in one case) on quality of life, functional capacity and prognosis will be evaluated longitudinally and prospectively.

We analyzed whether childhood craniopharyngioma predisposes to obesity and growth impairment. Height/length, body mass index (BMI), and hypothalamic involvement were evaluated in 90 patients at standardized ages and time points before, after, and at the time of diagnosis. Relevant decreases in height sd score (SDS) started at 10–12 months of age and persisted until diagnosis of childhood craniopharyngioma. Relevant increases in BMI SDS were detectable between 4 and 5 yr of age. Postoperative BMI SDS (yr 1–6) had a weak positive correlation with BMI SDS at the time of diagnosis. In linear regression analysis, hypothalamic tumor involvement (P < 0.001), ponderal index at birth (P = 0.014), and BMI SDS at age 6–7 months (P = 0.029) and at age 5 yr (P < 0.001) had relevant and independent impacts on the development of obesity. Patients with hypothalamic involvement (n = 48) presented lower ponderal index and BMI SDS at birth and higher BMI SDS at the time of diagnosis (P < 0.001) as well as during annual follow-up (P < 0.001) compared with patients without hypothalamic involvement (n = 42). From childhood (3.5–4 yr) to the time of diagnosis, growth rates were reduced for patients with hypothalamic tumor involvement. Patients without hypothalamic involvement presented reduced growth rates in early infancy (age 10–12 months) that persisted until diagnosis. We conclude that reduced growth rates occur quite early in history; BMI SDS increases occur later and are predictive of obesity. Hypothalamic involvement is the major risk factor for obesity in patients with childhood craniopharyngioma.

The substitution of dexamethasone during and after surgery of childhood craniopharyngioma is necessary in order to treat and/or prevent brain edema and adrenal insufficiency. Early post-operative weight gain is a predictor for severe obesity during long-term follow-up. In a retrospective analysis of 60 patients with childhood craniopharyngioma we inquired whether dose and duration of perioperative dexamethasone therapy (n = 68) had influence on short-term post-operative weight gain and long-term development of severe obesity. The median follow-up period was 4.2 years, ranging from 1 to 9 years. 24 patients (14 f/10 m) developed severe obesity (BMI > 3 SD). 28 patients (10 f/18 m) retained normal weight (BMI < 2 SD). Eight patients presented with a BMI between 2 and 3 SD at the final visit. Differences in terms of age at surgery or follow-up period were non-detectable between the analyzed groups of craniopharyngioma patients. Duration and cumulative dexamethasone doses (mg/m2 BSA) for perioperative dexamethasone therapy were similar for severely obese patients (duration: 8.7 d; 4.5 - 17 d, cumulative dose: 74; 42 - 177 mg/m2 BSA) and normal weight patients (duration: 10.0 d; 1 - 41 d; dose: 76; 9 - 390 mg/m2 BSA). Whereas cumulative dexamethasone doses positively (p < 0.01; rho: 0.424) correlated with weight gain during the first year following surgery, long-term development of severe obesity was not influenced by dose and duration of perioperative dexamethasone treatment. Patients who developed severe obesity during follow-up had a higher (p < 0.001) BMI already at the time of diagnosis. We conclude that dose and duration of perioperative dexamethasone treatment had short-term effects on post-operative weight gain, but not on the development of long-term severe obesity. The results of our retrospective analysis are currently tested in a prospective surveillance study Kraniopharyngeom 2000 (www.kraniopharyngeom.com).

Scientifically, it has been well established that breast-conserving treatment (BCT) in patients with breast cancer does not impair overall prognosis as compared to mastectomy. Several randomized clinical trials in the past two decades have shown that survival rates in breast cancer are stage-dependent, but independent of the extent of surgical breast tissue removal, as long as the resection margins are free of tumor infiltration. The particular importance the breast shows for female psychology and social interaction and the potential for feelings of mutilation and impaired physical integrity are another argument for carefully considering the implications connected with ablative surgical procedures. As a rational and informed basis for the shift in paradigms of invasiveness, the scientific community has felt the need to evidence the concept that local procedures have no detrimental impact on survival in such patients. Proof has been elaborated repeatedly by many investigators from different areas of the world. 1–3 The extent of tissue removed in breast cancer surgery, however, can be a predictor for local failure rate. Local relapse following mastectomy depends on tumor stage, nodal stage, and the biologic aggressiveness of the tumor and usually is an indicator of poor prognosis. By contrast, local recurrence after BCT does not necessarily have an impact on survival. In any case, the psychological and subjective burden of local failure following such interventions must never be underestimated. Therefore, BCT in general calls for adjuvant radiotherapy, although it has been shown that in a highly selected group of patients at very low risk for locoregional relapse, radiotherapy may indeed not be required. 4 This issue is under investigation in a number of prospective clinical trials. By accepted academic standards, BCT combined with adjuvant radiotherapy should be regarded as the surgical treatment of choice in patients with stage I and II breast cancer, as stated by the Consensus Development Conference as early as 1990. 5 Yet in contrast to these well-established standards, for various reasons BCT has not been fully accepted in general practice. This unfortunate discrepancy is linked to specific factors with regard to both patients and physicians. BCT rates are at considerable variance between different countries, but also within highly industrialized nations. For example, differences are reported to be marked between states in the United States. 6,7 In addition to geographic factors, the treatment level of a given hospital department is a key issue for the degree to which BCT is accepted. Women treated at university or teaching hospitals had doubled chances to have their breast preserved, while women over 70 and patients from rural areas were less likely candidates for BCT. 8 The most important factor influencing a patient’s decision on the surgical procedure to be used has proven to be the treating physician’s recommendation, which is rarely questioned in routine practice. 9 Thus, surgeons play the key role in patients’ decision-making processes. Surgeons participating in clinical trials should be particularly well educated and trained at the highest level of medical knowledge. After all, one chief argument for performing clinical trials is that quality control is given considerable attention under such circumstances. This refers to primary trial endpoints as much as general medical care for patients, including quality control measurements applied to surgical techniques and the standards of histopathology. Since 1984, the Austrian Breast & Colorectal Cancer Study Group (ABCSG) has been conducting nationwide, multicenter clinical trials in patients with stage I and II breast cancer. This framework has provided the opportunity, over one and a half decades, to investigate BCT rates in women participating in these investigations throughout Austria. To minimize potential selection bias, we selected subjects with identical basic prognostic characteristics (tumor and nodal stage, receptor status, and age) for the present analysis.

A randomised, controlled clinical trial was initiated in 1984 to test whether 1 cycle of anthracycline-containing adjuvant chemotherapy improves the outcome of breast cancer patients presenting with stage II disease and negative oestrogen and progesterone receptors (ER, PgR), as compared with 6 cycles of dose-reduced CMF.Within 7 years 263 women with stage II breast cancer were randomised either to receive 1 cycle of doxorubicin, vinblastine, cyclophosphamide, methotrexate and 5- fluorouracil (AV-CMF) or to receive 6 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF). Patients were stratified for tumour stage, nodal stage, menopausal status, type of surgery and participating centre.After a median follow-up of 100 months, neither disease-free (DFS) nor overall survival (OS) differed significantly between the two groups.Compared to 6 cycles of a non-standard low-dose CMF regimen 1 cycle of anthracycline- containing adjuvant chemotherapy failed to improve the outcome in women with stage II receptor-negative breast cancer in terms of DFS and OS.

Eine Pseudopubertas praecox kann in seltenen Fallen durch eine paraneoplastische Geschlechtshormonproduktion bedingt sein. Die gewissenhafte Inspektion des Genitales gehort zur kinderarztlichen Routine. Im Rahmen der Abklarung einer Pubertas praecox sollten neben zentralen Ursachen, adrenokortikalen Tumoren und Steroidsynthesedefekten auch primare Lebertumoren mit moglicher endokriner Aktivitat – in unserem Fall ein Hepatoblastom mit paraneoplastischer Testosteronproduktion – ausgeschlossen werden.

Haemophagocytic lymphohistiocytosis (HLH) in the context of malignancy is mainly considered a challenge of adult haematology. While this association is also observed in children, little is known regarding inciting factors, appropriate treatment and prognosis. We retrospectively analysed 29 paediatric and adolescent patients for presenting features, type of neoplasm or preceding chemotherapy, treatment and outcome. Haemophagocytic lymphohistiocytosis was considered triggered by the malignancy (M-HLH) in 21 patients, most of whom had T- (n = 12) or B-cell neoplasms (n = 7), with Epstein-Barr virus as a co-trigger in five patients. In eight patients, HLH occurred during chemotherapy (Ch-HLH) for malignancy, mainly acute leukaemias (n = 7); an infectious trigger was found in seven. In M- and Ch-HLH, median overall survival was 1·2 and 0·9 years, and the 6 month survival rates were 67% and 63%, respectively. Seven of 11 deceased M-HLH patients exhibited active malignancy and HLH at the time of death, while only two out of five deceased Ch-HLH patients had evidence of active HLH. To overcome HLH, malignancy- and HLH-directed treatments were administered in the M-HLH cohort; however, it was not possible to determine superiority of one approach over the other. For Ch-HLH, treatment ranged from postponement of chemotherapy to the use of etoposide-containing regimens.

In high-consequence engineering organizations, such as Sandia, quality assurance may be heavily dependent on staff competency. Competency-dependent quality assurance models are at risk when the environment changes, as it has with increasing attrition rates, budget and schedule cuts, and competing program priorities. Risks in Sandia's competency-dependent culture can be mitigated through changes to hiring, training, and customer engagement approaches to manage people, partners, and products. Sandia's technical quality engineering organization has been able to mitigate corporate-level risks by driving changes that benefit all departments, and in doing so has assured Sandia's commitment to excellence in high-consequence engineering and national service.

The kinetics of secondary crystallization during spherulite growth of isotactic poly(propylene) (iPP) and poly(vinylidene flouride) (PVF 2 ) is studied using a novel technique that employs a micron size X-ray beam. The data are combined with separate conventional simultaneous on-line SAXS/WAXS measurements and optical microscopy studies. In our experiments, crystallization takes place at low undercooling so that slowly growing large single spherulites are obtained. The data reveal that the main mechanism of secondary crystallization is the growth of new lamellae stacks within remaining amorphous regions. It is shown that a substantial amount of crystallites form as a result of secondary crystallization while the spherulite is growing. Furthermore, secondary crystallization is strongest directly behind the boundary of the spherulite and is independent of its size or growth state. A separate, off-line microfocus study on a quenched spherulite sample confirms this observation; the crystallinity is higher in the main body of the spherulite and lower near the boundary, where crystallization progressed to a lesser degree.

Fragestellung. Skelettale Manifestationen des Non-Hodgkin-Lymphoms sind selten. Ziel der Studie waren die Analyse charakteristischer Veranderungen in der Bildgebung vor und nach Therapie sowie die Korrelation mit dem Therapieerfolg. Methode. Die retrospektive Analyse von 2 Therapiestudien (NHL-BMF-90 und 95) schloss 1246 Patienten ein. Die bildgebenden Untersuchungen von 63 Patienten mit skelettalem Lymphombefall wurden reevaluiert. Ergebnisse. Die Inzidenz des initialen Skelettbefalls beim Non-Hodgkin-Lymphom lag bei 6,8%. Die Verteilung der Skelettherde wurde durch die Szintigraphie am sichersten erfasst, die MRT detektierte im Vergleich grosere Markraumbeteiligungen sowie zusatzliche Herdbildungen im Skelett. Pradilektionsorte waren die langen Rohrenknochen der unteren Extremitaten mit epiphysarer Beteiligung in 39% der Falle. Residuale Signalveranderungen im MRT verblieben trotz kompletter Remission in 71% der Falle. Osteonekrosen nach Chemotherapie waren haufig. Die therapeutische Ergebnisse wurden durch das Vorhandensein eines Skelettbefalls nicht beeinflusst. Schlussfolgerungen. Aufgrund der Beobachtung, dass die Therapieergebnisse vom Nachweis eines Skelettbefalls nicht wesentlich beeinflusst werden, erscheint der Wert der Screeninguntersuchung begrenzt. Die Kenntnis des Erscheinungsbilds vom NHL in der Bildgebung ist aber fur die Beurteilung der primar ossaren Lymphome und symptomatischer Herdbildungen sowie in der Therapiekontrolle notwendig.