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PURPOSE: Circulating tumor DNA in plasma may present a minimally invasive opportunity to identify tumor-derived mutations to inform selection of targeted therapies for individual patients, particularly in cases of oligometastatic disease where biopsy of multiple tumors is impractical. To assess the utility of plasma DNA as a “liquid biopsy” for precision oncology, we tested whether sequencing of plasma DNA is a reliable surrogate for sequencing of tumor DNA to identify targetable genetic alterations. METHODS: Blood and biopsies of 1–3 tumors were obtained from 4 evaluable patients with advanced breast cancer. One patient provided samples from an additional 7 tumors post-mortem. DNA extracted from plasma, tumor tissues, and buffy coat of blood were used for probe-directed capture of all exons in 149 cancer-related genes and massively parallel sequencing. Somatic mutations in DNA from plasma and tumors were identified by comparison to buffy coat DNA. RESULTS: Sequencing of plasma DNA identified 27.94 +/− 11.81% (mean +/− SD) of mutations detected in a tumor(s) from the same patient; such mutations tended to be present at high allelic frequency. The majority of mutations found in plasma DNA were not found in tumor samples. Mutations were also found in plasma that matched clinically undetectable tumors found post-mortem. CONCLUSIONS: The incomplete overlap of genetic alteration profiles of plasma and tumors warrants caution in the sole reliance of plasma DNA to identify therapeutically targetable alterations in patients, and indicates that analysis of plasma DNA complements, but does not replace, tumor DNA profiling. TRIAL REGISTRATION: Subjects were prospectively enrolled in trial NCT01836640 (registered April 22, 2013).

Wire-localized excision of non-palpable breast cancer is imprecise, resulting in positive margins 15–35% of the time. Women with a confirmed diagnosis of non-palpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) were randomized to a new technique using preoperative supine magnetic resonance imaging (MRI) with intraoperative optical scanning and tracking (MRI group) or wire-localized (WL group) partial mastectomy. The main outcome measure was the positive margin rate. In this study, 138 patients were randomly assigned. Sixty-six percent had IBC and DCIS, 22% had IBC, and 12% had DCIS. There were no differences in patient or tumor characteristics between the groups. The proportion of patients with positive margins in the MRI-guided surgery group was half that observed in the WL group (12 vs. 23%; p = 0.08). The specimen volumes in the MRI and WL groups did not differ significantly (74 ± 33.9 mL vs. 69.8 ± 25.1 mL; p = 0.45). The pathologic tumor diameters were underestimated by 2 cm or more in 4% of the cases by MRI and in 9% of the cases by mammography. Positive margins were observed in 68% and 58% of the cases underestimated by 2 cm or more using MRI and mammography, respectively, and in 15% and 14% of the cases not underestimated using MRI and mammography, respectively. A novel system using supine MRI images co-registered with intraoperative optical scanning and tracking enabled tumors to be resected with a trend toward a lower positive margin rate compared with wire-localized partial mastectomy. Margin positivity was more likely when imaging underestimated pathologic tumor size.

Wire-localized excision of nonpalpable breast cancer is imprecise, resulting in positive margins 25-30% of the time.Patients underwent preoperative supine magnetic resonance imaging (MRI). A radiologist outlined the tumor edges on consecutive images, creating a three-dimensional (3D) view of its location. Using 3D printing, a bra-like plastic form (the Breast Cancer Locator [BCL]) was fabricated, with features that allowed a surgeon to (1) mark the edges of the tumor on the breast surface; (2) inject blue dye into the breast 1 cm from the tumor edges; and (3) place a wire in the tumor at the time of surgery.Nineteen patients with palpable cancers underwent partial mastectomy after placement of surgical cues using patient-specific BCLs. The cues were in place in5 min and no adverse events occurred. The BCL accurately localized 18/19 cancers. In the 18 accurately localized cases, all 68 blue-dye injections were outside of the tumor edges. Median distance from the blue-dye center to the pathologic tumor edge was 1.4 cm, while distance from the blue dye to the tumor edge was5 mm in 4% of injections, 0.5-2.0 cm in 72% of injections, and2 cm in 24% of injections. Median distance from the tumor center to the BCL-localized wire and to the clip placed at the time of diagnosis was similar (0.49 vs. 0.73 cm) on specimen mammograms.Information on breast cancer location and shape derived from a supine MRI can be transferred safely and accurately to patients in the operating room using a 3D-printed form.

The effect of pre-operative MRI on the in-breast tumor recurrence rate (IBTR) of patients undergoing breast-conservation treatment (BCT) remains uncertain. We began to routinely perform pre-operative MRI in 2006. Our goal was to determine the effect of pre-operative MRI on IBTR. Retrospective review of a prospective database of all patients undergoing BCT (n = 1396) from 2000 to 2010. IBTR were calculated using Kaplan–Meier estimates. 664 (47.6%) patients underwent pre-operative MRI. The use of MRI increased from 13.9% in 2000–2005 to 80.7% in 2006–2010. Ten percent of patients who underwent MRI were found to have an additional ipsilateral cancer, with a mean diameter of 1.6 cm. The IBTR for patients with and without MRI were 4% vs. 8% at 8 years (p = 0.04). In multivariate analysis, radiation therapy and endocrine therapy were associated with decreased IBTR, but MRI was not (RR 0.77 (0.45–1.28)). For 1030 patients with invasive cancer, the IBTR at 8 years with and without MRI was 4.2% vs. 7.3% (p = 0.28). For 366 DCIS patients with and without MRI, the IBTR was 3.6% vs. 10.9% (p = 0.06). In the subgroup of DCIS patients who did not receive radiation, the IBTR with and without MRI was 0% vs. 18.2% (p = 0.08). Patients with an additional cancer found by MRI had a higher IBTR at 8 years (10.1% vs. 3.3%, p = 0.02). In a study analyzing BCT patients from one time period who rarely had a pre-operative MRI and a subsequent time period where most patients had MRI, the use of MRI was associated with a decrease in the IBTR on univariate, but not multivariate analysis. Patients who had additional cancers detected had a significantly higher IBTR.

Efficient injection of charge carriers from the contacts into the semiconductor layer is crucial for achieving high-performance organic devices. The potential drop necessary to accomplish this process yields a resistance associated with the contacts, namely the contact resistance. A large contact resistance can limit the operation of devices and even lead to inaccuracies in the extraction of the device parameters. Here, we demonstrate a simple and efficient strategy for reducing the contact resistance in organic thin-film transistors by more than an order of magnitude by creating high work function domains at the surface of the injecting electrodes to promote channels of enhanced injection. We find that the method is effective for both organic small molecule and polymer semiconductors, where we achieved a contact resistance as low as 200 Ωcm and device charge carrier mobilities as high as 20 cm2V−1s−1, independent of the applied gate voltage., Minimizing contact effects in organic semiconductor-based devices is a key step toward the development of a low-cost technology for next-generation electronics. Here, the authors reduce contact resistance in organic devices by engineering electrodes with high work function surface domains.

Single hadron azimuthal asymmetries of positive and negative hadrons produced in muon semi-inclusive deep inelastic scattering off longitudinally polarised deuterons are determined using the 2006 COMPASS data and also combined all deuteron COMPASS data. For each hadron charge, the dependence of the azimuthal asymmetry on the hadron azimuthal angle $\phi$ is obtained by means of a five-parameter fitting function that besides a $\phi$-independent term includes four modulations predicted by theory: $\sin\phi$, $\sin 2 \phi$, $\sin 3\phi$ and $\cos\phi$. The amplitudes of the five terms have been extracted, first, for the hadrons in the whole available kinematic region. In further fits, performed for hadrons from a restricted kinematic region, the $\phi$-dependence is determined as a function of one of three variables (Bjorken-$x$, fractional energy of virtual photon taken by the outgoing hadron and hadron transverse momentum), while disregarding the others. Except the $\phi$-independent term, all the modulation amplitudes are very small, and no clear kinematic dependence could be observed within experimental uncertainties., Comment: 15 pages, 5 figures

Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway has been implicated in anti-estrogen resistance in breast cancer. We tested the therapeutic potential of the novel PI3K/mTOR dual inhibitor P7170 in a panel of anti-estrogen-sensitive and anti-estrogen-resistant models of ER+ breast cancer. Estrogen receptor-positive (ER+) breast cancer cells were treated ±P7170. Fresh cores from primary ER+/HER2- tumors from two patients were treated ±P7170 ex vivo. Mice bearing breast cancer xenografts were randomized to treatment with vehicle, fulvestrant, P7170, or combinations, and tumor volumes were measured. Tissues and cells were analyzed for markers of pathway activity, cell viability, and apoptosis. In cell lines, P7170 exhibited IC50 values in the range of 0.9-7 nM and induced apoptosis. P7170 potently inhibited mTOR activity (≤ 25 nM) and inhibited PI3K at higher concentrations (≥ 200 nM). P7170 completely inhibited MCF-7 tumor growth, significantly inhibited growth of fulvestrant-resistant T47D tumors, and suppressed tumor cell proliferation but did not induce apoptosis. While P7170 inhibits PI3K and mTOR in ER+/HER2- human breast cancer cells and tumors ex vivo, in vivo data indicate that the primary mechanism of P7170 anti-tumor action is inhibition of mTOR and cell proliferation. P7170 is a novel agent worthy of further investigation for the treatment of ER+ breast cancer.

Lymph node biopsy is employed in many cancer surgeries to identify metastatic disease and to determine cancer stage, yet morbidity and diagnostic delays associated with lymph node biopsy could be avoided if noninvasive imaging of nodal involvement were reliable. Molecular imaging has potential in this regard; however, variable delivery and nonspecific uptake of imaging tracers have made conventional approaches ineffective clinically. Here we present a method of correcting for nonspecific uptake with injection of a second untargeted tracer that allows for quantification of tumor burden in lymph nodes. We confirmed the approach in an athymic mouse model of metastatic human breast cancer by targeting epidermal growth factor receptor, a cell surface receptor overexpressed by many cancers. We observed a significant correlation between in vivo (dual-tracer) and ex vivo measures of tumor burden (r = 0.97, P0.01), with an ultimate sensitivity of approximately 200 cells (potentially more sensitive than conventional lymph node biopsy).

Wire localization for excision of nonpalpable breast cancer is an inefficient and inexact technique. A total of 18 women with palpable invasive breast cancers underwent preoperative prone and supine magnetic resonance imaging (MRI). Intraoperatively, the edges of the tumor were palpated and marked on the skin surface. The breast was optically scanned, and the supine MRI was adjusted to match the actual breast position at the time of surgery. Image-defined tumor edges were marked on the surface of the breast. The main outcome measure was the distance between the image-defined and palpation-defined edges of the tumor. No significant difference was found between the mean maximal tumor diameter as measured by histopathology (29.6 ± 14.3 mm), supine MRI (25.3 ± 9.7 mm), prone MRI (27.6 ± 13 mm), or palpation (30.5 ± 9.3 mm). The distance from the tumor to the chest wall was markedly different in prone versus supine MRI (56.4 ± 38 vs 19.5 ± 20 mm, p = .002). The average distance between the palpated and supine MRI image-defined tumor edge locations was 7.2 mm (range, 0–19 mm). Accuracy improved over time; the average difference in edge locations in the last 7 patients was 4.0 mm. All 4 image-defined edge locations in the last 5 patients were ≤1 cm away from the palpated locations. We have developed a method of breast tumor localization using preoperative supine MRI and intraoperative optical scanning that defines tumor size and position as accurately as palpation.

The role of magnetic resonance imaging (MRI) in preoperative planning for women diagnosed with breast cancer remains controversial. The risks and benefits in women with newly diagnosed ductal carcinoma in situ (DCIS) are largely unknown.Retrospective chart review comparing women treated for DCIS who did and did not undergo MRI for preoperative planning. End points included number of additional biopsies prompted by MRI, surgical reexcision rates, weight of excisions, mastectomy rates, and conversion to mastectomy after attempted breast conservation.218 patients met study criteria. Sixty-four patients did not undergo preoperative MRI, and 154 patients did. There was no statistically significant difference (P = not significant, NS) in reexcision rates between the 34.1 % (42/123) of women who did and 20/51 (39.2 %) women who did not undergo MRI. Despite use of preoperative MRI, 11/123 women (8.9 %) were converted to mastectomy due to positive margins compared with 4/51 (7.8 %) in the women who did not undergo MRI (P = NS). In women undergoing MRI, average weight of excision at definitive surgery was 49.5 g, while in women who did not undergo MRI, average weight of excision at definitive surgery was 48.7 g.Our data show that MRI does not significantly decrease reexcision rates or conversion to mastectomy after attempted breast-conservation surgery. Based on our findings, we do not believe preoperative MRI adds benefit to the care of this patient population. Prospective trials are necessary to further investigate the risks and benefits of preoperative MRI in women with DCIS.

Moderne Chemotherapieprotokolle und neue Medikamente in der Onkologie fuhren haufig zu chemotherapieinduzierter peripherer Neurotoxizitat (CIPN). Die verfugbaren multimodalen Rehabilitationsstrategien ermoglichen trotz bestehender Sensibilitatsdefizite zur Alltagsbewaltigung relevante Funktionsverbesserungen, bei fruhzeitigem Einsatz sogar einen vollstandigen Funktionserhalt. Dem gegenuber bleiben medikamentose Behandlungsansatze abgesehen von der Schmerztherapie bei neuropathischem Schmerz unbefriedigend. Bei manifester CIPN werden von Betroffenen v. a. Ergotherapie und Physiotherapie als subjektiv effektiv bzw. sehr effektiv bewertet. Zusatzlich kann im Rahmen der Rehabilitation der gezielte Einsatz von Hilfsmitteln zum Erhalt der Selbststandigkeit und beruflichen Leistungsfahigkeit eingeubt werden.

This work considers a new class of finite-volume approximations for scalar and system nonlinear conservation laws with multiple sources of stochastic model parameter uncertainty. The deterministic propagation of model parameter uncertainty is achieved through the introduction of additional stochastic coordinates. Particular attention is given to the construction of specialized piecewise polynomial approximation spaces well suited to the high-order accurate approximation of solution discontinuities in both physical and stochastic dimensions without exhibiting Gibbs-like oscillations characteristic of polynomial approximation. The proposed discretization easily retrofits existing finite-volume CFD codes in use today. Numerical results are presented for inviscid Burgers equation with uncertain initial data as well as the compressible Reynolds-averaged Navier–Stokes equations with uncertain boundary data and turbulence model parameters.

Schadigungen des Herzens ereignen sich bei einem Unfall meist im Rahmen penetrierender und stumpfer Thoraxtraumen. Sie bestimmen oftmals die Prognose des Patienten. Dass auch emotionale Traumen zu einer stressinduzierten Kardiomyopathie fuhren konnen ist zwar bekannt, allerdings ist diese Erkrankung schlecht definiert. Tritt in unmittelbarem zeitlichem Abstand nach einem als Unfall zu kennzeichnenden Ereignis eine Myokardinfarktsymptomatik auf, die bei der diagnostischen Abklarung kein koronarangiographisches Korrelat, aber eine typische kontraktile Dysfunktion des linken Ventrikels aufweist, ist an eine Takotsubo-Kardiomyopathie zu denken. Vorgestellt werden 2 Falle dieser Erkrankung, bei denen sich unfallversicherungsrechtliche und begutachtungsrelevante Konsequenzen ergaben.

The incidence of preoperatively identified multifocal and multicentric breast cancer is rising with improved sensitivity of imaging modalities. Based on retrospective, historic data, breast conservation in women with multiple tumors has been discouraged because of high rates of local regional recurrence (LRR). These studies, however, do not extrapolate to contemporary practice as they do not incorporate the use of modern therapies and surgical techniques. This study is designed to evaluate the feasibility of breast conservation in women with multiple breast primaries.We retrospectively reviewed the charts of 22 women who underwent breast conservation surgery for 2 or more synchronous, ipsilateral cancers between 1998 and 2008. We extracted data including tumor size, nodal staging, receptor status, adjuvant therapies administered, and local-regional recurrence.A total of 22 patients were identified. Average follow up is 3.5 years. One patient (4.5%) experienced an in-breast recurrence. Both initial tumors in this patient were invasive ductal carcinoma, ER/PR, negative and HER2 positive. Time to LRR was 2.5 years.Our data are consistent with those of recent studies in which multifocal/multicentric local regional recurrence in multicentric/multifocal breast is equivalent to that seen in women with unifocal cancer. The single local recurrence in this study occurred in a premenopausal women with ER/PR- disease who were HER2+. Prior retrospective studies have identified ER/PR- and HER2 overexpression as independent risk factors for recurrence following breast conservation. Additional prospective trials are warranted to better assess the oncologic safety of breast conservation in this population.

Although it has been shown that magnetic resonance imaging (MRI) is more sensitive than mammography in the detection of breast cancer in high-risk populations, there is little data on the use of MRI as a screening tool to detect recurrence after breast-conserving surgery. Our objective was to determine the potential role of MRI in the screening of breast cancer patients treated with breast-conserving surgery.Retrospective chart review of all patients undergoing margin-negative lumpectomy and adjuvant radiation therapy for infiltrating breast carcinoma between 1(st) January 1993 and 1(st) January 2004. Patients were followed for recurrence in the ipsilateral or contralateral breast by physical exam and mammography.Four hundred and seventy-six primary tumor excisions were performed. Patients were followed for a median of 5.4 years. Ipsilateral breast recurrences developed in eight patients (1.7%) with a mean diameter of 1.6 cm. All of these women are alive and free of metastases. Contralateral cancers developed in 11 patients (2.3%) with a mean diameter of 1.5 cm. Ten of these 11 women are alive and free of disease.In a contemporary patient population the risk of local recurrence after lumpectomy and radiation therapy is very low. If screening MRI had been a part of annual follow-up, a total of 2570 MRIs would have been performed. Given the small tumor size at detection and the excellent survival of those who recurred, annual screening MRI would have incurred significant cost and would have been unlikely to improve overall survival.

Empiric treatment of hospital-acquired pneumonia (HAP) should be focused on the suspected pathogens. We evaluated the efficacy and safety of moxifloxacin vs ceftriaxone in patients with HAP without risk of infections with Pseudomonas aeruginosa and other non-fermentative Gram-negative bacteria. We performed a prospective, randomized, non-blind, multicentric and multinational study to compare the efficacy and safety of moxifloxacin 400 mg IV once daily followed by oral moxifloxacin 400 mg once daily to ceftriaxone 2 g IV once daily followed by oral cefuroxime axetil 500 mg twice daily to treat mild-to-moderate HAP in adult patients requiring initial parenteral therapy. The primary efficacy variable was clinical response 7–10 days after the end of a 7–14-day treatment period, secondary endpoints included clinical and bacteriologic response at different intervals for up to 31 days after treatment. The trial was terminated prematurely due to slow patient recruitment. A total of 161 subjects (87 men, 74 women) between 18 and 95 years of age were enrolled, 120 of whom were eligible for per protocol efficacy analyses (60 each in the moxifloxacin and the comparator groups). Clinical success rates were 87% for moxifloxacin and 83% for the comparator [95% CI (–9.77 to 15.96%)]. The results for secondary endpoints were comparable between groups. Both treatments were safe and well tolerated. Moxifloxacin IV/oral can be considered as a possible alternative for the antibiotic treatment of patients with mild-to-moderate nosocomial pneumonia without risk factors for highly resistant microorganisms.

Immunohistological analysis of 31 human spleens from the 11th week of gestation to the early postnatal period suggested that fetal organ development may be preliminarily divided into four stages. At stage 0 the organ anlage contained erythrocyte precursors, few macrophages and almost no lymphocytes. Fetal spleens of stage I exhibited arterial vascular lobules and lymphocytes just began colonizing the organ. At stage II, B and T lymphocytes formed periarteriolar clusters. B cell clusters predominated, because B cells aggregated around the more peripheral branches of splenic arterioles, while T cells occupied the more centrally located parts of the vessels. The vascular lobules of stage I and II consisted of central arterioles surrounded by B cells, capillaries and peripheral venules. The lobular architecture slowly dissolved at late stage II when sinuses grew out from the peripheral venules into the centre of the lobule. Interestingly, the B cell accumulations around peripheral arterioles did not represent the precursors of follicles, but apparently persisted as periarteriolar B cell clusters in the adult splenic red pulp, while follicles containing FDCs developed at late stage II from B cells in direct contact to T cell clusters around larger arterial vessels. At stage III before birth the lobular architecture was no longer recognized. The chemokine CXCL13 was already present in vascular smooth muscle and adjacent stromal cells at stage I before B cells immigrated. CCL21, on the contrary, was only demonstrated in fibroblast-like cells supporting T cell clusters from stage II onwards.

Bei einem 18-jahrigen, beschwerdefreien Feuerwehranwarter war auf einer Rontgenthoraxubersichtsaufnahme ein pathologischer Befund aufgefallen: Es zeigte sich eine charakteristische, krummsabelartige Verschattungsfigur im rechten parakardialen Mittelunterfeld, der das zugrunde liegende Krankheitsbild eines Scimitar-Syndroms seinen Namen verdankt. Das Scimitar-Syndrom ist eine seltene angeborene Fehlbildung mit ausgepragter Varianz des klinischen Erscheinungsbildes von asymptomatischen, zufallig diagnostizierten bis hin zu schweren Verlaufen mit Manifestation schon im Kindesalter. Im Einzelnen lassen sich folgende Anomalien feststellen: Hypoplasie eines Teils des rechten Lungenunterlappens mit verminderter pulmonalarterieller Perfusion bei erhaltenem Anschluss an das Bronchialsystem, abnorme arterielle Versorgung des betroffenen Lungenabschnitts aus der Aorta descendens sowie Fehlmundung einer dilatierten Lungenvene in den kleinen Kreislauf als Korrelat der typischen rontgenmorphologischen Verschattung. Abhangig vom Auspragungsgrad genannter Fehlbildungen und damit verbundener funktioneller Storungen ist mit der Entwicklung einer Rechtsherzinsuffizienz und rekurrierender pulmonaler Infekte zu rechnen, die eventuell ein operatives Vorgehen erfordert. Die moderne Schnittbilddiagnostik erlaubt eine prazise und rasche Aufklarung der komplexen Anatomie der Fehlbildung. Sie erbrachte bei unserem Patienten den Befund einer sehr seltenen Scimitar-Syndrom-Variante mit von der klassischen Befundkonstellation abweichender orthotoper Einmundung der dilatierten Lungenvene und resultierenden vollig differenten Auswirkungen auf die zentrale Hamodynamik, die im berichteten Fall funktionell ohne Bedeutung bleibt.

Case report describing the management of repeated perioperative bleeding probably due to Protein-Z-deficiency in a post-traumatic paraplegic patient. To describe the difficulty in diagnosing this rare form of hypocoagulability and the monitoring and substitution concept during three elective surgical interventions. Spinal Cord Injury Center, Bergmannstrost, Halle, Germany. A 19-year-old male suffering from a post-traumatic paraplegia sub Th8 (ASIA-A) since childhood had experienced two life-threatening intraoperative bleeding incidents before finally Protein-Z-deficiency as the underlying coagulation disorder was diagnosed. After substitution of 2000 IE PPSB (Beriplex P/N) a repeatedly postponed implantation of a sphincter-externus (Brindley-) stimulator could be performed without bleeding complications, and this was also true for two additional urological interventions 1 year later. Protein-Z levels were monitored before, during and after the operations. The preoperative application of between 1000 and 2000 IE PPSB was safe and sufficient to raise the patients' plasma Protein-Z level to almost normal and so prevent excessive intraoperative blood loss. In case of repeated bleeding tendency of unknown origin it is mandatory to look for rare causes of hypocoagulability such as Protein-Z-deficiency. We developed a substitution concept using a plasma concentrate with guaranteed Protein-Z amount (PPSB) allowing the safe performance of elective surgical interventions.

The reaction gamma p --> K0 Sigma+ was measured in the photon energy range from threshold up to 2.6 GeV with the SAPHIR detector at the electron stretcher facility, ELSA, in Bonn. Results are presented on the reaction cross section and the polarization of the Sigma+ as a function of the kaon production angle in the centre-of-mass system, cos(Theta_K^{c.m.}), and the photon energy. The cross section is lower and varies less with photon energy and kaon production angle than that of gamma p --> K+ Sigma0. The Sigma+ is polarized predominantly at cos(Theta_K^{c.m.}) \approx 0. The data presented here are more precise than previous ones obtained with SAPHIR and extend the photon energy range to higher values. They are compared to isobar model calculations.

Lungenembolien sind haufige und schwerwiegende Komplikationen einer Krankenhausbehandlung. Sie erfordern eine rasche und richtige Diagnostik, um die dem Schweregrad der Erkrankung entsprechende Behandlung unverzuglich einleiten zu konnen. Wegen der uncharakteristischen klinischen Befunde sollten zuerst schnell durchzufuhrende, nichtinvasive Untersuchungsmethoden wie Echokardiographie und Mehrschichtspiraltomographie Anwendung finden. Unter den laborchemischen Parametern hat der D-Dimer-Test hinsichtlich thrombembolischer Ereignisse eine grose Bedeutung. Bei unklaren Befunden ist eine weiterfuhrende, teilweise zeitaufwandigere Diagnostik (wie Ventilationsperfusionsszintigraphie und Pulmonalisangiographie) gerechtfertigt. Da eine akute Lungenembolie haufig als Komplikation einer tiefen Beinvenenthrombose auftritt, kommt der Thromboseprophylaxe eine besondere und wichtige Bedeutung zu.

Objective: This study aimed to investigate the efficacy, safety and tolerability of sequential intravenous (IV)/oral therapy with moxifloxacin in pneumonia under general hospital treatment conditions. Patients and methods: Patients with pneumonia were documented in this non-interventional multicentre study. The patients were treated with IV moxifloxacin or moxifloxacin sequential therapy (IV and oral) in hospitals throughout Germany. Exclusion criteria were limited to the contraindications mentioned in the summary of product characteristics. The participating hospital-based physicians documented the patients’ demography, anamnesis, antibiotic pretreatment, concomitant diseases and medications. Moxifloxacin therapy and symptom status were recorded daily up to the ninth day and on the last day of treatment. The physicians assessed the efficacy and tolerability of IV moxifloxacin therapy and reported all adverse events observed within the treatment period. Results: The 1749 documented patients had a mean age of 66.2 (SD 15.5) years; 56.4% were males and 43.5% females. The majority (99.3%) were treated with moxifloxacin 400mg once daily. On average, moxifloxacin was given for 7.6 days (SD 3.2). In cases of sequential therapy (78.9% of patients), IV moxifloxacin was switched to oral moxifloxacin after a mean of 4.1 days (SD 1.8). Moxifloxacin produced a significant clinical improvement in 58.2% of patients by day 3 of therapy, in 84.2% by day 5 and in 89.4% by day 7. Recovery occurred in 27.0% of patients by day 5, in 54.0% by day 7 and in 87.0% by day 14. It took a mean of 3.4 days (SD 1.9) until improvement and 7.2 days (SD 3.0) until cure. Overall efficacy of IV moxifloxacin therapy was rated by the physicians as ‘very good’ or ‘good’ in 82.9% of patients. Tolerability was rated in 94.3% of patients as ‘very good’ or ‘good’. Adverse events were recorded for 92 (5.3%) patients, but events were considered by the attending physician to be related to moxifloxacin therapy for only 45 patients (2.6%). Conclusions: IV moxifloxacin shows high efficacy in the treatment of pneumonia under routine clinical treatment conditions. IV moxifloxacin relieves pneumonia-associated symptoms rapidly and allows an early switch to oral administration. Because of its high efficacy and very good safety and tolerability profile, moxifloxacin delivers excellent benefits as first-line therapy for pneumonia.

The photoproduction of ρ0-mesons and Δ-baryons at photon energies up to 2.6 GeV has been studied with the SAPHIR detector at the electron stretcher ELSA. Total and differential cross-sections were obtained. The decay angular distributions of ρ0-mesons show that s-channel helicity conservation, which is valid at high photon energies, is broken near threshold. The energy dependencies of the decay angular distributions in the helicity system as well as in the Gottfried-Jackson system hint at small s- or u-channel resonance contributions. For the reactions γp → Δ{++}π- and γp → Δ0π+ new data on cross-sections are presented.

The reactions gamma p --> K+ Lambda and gamma p --> K+ Sigma0 were measured in the energy range from threshold up to a photon energy of 2.6 GeV. The data were taken with the SAPHIR detector at the electron stretcher facility, ELSA. Results on cross sections and hyperon polarizations are presented as a function of kaon production angle and photon energy. The total cross section for Lambda production rises steeply with energy close to threshold, whereas the Sigma0 cross section rises slowly to a maximum at about E_gamma = 1.45 GeV. Cross sections together with their angular decompositions into Legendre polynomials suggest contributions from resonance production for both reactions. In general, the induced polarization of Lambda has negative values in the kaon forward direction and positive values in the backward direction. The magnitude varies with energy. The polarization of Sigma0 follows a similar angular and energy dependence as that of Lambda, but with opposite sign.

The photoproduction of the vector meson $\omega$ has been studied between threshold and W = 2.4 GeV with the SAPHIR detector at the Bonn electron stretcher ring ELSA. Besides, the total cross-sections angular distributions in the CMS and decay angular distributions in the helicity and Gottfried-Jackson systems have been measured.

Gelenknahe periprothetische Frakturen sind meist als Problemfrakturen zu betrachten. Die Fruhmobilisation und eine geringe Belastung des Patienten stellen die wesentlichen Auswahlkriterien fur die Operationsmethode dar. In seltenen Fallen ist die Anwendung eines Ilizarov-Fixateurs die gunstigste Alternative fur den Patienten. Der Hybridaufbau des Fixateurs reduziert die Operationszeit betrachtlich. Anhand von 2 Fallen wird diese Versorgung dargestellt.

Photoproduction of Φ-vector-mesons has been studied from reaction threshold up to W = 2.4 GeV with the SAPHIR spectrometer at the Bonn electron stretcher ring ELSA. Total cross-sections, differential cross-sections and decay angular distributions were measured. We find evidence for strong non-diffractive contributions to Φ photoproduction.

Knowledge of the properties of γ-ray bursts has increased substantially following recent detections of counterparts at X-ray, optical and radio wavelengths. But the nature of the underlying physical mechanism that powers these sources remains unclear. In this context, an important question is the total energy in the burst, for which an accurate estimate of the distance is required. Possible host galaxies have been identified for the first two optical counterparts discovered, and a lower limit obtained for the redshift of one of them, indicating that the bursts lie at cosmological distances. A host galaxy of the third optically detected burst has now been identified and its redshift determined to be z = 3.42. When combined with the measured flux of γ-rays from the burst, this large redshift implies an energy of 3 10^(53) erg in the γ-rays alone, if the emission is isotropic. This is much larger than the energies hitherto considered, and it poses a challenge for theoretical models of the bursts.

Interleukin-10 (IL-10) is a cytokine secreted by the TH2 class of murine lymphocytes that suppresses the secretion of interferon-gamma (IFN-gamma) by TH1 lymphocytes and inhibits macrophage-mediated T-cell stimulation and cytotoxicity. The observation that IL-10 is produced by human carcinomas in vitro and in vivo led to the hypothesis that this cytokine plays a role in the suppression of the human anti-tumor immune response. We tested this hypothesis in a murine model.To evaluate the effect of IL-10 on the induction of an anti-tumor immune response, mice were immunized with tumor cells transfected with the IL-10 gene and then challenged with parental tumor. The effect of the local secretion of IL-10 on an established immune response was tested by immunizing mice with parental tumor and then challenging with IL-10-secreting tumors.IL-10-secreting tumors were as effective immunogens as control tumors. Immune mice rejected IL-10-secreting tumors as readily as control challenge tumors. In an in vitro assay, IL-10 did not inhibit CD8 lymphocyte secretion of IFN-gamma in response to tumor stimulation. One IL-10-secreting tumor clone regressed when injected into naive mice and induced an antigen-specific immune response capable of protecting mice from subsequent tumor challenge.The local secretion of IL-10 did not inhibit either the induction of an antitumor immune response or the ability of established effector cells to reject challenge tumors. In contrast to its effect on TH1 lymphocytes, IL-10 does not inhibit IFN-gamma secretion by CD8 lymphocytes.

Human breast cancers progressively grow despite the presence of extensive lymphocytic infiltration and specific antitumor immune recognition, thereby calling into question the competency of breast tumor-infiltrating lymphocytes (TIL). The function of breast TILs in vivo and their possible role in the suppression of an antitumor immune response are largely unknown.The cytokines produced in situ by lymphocytes in 89 breast carcinomas and 14 benign breast lesions were assessed using immunohistochemistry.The majority of tumor and benign breast samples contained T-cell infiltrates, which were disclosed using an anti-CD3 antibody stain. The percentage of tumor samples in whichor =3% of the lymphocytes were producing cytokines was as follows: interleukin (IL)-2 45%, IL-4 36%, tumor necrosis factor-alpha (TNF-alpha) 28%, transforming growth factor-beta 1 (TGF-beta 1) 20%, IL-10 11%, interferon-gamma (IFN-gamma) 4%, and granulocyte-macrophage colony-stimulating factor (GM-CSF) 3%. Production of IL-2, IL-4, and TGF-beta 1 by TILs in breast cancers exceeded that detected in benign breast lesions (p0.005). Significantly more tumor samples contained lymphocytes producing IL-2, IL-4, TGF-beta 1, and TNF-alpha than IFN-gamma and GM-CSF (p0.002 for each comparison). One or more of the potentially immunoinhibitory cytokines-IL-4, IL-10, or TGF-beta 1-were produced by lymphocytes in 44% of the specimens. No significant associations were seen between lymphocyte production of a particular cytokine and disease-free survival (median follow-up 43 months).Immunohistochemical techniques can be used to detect cytokine secretion by TILs in preserved tissue. The relative lack of secretion of IFN-gamma and GM-CSF, rather than a deficiency of IL-2, may explain why the antitumor immune response to breast cancer is impaired.

The reaction $\gamma p \TO K^+\Lambda(1520)$ was measured in the energy range from threshold to 2.65 GeV with the SAPHIR detector at the electron stretcher facility ELSA in Bonn. The $\Lambda(1520)$ production cross section was analyzed in the decay modes $pK^-$, $n \bar{K}^0$, $\Sigma^{\pm}\pi^{\mp}$, and $\Lambda\pi^+\pi^-$ as a function of the photon energy and the squared four-momentum transfer $t$. While the cross sections for the inclusive reactions rise steadily with energy, the cross section of the process $\gamma p \TO K^+\Lambda(1520)$ peaks at a photon energy of about 2.0 GeV, falls off exponentially with $t$, and shows a slope flattening with increasing photon energy. The angular distributions in the $t$-channel helicity system indicate neither a $K$ nor a $K^\star$ exchange dominance. The interpretation of the $\Lambda(1520)$ as a $\Sigma(1385)\pi$ molecule is not supported.

The reaction γp → K + Λ(1520) was measured in the energy range from threshold to 2.65 GeV with the SAPHIR detector at the electron stretcher facility ELSA in Bonn. The Λ(1520) production cross-section was analyzed in the decay modes pK −, $$ n\bar K^0 $$ , Σ ± π ∓, and Λπ + π − as a function of the photon energy and the squared four-momentum transfer t . While the cross-sections for the inclusive reactions rise steadily with energy, the cross-section of the process γp → K + Λ(1520) peaks at a photon energy of about 2.0 GeV, falls off exponentially with t , and shows a slope flattening with increasing photon energy. The angular distributions in the t-channel helicity system indicate neither a K nor a K * exchange dominance. Rather, the rapid change of the angular distribution with energy suggests that, in addition to t -channel K and K* exchange, amplitudes for formation of nucleon resonances in the s-channel play an important role.

The reactions γp → K+ Σ± π∓ were studied with the SAPHIR detector using a tagged photon beam at the electron stretcher facility ELSA in Bonn. The decays Σ − → nπ − and Σ + → nπ +, pπ 0 were fully reconstructed. Reaction cross-sections were measured as a function of the photon energy from threshold up to 2.6 GeV with considerably improved statistics compared to a previous bubble chamber measurement. The cross-sections rise monotonically with increasing photon energy. The two-particle mass distributions of Σ ± π ∓ and K + π − show substantial production of resonant states.

We have studied 15 patients with slight or moderate bronchial obstruction, all of whom were being treated by inhalation of the beta-mimetic fenoterol 4 x 400 micrograms/day, and 7 of whom were also receiving inhaled flunisolide 2 x 500 micrograms/day. The therapy had been given for longer than 1 month in each case. Bronchoscopy and bronchoalveolar lavage (BAL) was done for diagnosis or follow up of bronchial diseases. None of the patients showed signs of any interstitial lung disease. Conditioned culture supernatants were produced by cultivating alveolar macrophages (AM) for 24 h using standard conditions. To detect all the biological effects both of IL-1 alpha and IL-1 beta in the culture supernatants a modification of the standard mouse IL-1 thymocyte bioassay was used. The TNF concentration in culture supernatants was measured by ELISA. Free oxygen radical release by alveolar macrophages was determined by the detection of chemiluminescence. Both IL-1 and TNF production were significantly lower in patients receiving fenoterol plus flunisolide than in patients on fenoterol alone. In contrast, no difference could be observed in the release of free oxygen radicals from alveolar macrophages. Thus, for the first time an ex vivo study has revealed an interrelation between inhaled glucocorticoid therapy and inhibition of important mediators of inflammatory processes in the lower respiratory tract.

An asymptotic analysis of the near tip fields is given for a steadily propagating crack. The power hardening material is characterized by J 2 flow theory as well as deformation theory. A further condition for steady state crack growth is obtained. By using a new path independent integral, explicit results are given for the order of the crack tip singularity. It was found that the singularities calculated by using the different material models are not the same.

A mesh-vertex finite volume scheme for solving the Euler equations on triangular unstructured meshes is implemented on a MIMD (multiple instruction/multiple data stream) parallel computer. Three partitioning strategies for distributing the work load onto the processors are discussed. Issues pertaining to the communication costs are also addressed. We find that the spectral bisection strategy yields the best performance. The performance of this unstructured computation on the Intel iPSC/860 compares very favorably with that on a one-processor CRAY Y-MP/1 and an earlier implementation on the Connection Machine.

Excising a breast tumor with negative margins minimizes local recurrence. With a positive margin, the standard re-excision consists of excising the whole cavity and all surrounding breast tissue. By marking the sides of the lumpectomy specimen with six different colored inks, the surgeon can limit the re-excision to the involved margin. We compared the local recurrence rate after these two re-excision methods.Records were reviewed of 527 women (546 breasts) treated with lumpectomy at two institutions. The log-rank test was used to compare the local recurrence-free survival.Of 546 tumors, 245 (45%) had negative margins on the initial lumpectomy and were not re-excised. Fifty-five percent had a positive or close margin; 181 underwent whole-cavity re-excision, and 120 had ink-directed re-excision. The mean follow-up time was 3.4 years. There was no significant difference in local recurrence for the patients whose initial margin was negative (3.7%) compared with the 243 patients with initially positive margins who underwent a re-excision (3.3%). Eleven of 181 (6%) patients undergoing a whole-cavity re-excision developed a local recurrence, compared with none of 120 (0%) patients with an ink-directed re-excision (P = not significant). Tissue mass excised was significantly smaller in the ink-directed group (23 vs. 83 g, P.05).Ink-directed re-excision of lumpectomy specimens with positive margins minimizes the amount of breast tissue removed without increasing the incidence of local recurrence and is therefore preferable to the standard whole-cavity method.

The XXZ spin-chain Hamiltonian has been constructed to be su(2) q -invariant, but naively does not appear to be su(2)-invariant. However, using recently discovered deforming maps between representations of su(2) q and corresponding representations of su(2), we prove a theorem which states that if a Hamiltonian is su(2) q -invariant, it is also su(2)-invariant. The theorem generalizes to any quantized Lie algebra.

Al-spiking in contacts to Si were studied on a microscopic scale by a detailed cross sectional TEM analysis. Electron spectroscopic imaging and energy dispersive x-ray microanalysis with a I nm high-current electron probe formed by a field emission gun helped to identify the Al-diffusion paths and the reaction mechanisms which lead to contact failure. Combinations of advanced PVD-Ti/TiN barrier layers and cold/hot or high-pressure AlSiCu-fills revealed that the highly rugged TiN barrier sidewalls and thick Ti sidewall layers are the weak points which cause Al-spiking.