Engineering new limits to magnetostriction through metastability in iron-gallium alloys.

Magnetostrictive materials transduce magnetic and mechanical energies and when combined with piezoelectric elements, evoke magnetoelectric transduction for high-sensitivity magnetic field sensors and energy-efficient beyond-CMOS technologies. The dearth of ductile, rare-earth-free materials with high magnetostrictive coefficients motivates the discovery of superior materials. Fe1-xGax alloys are amongst the highest performing rare-earth-free magnetostrictive materials; however, magnetostriction becomes sharply suppressed beyond x = 19% due to the formation of a parasitic ordered intermetallic phase. Here, we harness epitaxy to extend the stability of the BCC Fe1-xGax alloy to gallium compositions as high as x = 30% and in so doing dramatically boost the magnetostriction by as much as 10x relative to the bulk and 2x larger than canonical rare-earth based magnetostrictors. A Fe1-xGax - [Pb(Mg1/3Nb2/3)O3]0.7-[PbTiO3]0.3 (PMN-PT) composite magnetoelectric shows robust 90° electrical switching of magnetic anisotropy and a converse magnetoelectric coefficient of 2.0 × 10-5 s m-1. When optimally scaled, this high coefficient implies stable switching at ~80 aJ per bit.

Use of simulation patients in the third section of the medical examination.

In order to protect patients and students during the Covid 19 pandemic, the third section of the medical examination (M3) in Halle (Saale) was conducted in a modified form in accordance with the "Verordnung zur Abweichung von der Approbationsordnung für Ärzte bei einer epidemischen Lage von nationaler Tragweite" [1]. The one-day examination took place at the Dorothea Erxleben Learning Center (DELH) of the Martin Luther University Halle-Wittenberg on standardized simulation subjects. In contrast to previous years, all examiners were examined individually in internal medicine, surgery and their elective subject of the practical year. In the evaluations carried out, the standardized cases were assessed as consistent and fair by examiners and exam takers. Approximately 90% of the examiners could imagine to test a state examination with simulated patients again. After successful pilot testing, a study will be conducted in the coming exam to determine whether the substitution of real patients with simulated patients in the M3 exam can contribute to better standardization and objectivity while maintaining the same high level of acceptance in the exam. Whether the high acceptance will remain constant can only be checked in the course of the study.

Electrochemical sensor system for breath analysis of aldehydes, CO and NO.

Bulky and hyphenated laboratory-based analytical instrumentation such as gas chromatography/mass spectrometry is still required to trace breath biomarkers in the low ppbV level. Innovative sensor-based technologies could provide on-site and point-of-care (POC) detection of volatile biomarkers such as breath aldehydes related to oxidative stress and cancer. An electrochemical sensor system was developed for direct detection of the total abundance of aldehydes in exhaled breath in the ppbV level and for simultaneous determination of the airway inflammation markers carbon monoxide (CO) and nitric oxide (NO). The sensor system was tested in vitro with gaseous standard mixtures and in vivo in spontaneously breathing patients and under mechanical ventilation in an animal model. The sensor system provided in vitro and in vivo detection of trace levels of aldehydes, CO and NO. Inertness of the tubing system was important for reliable results. Sensitivity of the aldehyde sensor increased with humidity. Response time for analysis of breath samples was about 22 s and relative standard deviations of sensor amplitudes were <5%. Detection limits in the low ppbV range and a linear range of more than two orders of magnitude could be achieved for volatile aldehydes. Cross sensitivities were moderate for alcohols such as ethanol or isopropanol and negligible for other typical breath volatile organic compounds such as acetone, isoprene or propofol. In proof of concept analyses in patients suffering from lung cancer and diabetes, aldehyde and CO sensor signals differed between the groups. Elevated CO levels indicated previous smoking. In a mechanically ventilated pig, continuous monitoring of breath aldehyde concentrations in the low ppbV was realized. Cumulative aldehyde measurements may add interesting and complementary information to the conventional parameters used in clinical breath research. POC applicability, easy handling and low cost of sensors facilitate measurements in large patient cohorts.

Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib.

UNLABELLED: Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS: (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Bacterial colonization of microbial biofilms in oral squamous cell carcinoma.

OBJECTIVES: The purpose of this prospective clinical study was to identify the bacterial spectra on the surface of oral squamous cell carcinomas (OSCC) in comparison to oral mucosa of patients with a higher risk to emerge an OSCC and a control group to determine their susceptibility to various common antibiotics. MATERIAL AND METHODS: Swabs from 90 patients, 30 patients of each group, were cultured on media for aerobes and anaerobes and tested with agar diffusion and Etest. RESULTS: The predominant pathogens of the normal healthy oral mucosa were aerobes. The ratio between aerobes and anaerobes was 2:1, balanced in risk patients and inverted in the OSCC group. Altogether, 1,006 isolates were cultured. The most frequent strains were 47 viridans streptococci, 30 Staphylococcus species, 14 Enterococcus faecalis, 36 Neisseria species, 14 Escherichia coli, and 23 other aerobes, 66 Peptostreptococcus species, 39 Fusobacterium species, and 34 Prevotella species. The resistance rates in the OSCC group were penicillin 40%, ampicillin 57%, doxycycline 23%, clindamycin 47%, and amoxicillin/clavulanic acid 20%, but up to 100% of pathogens were susceptible to azithromycin, telithromycin, levofloxacin, and moxifloxacin. CONCLUSION: Gram-negative anaerobes play a decisive role in the development of postoperative infections in patients with OSCC. This tumor special type of colonization does not agree with the normal flora of the oral cavity. CLINICAL RELEVANCE: Biofilms on OSCC surfaces provide an important reservoir for anaerobic bacteria. As a consequence, a proposal for an antibiotic prophylactic regime should be given.

[Local flaps for the closure of facial defects]. / Defektdeckung mittels Nahlappenplastiken im Gesicht.

Local flaps for the closure of facial defects after trauma, tumor resection or due to malformations have been well known since ancient times and allow good to satisfying functional and aesthetic results. Based on the characteristics of skin and soft tissue nearly all clinical situations can be resolved by stretching, rotating and transposing flaps depending on the localization. A good surgical technique is essential for the success. The basic principles are briefly described and suggestions for the application of flaps to different localizations are given. For analgesia local anesthesia is sufficient. As could be demonstrated multitudinously the method is ideal for closure of small to large defects in the face; therefore, microvascular surgery can be extremely restricted in treating defects of the face.

Correlation of expression of hypoxia-related proteins with prognosis in oral squamous cell carcinoma patients.

INTRODUCTION: Hypoxia plays a major role in tumor progression, therapy resistance and for prognosis of oral squamous cell carcinoma (OSCC). The crucial step as a response to hypoxia is the activation and stabilization of the alpha subunit of hypoxia inducible factor 1 (HIF-1α). HIF-1: HIF-1 regulates the expression of different genes to adapt the tumor cells to reduced oxygenation. The HIF-1 system is intrinsic regulated by von Hippel-Lindau protein (pVHL). Main downstream proteins are the glucose transporter 1 (GLUT-1), carbonic anhydrase IX (CAIX), and vascular endothelial growth factor (VEGF). For therapeutical stratification in OSCC, it is important to understand the mechanism caused by hypoxic stress and to comprehend the resulting adaptive process in cancer cells. Therefore, an overview of HIF-1α-depending protein expression, focussed on the expression of GLUT-1, CAIX, and VEGF and their prognostic significance in OSCC is given. CONCLUSION: Several unique roles of hypoxic pathway in the context of tumor progression are described in this review. As a consequence, a marker panel is proposed to allow a more individualized prognosis in OSCC patients. This marker panel should include beside HIF-1α, pVHL, and GLUT-1.

Prognostic impact of meningeal dissemination in primary CNS lymphoma (PCNSL): experience from the G-PCNSL-SG1 trial.

BACKGROUND: We evaluated the frequency and prognostic impact of meningeal dissemination (MD) in immunocompetent adult patients with primary central nervous system lymphoma treated in a randomized phase III trial. PATIENTS AND METHODS: MD was evaluated at study entry and defined by lymphoma proof in the meningeal compartment detected by at least one of the following methods: cerebrospinal fluid (CSF) cytomorphology, detection of clonal B cells by IgH PCR in CSF or contrast enhancement of the leptomeninges on magnetic resonance imaging (MRI). RESULTS: Data on MD were available in 415 patients, of those, MD was detected in 65 (15.7%): in 44/361 (12.2%) by CSF cytomorphology, in 16/152 (10.5%) by PCR and in 17/415 (4.1%) by MRI. Major patients' characteristics and therapy did not significantly differ between patients with MD (MD+) versus those without MD (MD-). There was a significant correlation of MD with CSF pleocytosis (>5/µl; P < 0.0001), but no correlation with CSF protein elevation (>45 mg/dl). Median progression-free survival was 6.7 months [95% confidence interval (CI) 0-14.5] in MD+ and 8.3 months (5.7-10.8) in MD- patients (P = 0.95); median overall survival was 21.5 months (95% CI 16.8-26.1) and 24.9 months (17.5-32.3), respectively (P = 0.98). CONCLUSION: MD was detected infrequently and had no impact on outcome in this trial.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML).

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with ≤1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with ≤35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with ≤1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.

In vitro investigation of the secondary palate development in two strains of mice.

The pathogenesis of cleft lip and palate (CL/P) is studied in animal experiments. This study revealed significant differences in foetal secondary palate development in two strains of mice (NMRI, A/WySnJ) using a palatal organ model. Palatal shelves of 114 NMRI embryos, resistant to cleft occurrence, and 93 A/WySnJ embryos, a strain with a high spontaneous CL/P rate, were micro-dissected at 14.25 GD (gestational day), before palatal fusion takes place. After cultivation in serum-free medium, palatal development was investigated microscopically and scored in a six-step system. At death (14.25 GD) the palatal shelves of the NMRI embryos (mean 3.5) were significant more developed than those of A/WySnJ (mean 2.7; p=0.05). After incubation, 53% (60/114) NMRI and 14% (13/93) A/WySnJ cultures had over two-thirds fusion to stage V-VI, therefore in 17% NMRI (19/114) and 1% A/WySnJ cultures (1/93) fusion was macroscopically complete. 62% of the A/WySnJ cultures showed no significant development in vitro (mean 2.84; p=0.094). There is a significant palatal development difference between normally developed NMRI (mean 4.45, p=0.05) and CL/P appearance in A/WySnJ mice (mean 2.84). Palatal development of both strains was significantly delayed in organ culture (p=0.05). The A/WySnJ strain was more susceptible to manipulation and vulnerable.

Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy-induced leukocytopenia.

BACKGROUND: To study the effects of deferring pegfilgrastim until day 4 on the reduction of chemotherapy-induced leukocytopenia. PATIENTS AND METHODS: Patients of age 61-80 years with aggressive lymphoma were randomly assigned to receive 6 mg pegfilgrastim on day 2 or 4 of a 2-week chemotherapy regimen (R-CHOP-14). RESULTS: Two hundred and ninety-two and 313 chemotherapy cycles were evaluable in 103 patients. Post-nadir pegfilgrastim serum levels were higher after day 4 than after day 2 application. This was associated with an attenuated leukocyte nadir after day 4 pegfilgrastim and there were fewer days with leukocytes <2 × 10(3)/mm(3) compared with day 2 pegfilgrastim. Grade 3 and 4 leukocytopenias (70% versus 43.3%; P < 0.001) and grade 4-only leukocytopenias (47% versus 20.5%; P < 0.001) were more frequent after day 2 pegfilgrastim. There were more chemotherapy cycles with grade 3 and 4 infections after day 2 than day 4 pegfilgrastim (9.4% versus 6.0%; P = 0.118). Interventional antibiotics were given more often after day 2 than after day 4 pegfilgrastim (30.7% versus 21.9% of cycles; P = 0.008). There were five deaths during leukocytopenia after day 2 and none after day 4 pegfilgrastim (P = 0.027). CONCLUSIONS: Administration of pegfilgrastim on day 4 was more effective in reducing severe leukocytopenias and resulted in fewer deaths during leukocytopenia. Pegfilgrastim should be given on day 4 to better exploit its myeloprotective potential.

Retrospective web-based multicenter evaluation of ¹8F-FDG-PET and CT derived predictive factors. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan in follicular non Hodgkin's lymphoma.

AIM: Although predictive factors (PF) for conventional lymphoma therapy are established and frequently used in clinical practice and medical research, the PF for radioimmunotherapy (RIT) have not been fully defined until now. The aim of this multicenter evaluation is to prove the feasibility of the multicenter web-based data collection and to preliminary explore imaging findings and prediction of therapy response in patients with follicular lymphoma (FL) following radioimmunotherapy (RIT) with 90Y-ibritumomab tiuxetan. PATIENTS, METHODS: We retrospectively analyzed and correlated clinical and imaging data (CT and FDG-PET) before and after RIT as documented by the RIT-Network. Evaluation of treatment response was done on both patient and lesion basis. Every measurable lesion was analyzed in terms of standardized uptake value (SUV), volume (CT and PET) and response. PF were identified using a uni- and multivariate model. A web-based system was used for the documentation and evaluation of clinical and imaging data. RESULTS: 16 patients with at least one PET before and after RIT were eligible for analysis. Concerning response three months postRIT, 5 patients achieved a CR, 6 patients a PR and 4 patients remained with NC. A total of 159 lesions were measured (mean 10±8). In the multivariate model the log lesion volume (p < 0.0001), the total (p = 0.03) and maximum lesion volume (p = 0.05) were predictors for response (CR + PR). Concerning the lesional CR initial small lesion volume (p = 0.009) and its high metabolic activity (p = 0.01) were identified as predictors. The web-based system showed no major disturbances allowing secure data transfer and central image interpretation in a reasonable time. CONCLUSION: The use of a web-based multicenter archiving system for clinical and imaging data is technically feasible in a multicenter setting and allows a central analysis. This preliminary analysis suggests that FDG-PET may predict the likelihood of response to RIT.

Co-expression of Hif1alpha and CAIX is associated with poor prognosis in oral squamous cell carcinoma patients.

BACKGROUND: This study investigates the prognostic impact of the expression of hypoxia-inducible factor 1alpha (Hif1alpha) and carbonic anhydrase IX (CAIX) detected by immunohistochemistry in oral squamous cell carcinoma (OSCC). METHODS: Statistical analysis of immunohistochemical results with clinical parameters including survival outcomes was performed for 80 OSCC patients. RESULTS: Patients with a low expression of both proteins survived on average 54.8 months, whereas those with an increased expression of Hif1alpha in their tumors combined with a low expression of CAIX survived on average only 37.6 months (P = 0.026). In multivariate Cox's regression hazard analysis, again patients with a low expression of Hif1alpha/CAIX had the best prognosis, whereas patients with increased Hif1alpha and low CAIX expression carried a 4.97-fold increased risk of tumor-related death (P = 0.042). CONCLUSION: A co-detection of low Hif1alpha/CAIX expression is significantly correlated with a better prognosis for OSCC patients, which may have implications for therapy options for these patients.

[Paroxysmal nocturnal hemoglobinuria (PNH). Pathogenesis, diagnosis and treatment]. / Paroxysmale nächtliche Hämoglobinurie (PNH). Pathogenese, Diagnostik und Therapie.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the classic clinical triad of corpuscular hemolytic anemia, thrombophilia and cytopenia. This is caused by an acquired mutation of the PIG(phosphatidylinositol glycan)-A gene of the pluripotent hematopoetic stem cell. This results in a deficiency of GPI(glycosylphosphatidylinositol)-anchors and GPI-anchored proteins on the surface of affected blood cells. Flow cytometry is the standard for diagnosis and measurement of type and size of the PNH clone. Treatment of PNH is mainly symptomatic. Allogeneic bone marrow transplantation is the only curative option in case of severe complications during the course of the diseases. A new targeted treatment strategy is the inhibition of the terminal complement cascade with a monoclonal antibody (eculizumab). As shown in clinical studies this is efficient to reduce complement mediated intravascular hemolysis, reduce the need for transfusions, improve the quality of life in patients with PNH and reduce the risk for thromboembolic complications, which are the main cause of mortality in PNH.

[Tumor profiling of renal cell tumors: relevance for diagnostics and therapy]. / Molekulares Tumorprofiling von Nierenzelltumoren: Relevanz für Diagnostik und Therapie.

Molecular biological tumor markers and prognostic parameters are necessary for differential diagnosis, individual prognosis, and therapy in patients with renal cell tumors. By using high throughput technologies, it is possible to characterize tumor samples comprehensively. Based on specific genetic alterations, histopathological subtypes were defined as independent tumor entities. Genetic characteristics can be used for diagnosis of primary tumor samples and also of biopsies. Furthermore, specific molecular patterns of metastatic tumors are known, allowing the determination of the primary tumor's metastatic potential. The specific protein patterns of serum samples of tumor patients were analyzed, and several candidate proteins have been identified. One of these is SAA-1, which is elevated in patients with clear cell renal cell carcinomas (RCC). New therapeutic options are now available for patients with metastatic RCC. Therefore, it is necessary to select the best therapy for each patient and to detect therapy resistance very early. Biomarkers in tumor tissue and serum were found to correlate with therapy response.

[Prognostic factors for oral squamous cell carcinoma]. / Prognostische Aussagen zum Mundhöhlenkarzinom.

The aim of the present study was to analyze different prognostic factors to calculate the overall survival in oral squamous cell carcinoma (OSCC). Samples retrospectively collected from 99 patients with primary OSCC were analyzed with regard to tumor node metastasis stage, grading, and 5-year survival time and summarized at an SPSS 11.0 databank. Treated were 72 men and 27 women (average age 59 years) due to oral squamous cell carcinoma. A general 5-year survival time of 57.3% was found. Patient survival depended on tumor size and the extent of lymph node metastasis: survival was 80.1% (n=23) for T1 tumors and only 16.2% (n=28) for T4 tumors, 68.7% (n=55) at the N0 stage and 42.8% at >N0 (n=44, chi(2) test P=0.01, Fischer's exact test P=0.014). Highly differentiated carcinomas (n=26) had a survival probability of 78.9% and G2 and G3 tumors of only 48.9% (n=73, chi(2) test P<0.001). Tumor size and lymph node metastases are decisive.

Expression of Glut-1 is a prognostic marker for oral squamous cell carcinoma patients.

Oral squamous cell carcinoma (OSCC) is among the tenth most common human cancers worldwide with evidence of an increase in incidence rate and mortality. Despite advances in treatment modalities, the prognosis of this cancer is still very poor and has not changed over the past two decades. This study is based on samples collected from 42 patients with a primary OSCC. Immunohistochemical staining for Glut-1 was carried out and compared with the clinicopathological data. Thirty-two patients showed in their tumors a weak or undetectable Glut-1 expression, whereas in tumors of 10 patients a moderate to strong Glut-1 expression was detected. In multivariate Cox's regression hazard analysis, patients whose tumors had a moderate to strong Glut-1 expression possessed a 4.9-fold increased risk of tumor-related death compared to the other patients. Our results suggest that Glut-1 expression is an independent prognostic marker for routine assessment of OSCC.

[Laser-supported partial nephrectomy for renal cell carcinoma]. / Lasergestützte partielle Nephrektomie beim Nierenzellkarzinom.

To decrease the disadvantages of vascular hilar clamping, we tested the use of a laser for partial nephrectomy. We conclude that laser-supported partial nephrectomy without clamping of the renal vessels, particularly in carefully selected patients, is a safe alternative to classic partial nephrectomy.

[The German Renal Cell Tumor Network]. / Deutsches Netzwerk Nierenzelltumoren.

To provide complex experimental and clinical analysis of renal cell tumors, it is necessary to investigate this tumor entity interdisciplinarily. The aim of the German Renal Cell Tumor Network is to answer current problems through interdisciplinary cooperation among clinicians and basic researchers from different fields. It is thus now possible to analyze more than 500 well-characterized tumor samples using different techniques.

[Molecular characterization of metastatic renal cell carcinomas. Differentiation of prognosis and therapy]. / Molekulare Charakterisierung der metastasierten Nierenzellkarzinome. Individuelle Prognosebewertung und Therapiewahl.

Molecular biological tumor markers and prognostic parameters are necessary for differential diagnosis, individual prognosis, and therapy in patients with renal cell tumors. By using high throughput technologies for DNA, RNA, and protein analysis, it is possible to comprehensively characterize tumor samples. We identified specific molecular patterns of metastatic tumors, allowing the determination of metastatic potential of the primary tumor. Different therapeutic options are now available for patients with metastatic renal cell carcinoma. Therefore, it is necessary to select the best therapy for each patient and to detect therapy resistance very early. Biomarkers in tumor tissue and serum were found correlating with therapy response.