Monocentric evaluation of Ki-67 labeling index in combination with a modified RPA score as a prognostic factor for survival in IDH-wildtype glioblastoma patients treated with radiochemotherapy.

PURPOSE: The prognosis for glioblastoma patients remains dismal despite intensive research on better treatment options. Molecular and immunohistochemical markers are increasingly being investigated as understanding of their role in disease progression grows. O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been shown to have prognostic and therapeutic relevance for glioblastoma patients. Other markers implicated in tumor formation and/or malignancy are p53, Alpha thalassemia/mental retardation syndrome X-linked (ATRX), Epidermal Growth Factor Receptor splice variant III (EGFRvIII), and Ki-67, with loss of nuclear ATRX expression and lower Ki-67 index being associated with prolonged survival. For p53 and EGFRvIII the data are contradictory. Our aim was to investigate the markers mentioned above regarding progression-free (PFS) and overall survival (OS) to evaluate their viability as independent prognostic markers for our patient collective. METHODS: In this retrospective study, we collected data on patients undergoing radiotherapy due to isocitrate dehydrogenase (IDH) wildtype glioblastoma at a single university hospital between 2014 and 2020. RESULTS: Our findings confirm Ki-67 labeling index ≤ 20% as an independent prognostic factor for prolonged PFS as well as MGMT promoter methylation for both prolonged PFS and OS, in consideration of age and Eastern Cooperative Oncology Group (ECOG) status, chemotherapy treatment, and total radiation dose for PFS as well as additionally sex, resection status, and receipt of treatment for progression or recurrence for OS. Additionally, Ki-67 labeling index ≤ 20% showed a significant correlation with prolonged OS in univariate analysis. Modification of the recursive partitioning analysis (RPA) score to include Ki-67 labeling index resulted in a classification with the possible ability to distinguish long-term-survivors from patients with unfavorable prognosis. CONCLUSION: MGMT promoter methylation and Ki-67 labeling index were independent predictors of survival in our collective. We see further studies pooling patient collectives to reach larger patient numbers concerning Ki-67 labeling index as being warranted.

Comparison of carbon ion and photon reirradiation for recurrent glioblastoma.

PURPOSE: Purpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation. MATERIALS AND METHODS: In this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan-Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out. RESULTS: The type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival-8.0 months vs. 6.5 months (univariate: p = 0.046)-and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1­year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia. CONCLUSION: In conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center.

IgM-enriched solution BT086 improves host defense capacity and energy store preservation in a rabbit model of endotoxemia.

INTRODUCTION: The therapeutic value of intravenous immunoglobulin (IVIG) as an adjuvant therapy in sepsis remains debatable. We hypothesized that intravenous administration of BT086, a predominantly IgM IVIG solution, would improve host defense in an established rabbit model of endotoxemia and systemic sepsis. METHODS: New Zealand white rabbits were randomized into the following four groups: (1) the negative control group without lipopolysaccharide (LPS, control), (2) the positive control group with LPS infusion (LPS group), (3) the albumin-treated LPS group (ALB+LPS group), and (4) the BT086-treated LPS group (BT086 + LPS group). A standardized amount of E. coli was intravenously injected into all of the animals. The vital parameters, the concentration of E. coli in the blood and other organs, the residual granulocyte phagocytosis activity, and the levels of the inflammatory mediators were measured. Histological changes in the lung and liver tissue were examined following autopsy. RESULTS: The elimination of E. coli from the bloodstream was expedited in the BT086-treated group compared with the LPS- and albumin-treated groups. The BT086 + LPS group exhibited higher phagocytic activity of polymorphonuclear neutrophils (PMNs) than the control and ALB+LPS groups. The liver energy stores were higher in the BT086 + LPS group than in the other groups. CONCLUSION: Our data suggest that the IgM-enriched IVIG has the potential to improve host defense in a rabbit model of endotoxemia. Studies using different animal models and dosages are necessary to further explore the potential benefits of IgM-enriched IVIG solutions.

International Mycoplasma pneumoniae typing study: interpretation of M. pneumoniae multilocus variable-number tandem-repeat analysis.

Typing of Mycoplasma pneumoniae by multiple-locus variable-number tandem repeat analysis (MLVA) is increasingly in use. However, no specific internationally agreed guidance is available. Thirty M. pneumoniae DNA samples including serial dilutions of a type strain were sent to six international laboratories to perform MLVA and results were compared. Good correlation was observed, indicating that this methodology can be robustly performed in multiple sites. However, differences due to interpretation of fragment size, repeat sequence identification and repeat numbering led to inconsistency in the final profiles assigned by laboratories. We propose guidelines for interpreting M. pneumoniae MLVA typing and assigning the number of repeats.

Adsorbate electric fields on a cryogenic atom chip.

We investigate the behavior of electric fields originating from adsorbates deposited on a cryogenic atom chip as it is cooled from room temperature to cryogenic temperature. Using Rydberg electromagnetically induced transparency, we measure the field strength versus distance from a 1 mm square of yttrium barium copper oxide (YBCO) patterned onto a yttria stabilized zirconia chip substrate. We find a localized and stable dipole field at room temperature and attribute it to a saturated layer of chemically adsorbed rubidium atoms on the YBCO. As the chip is cooled towards 83 K we observe a change in sign of the electric field as well as a transition from a localized to a delocalized dipole density. We relate these changes to the onset of physisorption on the chip surface when the van der Waals attraction overcomes the thermal desorption mechanisms. Our findings suggest that through careful selection of substrate materials, it may be possible to reduce the electric fields caused by atomic adsorption on chips, opening up experiments to controlled Rydberg-surface coupling schemes.

Subtypes and variants of Mycoplasma pneumoniae: local and temporal changes in Germany 2003-2006 and absence of a correlation between the genotype in the respiratory tract and the occurrence of genotype-specific antibodies in the sera of infected patients.

Mycoplasma pneumoniae is a frequent cause of community-acquired pneumonia. Three subtypes and three variants of M. pneumoniae have been described showing sequence differences in the main P1 adhesin. Between 2003 and 2006 we collected respiratory tract samples of adult outpatients with symptoms of pneumonia in a German nationwide network and detected M. pneumoniae by real-time PCR in 140 specimens. The strains were typed by sequencing and demonstrated the circulation of subtypes 1 and 2 and variants 2a and 2b. The overall number of isolates belonging to the two variant genotypes increased during the investigation period but the relationship of subtypes and variants within the participating local centres varied strongly. ELISA experiments using sera of acute-phase patients with a known M. pneumoniae type in the respiratory tract resulted in no correlation of IgA and IgG antibodies to subtype- and variant-specific regions of the P1 gene with the genotype of the M. pneumoniae strain causing the actual infection.

Occurrence of macrolide-resistant Mycoplasma pneumoniae strains in Germany.

In a total of 167 respiratory tract specimens from adult outpatients with confirmed Mycoplasma pneumoniae pneumonia, sampled between 2003 and 2008, and a further 99 isolates obtained from patients between 1991 and 2009 in Germany, M. pneumoniae was tested for macrolide resistance. Using PCR, real-time PCR and sequencing of the 23S rRNA gene, 1.2% of M. pneumoniae in the respiratory tract samples and 3.0% of the isolates were found to be resistant. The results indicate a limited but not negligible importance of macrolide-resistant M. pneumoniae in the population investigated, which requires the monitoring of macrolide susceptibility of isolates or the testing of respiratory samples by molecular methods.

Detection of phages carrying the Shiga toxin 1 and 2 genes in waste water and river water samples.

AIMS: To evaluate the occurrence and abundance of phages that carry the stx(1) and stx(2) gene in water samples of different quality. METHODS AND RESULTS: Phages growing on the Shiga toxin-negative Escherichia coli O157:H7 (ATCC 43,888) strain were enumerated by a plaque assay in concentrated raw and treated waste water samples and river water samples. Plaques were investigated for the presence of stx(1) and stx(2) genes by a multiplex/nested PCR procedure. An overall number of 805 plaques were tested for the presence of stx-carrying phages. Stx genes could be demonstrated in 2% (stx(1)) and 16% (stx(2)) of the plaques. Stx-phages were eliminated with approximately the same efficiency in comparison with somatic coliphages during the waste water treatment process. CONCLUSIONS: Due to the low numbers of phages carrying the stx genes 1 and 2 in treated waste water and river water, the dilution and inactivation of host bacteria and the unsuitable conditions for the transduction of host organisms in aquatic environments, it is difficult to derive from the data the direct evidence for a public health problem. SIGNIFICANCE AND IMPACT OF THE STUDY: The results show the quantitative occurrence of stx-carrying phages in waste and river water and confirm the frequent circulation of these viruses in the aquatic environment.

Detection of enteric viruses and bacterial indicators in German environmental waters.

A German mining lake and the supplying surface waters, which are located downstream of a sewage plant, were examined regarding their microbiological and virological quality. Between October 2002 and September 2003, specific PCR methods were used to determine the occurrence of enteric viruses in 123 water specimens drawn at different sites downstream of the waste water treatment plant and in 9 samples from the sewage plant influent. Detection rates in sewage plant effluents and surface water samples depended on sampling sites and were: 29-76% for enterovirus (EntV), 24-42% (astrovirus, AstV), 15-53% (norovirus, NV), 3-24% (rotavirus, RoV), 5-20% (hepatitis A virus, HAV) and 20% (adenovirus, AdV). AstV genome load of selected samples was between 3.7 x 10(3) to 1.2 x 10(8) genome equivalents per liter (gen.equ./l), depending on sampling location; NV average genome load ranged from 1.8 x 10(4) to 9.7 x 10(5) gen.equ./l. Cell culture methods showed that three out of 18 PCR positive samples contained infectious EntV. Even though microbiological parameters such as Escherichia coli, enterococci and coliphages indicated acceptable microbiological water quality, the virological data of this study suggest the possibility that surface waters may be a source for enteric viral infections.

Coherence properties of guided-atom interferometers.

We present a detailed theoretical investigation of the coherence properties of beam splitters and Mach-Zehnder interferometers for guided neutral atoms. We show that such a setup permits coherent wave packet splitting and leads to the appearance of interference fringes for both single-mode and thermal input states, evidencing thus the robustness of the interferometer.

Interferometer-type structures for guided atoms.

We experimentally demonstrate interferometer-type guiding structures for neutral atoms based on dipole potentials created by microfabricated optical systems. As a central element we use an array of atom waveguides being formed by focusing a red-detuned laser beam with an array of cylindrical microlenses. Combining two of these arrays, we realize X-shaped beam splitters and more complex systems like the geometries for Mach-Zehnder and Michelson-type interferometers for atoms.

Micro-optical realization of arrays of selectively addressable dipole traps: a scalable configuration for quantum computation with atomic qubits.

We experimentally demonstrate novel structures for the realization of registers of atomic qubits: We trap neutral atoms in one- and two-dimensional arrays of far-detuned dipole traps obtained by focusing a red-detuned laser beam with a microfabricated array of microlenses. We are able to selectively address individual trap sites due to their large lateral separation of 125 microm. We initialize and read out different internal states for the individual sites. We also create two interleaved sets of trap arrays with adjustable separation, as required for many proposed implementations of quantum gate operations.

Formation of Rydberg atoms in an expanding ultracold neutral plasma.

We study the formation of Rydberg atoms in expanding plasmas at temperatures of 1-1000 K and densities from 10(5)-10(10) cm(-3). Up to 20% of the initially free charges recombine in about 100 micros, and the binding energy of the Rydberg atoms approximately equals the increase in the kinetic energy of the remaining free electrons. Three-body recombination is expected to dominate in this regime, yet most of our results are inconsistent with this mechanism.

Wave packet echoes in the motion of trapped atoms.

We experimentally demonstrate and systematically study the stimulated revival (echo) of motional wave packet oscillations. For this purpose, we prepare wave packets in an optical lattice by nonadiabatically shifting the potential and stimulate their reoccurrence by a second shift after a variable time delay. This technique, analogous to spin echoes, enables one even in the presence of strong dephasing to determine the coherence time of the wave packets. We find that for strongly bound atoms it is comparable to the cooling time and much longer than the inverse of the photon scattering rate.

Influence of fibrinogen levels in dogs on mortality from hemorrhagic and traumatic shock.

1) Fibrinogen levels appear related to the outcome of hemorrhagic shock in dogs. 2) Fibrinogen levels can vary with different animals based on location, disease, stress, nutrition, or other factors. 3) Any experiments in hemorrhagic shock (or anything else) should utilize simultaneous and paired controls of animals from the same source or they may be subject to major error.

The danger of hemolysis in shock.

Intravascular hemolysis is sometimes harmful and often fatal. Other times it is harmless. Dogs were paired and subjected to hemorrhagic shock. One of the pair was given 2 ml/kg of autologous hemolyzed blood before bleeding. The other of the pair was given 2 ml/kg of heparinized autologous blood. All of the animals given heparinized blood survived, whereas, all of the animals given hemolyzed blood died. The animals given hemolyzed blood developed coagulation changes indicative of Disseminated Intravascular Coagulation (DIC), whereas, the dogs given nonhemolyzed blood did not. It is concluded that hemolysis in the presence of shock (slow capillary flow) causes DIC and death. Hemorrhagic shock alone or hemolysis alone was harmless.