Blood immune cell biomarkers in lung cancer.

Characterization of host immune cell parameters prior to treatment is expected to identify biomarkers predictive of clinical outcome as well as to elucidate why some patients fail to respond to immunotherapy. We monitored blood immune cells from 58 patients with non-small- cell lung cancer (NSCLC) undergoing surgery of the primary tumor and from 50 age-matched healthy volunteers. Complete leukocyte blood count, the number of circulating dendritic cells (DC), HLA-DRlow monocytes and several lymphocytic subpopulations were determined by eight-color flow cytometry. Furthermore, the prognostic value of the immune cell parameters investigated was evaluated by patients' survival analysis. Compared to the control group, blood of NSCLC patients contained more neutrophils resulting in a higher neutrophil-to-lymphocyte ratio (NLR), but a lower number of blood DC, in particular of plasmacytoid DC (pDC), natural killer (NK) cells and naive CD4+ and CD8+ T cells. Furthermore, a higher frequency of CD4+ regulatory T cells (Treg) and HLA-DRlow monocytes was detected, and smoking had a significant impact on these values. HLA-DRlow monocytes were positively correlated to the number of neutrophils, monocytes and NLR, but negatively associated with the number of pDC and naive CD4+ T cells. The frequency of Treg, HLA-DRlow monocytes and naive CD4+ and CD8+ T cells as well as the ratios of CD4/HLA-DRlow monocytes and HLA-DRlow monocytes/pDC correlated with patient's overall survival. Next to Treg, HLA-DRlow monocytes and naive T cells represent prognostic markers for NSCLC patients and might be useful for monitoring of patients' responses to immunotherapies in future studies.

[Rebiopsy for Patients with Lung Cancer - Joint Opinion from both the Endoscopic and Thoracic Oncology Sections of the German Society of Pneumology (DGP)]. / Empfehlung der Sektionen 2 und 11 der DGP zur Rebiopsie bei Lungenkarzinomen.

Performing rebiopsies for primary lung cancer and/or their metastases is becoming more and more prominent in daily practice, as the therapeutical spectrum increases and some newer strategies are dependent on immunohistochemical and/or molecular factors. In general, nearly all recurrent lesions or metastases can be reached. However, frequently invasive procedures are necessary with the need to carefully weigh risks and benefits of rebiopsies for the patient in each case. In this review indications for recurrent and progressive disease as well as risks are discussed and alternatives to rebiopsies are shown. This work is the joint opinion from both the endoscopic and thoracic oncology sections of the German Society of Pneumology (DGP).

[Implementation of the German guideline for the prevention, diagnosis, treatment and follow-up of non-small cell lung cancer at the Diakoniekrankenhaus Halle/Saale]. / Umsetzung der aktuellen S3-Leitlinie zur Prävention, Diagnostik, Therapie und Nachsorge des nicht-kleinzelligen Lungenkarzinoms am Diakoniekrankenhaus Halle/Saale.

BACKGROUND: More than three years since the release of the german guideline for the prevention, diagnosis, treatment and follow-up of lung cancer the database in terms of the implementation of guideline recommendations is deficient. The aim of this article is to analyze the implementation of the recommended algorithms for first-line therapy of non-small cell lung cancer. PATIENTS AND METHODS: On the basis of the patients records we determined all cases of newly diagnosed non-small cell lung cancer which received a first-line therapy at the Diakoniekrankenhaus Halle/Saale between January 2010 and December 2011. The demographic data, tumor stage, time of diagnosis and performed first-line therapy were documented. Each case was assigned to the groups "guideline-adherent treatment" or "deviation from guideline recommendation" in dependency of its tumor stage. For this assignment the corresponding algorithms from guideline chapter "Therapy of non-small lung cancer" were used. RESULTS: A total of 126 from 148 cases (85%) received guideline-adherent treatment. Deviation from guideline recommendation was found in 22 cases (15%). The categories "poor performance status", "technical factors", "patient decision" and "others" were determined as the main reasons for non guideline-adherent treatment. CONCLUSIONS: Based on the analyzed population this study determined a high grade of guideline adherence at the period of investigation. Otherwise it shows that guideline recommendations cannot include each individual factor of the complex lung cancer disease. It could be found a wide range of reasons for deviation from the guideline recommendations.

[Prognostic Relevance of the Metastatic Localisation in Patients with Stage IV NSCLC - Results of a Prospective Epidemiological Study]. / Prognostische Relevanz der Metastasenlokalisation bei nicht kleinzelligem Bronchialkarzinom im Tumorstadium IV - Ergebnisse einer prospektiven epidemiologischen Studie.

Patients with non-small cell lung cancer (NSCLC) frequently suffer from stage IV disease at the time of presentation. Survival of these patients is disadvantageous although they may benefit from chemotherapy. The main purpose of this investigation was to evaluate the prognostic relevance of the metastatic localisation in unselected patients. The second purpose was to evaluate the impact of clinical characteristics on the kind of decision-making in patients with stage IV NSCLC in an epidemiological manner.[nl]Clinical data as well as survival of 336 patients with stage IV NSCLC were analysed. The recruitment period was 3? years, mean follow-up was 24 months. This investigation was part of the HALLUCA studies which were sponsored by the German Ministry of Health.[nl]Localisation-dependent median and 1-year survivals were significantly different and varied between 2.2 months and 4.7 % (liver metastases) and 11.0 months and 44.5 % (lung metastases). The different survival remained significant in the multivariate analyses with age, performance status, treatment and histology as co variables. The chemotherapy rate of all patients with stage IV NSCLC was 39 %. Patients with liver, bone and multiple metastases received less often chemotherapy compared to patients with other metastases although the performance status was not different to the other groups.[nl]Although there are some limitations in this investigation, these epidemiological data demonstrate the prognostic heterogeneity of stage IV NSCLC patients which should be considered for stratification in controlled clinical trials. Regional treatment decision-making is different from guidelines and controlled clinical trials. Further regionally orientated trials are necessary to improve the transformation from clinical trials to regional medical care.

Formaldehyde and organic molecule production in astrophysical ices at cryogenic temperatures.

Thermally promoted formaldehyde (H2CO) reactions in cryogenic ices have been studied to test their importance as a source of organic molecules in comets and interstellar ices. Ices containing H2CO, H2O, CH3OH, CO, and NH3 were investigated by using infrared spectroscopy. Small traces of NH3 (NH3/H2CO > or = 0.005) are sufficient to convert significant fractions (> or = 40%) of the H2CO into more complex organics. However, H2CO reactions do not proceed without NH3. Spectral evidence for reaction onset appeared between 40 and 80 kelvin, depending on the ice. Five distinct products were formed. These principally consist of polyoxymethylene and related derivatives. Polyoxymethylene itself was not made in significant amounts in cometary analogs. These products differ from those produced by ultraviolet and particle irradiation. The nature and relative amounts of the products depend on the initial composition, making these materials excellent tracers of a comet's history. About 3% of the organics in p-Halley's coma could have been produced by thermal H2CO reactions.

[Treatment of respiratory papillomatosis--a case report on systemic treatment with bevacizumab]. / Behandlung der respiratorischen Papillomatose--Kasuistik zur systemischen Therapie mit Bevacizumab.

BACKGROUND: Recurrent respiratory papillomatosis (RRP) is a known but rare disease, caused by human papilloma virus and characterised by multiple exophytic lesions and uncontrolled growth of papilloma in the respiratory tract. The most common complication of RRP is stenosis of the trachea. Medical therapeutic options have so far been less effective. However, inhibition of vascular endothelial growth factor (VEGF) by bevacizumab does appear to be an effective treatment option for RRP. CASE REPORT: The case of a 32-year-old male patient with RRP who has been treated for his symptomatic tracheal stenosis four times a year since 1996 is described. Only treatment by laser ablation showed any efficacy. Alternative treatment options did not show any effect. In May 2006 intrapulmonary lesions of RRP were also diagnosed but without any malignancy. From December 2007 to June 2008 the patient has been treated with bevacizumab. A visible regression of RRP and markedly less symptoms were observed. During this treatment no further laser ablation was necessary. CONCLUSION: Inhibition of VEGF by bevacizumab seems to offer a new and effective option in the medical management of RRP.

[Palliative care in respiratory medicine]. / Palliativmedizin in der Pneumologie.

Palliative care should be part of respiratory medicine for two reasons: first, many respiratory diseases--besides thoracic tumours--need palliative care in the late stages of the disease. Second, dyspnoea is a common symptom in advanced, primary extrapulmonary diseases and the knowledge of respiratory specialists can be beneficial in the treatment of this symptom. In this paper we describe frequent symptoms of advanced pulmonary diseases and their treatment. Moreover, we focus on the structure of palliative care in Germany.

[Hypercapnic failure in patients with COPD under 4 weeks non-invasive, home mechanical ventilation]. / Rekompensation von schwerem hyperkapnischem Versagen bei Patienten mit COPD unter 4 Wochen intermittierender nicht invasiver Heimbeatmung.

BACKGROUND: In patients with severe COPD, ventilatory pump failure is a separate pathophysiological factor. Non-invasive ventilatory support has been introduced in COPD with acute-on-chronic respiratory failure according to evidence-based medicine, but the benefit of long-term ventilation is still not proven. The purpose of this investigation was to evaluate the feasibility of carbon dioxide-reducing, non-invasive, home mechanical ventilation in patients with chronic hypercapnic respiratory failure due to stable COPD. METHODS: In 40 patients (median age 72.2/61.1 - 78.1 years), with chronic ventilatory failure due to COPD who received non-invasive, home mechanical ventilation (NIV) successfully we analysed blood gases, lung function, 6-minute walking distance and quality of life before NPPV and after a period of at least 4 weeks of home therapy. RESULTS: Successful home mechanical ventilation could be proven by a significant decrease of hypercapnia during spontaneous breathing: 8.5 kPa (64.6 mmHg) before NIV to 5.9 kPa (45.2 mm Hg) during NIV. Six-minute walking distance increased significantly from 89 m to 230 m. General health perception (SF 36) improved from 27 to 56 significantly as did other quality of life categories. CONCLUSION: Although this investigation has some limitations such as lack of controls and highly selected patients, it could be proven that CO (2)-decreasing, non-invasive mechanical ventilation is feasible in terms of home therapy and effective to recompensate chronic ventilatory failure in stable COPD. Under such treatment, patients can reestablish their physical ability and report quality of life improvements.

Gabapentin potentiation of the antiepileptic efficacy of vigabatrin in an in vitro model of epilepsy.

1. An enhancement of promoted release of gamma-aminobutyric acid (GABA) and a change in GABA-metabolism have been suggested as mechanisms of action of gabapentin. Vigabatrin is supposed to act mainly via inhibition of GABA-transaminase but it also interferes with GABA-release and GABA-uptake. On the basis of these mechanisms of action, a pharmacodynamic interaction of the two antiepileptic drugs could be supposed which might be of relevance in the sense of a rational polypharmacy. 2. To address the aforementioned hypothesis, experiments were carried out on hippocampal slices (n=107) of guinea-pigs (n=70). Epileptiform field potentials (e.f.p.) were induced by omission of magnesium from the bath solution and recorded in the stratum pyramidale of the CA3 region. Gabapentin (30-600 microM; 5.1-102.72 microg ml(-1)), vigabatrin (50-200 microM, 6.45-25.8 microg ml(-1)) and the GABA(A)-receptor antagonist bicuculline (100 microM) were added to the bath solution for 3 h. 3. Gabapentin, in concentrations up to 600 microM, failed to decrease the repetition rate or duration of e.f.p. (n=19). However, vigabatrin, evoked a dose-dependent reduction of the repetition rate of e.f.p. For a concentration of 100 microM (12.9 microg ml(-1)) there was a reduction down to 48+/-5% (mean+/-s.e.mean) of the initial value within 3 h (n=11). With simultaneous administration of vigabatrin (100 microM) and gabapentin (60 microM) for 3 h (n=15), the repetition rate of e.f.p. decreased down to 8+/-3%, which is significantly different from the values obtained after administration of 100 microM vigabatrin alone (P<0.0001). Both, the antiepileptic effect of vigabatrin alone and the enhancement by gabapentin were blocked by the GABA(A)-receptor antagonist bicuculline (100 microM, n=16). 4. These results demonstrate that gabapentin is able to augment the antiepileptic effects of vigabatrin significantly. It is possible that a change in the GABA-release machinery is induced by vigabatrin which then can be augmented by gabapentin.

Ultrafiltration and absorption characteristics of hydroxyethylstarch and dextran during long dwell peritoneal dialysis exchanges in rats.

Glucose has several disadvantages such as low pH, high osmolality and hyperglycemia. Rapid glucose absorption contributes to hyperlipidemia, obesity and ultrafiltration failure in peritoneal dialysis patients. Two commercially available plasma substitutes 10% hydroxyethylstarch (HES) and 6% dextran were studied for ultrafiltration and absorption patterns. 18 ml of each solution were instilled into the peritoneal cavity of 6 non-uremic rats. HES yielded a significantly (p less than 0.02) greater ultrafiltration after 6 h of dwell, whereas 2.3% glucose solution showed the typical ultrafiltration pattern of an easily absorbable osmotic agent. With 6% dextran ultrafiltration was markedly lower. At the end of cycle time the mean absorption rates for HES were 62.7% and 41.5% for dextran. It is concluded that HES is a potent osmotic agent due to sustained colloidal ultrafiltration. However, despite their high molecular weights both solutions were markedly absorbed probably by lymphatics. However, accumulation in tissues and undefined metabolic pathways might prove disadvantageous in patients with ESRD.

The formation of organic molecules in astronomical ices.

An absorption feature at 3.4 micrometers has been observed in various lines-of-sight through the diffuse interstellar medium. Its position and width lead to an identification with the C-H stretching mode of solid organic material. A possible mechanism for the production of organic solids in the interstellar medium is UV photoprocessing of icy mantles which accrete on dust grains in dense clouds. Furthermore, thermally induced reactions involving formaldehyde molecules in the mantles could be an important source of organics. Laboratory simulation of these processes shows that a large variety of oxygen- and nitrogen-rich species may be produced. It is shown that the occurrence of periodic transient heating events plays an important role in the production of organic material in the ice mantles. Finally, it is pointed out how future missions like the Infrared Space Observatory (ISO) as well as analysis of comet material by Rosetta may be able to clarify the nature and evolution of interstellar organics.

Chemical and biological evolution in space.

Astronomical infrared spectra are used to confirm the existence of complex organic molecules produced by ultraviolet photoprocessing of interstellar grain mantles. This material is shown to be the major component of the interstellar grains between the sun and the galactic center and, by inference, constitutes more than 10 million solar masses--or close to one part in a thousand of the entire mass of the milky way galaxy. It may be demonstrated that the primitive chemistry of the earth's surface was dominated by these extraterrestrial molecules after aggregated into comets if the rate of comet impacts with the earth was comparable with that required to account for the extinction of species over the past 300 million years. Ultraviolet irradiation of bacterial spores has been studied for the first time under simulated interstellar conditions. The inactivation time predicted for the less dense regions of space is at most several hundred years. Within molecular clouds it is shown on theoretical and experimental grounds that this time may be extended to tens of million of years which is the estimated time required for their transport from one solar system to another by a molecular cloud. However survival of spores during their initial exposure to the solar ultraviolet presents a problem for panspermia because it requires that in the process of ejection from the earth's surface they must be enclosed within a cocoon (or mantle) of ultraviolet absorbing material of approximately 0.6 micrometer thickness. Thus, although panspermia can not be rejected on the basis of lack of interstellar survival there may remain insurmountable obstacles to its occurring because of the very special protective shield requirements during ejection from its planetary source.

Laboratory simulation of the photoprocessing and warm-up of cometary and pre-cometary ices: production and analysis of complex organic molecules.

The possibility that the organic molecules that have been found near comets could have formed by UV photolysis of interstellar ices was investigated by simulating this process in the laboratory. It is found that oxygen rich organics containing C-OH, C-H and C=O groups are readily produced in this way. These results indicate that part of the organic material in comets may have formed by UV irradiation of ices, either in the pre-solar nebula or in the interstellar phase.

Very low temperature formaldehyde reactions and the build-up of organic molecules in comets and interstellar ices.

We have investigated thermally promoted reactions of formaldehyde (H2CO) in very low temperature ices. No such reactions occurred in ices of pure formaldehyde. However, addition of trace amounts of ammonia (NH3) were sufficient to catalyze reactions at temperatures as low as 40 K. Similar reactions could take place in interstellar ices and in Comets and produce considerable amounts of organic molecules.

Simulated cometary matter as a test for enantiomer separating chromatography for use on comet 46P/Wirtanen.

The Cometary Sampling and Composition Experiment on board of European Space Agency's cornerstone mission ROSETTA is designed to identify organic molecules in cometary matter in situ by a combined pyrolysis gas chromatographic and mass spectrometric technique. Its capillary columns coated with chiral stationary phases received considerable attention, because they are designed for separations of non-complex enantiomers to allow the determination of enantiomeric ratios of cometary chiral organic compounds and consequently to provide information about the origin of molecular parity violation in biomolecules. To get gas chromatographic access to organic compounds on the comet, where macromolecules and complex organic polymers of low volatility are expected to make up the main organic ingredients, the combination of two injection techniques will be applied. The pyrolysis technique performed by heating cometary samples stepwise to defined temperatures in specific ovens resulting in thermochemolysis reactions of polymers and a chemical derivatization technique, in which the reagent dimethylformamide dimethylacetal assists pyrolysis derivatization reactions in producing methyl esters of polar monomers. The combination of the reagent assisted pyrolysis gas chromatographic technique with enantiomer separating chromatography was tested with laboratory-produced simulated cometary matter.

Origin of organic matter in the protosolar nebula and in comets.

Comet organics are traced to their origin in interstellar space. Possible sources of comet organics from solar nebula chemistry are briefly discussed. The infrared spectra of interstellar dust are compared with spectra of solar (space) irradiated laboratory organic residues and with meteorites. The spectra compare very favorably. The atomic composition of first generation laboratory organic residues compares favorably with that of comet Halley organics if divided into appropriate "volatile" (less refractory) and "refractory" (more refractory) complex organics.