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.

[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.

[Second-line treatment of malignant pleural mesothelioma with Pemetrexed (Alimta) -- a case report]. / Second-line-Behandlung des malignen Pleuramesothelioms mit Pemetrexed (Alimta) -- eine Kasuistik.

Malignant Pleural Mesothelioma is regarded as a tumour, which lacks chemo-sensitivity. However, patients are able to benefit from a first line chemotherapy, as indicated in a currently published randomised study. Here the case of a 75 year old patient will be reported, who has been diagnosed with malignant pleural mesothelioma for 4 years. After a first line therapy with Gemcitabine/Oxaliplatin, partial remission was assessed. 15 months later a distinct progress was detected. After a second line therapy with Pemetrexed a sound partial response could be determined radiologically and clinically. This case history is supposed to exemplify that patients with malignant pleural mesothelioma should not only be considered for a first line therapy, but that a second line therapy may also be offered to a certain group of patients. The new substance Pemetrexed (Alimta) offers an excellent alternative with a very good efficacy profile and a favourable spectrum of side effects.

[Cardiac efficiency in patients with Cheyne-Stokes respiration as a result of heart insufficiency during long-term nasal respiratory treatment with adaptive servo ventilation (AutoSet CS)]. / Kardiale Leistungsfähigkeit bei Patienten mit Cheyne-Stokes-Atmung infolge Herzinsuffizienz während langfristiger nasaler Beatmungstherapie mittels adaptiver Servoventilation (AutoSet CS).

Cheyne-Stokes respiration (CSR) is known to be an important negative predictor of outcome in patients with congestive heart failure. The goal of this study was to investigate whether the use of adaptive servo ventilation (AutoSet CS) would permit sufficient suppression of this pathological breathing pattern and improve cardiac function in longterm use over 1 year. Inclusion criteria for the study were congestive heart failure (left ventricular ejection fraction 20-50%), proven CSR with a central apnea-hypopnea index (AHI) > 15/h and stable clinical status with standard medical therapy. Patients with obstructive sleep apnea and COPD were excluded. Twenty consecutive patients (16 male) age 65.5 years (range 48-77) were followed with full blood counts, blood gas analysis, lung function tests and questionnaires for cardiopulmonary capacities (Minnesota, MRC Scale) and sleepiness (Epworth Sleepiness Scale). In addition, we performed 6-min walk distance (6MWD), echocardiography and polysomnography just before and after adjusting to adaptive servo ventilation and 3 and 12 months later. Mean usage of adaptive servo ventilation was sufficient (4.3 +/- 2.1 h/day at 12 months). No significant changes in blood gas analysis, blood counts and pulmonary function were detectable. CSR disappeared almost completely in all patients (AHI pre-study 44.3 +/- 13.4/h vs 3.4 +/- 8.0/h at 12 months; p < 0.0001). Saturation normalized steadily over the course of the study. The desaturation index decreased from 45.3 +/- 17.8/h to 5.2 +/- 11.5/h at 12 months (p < 0.0001). Mean saturation increased with the first night of sleep with adaptive servo ventilation from 92.0 +/- 2.5% to 93.0 +/- 1.6% (p < 0.05) and then to 94.1 +/- 1.9% at 3, and 94.2 +/- 1.9% at 12 months (p < 0.001). Quality of sleep was significantly improved with an increase of slow-wave sleep from 4.5 +/- 4.6% to 13.7 +/- 6.9% at 12 months (p < 0.0001). The arousal index concomitantly decreased from 29.8 +/- 17.9/h pre-study to 12.0 +/- 10.3/h at 12 months (p < 0.01). REM-sleep and sleep efficiency remained unchanged. The Epworth Sleepiness Scale showed only a trend to improvement. Cardiac function improved significantly during the course of the study. The ejection fraction increased from mean 37.1 +/- 12.5% pre-study to 41.7 +/- 8.8% at 12 months (p < 0.05). The 6-min walk distance increased from 192 +/- 110 m to 277 +/- 130 m at 12 months (p < 0.01). The MRC and Minnesota score were not significantly different pre- and post-study. We conclude that long-term respirator therapy with adaptive servo ventilation has sufficiently suppressed CSR and improved cardiac function in patients with congestive heart failure. Thus, safety and feasibility of this respirator therapy could be demonstrated. However, due to methodological reasons (no control group, no randomization) a direct effect on cardiac function could not be confirmed.

Amino acids from ultraviolet irradiation of interstellar ice analogues.

Amino acids are the essential molecular components of living organisms on Earth, but the proposed mechanisms for their spontaneous generation have been unable to account for their presence in Earth's early history. The delivery of extraterrestrial organic compounds has been proposed as an alternative to generation on Earth, and some amino acids have been found in several meteorites. Here we report the detection of amino acids in the room-temperature residue of an interstellar ice analogue that was ultraviolet-irradiated in a high vacuum at 12 K. We identified 16 amino acids; the chiral ones showed enantiomeric separation. Some of the identified amino acids are also found in meteorites. Our results demonstrate that the spontaneous generation of amino acids in the interstellar medium is possible, supporting the suggestion that prebiotic molecules could have been delivered to the early Earth by cometary dust, meteorites or interplanetary dust particles.

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.

Gabapentin add-on treatment: how many patients become seizure-free? An open-label multicenter study.

The aim of the study was to find out the percentage of patients with localization-related epilepsy achieving complete seizure control with gabapentin (GBP) add-on therapy. Patients under anti-epileptic drug monotherapy during 8 weeks baseline (BSL) with 6 or more seizures were treated with GBP for 26 weeks up to 2400 mg/day. Patients obtaining complete seizure control of all seizures or any partial seizure type during the last 8 weeks were calculated. Seizure frequency was compared between BSL and last 8 weeks. In all, 110 patients were enrolled (92 completed, 18 discontinued): mean age of the completers: 37.6 years (range 16-72), median seizure frequency per 28 days at BSL: 6.8 (2.5-24.5), mean duration of epilepsy: 17.6 years (0.2-51.4), mean duration with GBP for completers: 182.8 days (144-187). Complete seizure control of all seizures was achieved in 8.7% of patients (simple partial seizures: 13.3%, complex partial seizures 24.3%, secondarily generalized seizures: 61.5%): 38% of the patients became seizure-free in at least 1 seizure-type; 40% experienced adverse events. Assessment for quality of life (QoL) and trough plasma levels of GBP did not correlate with the good effect of GBP.

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.

Regulation by transforming growth factor-beta1 of class II mRNA and protein expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Transforming growth factor (TGF)-beta1 is an immunosuppressive cytokine that modulates the expression of class II histocompatibility antigens on human cells. Aberrant HLA class II expression on synovial lining cells of rheumatoid arthritis synovial membrane has been described, and the extent and intensity of class II expression on the cells was claimed to be linked with the severity of the disease. In this study, the effects of TGF-beta1 on HLA class II antigen expression in fibroblast-like synoviocytes (SFC) from rheumatoid synovectomy tissues were determined by flow cytometric analysis and quantitative RT-PCR. We found that pre-incubation of cells with TGF-beta1 was able to down-regulate IFN-gamma-induced DR protein expression in SFC. TGF-beta1, additionally, down-regulated IFN-gamma-stimulated class II transactivator (CIITA) and DRB mRNA expression. The constitutive expression of CIITA mRNA was completely abolished and the constitutive expression of DRB mRNA was decreased after treatment of SFC with TGF-beta1 for 24 h. Addition of the TGF-beta inhibitor decorin to SFC for 24 h before TGF-beta1/IFN-gamma treatment was able to reduce the down-regulatory effect of TGF-beta1 on DR antigen expression induced by IFN-gamma. Using competitive RT-PCR, we found that SFC constitutively expressed decorin mRNA and that treatment of cells with TGF-beta1 for 24 h reduced the constitutive expression of decorin mRNA by 65%. Our results show that TGF-beta1 is able to reduce the expression of HLA class II mRNA and protein, and suggest a tight regulation between TGF-beta1 and decorin in SFC of the rheumatoid synovium.