Structure and dynamics of the radical cation of ethane arising from the Jahn-Teller and pseudo-Jahn-Teller effects.

The pulsed-field-ionization zero-kinetic-energy photoelectron spectrum of C2H6 has been recorded in the region of the adiabatic ionization threshold. The partially rotationally resolved spectrum indicates the existence of several vibronic states of C2H6+ with less than 600 cm-1 of internal excitation. The analysis of the rotational structures assisted by ab initio calculations enabled the determination of the adiabatic ionization energy of C2H6 and the investigation of the structure and dynamics of C2H6+ at low energies. The ground state of C2H6+ is found to be a 2Ag state of diborane-like structure with strongly mixed (a1g)-1 and (eg)-1 configurations. The vibrational structure reveals the importance of large-amplitude nuclear motions involving the diborane distortion modes, the C-C stretching motion, and the internal rotation at elongated C-C distances. The spectrum is analyzed in the light of the information obtained in earlier studies of C2H6+ by ab initio quantum chemistry, EPR spectroscopy and photoelectron spectroscopy.

[Evaluation of intrauterine death: importance of examination of fetal, placental and maternal factors]. / Evaluierung des intrauterinen Fruchttods: Stellenwert der Untersuchung fetaler, plazentarer und maternaler Faktoren.

AIMS: Intrauterine death is a multifactorial major complication during pregnancy. In this retrospective analysis the pathological anatomical findings of fetuses and placentas as well as maternal factors were evaluated. MATERIAL AND METHODS: A retrospective screening of post-mortem examinations, corresponding placental examinations and clinical data on maternal status (1998-2008) was carried out. A classification of all findings was made with the ReCoDe system and induced abortions and cases with incomplete data were excluded from the study. RESULTS: A total of 84 pregnancies involving 87 fetuses (9 siblings) were evaluated. The median gestation age was 20 weeks (range 12-41). The evaluation based on the ReCoDe system revealed that intrauterine death was mainly associated with placental diseases (n = 63) and to a lesser extent with fetal malformations (n = 15) or maternal diseases (n = 4). Idiopathic cases were rare (n = 2). CONCLUSIONS: Placental examination is important for explaining intrauterine death because in most cases an association with placental diseases can be found but fetal malformation and maternal diseases must be taken into account.

[Role of pretherapeutic biomarkers in lung cancer with special regards to bronchoscopic procedures]. / Prätherapeutische Biomarker des Lungenkarzinoms unter besonderer Berücksichtigung der Bronchoskopie.

Molecular biomarkers are becoming increasingly significant in the workup of lung carcinoma patients. They assist in diagnosis, selecting the most adequate therapy and determining prognosis. Obtaining blood based biomarkers or volatile markers in exhaled breath may provide a less invasive method in the future. For the time being, bronchoscopy is still the method of choice to obtain specimen and assess tissue based biomarkers. The techniques how specimen are collected and processed for analysis are of paramount importance.

2-diethylaminoethyl-dextran methyl methacrylate copolymer nonviral vector: still a long way toward the safety of aerosol gene therapy.

Revealing the lung tumor genome has directed the current treatment strategies toward targeted therapy. First line treatments targeting the genome of lung tumor cells have been approved and are on the market. However, they are limited by the small number of patients with the current investigated genetic mutations. Novel treatment administration modalities have been also investigated in an effort to increase the local drug deposition and disease control. In the current study, we investigated the safety of the new nonviral vector 2-diethylaminoethyl-dextran methyl methacrylate copolymer (DDMC; Ryujyu Science), which belongs to the 2-diethylaminoethyl-dextran family by aerosol administration. Thirty male BALBC mice, 2 month old, were included and divided into three groups. However, pathological findings indicated severe emphysema within three aerosol sessions. In addition, the CytoViva technique was applied for the first time to display the nonviral particles within the pulmonary tissue and emphysema lesions, and a spectral library of the nonviral vector was also established. Although our results in BALBC mice prevented us from further investigation of the DDMC nonviral vector as a vehicle for gene therapy, further investigation in animals with larger airways is warranted to properly evaluate the safety of the vector.

Assessment of SHOX2 methylation in EBUS-TBNA specimen improves accuracy in lung cancer staging.

BACKGROUND: Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) is a well-established method to assess mediastinal lymph nodes for lung cancer. However, a proportion of patients require further investigation, due to the low negative predictive value (NPV). The objective of this study was to determine whether the assessment of short stature homeobox 2 (SHOX2) DNA methylation level in lymph node tissue obtained by EBUS-TBNA improves the accuracy of mediastinal staging. PATIENTS AND METHODS: EBUS-TBNA was carried out for suspicious lymph nodes of 154 patients. Negative or ambiguous histological results were confirmed by surgical means and clinical follow-up over 6 months. EBUS-TBNA was assessed on 80 positive and 85 negative classified lymph nodes and compared with the result of the SHOX2 DNA methylation real-time PCR analysis. Relative methylation measured by delta-delta cycle threshold (ΔΔCt) was used to classify the samples. Clinical performance of the EBUS-TBNA procedure with and without the additional SHOX2 assessment was calculated against the final classification according to the gold standard. RESULTS: Based on data from 105 patients, an average 80-fold increase in the SHOX2 methylation level was measured for positive compared with negative lymph nodes. SHOX2 results with a ΔΔCt value of <6.5 indicate positive lymph nodes. Applying this molecular analysis to EBUS-TBNA cases, not diagnosed by pathologic assessment, the sensitivity of staging was improved by 17%-99%. The NPV increased from 80% to 99%. CONCLUSIONS: The combination of EBUS-TBNA and SHOX2 methylation level strongly improves the assessment of the nodal status by identifying additional malignant lesions and confirming benign nodes and therefore avoiding invasive follow-up procedures.

Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial.

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

[Rapid on-site evaluation (ROSE) in cytological diagnostics of pulmonary and mediastinal diseases]. / "Rapid on-site evaluation" (ROSE) in der zytologischen Diagnostik von Lungen- und Mediastinalerkrankungen.

Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) has become an important tool in the diagnosis and staging of malignant tumors of the lungs and mediastinum. Rapid on-site evaluation (ROSE) denotes a cytomorphological diagnostic procedure that allows assessment of the adequacy and accuracy of the material obtained during bronchoscopy within a few minutes in or near the bronchoscopy suite (on-site) using a quick staining of smears. This results in a significant decrease in the number of repeated bronchoscopy procedures required to recover an adequate biopsy sample and is therefore both time and cost effective. The obtained material can be further assessed as conventional cytological specimens or alternatively using the thin-prep technique for definitive cytopathology diagnosis and/or embedded in paraffin for immunohistochemical or molecular analyses such as DNA sequencing or flow cytometry.

[Successful treatment of subglottic tracheal stenosis with a mucosa-lined radial forearm fascia flap]. / Erfolgreiche Behandlung einer subglottischen Trachealstenose mittels Mukosa-Radialisfaszien-Lappen.

Short-segment tracheal stenosis is often treated by segmental resection and end-to-end anastomosis. Longer-segment stenosis can sometimes be treated using dilation, laser therapy, bronchoscopic stent insertion and segmental resection and reconstruction. Long-segment restenosis with a buildup of scar tissue due to successful resection surgery in the past represents a particular therapeutic challenge and a sufficiently vascularized transplant may be the only option. We describe the case of a 37-year-old patient who underwent a tracheal reconstruction using a mucosa-lined radial forearm flap. Subsequent to a traumatic laryngotracheal fracture, long-term ventilation and multiple surgical interventions, the patient had developed a functionally relevant subglottic stenosis (5.5 cm). Following longitudinal anterior resection of the trachea 1 cm above and below the stenosis, a Dumon® stent was inserted. Simultaneously, a radial forearm fascia flap was harvested, as were two full-thickness buccal mucosa grafts, which were sutured onto the subcutaneous tissue and fascia of the forearm flap. Beginning caudally, the mucosa-lined flap was then sutured, air-tight, into the anterior tracheal defect with the mucosa facing the lumen. Finally, end-to-end anastomosis connected the blood vessels of the radial forearm flap to the recipient blood vessels in the neck. The patient was successfully extubated after 24 h and discharged after 5 days. A postoperative CT scan revealed optimal placement of the stent and the patient's speech and breathing were sufficiently re-established. The stent was removed bronchoscopically 6 weeks after surgery. Examinations during the 6-month follow-up period showed that the diameter of the reconstructed airway was retained and the patient remained symptom-free.

Ion mobility spectrometry for the detection of volatile organic compounds in exhaled breath of patients with lung cancer: results of a pilot study.

BACKGROUND: Analysis of exhaled breath, especially of volatile organic compounds (VOCs), is of increasing interest in the diagnosis of lung cancer. Compared with other methods of breath analysis, ion mobility spectrometry (IMS) offers a tenfold higher detection rate of VOCs. By coupling the ion mobility spectrometer with a multicapillary column as a pre-separation unit, IMS offers the advantage of an immediate twofold separation of VOCs with visualisation in a three-dimensional chromatogram. The total analysis time is about 500 s compared with gas chromatography/mass spectrometry (GC/MS) of about 1 h. It therefore seemed reasonable to test IMS in breath analysis. METHODS: In a pilot study, 32 patients with lung cancer were subjected to a breath analysis by IMS. Their IMS chromatograms were compared with those of 54 healthy controls. An IMS that was built for special clinical application was used to identify characteristic peaks of VOCs which might be relevant for the diagnosis of lung cancer in exhaled air of 10 ml volume. RESULTS: By a combination of 23 peak regions within the IMS chromatogram, patients with lung cancer, including a patient with carcinoma in situ, were classified and differentiated from healthy persons with an error rate of zero. CONCLUSION: Breath analysis by IMS can detect a discriminating combination of VOCs in patients with lung cancer. By pattern recognition without the need for chemical analysis of the underlying VOCs, IMS has the potential to facilitate lung cancer diagnosis.

Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer.

ASA404 (5,6-dimethylxanthenone-4-acetic acid or DMXAA) is a small-molecule tumour-vascular disrupting agent (Tumour-VDA). This randomised phase II study evaluated ASA404 plus standard therapy of carboplatin and paclitaxel in patients with histologically confirmed stage IIIb or IV non-small cell lung cancer (NSCLC) not previously treated with chemotherapy. Patients were randomised to receive

Phase III trial comparing paclitaxel poliglumex vs docetaxel in the second-line treatment of non-small-cell lung cancer.

Paclitaxel poliglumex (PPX), a macromolecule drug conjugate linking paclitaxel to polyglutamic acid, reduces systemic exposure to peak concentrations of free paclitaxel. Patients with non-small-cell lung cancer (NSCLC) who had received one prior platinum-based chemotherapy received 175 or 210 mg m(-2) PPX or 75 mg m(-2) docetaxel. The study enrolled 849 previously treated NSCLC patients with advanced disease. Median survival (6.9 months in both arms, hazard ratio=1.09, P=0.257), 1-year survival (PPX=25%, docetaxel=29%, P=0.134), and time to progression (PPX=2 months, docetaxel=2.6 months, P=0.075) were similar between treatment arms. Paclitaxel poliglumex was associated with significantly less grade 3 or 4 neutropenia (P<0.001) and febrile neutropenia (P=0.006). Grade 3 or 4 neuropathy (P<0.001) was more common in the PPX arm. Patients receiving PPX had less alopecia and did not receive routine premedications. More patients discontinued due to adverse events in the PPX arm compared to the docetaxel arm (34 vs 16%, P<0.001). Paclitaxel poliglumex and docetaxel produced similar survival results but had different toxicity profiles. Compared with docetaxel, PPX had less febrile neutropenia and less alopecia, shorter infusion times, and elimination of routine use of medications to prevent hypersensitivity reactions. Paclitaxel poliglumex at a dose of 210 mg m(-2) resulted in increased neurotoxicity compared with docetaxel.

Ion mobility spectrometry in the diagnosis of sarcoidosis: results of a feasibility study.

A feasibility study with ion mobility spectrometry (IMS) was started to find characteristic peaks of volatile organic compounds in exhaled air of 10 mL sampling volume, which might be relevant for the diagnosis of sarcoidosis. Therefore, breath samples of 9 patients with sarcoidosis and suspicion of sarcoidosis because of mediastinal lymph node enlargement were investigated. The 5 patients with confirmed sarcoidosis showed a highly congruent distribution of metabolites in exhaled air which was different in main component analyses from patients with unspecific mediastinal lymph node enlargement. These results are a first step in breath analysis by IMS in patients with sarcoidosis. The IMS as a new method in breath analysis and the first results of the investigations are presented and discussed in detail.

Lipoamide dehyrogenase immobilized on porous glass.

Lipoamide dehydrogenase (NADH:lipoamide oxidoreductase, EC 1.6.4.3) isolate from pig heart and Escherichia coli was covalently coupled by both diazonium and amide bonds to controlled pore glass beads (96% silica). When the enzyme was immobilized in the presence of NAD+, the enzyme no longer exhibited its normal requirement for NAD+ for full activity. If the immobilized enzyme was then treated with NADase, the requirement for NAD+ was restored. Enzyme immobilized in the absence of NAD+ exhibited normal NAD+ dependence both prior to an after NADase treatment. These results are discussed in terms of co-immobilization of NAD+ at or near the allosteric site of the enzyme.

Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer.

PURPOSE: The objective of this prospective study was to assess the feasibility, toxicity, and efficacy of an intensive trimodality approach in stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-four patients with NSCLC and biopsy-proven N2 nodes (IIIA; n = 25) or N3 nodes or T4 lesions (IIIB; n = 29) were administered two initial cycles of ifosfamide, carboplatin, and etoposide; subsequent radiotherapy (45 Gy, twice-daily 1.5 Gy) with concurrent carboplatin and vindesine; and surgery if the patient's disease was resectable or conventional radiotherapy (16 Gy, 2 Gy/d) if the patient's disease was not resectable or incompletely resectable. RESULTS: Thirty-seven patients (69%) responded to preoperative induction. Forty of 54 patients (74%) had disease that was resectable, with 34 (63%) complete resections (R0). A substantial pathologic response (tumor regression [TR] > 90%) was achieved in 27 of 54 patients (50%) and is revealed as an independent predictor for long-term survival after surgery. Five treatment-related deaths (9%) occurred. With a median follow-up period of 44 months, calculated survival rates at 3 years were 35% for patients with stage IIIA disease, 26% for patients with stage IIIB disease, and 56% for patients with R0 disease and TR > 90%. CONCLUSION: This trimodality approach is feasible and results in encouraging 3-year survival rates in prognostically unfavorable patients with stage III NSCLC. Patients experiencing a 90% degree of pathologic TR were most likely to achieve long-term survival.

The role of bronchoscopy in pulmonary complications due to mustard gas inhalation.

Over the last five years we have repetitively treated a group of 21 Iranian soldiers who developed pulmonary complications as a result of severe inhalation injury due to mustard gas during the Iran-Iraq war. Early respiratory manifestations included hemorrhagic inflammation of the tracheobronchial tree accompanied by severe erosions. Secondary complications consisted of chronic infections, suppurative bronchitis, and extensive stenotic process of the entire tracheobronchial tree with life-threatening sequelae. After a delay of up to 15 months, scars, ulcers, and strictures developed in the central airways. Progressive deterioration of gas exchange was common. At this point, bronchoscopy, both diagnostic and therapeutic, was invaluable in evaluating the conditions in these patients since many required multiple therapeutic bronchoscopies. Repeated bougienage of the stenotic tracheobronchial lesions and laser photoresection of scarring tissue was life-saving. The recurrence rate of stenosis was very high, with intervals of less than six months on the average. One pneumonectomy was necessary, with the excised lung showing bronchiectasis and chronic pneumonia. To this date we have performed 146 therapeutic bronchoscopies. In four patients, silicone stents had to be implanted. One patient received brachytherapy and external beam radiation therapy in an effort to prevent continued scarring and life-threatening stenoses of the tracheobronchial tree. Our experience demonstrates the extreme usefulness of bronchoscopy in the diagnosis and treatment of pulmonary complications due to inhalation of poisonous gases.

Management of malignant esophagotracheal fistulas with airway stenting and double stenting.

Prognosis of inoperable or recurrent esophageal carcinoma is, at best, poor. Once an esophagotracheal fistula has developed, the overall condition of the patient declines rapidly. Aspiration pneumonia and severe coughing are common. The introduction of esophageal tubes does not always seal the fistula sufficiently and may compromise the airway causing stridor and dyspnea. In 30 patients (25 male, 5 female; age 23 to 74 years; mean, 56 years) with very large fistulas and airway problems, we inserted an airway stent (Dynamic) (n = 12) or an esophageal tube combined with a Dynamic airway stent (n = 18) with the aim of sealing the fistula and restoring patency of the airway and GI passage. The tracheobronchial Dynamic stent was chosen because its slightly concave, flexible posterior silicone membrane adapts ideally to the convex esophageal tube. The stents were well tolerated and significantly improved the quality of life. Of 30 patients, 16 could breathe and swallow unimpaired until shortly before their death. Moderate complaints persisted in five patients, dysphagia in eight patients, and dyspnea in one patient. Mean survival time in the double stent group was significantly greater (110 days) than in the airway stent-only group (24 days) or comparable groups in the literature treated with esophageal tubes only. We conclude that carefully selected patients can benefit from double stenting of esophagus and airways.

Modeling expiratory flow from excised tracheal tube laws.

Flow limitation during forced exhalation and gas trapping during high-frequency ventilation are affected by upstream viscous losses and by the relationship between transmural pressure (Ptm) and cross-sectional area (A(tr)) of the airways, i.e., tube law (TL). Our objective was to test the validity of a simple lumped-parameter model of expiratory flow limitation, including the measured TL, static pressure recovery, and upstream viscous losses. To accomplish this objective, we assessed the TLs of various excised animal tracheae in controlled conditions of quasi-static (no flow) and steady forced expiratory flow. A(tr) was measured from digitized images of inner tracheal walls delineated by transillumination at an axial location defining the minimal area during forced expiratory flow. Tracheal TLs followed closely the exponential form proposed by Shapiro (A. H. Shapiro. J. Biomech. Eng. 99: 126-147, 1977) for elastic tubes: Ptm = K(p) [(A(tr)/A(tr0))(-n) - 1], where A(tr0) is A(tr) at Ptm = 0 and K(p) is a parametric factor related to the stiffness of the tube wall. Using these TLs, we found that the simple model of expiratory flow limitation described well the experimental data. Independent of upstream resistance, all tracheae with an exponent n < 2 experienced flow limitation, whereas a trachea with n > 2 did not. Upstream viscous losses, as expected, reduced maximal expiratory flow. The TL measured under steady-flow conditions was stiffer than that measured under expiratory no-flow conditions, only if a significant static pressure recovery from the choke point to atmosphere was assumed in the measurement.