Andreas Kirschbaum

Sublobar resections in stage IA non-small cell lung cancer: segmentectomies result in significantly better cancer-related survival than wedge resections.

OBJECTIVE Sublobar resections spare pulmonary function and offer a method of increasing resection rates in patients with lung cancer and limited functional operability. Previous studies demonstrated an increased local recurrence rate following wedge resections compared to segmentectomies in stage IA non-small cell lung cancer (NSCLC). However, a prognostic impact of this observation has never been shown and is still under debate. Therefore, this study has been performed to analyse the cancer-related survival of sublobar resections in stage IA patients. METHODS Over a 17-year period 87 patients underwent sublobar complete resection (R0) of stage IA NSCLC via thoracotomy. Sublobar resection was reserved for patients with cardiopulmonary impairment. Wedge resections with selective lymphadenectomy were performed in 31 patients (36%) and segmentectomies with systematic lymphadenectomy in 56 patients (64%). Patient characteristics, functional parameters, tumour specifics and follow-up duration were analysed concerning their distribution between the two groups. Kaplan-Meier curves were compared and possible joint effects between prognostic parameters were analysed by multivariate Cox regression analysis. RESULTS The median follow-up duration was 45 months. There was no significant difference between the two groups in gender (p=0.11), age (p=0.08), American Society of Anesthesiology physical performance status (ASA)-score (p=0.32), forced expiratory volume in 1s FEV(1) (p=0.08), tumour size (p=0.30), histology (p=0.17), grading (p=0.12), complication rate (p=0.15) and follow-up duration (p=0.29). The mean number of dissected lymph nodes in segmentectomies (12+/-6) was higher than in wedge resections (6+/-3) (p=0.0001). The 5-year survival rate was 63%. There were significantly less locoregional recurrences (p=0.001), an equal distribution of distant metastases (p=0.53) and a better cancer-related survival (p=0.016) following segmentectomies compared to wedge resections. Cox regression analysis showed that the prognostic effect of the resection type was independent from gender, age, ASA-score, respiratory function, tumour size, tumour histology, grading and number of dissected lymph nodes (p=0.04, relative risk 1.16). CONCLUSIONS Studies investigating survival after sublobar resection of stage IA NSCLC should always distinguish between anatomical segmentectomies and wedge resections. If limited functional operability requires a sublobar resection of stage IA NSCLC, segmentectomy with systematic lymphadenectomy should be preferred.

Elevated expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) is associated with increased angiogenic potential in non-small-cell lung cancer.

Recent studies have challenged the previously postulated concept of a tumor-suppressive effect of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1). A possible angiogenic influence of CEACAM-1 in non-small-cell lung cancer (NSCLC) has not been investigated so far. Therefore, we examined microvessel density (MVD) and CEACAM-1 expression in primary NSCLC and analyzed their possible correlations under consideration of their prognostic effects. Specimens from 82 consecutive patients with completely resected NSCLC were stained immunohistochemically using the monoclonal anti-CEACAM-1 antibody 4D1/C2 and the monoclonal anti-CD31 antibody JC70A. The prognostic relevance of CEACAM-1 expression and MVD was evaluated by univariate Kaplan-Meier and multivariate Cox regression analysis. The median follow-up period was 75 months (range 10-156 months). A high MVD (i.e., > or =31microvessels/400x microscopic field) was observed more frequently in tumors with high CEACAM-1 expression (i.e., >/=66% stained tumor cells) than in tumors with low CEACAM-1 expression (61.8% vs. 33.3%, respectively; p=0.01). In univariate survival analyses, high CEACAM-1 expression and high MVD were associated with development of distant metastasis (p=0.011 and 0.022, respectively) and decreased cancer-related survival (p=0.046 and 0.006, respectively). Multivariate Cox regression analysis demonstrated that the prognostic impact of CEACAM-1 depended on the prognostic influence of MVD, while MVD itself represented an independent prognosticator for unfavorable cancer-related survival (p=0.021; relative risk 2.1; 95% confidence interval, 1.1-4.0). Here we show for the first time that high CEACAM-1 expression is associated with an increased angiogenic activity in NSCLC, and that the prognostic influence of CEACAM-1 might be derived from this association.

Detection of MAGE-A Transcripts in Bone Marrow Is an Independent Prognostic Factor in Operable Non–Small-Cell Lung Cancer

Purpose: MAGE-A gene expression in humans is mostly restricted to tumor cells, and the role of MAGE-A transcripts and peptides as diagnostic markers and therapeutic targets is currently under investigation. Thus far, the clinical relevance of MAGE-A transcripts as marker for disseminated tumor cells in bone marrow of patients with operable lung cancer without overt metastases is still unclear. Experimental Design: Preoperative bone marrow aspirates from 50 consecutive patients with operable non–small-cell lung cancer free of distant metastases (i.e., pT1-4 pN0-2 M0 R0) were admitted to the study. Each bone marrow sample was divided and examined using multimarker MAGE-A reverse transcription-PCR (RT-PCR) and immunocytochemical staining with the anti-pancytokeratin antibody A45-B/B3. Multimarker MAGE-A RT-PCR consisted of multiple subtype-specific nested RT-PCRs with primers for MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12. The median follow-up duration was 92 months (range, 18-110 months). Results: Twenty-six (52%) lung cancer patients harbored MAGE-A transcripts in their bone marrow, as opposed to none of the 30 healthy controls tested. In all 7 patients with immunocytochemically positive bone marrow, MAGE-A transcripts were also detected. All different MAGE-A subtypes (MAGE-A1, MAGE-A2, MAGE-A3/6, MAGE-A4, and MAGE-A12) were observed. Sixty-five percent of patients with MAGE-A transcripts in bone marrow exhibited only one subtype. Univariate (P = 0.03, log-rank-test) and multivariate survival analysis showed that MAGE-A transcripts in bone marrow were associated with poor outcome in pN0 patients (P = 0.02; relative risk, 7.6). Conclusions: Detection of MAGE-A transcripts in bone marrow predicts an unfavorable outcome in patients with early-stage operable lung cancer. This finding indicates that MAGE-A transcripts are clinically relevant markers of micrometastatic spread in lung cancer and supports further investigation of MAGE-A as potential future therapeutic target.

The future in diagnosis and staging of lung cancer : Molecular techniques

Lung cancers at the same stage of disease have markedly different rates of disease progression. In this review, we will address current molecular techniques which provide new opportunities according to diagnosis, prediction of survival or selection of therapy. New molecular techniques might be helpful in TNM staging and lead to additional individual prognostic information. A revised TNM system could include a TNM component and a molecular supplemental component allowing new markers to be evaluated without undermining the value of classic TNM staging. Furthermore, molecular techniques might be helpful in the early or differential diagnosis of lung cancer. Since many new targeted agents are effective only if their respective molecular markers are mutated or expressed at sufficient levels, DNA-based or RNA-based techniques have the potential to influence treatment selection in the future. Overall, we can expect that molecular markers will contribute to a more personalized lung cancer treatment.

Airtightness of lung parenchyma without a closing suture after atypical resection using the Nd:YAG Laser LIMAX® 120

OBJECTIVES Lung metastases can be non-anatomically resected with a Nd:YAG Laser. It is recommended that the resected lung surface be sealed by slowly resorbable sutures. However, the lung tissue may be restricted by the sutures once it is re-ventilated. Thus, it was analysed whether the lung parenchyma is airtight after laser resection without suturing the defect. METHODS The pulmonary artery of unimpaired paracardial lung lobes of freshly slaughtered pigs (mean weight 46 g) was cannulated and rinsed out via a hypotonic saline-heparin solution (5000 IE) until the perfusate was clear of body fluid. The lobular bronchus was connected to an airtight ventilation tube (Fa. VYGON 520 3.5 oral tube) and ventilated pressure-controlled (PEEP + 5 cm H₂O, P₁ = 20 cm H₂O, frequency = 10/min) via a respirator. All lobes were perfused with Ringer solution at 42°C at normothermia and normotonia. In group 1 (n = 8), an atypical peripheral parenchymal resection (average resected surface: 2 × 2 cm(2)) and in group 2 (n = 8), a deep atypical parenchymal resection (average resected surface: 4 × 4 cm(2)) were performed with the Nd:YAG Laser LIMAX 120 (output power at 100 watts). After post-resection ventilation of 15 min, the resection surface was tested for airtightness and burst pressure. RESULTS All group 1 lobes tested airtight under pressure-controlled ventilation. The mean burst pressure was 34.4 mbar (SD ± 3.2 mbar). Six lobes of group 2 were also completely airtight. The remaining two lobes, however, revealed a serious parenchymal leak (score 3). This was caused by the cross-opening of a segmental bronchus, although the surrounding lung parenchyma was also airtight. The mean burst pressure of these lobes was 31.7 mbar (SD ± 4.08 mbar). There was no significant difference between the two groups (P = 0.12). CONCLUSIONS Peripheral lung defects after Nd:YAG Laser resection might not be sutured, since the laser-induced vaporization of the lung parenchyma seems to be initially airtight. These experimental data warrant confirmation in a controlled clinical study.

Local effects of high-powered neodymium-doped yttrium aluminium garnet laser systems on the pulmonary parenchyma: an experimental study on the isolated perfused pig lung lobe.

Neodymium-doped yttrium aluminium garnet (Nd:YAG) laser systems (with a power output up to 100 W, wavelength 1318 nm) have been introduced into clinical practice for resecting lung metastases. However, the extent of the local effect on the lung parenchyma and the role of the application time are unknown. All experiments were performed on normothermal, whole-blood-perfused paracardiac pig lung lobes (n = 6). Lobes were not ventilated during the laser application. The laser itself was clamped into a hydraulic feed system that moves horizontally at two different constant rates (10 and 20 mm/s). A 30-mm focus distance from the pulmonary parenchyma was maintained at all times. At each feed rate, the laser was applied thrice along a horizontal path using laser power outputs of 40, 60 and 100 W. After lasering, we recruited the lungs via a ventilation tube using pressures of up to 40 cm H(2)O and tested lung tightness. Both a gross inspection and a histological examination revealed larger coagulation zones for higher power outputs and lower laser feed rates. Exposure to higher outputs for shorter application times reduced the laser effect. When lungs were manually recruited, all lungs were airtight up to a pressure of 40 mmHg. Reducing the exposure time reduces local tissue coagulation even when the laser power output is increased.

Whole-body vibration therapy in intensive care patients: A feasibility and safety study.

BACKGROUND Admission to the intensive care unit is associated with sustained loss of muscle mass, reduced quality of life and increased mortality. Early rehabilitation measures may counteract this process. New approaches to rehabilitation while the patient remains in bed are whole-body vibration alone and whole-body vibration with a dumbbell. The aims of this study are to determine the safety of whole-body vibration for patients admitted to the intensive care unit, and to compare the effects of these techniques in intensive care unit patients and healthy subjects. METHODS Twelve intensive care unit patients and 12 healthy subjects using whole-body vibration for the first time were examined while lying in bed. First both groups performed whole body vibration over 3 min. In a second step whole body vibration with dumbbell was performed. In order to determine the safety of the training intensity, heart rate, oxygen saturation and blood pressure were measured. The study was approved by the Marburg ethics committee. RESULTS There were minor reversible and transient increases in diastolic blood pressure (p = 0.005) and heart rate (p = 0.001) in the control group with whole-body vibration with a dumbbell. In intensive care patients receiving whole-body vibration alone, there were increases in diastolic blood pressure (p = 0.011) and heart rate (p < 0.001). CONCLUSION This study demonstrates the feasibility of using whole-body vibration and whole-body vibration with a dumbbell for intensive care unit in-bed patients. No clinically significant safety problems were found. Whole-body vibration and whole-body vibration with a dumbbell might therefore be alternative methods for use in early in-bed rehabilitation, not only for hospitalized patients.

[Epidural analgesia in thoracic surgery--optimising postoperative rehabilitation].

INTRODUCTION A multimodal perioperative therapy strategy (fast-track) decreases the morbidity of general thoracic interventions and increases postoperative reconvalescence after lung resections. Thoracic surgery is associated with relevant pain and sufficient pain relief is essential for postoperative recovery. Epidural analgesia leads to adequate pain control with only minor side effects and complications and can therefore be a reasonable supplementation in a modern fast-track setting. The purpose of this study was to evaluate the benefits and risks of an epidural catheter placed prior to surgery and to analyse the postoperative recovery of patients undergoing thoracic surgery. METHODS 277 patients undergoing pulmonary resection through an anterolateral thoracotomy were included in our study. Epidural analgesia was carried out through placement of an epidural catheter equipped with Naropine-Sufenta perfusor prior to surgery. Perioperative clinical parameters as well as postoperative management were evaluated. Pain intensity was documented using the visual analogue scale (VAS). Side effects and complications were summarised in five grades of severity (1-5). Insufficient pain relief was recognised when a VAS > 4 was registered. RESULTS Median patient age was 59 years, the male / female relation was precisely 2 : 1, on average epidural analgesia was carried out for 4.9 days. Severe complications (grade 4 or 5) were not found. In 37 % of the cases, minor complications and side effects were found, in 1 % clinical relevant complications led to further diagnostic measures. For sufficient pain relief, 10 % of the studied population needed additional treatment with systemic opioids. CONCLUSION We have shown that epidural analgesia in patients undergoing thoracotomy leads to sufficient pain control with only minor disadvantages and complications. These are easily mastered without expensive diagnostic or therapeutic interventions. Therefore, epidural analgesia is a safe and helpful tool for increased postoperative recovery within a modern fast-track setting.

Comparison of local tissue damage: monopolar cutter versus Nd:YAG laser for lung parenchyma resection. An experimental study

OBJECTIVES Lung metastases are non-anatomically resected while sparing as much parenchyma as possible. For this purpose, a few surgeons use the Nd:YAG Laser LIMAX 120, whereas the majority of surgeons use a monopolar cutter like the MAXIUM. The aim of this experimental study was to investigate which instrument causes less lung-tissue damage at the same power output. METHODS These experiments were conducted on left lungs (n = 6) taken from freshly slaughtered pigs. The laser and the monopolar cutter were fixed in a hydraulic mover. The laser was focused at a distance of 3 cm to the lung tissue and the monopolar cutter was fixed in pressure-free contact with the lung surface. Both instruments were manoeuvred at a speed of 5, 10 and 20 mm/s in a straight line at an output of 100 watts over the lung surface. The lung lesions that ensued were then examined macro- and microscopically. The same procedures were repeated at a distance of 1 cm creating parallel lesions in order to analyse the lung tissue in between the lesions for thermal damage. In addition, two implanted capsules in the lung tissue simulating a lung nodule were resected with either the laser or the monopolar cutter. The resection surfaces were then examined by magnetic resonance imaging and histology for tissue damage. Finally, we created a 2-cm wide mark on the lung surface to test the resection capacity of both instruments within 1 min. RESULTS The laser created sharply delineated lesions with a vaporization and coagulation zone without thermal damage of the surrounding lung tissue. With lowering the working speed, each zone was extended. At a working speed of 10 mm/s, the mean vaporization depth using the laser was 1.74 ± 0.1 mm and the mean coagulation depth was 1.55 ± 0.09 mm. At the same working speed, the monopolar cutter demonstrated a greater cutting effect (mean vaporization depth 2.7 ± 0.11 mm; P < 0.001) without leaving much coagulation on the resection surface (mean coagulation depth 1.25 ± 0.1 mm; P = 0.002). In contrast to the laser, the monopolar cutter caused thermal damage of the adjacent lung tissue. The adjacent tissue injury was detected in histological examination as well as in the MRI findings. Adjacent lung tissue after lung metastasectomy using the monopolar cutter was hyper-intensive in T2-weighted MR imaging, indicating a severe tissue damage. No significant changes in signal intensity were observed in T2-weighted imaging of the adjacent lung tissue after using the laser for lung resection. One minute of laser applied at a 100-watt output penetrated a lung surface area of 3.8 ± 0.4 cm(2) compared with 4.8 ± 0.6 cm(2) of surface after application of the monopolar cutter (P = 0.001). CONCLUSIONS The monopolar cutter possesses indeed a greater cutting capacity than the laser, but it also causes more adjacent tissue injury. Thus, laser resection might be preferred for lung metastasectomy.

Multimodal therapy for malignant pleural mesothelioma including extrapleural pneumonectomy

Multimodal therapy including neoadjuvant chemotherapy with subsequent extrapleural pneumonectomy and postoperative radiotherapy has been shown to improve the survival of patients with malignant pleural mesothelioma (MPM) if they are selected carefully. Careful patient selection is required in order to administer aggressive multimodal therapy only to patients who will benefit from such a treatment. To achieve an accurate staging (<or= cT3, < pN2, cM0), mediastinoscopy is recommended in addition to computed tomography of the chest and upper abdomen. Currently, neoadjuvant chemotherapy with pemetrexed and cisplatin followed by extrapleural pneumonectomy and postoperative radiotherapy is claimed to afford the best treatment results. We have treated 17 patients with such a regimen and achieved a 3-year survival rate of 76 % so far. During the follow-up duration of 23 months, 3 patients (18 %) developed distant metastasis and one (6 %) a mediastinal local recurrence. Multimodal therapy of malignant pleural mesothelioma including extrapleural pneumonectomy should only be performed in specialised centres for thoracic surgery where uncomplicated interdisciplinary communication is the rule and which provide the required expertise in patient selection, operative technique and postoperative care.