Heart dose exposure as prognostic marker after radiotherapy for resectable stage IIIA/B non-small-cell lung cancer: secondary analysis of a randomized trial.

Background: Heart exposure to ionizing irradiation can cause ischaemic heart disease. The partial heart volume receiving ≥5 Gy (heartV5) was supposed to be an independent prognostic factor for survival after radiochemotherapy for locally advanced non-small-cell lung cancer (NSCLC). But validation of the latter hypothesis is needed under the concurrent risks of lung cancer patients. Patients and methods: The ESPATUE phase III trial recruited patients with potentially operable IIIA(N2)/selected IIIB NSCLC between 01/2004 and 01/2013. Cisplatin/paclitaxel induction chemotherapy was given followed by neoadjuvant radiochemotherapy (RT/CT) to 45 Gy (1.5 Gy bid/concurrent cisplatin/vinorelbine). Operable patients were randomized to definitive RT/CT(arm A) or surgery (arm B) and therefore were treated at two different total dose levels of radiotherapy. HeartV5 and mean heart dose (MHD) were obtained from the 3D radiotherapy plans, the prognostic value was analysed using multivariable proportional hazard analysis. Results: A total of 161 patients were randomized in ESPATUE, heartV5 and MHD were obtained from the 3D radiotherapy plans for 155 of these [male/female:105/50, median age 58 (33-74) years, stage IIIA/IIIB: 54/101]. Power analysis revealed a power of 80% of this dataset to detect a prognostic value of heartV5 of the size found in RTOG 0617. Multivariable analysis did not identify heartV5 as an independent prognostic factor for survival adjusting for tumour and clinical characteristics with [hazard ratio 1.005 (0.995-1.015), P = 0.30] or without lower lobe tumour location [hazard ratio 0.999 (0.986-1.012), P = 0.83]. There was no influence of heartV5 on death without tumour progression. Tumour progression, and pneumonia were the leading causes of death representing 65% and 14% of the observed deaths. Conclusions: HeartV5 could not be validated as an independent prognostic factor for survival after neoadjuvant or definitive conformal radiochemotherapy. Tumour progression was the predominant cause of death. Register No: Z5 - 22461/2 - 2002-017 (German Federal Office for Radiation Protection).

[Functional Outcome after Chest Wall Stabilisation]. / Rippenosteosynthesen - funktionsverbessernd?

This overview reviews the current literature to compare the functional results after surgical and conservative treatment of patients with flail chest and multiple rib fractures. Regarding functional aspects, patients in the early phase after a thoracic trauma are those that benefit most from the stabilisation of the chest wall by internal fixation of the ribs. Patients recover faster from restrictive respiratory disorders, have less pain and return to the workplace earlier after an operation compared with those that receive conservative treatment. In the medium term, however, patients that are treated conservatively also achieve normal pulmonary function values and become free of pain. The period of convalescence after blunt thoracic trauma is generally underestimated. Future studies of the functional outcome after severe chest injuries should take this into account and the development of functional parameters should be monitored for at least 24 months. A prospective data collection of early and long-term surgical results in registries would be suitable to evaluate benefits and indications of chest wall stabilisation.

[Pulmonary Metastases of Colorectal Carcinoma]. / Pulmonale Metastasenchirurgie des kolorektalen Karzinoms.

Treatment strategies for patients with pulmonary metastases of colorectal carcinoma are continuously evolving. This applies mostly to new systemic therapeutic approaches. For carefully selected patients surgical removal of pulmonary metastases remains an important interdisciplinary therapeutic option and is recommended as first treatment option by the guidelines. Five-year survival rates of up to 60 % are reported following pulmonary metastasectomy. Parenchyma sparing resection has been well established in this setting with low morbidity and mortality. Prognostic factors are, among others, complete resection, thoracic lymph node involvement, the number of metastases and the disease free interval. Although data result mostly from retrospective studies, these factors currently help in patient selection.

Canine scent detection in the diagnosis of lung cancer: revisiting a puzzling phenomenon.

Patient prognosis in lung cancer largely depends on early diagnosis. The exhaled breath of patients may represent the ideal specimen for future lung cancer screening. However, the clinical applicability of current diagnostic sensor technologies based on signal pattern analysis remains incalculable due to their inability to identify a clear target. To test the robustness of the presence of a so far unknown volatile organic compound in the breath of patients with lung cancer, sniffer dogs were applied. Exhalation samples of 220 volunteers (healthy individuals, confirmed lung cancer or chronic obstructive pulmonary disease (COPD)) were presented to sniffer dogs following a rigid scientific protocol. Patient history, drug administration and clinicopathological data were analysed to identify potential bias or confounders. Lung cancer was identified with an overall sensitivity of 71% and a specificity of 93%. Lung cancer detection was independent from COPD and the presence of tobacco smoke and food odours. Logistic regression identified two drugs as potential confounders. It must be assumed that a robust and specific volatile organic compound (or pattern) is present in the breath of patients with lung cancer. Additional research efforts are required to overcome the current technical limitations of electronic sensor technologies to engineer a clinically applicable screening tool.

[Bronchial aspergillosis]. / Bronchiale Aspergillosen.

Bronchopulmonary aspergillosis is becoming more frequent, is often hard to diagnose and with today's antimycotics better to treat than before. It is therefore of current interest. This also concerns bronchial aspergillosis which is less common than pulmonary aspergillosis and the topic of this paper. A total of 39 patients with bronchial aspergillosis are presented: 1) 4 cases with endobronchial aspergilla, two which are visual bronchoscopically, 2) one case with chronic necrotising pulmonary aspergillosis (CNPA), where a bronchus has necrotised, 3) an invasive aspergillosis in the region of a bronchial anastomosis, 4) 7 cases with an Aspergillus invasion from endobronchial tumour tissue and 5) 26 cases with allergic bronchopulmonary aspergillosis (ABPA). 37 of the 39 cases are part of a single centre study with a total of 116 bronchopulmonary aspergilloses, which were collected over seven years. The focus of attention in this paper is on the bronchoscopic and radiological results.

Repeat 18F-FDG PET for monitoring neoadjuvant chemotherapy in patients with stage III non-small cell lung cancer.

PURPOSE: The relevance of (18)F-FDG PET for staging non-small cell lung cancer (NSCLC), in particular for the detection of lymph node or distant metastases, has been shown in several studies. The value of FDG-PET for therapy monitoring in NSCLC, in contrast, has not yet been sufficiently analysed. Aim of this study was to evaluate FDG-PET for monitoring treatment response during and after neoadjuvant radiochemotherapy (NARCT) in advanced NSCLC. METHODS: Sixty-five patients with histologically proven NSCLC stage III initially underwent three FDG-PET investigations, during NARCT prior to initiating radiation, and post-NARCT. Changes of FDG-uptake in the primary tumour at two time-points during NARCT were analysed concerning their impact on long-term survival. RESULTS: The mean maximum FDG uptake (standardized uptake value, SUVmax) of the whole group decreased significantly during NARCT (SUVmax PET 1: 14.9+/-4.0, SUVmax PET 3: 5.5+/-2.4, p=0.004). The difference between initial FDG uptake (PET 1) and uptake after induction chemotherapy (PET 2) was found to be highly predictive for long-term survival patients which had a greater than 60% decreases in their SUV change had a significantly longer survival than those below this threshold (5-year-survival 60% versus 15%, p=0.0007). Patients who had a lower than 25% decrease in their SUV change had a 5-years-survival lower than 5%. Furthermore, the difference between initial FDG uptake (PET 1) and uptake after completion of the whole NARCT (PET 3) was predictive for survival when 75% was applied as cut-off (p=0.02). However, the level of significance was considerably lower. CONCLUSION: FDG-PET is suitable for therapy monitoring in patients with stage III NSCLC. The decrease of FDG uptake during induction chemotherapy is highly predictive for patient outcome.

[Case studies of iatrogenic tracheal injury during intraoperative ventral positioning. Symptoms, diagnostics, and differential therapy]. / Iatrogene Trachealverletzung bei intraoperativer Bauchlagerung. Fallbeispiele mit Klinik, Diagnostik und Differenzialtherapie.

Two patients 16 and 21 years old developed tracheal rupture during elective surgery following trouble-free orotracheal intubation and intraoperative ventral positioning. The injuries remained undetected in both patients for more than 12 h. Diagnostic investigation after the onset of first symptoms indicated in each a tear in the posterior tracheal wall. Early operation prevented the development of serious complications in both patients. The casuistics indicate that tracheal injuries can emerge in minor elective surgery that may be carried out on an outpatient basis, and ventral positioning for surgery may represent a risk factor for their occurrence. Clinical symptoms, diagnostic procedure, findings, and therapy are discussed.

Enhanced uptake of doxorubicin into bronchial carcinoma: beta-glucuronidase mediates release of doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site.

Lack of tumor selectivity is a severe limitation of cancer chemotherapy. Consequently, reducing dose-limiting organ toxicities such as the cardiac toxicity of doxorubicin (Dox) is of major clinical relevance. Approaches that would facilitate a more tumor-selective anticancer therapy by using nontoxic prodrugs that are converted to active anticancer agents at the tumor site have been the subject of intensive research. One potential method to overcome the cardiac toxicity of Dox is to apply a nontoxic, glucuronide prodrug (HMR 1826) from which Dox is released by the action of beta-glucuronidase, an enzyme present at high levels in many tumors. Using a recently developed, isolated, perfused human lung model, we compared the uptake of Dox into normal lung and lung tumors after a 2.5-h lung perfusion with doxorubicin (n = 8) and with the novel doxorubicin glucuronide prodrug (n = 8). Dox showed a poor uptake into lung tumors as compared with normal lung [mean Dox concentration at the end of perfusion, 1.78 +/- 3.11 (median, 0.66) microg/g versus 22.03 +/- 10.4 (median, 18.5) microg/g; P < 0.001]. However, after perfusion with HMR 1826, the level of Dox in tumor tissue was about 7-fold higher than after perfusion with Dox itself [14.04 +/- 12.9 (median, 12.9) microg/g versus 1.78 +/- 3.11 (median, 0.66) microg/g, P < 0.05, n = 8]. In vitro experiments showed a significantly higher beta-glucuronidase expression and activity in the tumors. The extent of in vitro cleavage of HMR 1826 by homogenized lung tissue was closely related to the content of beta-glucuronidase (r = 0.9834, P < 0.0001). When D-saccharolactone, a specific inhibitor of beta-glucuronidase, was added to the perfusate containing HMR 1826, no accumulation of Dox in lung tissue was seen. These data indicate that the high Dox levels achieved in the tumors with HMR 1826 resulted from cleavage of the prodrug by beta-glucuronidase at the tumor site. Thus, the problem of poor Dox uptake into lung tumors could be circumvented by applying the doxorubicin glucuronide prodrug. Several lines of evidence based on both ex vivo and in vitro results indicate that the approach described using a glucuronide prodrug may be useful in facilitating more selective delivery of chemotherapy to tumors in humans.

[Surgical curriculum. A model from thoracic surgery]. / Chirurgisches Curriculum. Ein Modell aus der Thoraxchirurgie.

There is a shortage of new surgeons in Germany. The blame for this is laid on poor working and training conditions in German hospitals. Professional associations suggest restructuring teaching plans to improve surgical education. The study conditions, postgraduate education, and surgical training in a thoracic surgical department are presented as a model curriculum. Surgical training can be structured. Curricula can be delineated for colleagues and applicants and comply with quality management standards. Clear and fair courses would improve surgical training and satisfy the expectations of contemporary surgeons.

Analysis of CYP2D6 expression in human lung: implications for the association between CYP2D6 activity and susceptibility to lung cancer.

We have studied whether CYP2D6 is expressed in human lung tissue, using a specific and sensitive reverse transcriptase-polymerase chain reaction method and immunohistochemistry. Seven out of the eight patients were extensive metabolizers as shown by genotyping for the CYP2D6 (debrisoquine-sparteine) polymorphism. To investigate whether expression of CYP2D6 in lung tumours is different from that in normal lung tissue, tumour tissue samples were also obtained from the same eight patients. Correctly spliced CYP2D6 mRNA was detected by RT-PCR analysis in human liver and duodenum but not in any of the lung samples. In accordance with these negative results, immunoreactivity for CYP2D6 protein, using specific monoclonal and polyclonal antibodies, was very low or absent. No specific cell type of lung tissue showed strong immunoreactivity for CYP2D6, although expression of CYP3A could be clearly demonstrated in the same tissue samples. Moreover, a Western blot analysis revealed no signal in lung microsomes from two additional extensive metabolizers. Taken together, these results indicate that expression of CYP2D6 in human lung is absent or very low. These findings thus argue against a significant local metabolic activation of procarcinogenic agents by CYP2D6 in the lung.

Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases.

OBJECTIVES: The International Registry of Lung Metastases was established in 1991 to assess the long-term results of pulmonary metastasectomy. METHODS: The Registry has accrued 5206 cases of lung metastasectomy, from 18 departments of thoracic surgery in Europe (n = 13), the United States (n = 4) and Canada (n = 1). Of these patients, 4572 (88%) underwent complete surgical resection. The primary tumor was epithelial in 2260 cases, sarcoma in 2173, germ cell in 363, and melanoma in 328. The disease-free interval was 0 to 11 months in 2199 cases, 12 to 35 months in 1857, and more than 36 months in 1620. Single metastases accounted for 2383 cases and multiple lesions for 2726. Mean follow-up was 46 months. Analysis was performed by Kaplan-Meier estimates of survival, relative risks of death, and multivariate Cox model. RESULTS: The actuarial survival after complete metastasectomy was 36% at 5 years, 26% at 10 years, and 22% at 15 years (median 35 months); the corresponding values for incomplete resection were 13% at 5 years and 7% at 10 years (median 15 months). Among complete resections, the 5-year survival was 33% for patients with a disease-free interval of 0 to 11 months and 45% for those with a disease-free interval of more than 36 months; 43% for single lesions and 27% for four or more lesions. Multivariate analysis showed a better prognosis for patients with germ cell tumors, disease-free intervals of 36 months or more, and single metastases. CONCLUSIONS: These results confirm that lung metastasectomy is a safe and potentially curative procedure. Resectability, disease-free interval, and number of metastases enabled us to design a simple system of classification valid for different tumor types.

Neoadjuvant chemoradiotherapy of stage III non-small-cell lung cancer.

Twenty to 30% of patients with non-small-cell lung cancer (NSCLC) in stage III are not resectable primarily with 5-year survival less than 10%. Since the majority of patients die from metastases, efforts have been made in the past to improve prognosis by application of neoadjuvant chemoradiotherapy regimens followed by subsequent resection. In a phase II study performed between 1993 and 1998, 93 patients in stage III (IIIA, 16%; IIIB, 84%) received an induction chemotherapy consisting of two cycles cisplatin (100 mg/m2) and vindesine (3 mg/m2) with subsequent sequential radiotherapy of 36 Gy. Sixty-five patients demonstrated partial or complete remission. Sixty underwent surgery; in 49 of them complete resection was possible. Five-year survival in the whole group was 24%, and that in the surgical cohort 39%. Six patients had no residual tumor. Postoperative N0 status was associated with a 5-year survival of 75%, and stage N1-3 with 13%. Thirty-day mortality was 7% postoperatively. Neoadjuvant chemoradiotherapy can significantly improve long-term survival in stage III NSCLC with an acceptable therapy-induced mortality.

Immunohistochemical localization of cytochrome P450 2E1 in human pulmonary carcinoma and normal bronchial tissue.

Cytochrome P450 2E1 (CYP2E1) is a major xenobiotic-metabolizing enzyme but data concerning its extrahepatic expression are few. CYP2E1 can metabolically activate many procarcinogens and therefore its presence in the lung might play a role in bioactivation of procarcinogens, so we studied the expression and localization of CYP2E1 in primary pulmonary carcinomas and surrounding normal bronchial tissue from 28 patients. Seromucous glands showed expression of CYP2E1 in 19 and bronchial epithelium in 18 of the 28 samples of normal bronchial tissue. Thirteen of the corresponding cases of primary pulmonary carcinoma showed staining for CYP2E1. In 11 of these 13 cases, CYP2E1 was also present in normal bronchial tissue. There was no statistically significant difference in the expression of CYP2E1 between adenocarcinomas and squamous cell carcinomas. No association was observed between the expression of CYP2E1 in tumour tissue and normal bronchial tissue. However, there was a significant correlation between the expression of CYP2E1 in seromucous glands and bronchial epithelium (r = 0.61, P < 0.01) of normal tissue. We conclude that CYP2E1 can be present in both normal and neoplastic bronchial tissue.

Variability of cyclophosphamide uptake into human bronchial carcinoma: consequences for local bioactivation.

PURPOSE: The alkylating cytostatic prodrug cyclophosphamide is bioactivated by the human cytochrome P450 enzyme system. Since these enzymes are not only expressed in human liver, but also in extrahepatic tissue, local bioactivation of this drug may play an important role in its antineoplastic effects, e.g., chemotherapy of lung tumors. This would require uptake of significant amounts of cyclophosphamide into tumor tissue, which has not yet been demonstrated. METHODS: We used a recently developed, ex vivo isolated, ventilated and perfused human lung model to study cyclophosphamide uptake into bronchial carcinoma and healthy lung tissue. Following a standard lobectomy, lung samples containing the tumor were perfused with buffer containing 2 mM cyclophosphamide for 2 h. Cyclophosphamide concentrations in perfusate and healthy peripheral tissue were measured during the perfusion and in tumors at the end of perfusion. RESULTS: In all tissue samples, cyclophosphamide uptake was relatively poor, indicated by a tissue to perfusate ratio of 0.021. Moreover, in tumor samples, cyclophosphamide concentrations were significantly lower (P < 0.05) than in healthy lung tissue and showed pronounced interindividual variability. Median concentrations were 36.8 microg/g (26.9 44.2 microg/g) in healthy tissue and 5.1 microg/g (0.0-26.8 microg/g) in tumor samples. Tumor cyclophosphamide concentrations varied between 0 and 75% of those reached in healthy tissue. CONCLUSIONS: Our results indicate that CP tumor concentrations are modulated by factors different from dose and that expression of bioactivating enzymes in human lung or transfection of genes encoding these enzymes into tumor cells does not necessarily lead to local bioactivation of cyclophosphamide.

Resection of pulmonary metastases from renal cell carcinoma.

Between 1980 and 1995, 77 patients underwent complete resection of pulmonary metastases from a renal cell carcinoma after exclusion of a primary tumor recurrence and other metastatic localizations. 30-day mortality was 3%. The Median follow-up was 34 months (M). Cumulative 5-year survival (5-YS) was 39%. Prognostic criteria are the duration of the disease-free interval (DFI) and the number of metastases. Patients with a DFI > or = 48 M had a 5-YS of 46% compared to 26% for a DFI of < 48 M. Patients with a solitary metastasis had a 5-YS of 49% compared to 19% for multiple metastases. There was no significant difference in terms of sex, kind of access, kind of operation, and unilateral or bilateral affection. Since metastases from renal cell carcinomas are almost resistant to chemotherapy and radiotherapy and immunotherapy at present does not considerably improve long-term survival, surgical resection currently is the only effective therapeutic access in renal cell cancer metastasized to the lung.

Mediastinoscopic ultrasonography (MUS).

Correct pre-therapeutic T4 staging is mandatory for neo-adjuvant studies and for the decision on surgical therapy of high-risk patients. T4-staging of centrally located lung-cancer by means of non-invasive imaging techniques is either of low accuracy (CT and NMR) or important regions are not accessible due to air interference with the tracheo-bronchial tree (trans-esophageal-endosonography, TEE). We here describe for the first time the new technique of mediastinoscopic ultrasonography (MUS). A fingertip ultrasound probe is introduced through the video-mediastinoscope. The probe lies in front of the tracheo-bronchial tree and in direct contact with the vena cava and pulmonary artery. This position allows examining those regions that are not accessible with TEE. In a pilot study with 12 patients, visualization of central vessels and their relation to the tumor was excellent and without artifacts. In 3 patients, MUS did not confirm the T4 stage predicted by CT Scan. Those three patients underwent successful pneumonectomy (R0-resection) while the other nine patients received induction treatment. MUS is a promising addition to CT scanning, NMR, and transesophageal ultrasound in staging of centrally located tumors.

Reduced blood loss by aprotinin in thoracic surgical operations associated with high risk of bleeding. A placebo-controlled, randomized phase IV study.

OBJECTIVE: Although the blood-saving effect of aprotinin has been well documented in cardiac surgery and lung transplantation, its use in lung surgery has received less attention. We present our experience with the intraoperative application of aprotinin in lung resections with a predicted high risk of bleeding. METHODS: Thirty-eight patients undergoing major thoracic surgical procedures were randomized into treatment and placebo groups. The treatment group (n=18) received a bolus of 2 x 10(6) kallikrein inhibitor units (KIU) of aprotinin followed by 5 x 10(5) KIU/h during surgery. The placebo group (n=20) received an isotonic saline infusion instead. RESULTS: There was no significant difference between the groups concerning diagnosis, co-morbidity, age, sex, height, and weight. The mean intraoperative blood loss in the treatment group was significantly reduced (342 vs. 808 ml, P<0024), postoperative blood loss was also reduced (623 vs. 1282 ml, P<0.0007) and the need for blood transfusion was less (14 vs. 60, n.s.). No severe side effects of aprotinin were registered. Re-thoracotomy was necessary in two patients of the placebo group because of postoperative bleeding. CONCLUSION: Aprotinin reduces the perioperative blood loss and the need for blood transfusion in thoracic surgical procedures in patients with an increased risk of bleeding.