Evidence for a role of FGF-2 and FGF receptors in the proliferation of non-small cell lung cancer cells.

Basic fibroblast growth factor (FGF-2) has been implicated in the progression of human tumours via both autocrine and paracrine (angiogenic) activities. We investigated the expression of FGF-2 and FGF receptors (FGFR-1 to -4) in NSCLC cell lines (N = 16), NSCLC surgical specimens (N = 21) and 2 control cell lines. Our data show that almost all NSCLC cells produce elevated levels of FGF-2 and FGFR in vitro and in vivo. FGF-2 expression did correlate with a short doubling time as well as with potent anchorage-independent growth of NSCLC cell lines. In contrast with control cells, NSCLC cells did not secrete considerable amounts of FGF-2 into the extracellular space. Expression levels of FGFR-1 and -2 in NSCLC cell lines correlated with FGF-2 production. FGFR were located at the plasma membranes in some low FGF-2-producing NSCLC and control cell lines. These cells were sensitive to the proliferative effect of recombinant FGF-2 (rFGF-2). In NSCLC cell lines with an enhanced FGF-2 production, representing the majority studied, FGFR localisation was predominantly intracellular. These cells were insensitive to both the proliferative effect of rFGF-2 and growth inhibition by FGF-2-neutralising antibodies. In contrast, several agents antagonised FGF-2 intracellularly impaired growth of almost all NSCLC cell lines. Our data suggest a role of FGF-2 and FGFR in the growth stimulation of NSCLC cells possibly via an intracrine mechanism.

The TP53 genotype but not immunohistochemical result is predictive of response to cisplatin-based neoadjuvant therapy in stage III non-small cell lung cancer.

BACKGROUND: The cytotoxic effects of cisplatin and anthracyclins have been attributed to apoptosis induction, which has been recognized as a major function of the TP53 gene. The TP53 gene appears to be mutated in about 50% of cases of non-small cell lung cancer. A possible dependence of chemotherapy response on TP53 genotype was evaluated retrospectively in a group of patients with advanced non-small cell lung cancer and induction treatment. METHODS: Patients with complete or partial remission were compared with those with stable or progressive disease with respect to TP53 genotype and overall survival. Mutations in the TP53 gene were detected by complete direct sequencing (exons 2-11). RESULTS: A normal TP53 genotype proved to be significantly associated with major response to chemotherapy (P <.001). Overall, no association was found between p53 protein expression and TP53 genotype. A normal TP53 genotype was found to be highly sensitive in predicting response to treatment, whereas a mutant genotype was revealed to be specific in predicting lack of response. The difference in overall length of survival was significant between patients exhibiting a normal TP53 genotype (corresponding to those whose disease responded to chemotherapy) and patients showing mutant TP53 genotype (corresponding to those who had disease resistant to chemotherapy, P =.027). CONCLUSIONS: In a small cohort of patients with advanced non-small cell lung cancer we found a direct link between normal TP53 genotype and response to cisplatin-based induction treatment and also between mutant genotype and resistance to treatment, whereas p53 immunohistochemical result was predictive of neither.

Long-term results after repeated surgical removal of pulmonary metastases.

BACKGROUND: Although surgical resection is accepted widely as first-line therapy for pulmonary metastases, few data exist on the surgical treatment of recurrent pulmonary metastatic disease. In a retrospective study, we analyzed patients who were operated on repeatedly for recurrent metastatic disease of the lung with curative intent over a 20-year period. METHODS: From 1973 to 1993, 396 metastasectomies were performed in 330 patients. The study population included patients with any histologic tumor type who had undergone at least two (range, 2 to 4) complete surgical procedures because of recurrent metastatic disease. Surgical and functional resectability of the recurrent lung metastases and control of the primary lesion served as objective criteria for reoperation. A subgroup of 35 patients that included patients with histologic findings such as epithelial cancer and osteosarcoma then was analyzed retrospectively to calculate prognosis and define selection criteria for repeated pulmonary metastasectomy. RESULTS: The 5- and 10-year survival rates after the first metastasectomy were 48% and 28%, respectively. The overall median survival was 60 months. A mean disease-free interval (calculated for all intervals, with a minimum of two) of greater than 1 year was significantly associated with a survival advantage beyond the last operation. Univariate analysis failed to show size, number, increase or decrease in number or size, or distribution of metastases as factors related significantly to survival. CONCLUSIONS: Although patients with different histologic tumor types were included, the study population appeared to be homogeneous in terms of survival benefit and prognostic factors, and it probably represented the selection of biologically favorable tumors in which histology, size, number, and laterality are of minor importance. We conclude that patients who are persistently free of disease at the primary location but who have recurrent, resectable metastatic disease of the lung are likely to benefit from operation a second, third, or even fourth time.

[Guidelines in minimal invasive surgery in oncologic thoracic surgery]. / Leitlinien zur Minimal-Invasiven Chirurgie in der onkologischen Thoraxchirurgie.

Due to the development of video-assisted thoracoscopic surgery (VATS) over the past 7 years, many procedures are now technically feasible. A side from indication in benign disease, VATS became important for the presectional staging of lung cancer, the biopsy of pulmonary lesions and extrapulmonary intrathoracic tumors, wedge resections of isolated pulmonary nodules and the treatment of pleural or pericardial effusions, as pleurodesis and pericardial window. The current status of VATS metastasectomy, lobectomy and pneumonectomy is controversial and there are no clear indications for VATS lobectomy or pneumonectomy.

Video-assisted thoracic surgery in patients with spontaneous pneumothorax.

Following the development of video-assisted technologies and the principle of minimally-invasive surgery thoracoscopy has finally established itself as an integral part of the surgeon's armamentarium in the treatment of spontaneous pneumothorax. This procedure was performed on 18 patients at the Department of Cardio-Thoracic Surgery of the Medical University in Vienna from October 1995 to April 1996 and on 5 patients at the Department of Thoraco-Abdominal Surgery of the Medical University in Plovdiv from October 1996 to January 1997, all of which had been diagnosed as having complicated spontaneous pneumothorax. The main indications were: recurrent spontaneous pneumothorax or persistent pneumothorax following a five-day unsuccessful drainage of the pleural cavity. All our patients underwent partial parietal pleurectomy down to the level of the third intercostal space. Apical blebs were found in 14 patients and atypical wedge resection was performed. The authors used three trocars 5-12 mm in diameter. The thoracoscope was inserted in the fifth intercostal space in the midaxillary line. The other two operative trocars were inserted in the anterior and posterior axillary lines, respectively. The mean postoperative stay was 6 days. Our results support the view that video-assisted thoracic surgery is technically feasible and safe, associated with decreased perioperative pain and opiate requirements, shorter hospital stay, excellent cosmetic results, low recurrence rate, early return to routine activity and minimal morbidity and is therefore superior to conventional thoracotomy.

Survival after surgical treatment of recurrent pulmonary metastases.

OBJECTIVE: Resection of lung metastases is a generally accepted therapeutic strategy today. This retrospective study was performed in order to estimate the value of an aggressive surgical approach in recurrent metastatic disease of the lung. METHODS: The survival rates of 42 patients undergoing repeated resectional treatment for recurrent lung metastases (group A) were compared to the outcome of a total of 288 patients after a single surgical intervention for lung metastases (group B). Survival rates and the relative effects of the various prognostic factors were calculated according to Kaplan-Maier and Mantel Cox or Wilcoxon test. Histology of the primary tumors in group A consisted of 18 carcinomas, 22 sarcomas and two melanomas, in group B the distribution was 64% carcinoma, 27% sarcoma and 9% melanoma. The mean follow-up period was 88.5 months for group A and 27 months for group B. RESULTS: The overall survival rate for group A was 48% at 5 years and 30% at 10 years, the survival rate for group B was 34% at 5 years. CONCLUSION: Long-term survival rates superior to those after single resectional treatment for lung metastases encourage an aggressive surgical approach for this disease.

Tracheobronchial ruptures in children.

Tracheobronchial ruptures in children after blunt trauma are rare, with an incidence at our clinic of 0.17% of juvenile thoracic injuries in the years 1985 to 1994. The symptoms are variable, and these injuries frequently occur in conjunction with other thoracic injuries, leading to delays in diagnosis. Diagnosis, conservative and operative treatment, and late complications are discussed by presenting four different cases of children with lesions of the tracheobronchial tree after blunt trauma.

Molecular genetic differentiation between primary lung cancers and lung metastases of other tumors.

When solitary pulmonary tumors are observed in patients with a history of cancer, differentiation between metastasis and primary lung cancer is crucial for appropriate therapy. Assuming that p53 mutations are conserved in metastases, mutation analysis of the p53 gene would be a valuable tool in differentiating metastases from primary carcinomas of the lung. In nine of 267 resected lung tumors, the origin of the lung tumor could not be defined histologically. Five patients had a history of colorectal carcinoma, one had a history of breast carcinoma, one had a history of soft-tissue carcinoma, and one had a history of head and neck carcinoma. One patient with a clear cell carcinoma of the lung had been surgically treated for both renal and thyroid cancer. Material from one patient with adenocarcinoma of the lung, histologically defined regional lymph nodes, and distant brain metastasis served as a control. We extracted deoxyribonucleic acid from the snap-frozen tissue of the unclassified lung tumors, from paraffin-embedded tissue of the previously removed primary cancers, and also from peripheral blood of the patients. Exons 2 to 11 of the p53 gene were amplified in separated polymerase chain reactions and directly sequenced. In all cases, the presence of germline mutations was excluded by analysis of peripheral blood deoxyribonucleic acid. The p53 mutation detected in the deoxyribonucleic acid of the lung tumor of the control patient proved to be conserved in the lymph nodes as well as in the brain metastasis. In two cases, the lung tumors exhibited a p53 mutation not present in the previously removed primary tumor and were therefore classified as new primary lung cancers. In five cases, the lung tumors proved to be metastases of the first tumor, exhibiting the identical p53 mutation. One of these lung tumor samples could be identified as a metastasis from the renal cancer, but the corresponding thyroid cancer material was different. For two cases, molecular analysis remained inconclusive. In one case, no p53 mutation could be found in the compared samples; in the other, no deoxyribonucleic acid could be extracted. Analysis of p53 mutations allowed exact classification in tumors for which standard methods failed to distinguish between metastasis or primary tumor. More than two thirds of lung tumors in patients with previous gastrointestinal carcinoma were revealed to be metastases, but second primary lung cancer could also be diagnosed. This diagnosis allowed correct surgical and adjuvant treatment of these patients.

[Diagnostic and therapeutic video thoracoscopy: conversion rate and costs]. / Diagnostische und therapeutische Videothoracoskopie: Umsteigeraten und Kosten.

With the further development of new surgical techniques, that allow for the performance of a variety of standard diagnostic and therapeutic procedures in a less invasive fashion, it is instructive to look at the complications of these new techniques, in order to define their role for general thoracic surgery. 372 patients have been treated by means of video-assisted thoracic surgery (VATS) between 1/1992 and 12/1994. A total of 934 open thoracic procedures were performed in the same time frame, 399 out of them for the same chest disorders as treated by VATS alternatively. In 40 cases (10.7%) the endoscopic procedure had to be converted to an open thoracotomy. The main reasons for conversion were inability to locate or resect lesions due to a deep or central position (n = 13), requirement of further resection (n = 10), adhesions (n = 9), fibrinopurulent empyema (n = 5), bleeding (n = 2) and single-lung-ventilation failure (n = 1). The mean operation time was significantly shorter with VATS compared to open procedures, except for decortications. The mean hospital stay was 4.2 days in the endoscopic and 7.9 days in the thoracotomy group. Cost analysis for both techniques included expenses for disposable instruments, the operation room, anesthesia, and total hospital charges. Higher costs for instruments for VATS procedures were compensated by shorter chest drainage, less postoperative need for analgetics and a significantly shorter hospital stay.(ABSTRACT TRUNCATED AT 250 WORDS)

[Video-assisted thoracic surgery]. / Video-assistierte Thoraxchirurgie.

Over the past two to three years video-assisted thoracic surgery has opened up new possibilities in diagnostic and therapeutic procedures. It is viewed as a sparing and quick alternative to thoracotomy and open operation for a number of indications including the treatment of pneumothorax, obtaining biopsies of undiagnosed diffuse or nodulary lung disease, as well as extirpation of peripheral pulmonary lesions. In oncological thoracic surgery it still remains to be verified whether the criteria of radicality are fulfilled by this new technique. Extipation of circumscribed, extrapulmonary benign tumours and cysts within the thoracic cavity will soon be routine procedures. The advantages lie in the minimally traumatizing surgical technique; as a result of avoiding thoracotomy postoperative pulmonary function is less restricted, there is less pain, earlier mobilization is possible and the period of hospitalization is reduced. In the majority of procedures the operative time is reduced as compared with open surgery. Our experiences in this field with 370 patients are briefly reported. Disadvantages are the loss of the possibility to palpate the lung and the thoracic cavity. The costs of employing this technique is discussed. Video-assisted thoracic surgery has a promising future; it is estimated that 20% to 30% of all thoracic interventions will be performed by this technique.

Evaluation of solitary pulmonary nodules with dynamic contrast-enhanced MR imaging--a promising technique.

The evaluation of a solitary pulmonary nodule (SPN) is one of the most frequently encountered challenges in thoracic radiology. In addition to a "state-of-the-art" evaluation of SPNs with CT and biopsy techniques, recently the assessment of the enhancement characteristics with iodinized contrast agents has shown its potential to improve the characterization of SPNs. We investigated whether dynamic contrast-enhanced MRI is suitable to assess the degree and kinetics of MR contrast enhancement and whether this technique could help in the noninvasive specification of SPNs. We studied prospectively 21 patients with SPNs. T1-weighted and proton density-weighted spoiled gradient-echo breath-hold images (2D-FLASH) were obtained before and after the administration of Gd-DTPA in a standard dosage of 0.1 mmol/kg body weight. The maximum enhancement and the initial velocity of contrast uptake were assessed and correlated with pathohistological findings. To quantify contrast enhancement, we used the relative signal intensity increase (S(rel)) and the recently introduced enhancement factor (EF) and contrast uptake equivalent (CE). Dynamic contrast-enhanced MRI proved to be well suited for the assessment of the contrast enhancement characteristics of SPNs. Significant differences were found in the degree and kinetics of contrast enhancement for specific types of nodules. Malignant neoplastic SPNs enhanced stronger and faster than benign neoplastic SPNs. The strongest and fastest enhancement, however, was found in a benign type of nodules where histology revealed inflammatory/fibrous lesions. These differences in contrast enhancement between the different pathohistological groups were more significant when EF and CE rather than S(rel) was used for the quantification of contrast enhancement. The results of this study indicate a potential role for dynamic contrast-enhanced MRI in the preoperative noninvasive evaluation of SPNs using EF and CE as contrast uptake assessment parameters.

[Bronchiolitis obliterans organizing pneumonia with acute respiratory insufficiency]. / "Bronchiolitis obliterans organizing pneumonia" mit akuter respiratorischer Insuffizienz.

A 22-year-old woman was hospitalized because of fever of 39 degrees C and increasing dyspnoea. The chest radiograph demonstrated coarse confluent opacities bilaterally. Despite antibiotic treatment the condition deteriorated acutely after 2 days. All efforts to find an infectious agent, including immunological tests, were unsuccessful. Artificial ventilation became necessary because of increasing respiratory failure with an arterial oxygen partial pressure of 56 mm Hg, CO2 of 41 mm Hg and a respiratory rate of 60/min. Histological examination of a transthoracic lung biopsy revealed bronchiolitis obliterans organizing pneumonia, which was treated with prednisolone. The initial dose was 500 mg/d, gradually reduced to 12.5 mg/d over 2 weeks. The clinical and radiological findings improved markedly after 2 days and the patient discharged herself after 3 weeks and there was no follow-up.

Carcinogen-specific mutations in the p53 tumor suppressor gene in lung cancer.

Mutations of the p53 tumor suppressor gene, whose encoded protein is one of the chief regulators of the cell cycle, are proving to be the most common genetic alteration in human cancer. Point mutations have been detected in numerous human solid tumors. The types of point mutations in the p53 gene vary considerably in different kinds of human cancers, suggesting that specific etiologic agents are responsible for typical kinds and sites of mutations in the p53 gene. This study reports the detection of two unusual p53 mutations in a series of patients with lung cancer. The first case showed a one-base pair deletion at the end of exon 8, which is rarely affected by mutations, leading to a frameshift involving the following intron 8, exon 9, and intron 9. The second case exhibited two point mutations in codon 273, both either localized in the same codon on one allele or each mutation localized on a different allele in codon 273. Interestingly, the two mutations can be attributed to different mechanisms of base substitution. This is the first report of this kind. Because of evidence that the nature and site of p53 mutations reflect not only the mutagens involved in tumorigenesis but also the capacity for malignant transformation, the characterization of mutations of the p53 gene may provide a basis for assessing further risk factors, as well as for estimating prognosis in patients with lung cancer.

[Bronchial carcinoma]. / Bronchuskarzinom.

Carcinoma of the lung constitutes 20% of all cancer in men and 11% of all cancer in women. It is the most common cause of death from malignancy in both sexes. The number of patients is increasing every year. In the epidemiology and in the experiment smoking is to be found the real factor in the pathogenesis of lung cancer.

Clinical experience with minimally invasive thoracic surgery.

From October 1991 to June 1992 video-endoscopic lung surgery was applied in a total of 109 patients. In the first case a pulmonary cyst measuring 15 x 18 cm was resected. In 21 patients lung nodules were exstirpated by means of wedge resection. Moreover, metastasectomies, open lung biopsies, parietal pleurectomies, resections of bullae, and decortications, as well as 3 lower-lobe lobectomies were performed using video-endoscopic procedures. Closure of lung parenchyma was carried out using the 3 cm Endo-GIA stapler (Autosuture). In none of the patients were we forced to enlarge the intervention to a thoracotomy because of technical problems. Indications, operative technique and results are presented. This new technique offers all the known advantages of minimally invasive surgery to patients requiring thoracic surgery.

Postoperative complication rate of thoracotomy in patients with normal and abnormal pulmonary function.

Recent advances in perioperative monitoring, anesthesia, and postoperative care have resulted in a more generous attitude towards performing thoracic surgery in patients with reduced pulmonary function. In our hospital 100 patients admitted for thoracotomy with or without pulmonary resection were classified on the basis of their pulmonary function: group I (n = 33) normal, group II (n = 40) moderate reduction, group III (n = 27) marked reduction. The mean and standard deviation in groups I, II, and III were: FEV 1 in % VC: 78 +/- 6, 72 +/- 7, and 58 +/- 10; RV in % TLC: 24 +/- 7, 35 +/- 8, and 43 +/- 9; Resistance, kPal/1/sec: 0.2 versus 0.3 versus 0.5. After surgery there were three postoperative deaths from cardiovascular complications without respiratory failure; all 3 patients were in group II and younger than 70 years. Only one patient (classified as group III and 59 years old) died from a respiratory complication (respiratory insufficiency) after a palliative operation on a large adenocarcinoma. Our data demonstrate that markedly reduced preoperative lung function is not necessarily associated with high risk in thoracic surgery--even in elderly persons--provided intensive pre- and postoperative care is guaranteed.

[Isolated amyloidosis of hilar lymph nodes]. / Isolierte Amyloidose der Hiluslymphknoten.

Pseudotumoral mediastinal and pulmonary amyloidosis occur infrequently and may be confused with other tumors that are found more commonly in this region. Enlargement of hilar lymph nodes in the absence of pulmonary involvement is extremely rare. We report a case of nodular amyloidosis of the hilar lymph nodes that was studied using different diagnostic and radiologic methods. A previously healthy 79-year-old man presented with a large right hilar mass detected on routine chest roentgenography. The extensive mass behaved like a solid tumor and mimicked a bronchogenic carcinoma. At thoracotomy, frozen sections revealed the tumor to consist of kappa-light-chain amyloid. In light of the irresectibility of the tumor, thoracotomy was ended as open biopsy. Immunoelectrophoretic analyses of the plasma and urine showed no evidence of a paraprotein immunoglobulin or light chains. The patient was discharged without symptoms of disease. Different diagnostic procedures before and after surgery are discussed.

[Video-endoscopic interventions in thoracic surgery]. / Videoendoskopische Eingriffe in der Thoraxchirurgie.

Between October and December 1991 we performed videoendoscopic procedures, including resection of lung tissue, on 9 patients in our thoracic surgery unit. A lung measuring 15 x 18 was extirpated in 1 patient and parietal pleurectomy was performed after complicated pneumothorax in 4 patients. In one of these cases it was necessary to close a parenchymal leak and in 3 cases bullae had to be removed. Resection was undertaken in 4 patients for peripheral lung nodules, in one of them for metastases. Two patients proceeded to conventional lobectomy immediately after the frozen section results came through. Closure of lung parenchyma was carried out by means of the new ENDO-GIA stapler. Duration of the procedure was less than one hour except in the case of one patient. In one case it was necessary to use three cannulae. In the other cases two cannulae (one for videoendoscopy and fixating instrument, one for preparation instrument and stapler) sufficed for the operation to be undertaken without difficulty. This new technique brings all the known advantages of minimal invasive intervention to patients requiring thoracic surgery.

Contrast-enhanced MRI for the staging of bronchogenic carcinoma: comparison with CT and histopathologic staging--preliminary results.

Nineteen patients with potentially operable bronchial carcinoma were included in a prospective study to assess the staging capabilities of plain and contrast-enhanced magnetic resonance imaging (MRI) in comparison with computed tomography (CT) and to compare the results to post-operative histopathological staging (HS). The evaluation focused on the following T-staging criteria: (i) direct invasion of the pleura; (ii) neoplastic invasion of the mediastinum; (iii) differentiation of the primary tumour from alterations of the surrounding lung parenchyma such as inflammation or atelectasis; and (iv) intrathoracic lymph node involvement by tumour. MRI and CT produced similar results for pleural invasion (sensitivity of 0.4 and 0.75 respectively and a specificity of 0.86 and 0.93 respectively). Mediastinal invasion was overdiagnosed in four patients (no false negatives), whereas CT had only one false positive result (two false negatives). Our results showed CT to be superior to MRI for the preoperative evaluation of patients suffering from bronchogenic carcinoma.

[Results of transverse tracheal resection in post-intubation tracheal stenoses]. / Ergebnisse mit der queren Trachealresektion bei Postintubations-Trachealstenosen.

Tracheal problems in form of stenosis and malacia are a calculated risk of long-term tracheal intubation. Results with conservative treatment of such problems by bougienage, laser therapy, biopsy, cryotherapy, local steroids, tracheal stenting, and tracheostomy are not satisfactory in a higher percentage of cases. Resectional therapy of benign tracheal lesions has become an established technique, which combines excellent functional results with a low complication incidence. We have treated 40 patients of 17 to 76 years of age with postintubation tracheal lesions by cross resection of the affected segment. Of these patients 40% had received conservative therapeutical steps preoperatively. The mean resection length was 3.0 cm (1.5 to 6.5 cm). The perioperative morbidity was 7.8%, mortality was 2.5%. 85% of the patients operated between 1970 and 1989 were reached for a follow-up examination with x-ray, pulmonary function test and endoscopy. The patients subjective satisfaction with the operative result was good in 85%, minor in 12% and less in 3%. The objective investigations proved very good results in 90%. Our experience confirm the good results of other authors and recommend the resection treatment for cases of postintubation tracheal lesions.