Prognostic value of hTERT mRNA expression in surgical samples of lung cancer patients: the European Early Lung Cancer Project.

Lung cancer is the most important cause of cancer-related mortality. Resectability and eligibility for treatment with adjuvant chemotherapy is determined by staging according to the TNM classification. Other determinants of tumour behaviour that predict disease outcome, such as molecular markers, may improve decision-making. Activation of the gene encoding human telomerase reverse transcriptase (hTERT) is implicated in the pathogenesis of lung cancer, and consequently detection of hTERT mRNA might have prognostic value for patients with early stage lung cancer. A cohort of patients who underwent a complete resection for early stage lung cancer was recruited as part of the European Early Lung Cancer (EUELC) project. In 166 patients expression of hTERT mRNA was determined in tumour tissue by quantitative real-time RT-PCR and related to that of a house-keeping gene (PBGD). Of a subgroup of 130 patients tumour-distant normal tissue was additionally available for hTERT mRNA analysis. The correlation between hTERT levels of surgical samples and disease-free survival was determined using a Fine and Gray hazard model. Although hTERT mRNA positivity in tumour tissue was significantly associated with clinical stage (Fisher's exact test p=0.016), neither hTERT mRNA detectability nor hTERT mRNA levels in tumour tissue were associated with clinical outcome. Conversely, hTERT positivity in adjacent normal samples was associated with progressive disease, 28% of patients with progressive disease versus 7.5% of disease-free patients had detectable hTERT mRNA in normal tissue [adjusted HR: 3.60 (1.64-7.94), p=0.0015]. hTERT mRNA level in tumour tissue has no prognostic value for patients with early stage lung cancer. However, detection of hTERT mRNA expression in tumour-distant normal lung tissue may indicate an increased risk of progressive disease.

Expression of the p16(INK4a) gene product, methylation of the p16(INK4a) promoter region and expression of the polycomb-group gene BMI-1 in squamous cell lung carcinoma and premalignant endobronchial lesions.

It is generally assumed that squamous cell carcinoma develops in a stepwise manner from normal bronchial epithelium towards cancer by the accumulation of (epi)genetic alterations. Several mechanisms including mutations and homozygous deletions or hypermethylation of the p16(INK4a) promoter region can cause loss of p16 expression. Recent studies suggest overexpression of the polycomb-group gene BMI-1 might also down-regulate p16 expression. In this study, we analyzed the p16 expression in relation to the methylation status of the p16 promoter region of the p16(INK4a) gene and the expression of BMI-1 in bronchial squamous cell carcinomas (SCC) and its premalignant lesions. Nine (69%) SCC showed loss of p16 expression and 10 (77%) showed expression of BMI-1. Of four p16 positive samples two (50%) were BMI-1 positive, whereas among nine p16 negative samples, eight (89%) revealed BMI-1 staining. Four (44%) p16 negative samples were hypermethylated at the p16(INK4a) promoter region; the other p16 negative tumors that showed no hypermethylation revealed BMI-1 staining. Only two premalignant lesions showed absence of p16 expression, of which one (carcinoma in situ) was hypermethylated at the p16(INK4a) promoter region and the other (severe dysplasia) showed BMI-1 expression. In total, 11 precursor lesions (48%) revealed BMI-1 expression. In conclusion, the results of this study suggest that loss of p16 expression by promoter hypermethylation is inconsistently and occurs late in the carcinogenic process at the level of severe dysplasia. To what extent overexpression of the polycomb-group protein BMI-1 attributes to down regulating of p16 expression remains unclear.

New techniques for early detection of lung cancer.

The resurgence of interest in lung cancer screening and the application of new techniques for the management of early cancer have raised various issues regarding this global epidemic. In previous randomised clinical trials, the use of conventional chest radiographs and sputum cytology examinations for screening have been shown not to reduce lung cancer mortality. The use of biomolecular markers, autofluorescence bronchoscopy, low-dose spiral and high-resolution computed tomography, endobronchial ultrasonography, optical coherence tomography, confocal micro-endoscopy, positron emission tomography in combination with video-assisted thoracic surgery and intraluminal bronchoscopic treatments may provide new modalities with which to manage lung cancer at the earliest stage possible. New hopes arise that the combined use of more accurate and minimally invasive diagnostic and treatment techniques may justify screening and reduce mortality. More individuals may also benefit, as many in the target population already suffer from poor cardiovascular and pulmonary health due to their smoking history and are considered at risk for surgical intervention. The cost-effectiveness of lung cancer screening will strongly depend on the proper selection of the target population and the optimal application of these new techniques. Despite epidemiological controversy regarding lung cancer screening, the feasibility to define more precisely who are at risk and the use of less invasive techniques may preserve quality of life and improve the survival of many lung cancer patients.

The role of photodynamic therapy in the management of stage I/II NSCLC.

There is a resurgence of interest in lung cancer screening, motivated by the fact that many lung cancer patients cannot be cured due to advanced disease at presentation. Lung cancer screening may detect more early stage disease. Very early stage squamous cell type lung cancer in the central tracheobronchial tree can be detected and local bronchoscopic treatments such as photodynamic therapy can be applied if the tumor is strictly intraluminal and nodal disease is absent. So, accurate staging regarding tumor size and nodal disease is much more important than treatment per se. Bronchoscopic treatments are less morbid treatment alternatives than surgery and surgical bronchoplasty, especially for patients suffering from COPD and who have poor cardiovascular status due to their smoking history.

Combination of gemcitabine and cisplatin for advanced non-small cell lung cancer: a phase II study with emphasis on scheduling.

BACKGROUND: Many regimens of gemcitabine-cisplatin chemotherapy have proven activity in patients with advanced non-small cell lung cancer (NSCLC). However, the optimal dose and schedule still have to be established. PATIENTS AND METHODS: We conducted a phase II study with administration of cisplatin 50 mg/m(2) on days 1 and 8 and gemcitabine 800 mg/m(2) on days 2, 9 and 15. This schedule was selected to optimise the synergism between the two drugs and reduce toxicity due to high dose cisplatin. RESULTS: Thirty-six chemo-naive patients with stage IIIA, IIIB or IV NSCLC entered the study (26 men, 10 women; median age 58 years, range 29-74). Twenty patients achieved a partial response: 7 out of 10 stage IIIA patients, 7 out of 13 stage IIIB patients and 6 out of 13 stage IV patients. On intent-to-treat basis, the overall response rate (RR) was 58% (95% confidence interval, 42-74%). Ninety percent of stage IIIA patients and 46% of stage IIIB patients received adjuvant surgery or radiotherapy. Overall median duration of response was 28 weeks (range 6-147 weeks). For stage IIIA, IIIB and IV patients, these numbers were 91, 13 and 23 weeks, respectively. One-year survival was 49% with 90%, 23% and 42% for stage IIIA, IIIB and IV patients, respectively. The main toxicity was myelosuppression. WHO grades 3 and 4 leukopenia occurred in 67% of patients, whereas 61% experienced grade 3 or 4 thrombocytopenia. Although hematological toxicity was clinically tolerable, it frequently led to omission of gemcitabine administration on day 15. The incidence of non-hematological toxicity was very low. CONCLUSION: This regimen of cisplatin on days 1 and 8 and gemcitabine on days 2, 9 and 15 induced a high RR in patients with advanced NCSLC. Frequent omission of gemcitabine day 15 is a limitation of this schedule. This should be an important factor in a practical approach to decide on the most optimal schedule of the cisplatin plus gemcitabine combination.

Photodynamic therapy for treating early stage lung cancer.

The importance of treating lung cancer at the earliest stage possible has been increasingly recognised. With the resurgence of interest in lung cancer screening, the use of less invasive staging and treatment procedures has gained momentum. Technical advances have propelled the use of bronchoscopic procedures into clinical practice, providing alternatives for conventional diagnostic and treatment modalities. Many lung cancer patients are limited in their pulmonary reserve capacity due to their smoking history, making them unfit to undergo more invasive medical procedures such as surgery. Surgical resection for lung cancer may also result in a relatively wasteful removal of normal lung parenchyma. In the case of superficial early stage lung cancer in the central airways, a more conserving approach such as surgical bronchoplasty is acceptable. With the move towards early detection of lung cancer, even smaller cancer lesions will be detected. Therefore, these lesions will be suitable for bronchoscopic treatment if nodal disease is absent. The potential of photodynamic therapy and alternative bronchoscopic techniques for the management of early stage lung cancer, as an alternative to, or in combination with, surgical resection should be considered.

Photodynamic therapy, Nd-YAG laser and electrocautery for treating early-stage intraluminal cancer: which to choose?

The degree of healing and damage of the bronchial wall after photodynamic therapy, Nd-YAG laser and electrocautery for intraluminal early-stage cancer have been analysed. Review of the bronchoscopy reports and follow-up histology specimens of twenty-nine patients treated bronchoscopically with curative intent for their intraluminal tumor have been performed. Seventeen patients had been treated with bronchoscopic electrocautery (BE) only, six with photodynamic therapy (PDT) and six with Nd-YAG laser. Bronchial wall scarring seen during follow-up bronchoscopy was scored and subepithelial fibrosis were histologically evaluated using Alcian blue staining, Azan staining and polarised light. After BE, prominent airway scarring was seen in five patients (29%), with significant stenosis (>50% lumen) in one of these cases. Prominent scarring and significant stenosis were found in four (67%), after PDT. In five (83%) after Nd-YAG laser prominent scarring was found, one patient had significant stenosis. In three cases, two after BE and one after PDT, subepithelial tissue in the follow-up biopsies was insufficient for proper histologic examination. In the remaining biopsy specimen only one (7%) showed a moderate or excessive amount of fibroblasts after BE, whereas for PDT and Nd-YAG this was found in three (60%) and four patients (67%), respectively. Excessive matrix was found in none of the biopsies after BE, in two (40%) after PDT and in three (50%) after Nd-YAG laser. Compact collagen formations were seen in two (12%) biopsies after BE, in two (40 and 33%) after PDT and Nd-YAG, respectively. Compared to electrocautery, more airway scarring and more subepithelial fibrosis were seen after treatment with PDT and Nd-YAG laser. These findings, especially regarding PDT, is in contrast to the assumption that PDT is selective and may be important in the choice of treatment for patients with early stage cancer.

High resolution computed tomography in patients referred for intraluminal bronchoscopic therapy with curative intent.

In patients with so-called roentgenologically occult intraluminal lung tumours, an accurate assessment of tumour size, its location and peribronchial tumour extent is important prior to any intraluminal bronchoscopic therapy (IBT) with curative intent. In twenty patients with so-called occult early-stage lung cancers, clinical outcome was compared to high resolution computed tomography (HRCT) findings prior to IBT. HRCT showed peribronchial tumour extension or nodal enlargement in 7 of the 20 patients (35%), and consequently treatment policy was changed. Five of the seven died 1.5-6 months after diagnosis, one patient underwent a radical pneumonectomy after induction chemotherapy, and the remaining patient is alive with pleural metastasis. HRCT showed intraluminal tumours in 11 of the 20 patients and IBT with curative intent was given. Complete response (CR) was achieved in 10 of the 11 patients, follow-up has been 4-26 months. One patient underwent a radical lobectomy, pathological stage T1NO, after 3 months because of tumour recurrence. HRCT was inconclusive in 2 of the 20 patients with postobstructive infiltrates. IBT was unsuccessful in both these cases. High resolution computed tomography may provide supportive evidence of intra-and extraluminal tumour; thereby, helping in the assessment of patients who were judged to be suitable for intra-luminal bronchoscopic therapy with curative intent. This may lead to a change in the treatment policy. High resolution computed tomography findings are complementary to bronchoscopic, histological and cytological examinations for the proper evaluation of treatment indications in patients with occult lung cancer.

Video-assisted thoracoscopic surgery in patients with clinically resectable lung tumors.

To investigate the feasibility of thoracoscopic resection, a pilot study was performed in patients with clinically resectable lung tumors. In 40 patients, Video-assisted thoracic surgery (VATS) was performed because of suspicion of malignancy. There were 29 men and 11 women with a median age of 54.8 years (range 18 to 78). Preoperative indications were suspected lung cancer and tumor in 27 patients, assessment of tumor resectability in 7 patients, and probability of metastatic tumors in 6 patients. The final diagnoses in the 27 patients with suspected lung cancer were 12 primary lung cancers, 6 lung metastases, and 9 benign lesions. The success rates for VATS (no conversion to thoracotomy) were 1 of 12 (8.3%) for resectable stage I lung cancer, 8 of 12 (66.7%) for metastatic tumors, and 9 of 9 (100%) for benign tumors. With VATS, 6 of 7 patients (85.7%), possible stage III non-small cell lung cancer, an explorative thoracotomy with was avoided, significantly reducing morbidity. The reasons for conversion to thoracotomy were 1) oncological (N2 lymph node dissection and prevention of tumor spillage) and 2) technical (inability to locate the nodule, central localization, no anatomical fissure, or poor lung function requiring full lung ventilation). The ultimate diagnoses were 19 lung cancers, 12 metastatic lung tumors, and 9 benign lung tumors. Our data show the limitations of VATS for malignant tumors in general use. These findings, together with the fact that experience in performing thoracoscopic procedures demonstrates a learning curve, may limit the use of thoracoscopic resection as a routine surgical procedure, especially when strict oncological rules are respected.

Stent placement is justifiable in end-stage patients with malignant airway tumours.

Extraluminal tumour compression can be treated with the use of stenting. In 8 patients with end-stage malignant tumours of the tracheobronchial tree, tumor compression of the major airways became apparent after Nd-YAG laser debulking. Dumon-type stents (Endoxane), were inserted under general anaesthesia. There were no complications during and after stent insertion. All stents were well tolerated, with significant symptomatic relief in all patients. This symptomatic relief was considered worthwhile, despite the limited duration of palliation and the pre-terminal stage of the patients. Tumour progression after stent insertion was usually beyond any treatment possibility, except additional laser coagulation. The median survival was 2 months and the longest palliation was 11 months.

Fibreoptic bronchoscopic electrosurgery under local anaesthesia for rapid palliation in patients with central airway malignancies: a preliminary report.

BACKGROUND: Obstruction of a major airway by tumour causes serious morbidity. There is still scope for a widely applicable, simple and effective treatment to provide rapid palliation. METHODS: A fibreoptic bronchoscope prototype with an insulated inner sheath was used under local anaesthesia in 17 patients with locally advanced tracheobronchial malignancies. An insulated flexible electro-surgery probe was used to coagulate intraluminal tumour mass using standard electrosurgery equipment. RESULTS: Immediate reopening of the airway was obtained in 15 of the 17 patients. Two appeared to have extraluminal disease. Eleven patients had an obvious bronchoscopic response in whom a > 75% reopening of the normal airway diameter was achieved. Eight patients had subjective improvement of their dyspnoea, but only in four cases was there an objective improvement in physiological parameters. Haemoptysis resolved in four. There were no deaths resulting from treatment. Minor bleeding occurred in one patient and an aspiration pneumonia occurred in one. Three patients received additional treatment. CONCLUSIONS: Fibreoptic bronchoscopic electrosurgery is a simple technique for rapid palliation and immediate tumour debulking in patients with central tracheobronchial tumours. Further work is needed to compare its efficacy with other techniques.

Bronchoscopic treatment of lung tumors.

Several bronchoscopic techniques for the treatment of patients with tracheobronchial pathology have become available during the last decade. Technical development and additional instruments have provided the bronchoscopist with several alternatives for bronchoscopic therapeutic interventions. The majority of patients with malignant tracheobronchial neoplasm have a dismal prognosis. Palliation is the main aim of the treatment. However, in patients with an early-stage tumor, bronchoscopic treatment may have a curative potential. Resectability, after tumor reduction by a bronchoscopic treatment, may be improved. This article discusses various bronchoscopic techniques, the advantages and disadvantages of each method and the possible benefit which can be derived from such a treatment.

Treatment of patients with spontaneous pneumothorax during videothoracoscopy.

Thoracoscopy for spontaneous pneumothorax has been performed over the years by many pulmonologists. The aim of the procedure was merely diagnostic: the detection of blebs and bullae. Therapeutic modalities were restricted to chemical pleurodesis. The development of videothoracoscopy has made more complex interventions, such as bullectomy possible. A protocol for videothoracoscopic treatment of spontaneous pneumothorax, with all treatment modalities in one session, has been developed. All patients with spontaneous pneumothorax underwent videothoracoscopy under general anaesthesia with double lumen tube intubation. If no abnormalities were found on the visceral pleura, talc pleurodesis was performed. Small lesions, blebs or bullae < 2 cm, were coagulated prior to pleurodesis. In case of blebs or bullae > 2 cm, thoracoscopic resection with an EndoGIA stapling device was performed, followed by scarification, i.e. electrocoagulation, of the parietal pleura. In 43 patients, 44 procedures were performed. In 15 cases (34%) no blebs or bullae were found. In 6 cases (14%) only blebs < 2 cm were found. In 23 cases (52%) blebs and bullae > 2 cm were found. In 21 out of 44 cases (48%), talc pleurodesis was performed, and in 23 cases (52%) bullectomy was performed. No major complication occurred. The average hospital stay was 5.7 days after talc pleurodesis and 6.0 days after bullectomy. There were 2 recurrences (5%) after a follow-up of at least 18 months. In conclusion, the use of videothoracoscopy in spontaneous pneumothorax makes it possible to continue a diagnostic procedure as a therapeutic session.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose rate brachytherapy has a curative potential in patients with intraluminal squamous cell lung cancer.

Two patients presented with intraluminal T1N0 squamous cell lung cancer. Poor lung function precluded surgical resection and/or external radiotherapy. They were treated up to 3 times with high-dose rate brachytherapy (10 Gy at 1 cm each session) with curative intent. Follow-up has been 54 and 25 months. Brachytherapy is an effective and well-tolerated bronchoscopic treatment alternative with a curative potential in patients with small T1N0 intraluminal lung cancer.

Confocal sectioning of thick, otherwise undiagnosable cell groupings in cervical smears.

Confocal sectioning of thick, otherwise undiagnosable cell groupings in cervical smears results in detailed visualization of the diagnostic features of neoplastic fragments in the original Cytobrush smear. We argue that the large step forward due to confocal microscopy is the dramatic improvement of axial resolution, resulting in images with a high degree of detail. As a result, mitotic figures, chromatin patterns and glandular spaces materialize out of the blur. When the serial confocal sections are compared to the parallel thin, plastic sections, some differences in the images are observed mainly due to the absence of infiltration by plastic. This study showed that the confocal microscope can be very useful in the diagnostic laboratory because the information extracted from a sample containing these otherwise undiagnosable cell groupings is enhanced to such a degree that a final diagnosis can be made with confidence, maximizing the benefit of the sampling and thus increasing its value.