Detection of K-Ras mutations in tumour samples of patients with non-small cell lung cancer using PNA-mediated PCR clamping.

Non-small cell lung cancers (NSCLC), in particular adenocarcinoma, are often mixed with normal cells. Therefore, low sensitivity of direct sequencing used for K-Ras mutation analysis could be inadequate in some cases. Our study focused on the possibility to increase the detection of K-Ras mutations in cases of low tumour cellularity. Besides direct sequencing, we used wild-type hybridisation probes and peptide-nucleic-acid (PNA)-mediated PCR clamping to detect mutations at codons 12 and 13, in 114 routine consecutive NSCLC frozen surgical tumours untreated by targeted drugs. The sensitivity of the analysis without or with PNA was 10 and 1% of tumour DNA, respectively. Direct sequencing revealed K-Ras mutations in 11 out of 114 tumours (10%). Using PNA-mediated PCR clamping, 10 additional cases of K-Ras mutations were detected (21 out of 114, 18%, P<0.005), among which five in samples with low tumour cellularity. In adenocarcinoma, K-Ras mutation frequency increased from 7 out of 55 (13%) by direct sequencing to 15 out of 55 (27%) by clamped-PCR (P<0.005). K-Ras mutations detected by these sensitive techniques lost its prognostic value. In conclusion, a rapid and sensitive PCR-clamping test avoiding macro or micro dissection could be proposed in routine analysis especially for NSCLC samples with low percentage of tumour cells such as bronchial biopsies or after neoadjuvant chemotherapy.

Manubriosternal disjunction a new approach for surgical repair.

We report a case of manubriosternal disjunction and review the literature. We describe a new approach for surgical repair with direct suture with PDS ropes.

Allelic imbalance at loci containing FGFR, FGF, c-Met and HGF candidate genes in non-small cell lung cancer sub-types, implication for progression.

Fibroblast growth factors (FGF), hepatocyte growth factor (HGF) and their receptors, FGFR and c-Met, are essential components of the regulatory networks between the epithelium and mesenchyme in embryonic lung, but their respective roles in tumour growth are not clear. We performed allelotyping at loci containing the candidate genes FGFR-1-2-3-4, FGF-1-2-7-10, c-Met and HGF in 36 non-small cell lung cancer (NSCLC) (20 squamous-cell carcinomas (SQC) and 16 adenocarcinomas (ADC)), by surrounding each locus with two microsatellites (MS), as close as possible to the genes of interest. Unexpectedly, SQC and ADC were frequently altered at all of these loci, and SQC showed more simultaneously altered loci. In ADC, alterations at the 15q13-22 locus (FGF7 candidate gene) were significantly more frequent. Thus, these loci showed different patterns of molecular alterations between SQC and ADC. Finally, alterations at loci containing FGFR and HGF candidate genes were inversely correlated to the lymph node status in SQC and ADC, respectively.

Lung cancer following previous extrapulmonary malignancy.

OBJECTIVE: Having demonstrated a poor prognosis of operable lung cancer in patients with previous head and neck malignancies, we intended to evaluate prognosis of lung cancer in patients with a history of extrapulmonary and extracervical malignancies. METHODS: The population of this study included 55 patients; these were 40 males and 15 females, with a mean age 64.4+/-8.6 years. The previous malignancy was considered tobacco-induced in 15 patients (kidney, two; bladder, ten; esophagus, three), hormone-dependant in 18 (breast, six; female genital, eight; prostate, four), and miscellaneous in 22 (leukemia, four; skin, seven; colon, 11). Following complete resection, 25 patients were classified stage I, 13 were stage II, and 17 were stage IIIA. RESULTS: There were two early perioperative deaths (3.6%), and three during the second month owing to cardiovascular complications. At the conclusion of the study (July 1st, 1997), 32 further patients had died (58.2%): 25 had progression of lung cancer, one had progression of previous malignancy, and six were without evidence of disease. Five-year survival (Kaplan-Meier) was estimated 47+/-10.2% in stage I (median 44 months), 30.8+/-15.6% in stage II (median 26 months), and 16. 7+/-9.9% in stage IIIA (median 17 months). When excluding five early perioperative deaths, 5-year survival was 51.1+/-10.6% in stage I (median 93 months), 33.3+/-16.7% in stage II (median 36.5 months), and 19.0+/-11.2% in stage IIIA (median 20.5 months). Comparing the three groups defined according to location of previous malignancy, there was no significant difference neither in stage distribution (chi(2)=1.326; P=0.857), nor in 5-year survival estimates: 38.9+/-12. 9% (median 27 months) after tobacco-induced malignancies, 38.9+/-11. 5% (median 24 months) following hormone-dependant malignancies, and 28.4+/-10.2% (median 28 months) following miscellaneous cancers (chi(2)=0.059; P=0.9707). CONCLUSIONS: In opposition to data collected in patients with previous head and neck cancer, survival estimates according to stage were contained within the universally accepted range no high risk group has been identified. Resection of lung cancer with curative intent is a fair option in patients with previous extrapulmonary malignancy.

Prognostic implications of a positive bronchial resection margin.

OBJECTIVE: This retrospective study evaluates probability of survival and mode of recurrence in patients with a microscopically positive bronchial resection margin following resection for primary bronchogenic carcinoma, as well as influence of radiotherapy on survival. METHODS: From January 1986 to July 1997, 40 patients had a microscopically positive bronchial resection margin following a macroscopically complete resection (17 lobectomies, three bilobectomies, four sleeve-lobectomies, and 16 pneumonectomies). Tissue diagnosis was squamous cell carcinoma in 32 patients, adenocarcinoma in four, adenosquamous carcinoma in two and neuroendocrine carcinoma in two. Lymph node status was N0 in 14 patients, N1 in 10, and N2 in 16. The bronchial margin contained carcinoma in situ in 20 patients, invasive mucosal carcinoma in five, and peribronchial infiltration in 15. All patients except the three most recent underwent adjuvant radiation therapy. RESULTS: At the conclusion of the study (January 31st, 1999), 30 patients had died: two with post-operative complications, 17 with progressive disease, ten without relation to cancer, and one under undefined circumstances. Six of 10 unrelated deaths were interpreted as respiratory complications of radiotherapy. Recurrent disease appeared in 24 patients (60%). Nineteen had progression of initial disease (47.5%): metastatic spread in 12 (30%), isolated local recurrence in four (10%), and combined local recurrence and metastases in three (7.5%). Five patients developed metachronous cancer, with bronchial location in four (10%) and laryngeal in one (2.5%). 5-year survival (Kaplan-Meier) in 20 patients with carcinoma in situ was 38.7+/-13.7% (median 31 months), but rose to 55.0+/-16. 6% when excluding seven deaths not related to cancer (five of whom were secondary to radiotherapy) (chi(2)=3.080; P=0.0792). Survival in 13 patients classified N0 was 51.3+/-16.3% (median 61 months), and 71.1+/-18.0% following exclusion of unrelated deaths (chi(2)=3. 939; P=0.0472). Adverse prognosis of peribronchial infiltration was correlated to a positive N status (13 N2 and 2 N1), 5-year survival being 20.0+/-10.3% (median: 18 months). CONCLUSIONS: Prognosis of peribronchial infiltration is similar to N2 disease. In situ carcinoma does not influence survival per se. Local control of disease is probably in part due to radiotherapy. However, the high prevalence of unrelated late deaths suggests an adverse impact of radiotherapy on survival.

Local control of disease and survival following bronchoplastic lobectomy for non-small cell lung cancer.

BACKGROUND: This study was designed to determine whether bronchoplastic resection could be an alternative to pneumonectomy in patients with operable primary lung cancer. METHODS: From 1980 to 1996, 63 patients (59 males and four females; mean age 62 +/- 7 years) underwent a bronchoplastic lobectomy for non-small cell lung cancer, indicated because of a disabled respiratory function in 34 patients, and performed electively in 29 patients. There were 38 right upper lobectomies, four bilobectomies, one middle lobectomy combined with lower lobe apical segmentectomy, ten left upper and ten left lower lobectomies. The bronchoplasty was a full sleeve in 24 patients, and a bronchial wedge resection in 39. RESULTS: A single patient died post-operatively (1.6%). Specific procedure-related complications are summarized as follows: six anastomotic complications managed conservatively (9.5%), 15 space problems (23.8%), nine sputum retentions (14.2%). Pathologic staging classified 30 patients in stage I, 21 patients in stage II, and 12 in stage IIIA. Estimated 5-year survival was 69.7 +/- 9.8% in stage I, 37.1 +/- 12.1% in stage II, and 8.3 +/- 8.0% in stage IIIA. Fourteen patients (22.2%) developed locoregional recurrence. Three of them died with local recurrence alone, whereas 10 developed metastatic progression; a single patient is alive following completion pneumonectomy. According to stage, three recurrences occurred in stage I (10%), six in stage II (28%), and five in stage IIIA (38%). Actuarial freedom from local recurrence was significantly higher after elective procedures (P = 0.019); there was a trend towards improved outcome following right-sided procedures (P = 0.079) and following wedge bronchoplasty (P = 0.055). Five patients experienced a second primary cancer (7.9%), which was resected in four. CONCLUSION: Bronchoplastic resections achieve local control and long-term survival comparable to standard resections in patients with stage I or II disease, and may be considered as a valuable alternative to pneumonectomy.

Early complications. Esophagopleural fistula.

Esophagopleural fistulae complicate the outcome of approximately 0.5% of pneumonectomies, regardless of whether performed for benign or malignant conditions. Early postoperative fistulae result from operative injury to the esophagus: both direct tears of the mucosa and devascularization with secondary necrosis have been documented. Late esophagopleural fistulae, diagnosed beyond the third postoperative month, are due to cancer recurrence or various inflammatory disorders. The usual presentation is empyema thoracis. Diagnosis is suggested by drainage of food particles or saliva, and the presence of yeast cells within the pleural fluid. Confirmation relies on direct opacification of the fistulous tract during opaque swallow studies. Treatment is initiated by clearance of empyema with either tube thoracostomy or Clagett window, and feeding gastrostomy or jejunostomy.

Late complications. Late respiratory failure.

Late and progressive respiratory failure after pneumonectomy may result from a variety of causes. Non-specific causes include restrictive failure by loss of alveolar volume; pulmonary hypertension; initial disease recurrence (e.g. bronchogenic cancer, bronchiectasis); side-effects of radio- and chemotherapy; and benign or malignant pleural or pericardial effusions. Acute or subacute conditions are congestive or ischemic heart failure, pulmonary embolism, and pneumonia. Two causes are specific, benign, and curable: the postpnemonectomy syndrome and the platypneaorthodeoxia syndrome. The latter is related to a right-to-left interatrial shunt through a reopened patent foramen ovale. The hemodynamic and anatomical mechanisms are analyzed through an exhaustive review of the literature, together with the particular clinical presentation and the easy diagnosis if suspected.

Imaging of chest wall disorders.

Pathologic processes that may involve the chest wall include congenital and developmental anomalies, inflammatory and infectious diseases, and soft-tissue and bone tumors. Many of these processes have characteristic radiologic appearances that allow definitive diagnosis. Sternal deformities can be visualized at radiography and their severity quantified with computed tomography (CT). In cervical rib, CT with multiplanar reconstruction may demonstrate relevant anatomic detail and the relationship between bone deformity and arterial compression. In Poland syndrome, radiography reveals an area of hyperlucency on the affected side, whereas CT demonstrates the absence of the greater pectoral muscle and clearly depicts associated musculoskeletal anomalies. Tuberculosis typically manifests at radiography and CT as osseous and cartilaginous destruction and soft-tissue masses with calcification and rim enhancement. Aspergillosis involving the chest wall manifests as pulmonary consolidations and permeative osteolytic changes of the rib and spine at CT and as an area of increased signal intensity at T2-weighted magnetic resonance (MR) imaging. Neurogenic tumors and hemangiomas also typically have high signal intensity at T2-weighted MR imaging. Apparent mass extension or unequivocal bone destruction seen at CT or MR imaging may indicate chest wall involvement by lymphoma. Radiologically, soft-tissue sarcomas typically appear as areas of soft-tissue density or attenuation, often associated with necrotic areas of low density or attenuation. At radiography, plasmacytoma typically manifests as well-defined, "punched-out" lytic lesions with associated extrapleural soft-tissue masses. Chondrosarcoma frequently appears as a large, lobulated excrescent mass arising from a rib with scattered flocculent calcifications characteristic of its cartilaginous mix. Familiarity with these radiologic features facilitates accurate diagnosis and optimal patient treatment.

[Role of video-thoracoscopy in the pretreatment evaluation of lung carcinoma]. / Intérêt de la vidéothoracoscopie dans l'évaluation préthérapeutique des cancers bronchiques.

INTRODUCTION: Lung cancer is the first cause of cancer mortality in male patients in France. Treatment varies depending on the histological type and the disease extent at diagnosis. CURRENT KNOWLEDGE AND KEY POINTS: Videothoracoscopic staging appears to be an accurate method to assess the stage of lung cancer to guide rational management as it allows for 1) an accurate tissue diagnosis when standard methods failed, 2) the identification of a parietal or mediastinal invasion when suspected by CT-scan findings, 3) lymph node sampling of sites that are poorly or not reachable with mediastinoscopy, 4) the diagnosis of pleural or pericardial metastases in patients with effusion or indeterminate nodules, and finally 5) the conclusive answer to the diagnostic dilemma caused by the presence of a contralateral pulmonary nodule in patients with a potentially curable tumor. FUTURE PROSPECTS AND PROJECTS: Video-assisted thoracoscopy thus appears to have a complementary role in intrathoracic lung cancer staging when conventional methods are equivocal. Its main side-advantage is the opportunity to proceed without delay to the surgical treatment, when appropriate, in the same operative settings, or to perform in the same session various procedures, i.e., talc poudrage and pericardial window, to palliate adverse symptoms occurring in some of those patients. Obviously, equally efficient and less invasive approaches should have been considered previously. To date, however, videothoracoscopic evaluation of tumor resectability is not achievable. Finally, one may suppose that positron emission tomography will probably reduce the role of those invasive surgical procedures in a near future.

Optimizing the hemodynamic performance of the DDD pacemaker: impact of the atrioventricular delay on the pulmonary venous flow pattern.

UNLABELLED: This study evaluated the impact of the atrioventricular delay (AVD) on the pulmonary venous flow pattern (PVFP). METHODS: Transthoracic Doppler PVFP were obtained during atrial and ventricular pacing at a fixed rate of 70 beats/min in 20 patients equipped with a DDD pacemaker, diastolic dysfunction linked to an impaired relaxation, a mean ejection fraction of 49%, and AV block. Two subgroups were analyzed equally: group I: seven patients with a normal ejection fraction and group II: 13 patients with decreased ejection fraction. Three different AVDs were studied: short (50 ms), intermediate (150 ms), and long (250 ms). RESULTS: As the AVD increased, the diastolic filling time and the peak atrial reverse flow wave decreased (P < 0.001). There was a decreasing D wave and no significant change in the peak velocity of the S wave. The S wave became biphasic in all patients at the longest AVD of 250 ms. The systolic (S) velocity time integral (VTI) of the pulmonary wave and the systolic/total PVF-VTI ratio increased significantly (P < 0.001). A similar response was seen in both group of patients. CONCLUSIONS: These data correlated the AVD with PVFP, supplying critical systolic information completing the diastolic data obtained from mitral Doppler patterns. These systolic measurements were especially useful for patients with heart failure and a DDD pacemaker, in order to obtain the longest diastolic filling time at the lowest atrial pressure.

[Supraventricular arrhythmia after pneumonectomy. Apropos of 100 cases and review of the literature]. / Troubles du rythme supraventriculaire après pneumonectomie. A propos de 100 cas et d'une revue de la littérature.

Supraventricular arrhythmias are frequently observed in pneumonectomy surgery. We retrospectively studied a series of 100 consecutive patients undergoing pneumonectomy for cancer between 1994 and 1996. We found 24% of significant supraventricular arrhythmias, corresponding to atrial fibrillation in 75% of cases, occurring in 80% of cases until the third postoperative day. The only risk factor significantly associated with these arrhythmias was the patient's age. These arrhythmias are easily reduced, spontaneously in 25% of cases, and usually by amiodarone, alone or associated with digitalis alkaloids. While the mortality of the overall group was 12%, 8% of patients with arrythmia died. These deaths concerned patients whose arrythmias occurred after the fourth postoperative day in a context of a pulmonary infection.

Effect of lung volume reduction surgery on gas exchange and pulmonary hemodynamics at rest and during exercise.

Lung volume reduction surgery (LVRS) has become an extended surgery for emphysema in order to improve the dyspnea of severely affected patients. Because resection of lung areas may reduce the vascular bed, which is an important factor of pulmonary hypertension in emphysematous patients, especially during exercise, the aim of our study was to assess the outcome of pulmonary hemodynamics and gas exchange at rest and during exercise after LVRS. Nine patients had right heart catheterization before and 3 to 12 mo (mean, 4.5 mo) after LVRS. FEV1 increased from 705 to 1,005 ml (p < 0.05) after LVRS. PaO2, PaCO2 and mean pulmonary artery pressure (Ppa) did not change after LVRS, either at rest or during exercise. However, a significant overall decrease of the respiratory swings of the pulmonary artery diastolic pressure (DeltaPd) at rest (median value, from 12 to 8 mm Hg, p < 0.01) and during exercise (from 20 to 15 mm Hg, p < 0.05) was observed. There was a significant correlation between the change in resting Ppa (Ppa before minus Ppa after LVRS) and the change in resting DeltaPd (r = 0.73, p < 0.03), and also between the change in exercising Ppa and the change in resting DeltaPd (r = 0.80, p < 0.02). Significant correlations were also found between the change in exercising Ppa and the change in exercising PaO2 (r = -0.70, p < 0.05), and between the change in exercising Ppa and the change in exercising PaCO2 (r = 0.76, p < 0. 03). We conclude that pulmonary hemodynamics in most cases are not impaired by LVRS either at rest or during exercise. The possible mechanisms influencing hemodynamics after a lung volume reduction procedure are discussed.

Postoperative atelectasis.

Postoperative atelectasis is a common problem following any surgery. Limited atelectasis is usually well-tolerated and easily reversible. However, complete atelectasis of the remaining lung following partial lung resection may be poorly tolerated. Thoracic surgical procedures increase the risk because pain, thoracic muscle injury, chest wall instability, and diaphragmatic dysfunction impair clearance of secretions by cough. In addition, patients with lung diseases are prone to increased bronchial secretions. Prophylaxis includes preoperative and postoperative physiotherapy and medications, which should be graded in accordance to the individual patient's risk factors. Large atelectasis requires bronchoscopy to remove mucous plugs. Tracheostomy should be considered in patients with relapsing atelectasis or swallow disorders.

Minimally invasive management for first and recurrent pneumothorax.

Minimally invasive techniques for treatment of pneumothorax should yield the standard of results set with open procedures: the operative morbidity should remain less than 15%, and the recurrence rate less than 1%. In the era before video-assisted thoracic surgery, two minimally invasive variants were used. Chemical pleurodesis resulted in an unsatisfactory recurrence rate of at least 15%. In contrast, pleurectomy and apical stapling performed through a transaxillary minithoracotomy compared favorably with larger thoracotomy approaches, and allowed a reduced hospital stay. Evaluation of video-assisted thoracic surgical operations for spontaneous pneumothorax is hampered by a lack of controlled studies. The general impression is that morbidity did not decline significantly; the main determinant of complications is the patient's underlying health status. However, published recurrence rates range from 5% to 10%, in spite of a shorter follow-up time span. Optimized results are achieved when classic principles combining apical wedge resection and pleurodesis are applied. Reduction of hospital stay is not only a result of the new technology, but also changing drainage and discharge policies. Reduction of cost is debatable, because many studies do not consider the cost of video equipment. The main advantage when compared with open thoracotomy is reduction of postoperative pain. The only two available controlled studies conclude that there is no obvious advantage of video-assisted thoracic surgery when compared with conventional limited-access surgery. The future role of video-assisted thoracic surgery in this disease remains to be determined by a large-scale prospective evaluation.

Cervical bronchogenic cyst mimicking thyroid adenoma.

Bronchogenic cysts are congenital malformations of the foregut which are generally encountered within the mediastinum. We explored a patient presenting with a cystic, partially calcified tumor in a cervical and retrotracheal location. This lesion was interpreted as a thyroid adenoma preoperatively, but identified as a bronchogenic cyst at pathology.