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.

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.

Bronchoalveolar carcinoma: histopathologic study of evolution in a series of 105 surgically treated patients.

STUDY OBJECTIVE: The clinical characteristics, histopathologic condition, and outcome of bronchoalveolar carcinoma (BAC) were studied to detect possible prognostic indicators. DESIGN: A retrospective review was conducted of 97 patients who had a curative resection for BAC between 1975 and 1993. PATIENTS: There were 83 men and 14 women with a mean age of 59 years (30 to 75 years). INTERVENTIONS: Resection comprised lobectomy in 84 cases (87%), bilobectomy, pneumonectomy, and a wedge excision. RESULTS: Sixty-two percent of patients were asymptomatic. The radiographic pattern was a solitary nodule in 85% of patients and lobar pneumonitis or diffuse infiltrate in 15%. In 12% of patients, the solitary lesion had been stable for period of 2 to 7 years before diagnosis. The TNM staging of the disease included 71 patients with stage I, 14 with stage II, and 12 with stage IIIA. Review of the gross pathologic features revealed well-circumscribed tumors in 88% of patients and diffuse or multifocal tumors in 12%. Mucinous differentiation was present in 43% of patients, vascular invasion in 22%, and aerogenous spread in 49%. Overall survival was 89% at 1 year, 76% at 2 years, 48% at 5 years, and 39% at 10 years. The survival curves according to histologic features showed a statistically significant difference between diffuse lesions and nodular lesions, between lesions with and without aerogenous spread (diffuse lesions excluded), and between lesions with and without vascular invasion. CONCLUSIONS: The natural history of BAC is especially influenced by its nodular or diffuse nature, vascular invasion, and aerogenous spread.

Bronchogenic cancer associated with head and neck tumors. Survival analysis of 194 patients.

We reviewed a series of 194 lung opacities presumed to be bronchogenic carcinomas occurring either simultaneously with (n = 46) or metachronously to (n = 148) a head and neck cancer. The purpose of the study was to evaluate the operative mortality and morbidity and to assess with a survival analysis whether the lung lesions actually were primary carcinomas or metastases of the head and neck cancer. Operation was contraindicated in 77 patients: 36 for metastatic spread, 5 for small-cell carcinoma, and 35 for respiratory insufficiency. The remaining 118 underwent operation: lobectomy for 82, pneumonectomy for 30, wedge resection for 1, and exploratory thoracotomy for 5. The operative mortality was 5%, and the nonfatal morbidity was 22%. The survival at 5 years for patients who underwent operation for bronchogenic cancer was 19.7% (27.2% for stage I, 19% for stage II, 4.5% for stage IIIA, and 0% for stage IIIB). The survival of these patients was not significantly different with respect to the synchronous or metachronous occurrence or the histologic classification (squamous or non-squamous). We conclude that, despite the poor survival, several of these lung lesions associated with a head and neck cancer were most likely a primary bronchogenic cancer. Surgical management is justified because of the observed postoperative mortality.

Small cell carcinoma of the pleura. A case report.

Small cell carcinoma of the lung (SCLC) represents about 25% of all lung cancers. Extrapulmonary small cell carcinoma is a very uncommon feature, mostly described in the oesophagus. We report here a case of small cell carcinoma of the pleura with histopathological findings, clinical course and response to therapy typical of SCLC.

Weekly systemic combination of cisplatin and interferon alpha 2a in diffuse malignant pleural mesothelioma.

The treatment of diffuse malignant pleural mesothelioma (DMPM) remains grim. Neither surgery, radiotherapy nor chemotherapy can be considered as a standard therapy. Immunotherapy with interferon (IFN) in combination with chemotherapy may be an interesting new approach. In 13 consecutive patients with DMPM, we used a weekly combination of cisplatin (CDDP) (60 mg/m2; day 2) and IFN alpha 2a (6 MU/day; days 1-4) in a protocol of two cycles of 4 weeks on/4 weeks off followed by 3 weeks on/3 weeks off. Total treatment duration was thus 25 weeks. In responders, IFN as maintenance monotherapy was continued for a further 6 months. There were nine males and four females with an average age of 65.3 years (range 51-72 years). Eleven had epithelial, one had mixed and one had a sarcomatoid form of DMPM. Five patients were classified as stage II, six as stage III and two as stage IV, as per the International Mesothelioma Interest Group. Thirty-five cycles were administered with a median of three cycles/patient (range 0.75-4). The median total cumulative dose of CDDP was 596 mg/m2 (range 114-861) and that of IFN alpha 2a was 264 MU (range 72-336). Four patients received IFN maintenance therapy, one for 3 months and three for 6 months. One patient had a complete response, four had a partial response, six had a stable disease and the disease progressed in one. One patient was non evaluable for response. All patients were assessable for toxicity. Hematological toxicity was the most frequently observed but was manageable (grade 3 anemia in five patients, grade 3 thrombocytopenia in three patients, grade 3 neutropenia in five patients). Grade 1 renal toxicity was observed in six patients, grade 2-3 asthenia in six patients and an average 5-kg weight loss was noted in nine patients. In conclusion, systemic combination of CDDP and IFN alpha 2a in large doses is effective at the expense of non-negligible toxicity.

Bronchial-pulmonary artery fistula after unilateral lung transplantation: a case report.

We report on a right bronchial-pulmonary artery fistula resulting in fatal hemoptysis in a 54-year-old man, 3 months after right unilateral transplantation for end-stage emphysema. The posttransplantation period was complicated by ulcerative tracheobronchial aspergillosis. Early treatment with itraconazole was performed. All samples of bronchial washing, bronchoalveolar lavage, and bronchial and transbronchial biopsy specimens were free of aspergillus after 3 weeks of treatment. Necropsy showed a fistula between the right pulmonary artery and the main right bronchus, situated just beneath the suture line.

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.

The dendritic cell lineage: a ubiquitous antigen-presenting organization.

Dendritic cells are specialized antigen-presenting cells with two unique characteristics: the greatest stimulatory potential and the ability to stimulate naive T-lymphocytes. They originate from the bone marrow and reach their destination via hematogenous or lymphatic migration. Their phenotype is characterized by a high expression of major histocompatibility complex class II molecules and a high expression of adhesion molecules (CD25, CD54, CD58, CD72, and CD80). Pulmonary dendritic cells may be investigated by histologic examination, phenotype analysis, and function studies in a mixed lymphocyte reaction. Their isolation requires enzymatic digestion of lung tissue and subsequent steps of cell separation. The complexity of these manipulations makes it difficult to obtain large numbers of viable cells. A close anatomic relationship with alveolar macrophages underlines a functional interconnection: macrophages down-regulate the antigen-presenting function through release of tumor necrosis factor alpha. Dendritic cells most probably play a major role in lung diseases such as histiocytosis, primary and secondary cancers, and both acute and chronic lung graft rejection. Identification of the precise functional pathways might lead to therapeutic use of modulation of dendritic cell function.

Primary malignant melanoma of the esophagus.

Primary malignant melanoma of the esophagus is rare, and its symptoms are similar to those of squamous cell carcinoma. This tumor tends to be polypoid, pediculated, and irregular. Hematogenic and lymphogenic metastases are common. Surgical resection with reestablished continuity of the gastrointestinal tract is the treatment of choice, and postoperative irradiation may be useful. Despite these measures, however, the prognosis is poor, with a 5-year survival of 4.2%. The case of a 47-year-old man with esophageal melanoma is described, and a review of the world literature is presented.

Esophagopleural fistula: an early and long-term complication after pneumonectomy.

Over a 14-year period, we observed eight cases of esophagopleural fistula after pneumonectomy for cancer (n = 7) or infectious lung disease (n = 1). In 2 patients, the fistula was probably related to an intraoperative esophageal injury. Two others had mediastinal cancer recurrence, whereas a fistula developed in 4 without any malignancy. Patients presented with empyema, and a contrast swallow procedure disclosed an esophagopleural fistula. Two patients with recurrent cancer were managed conservatively with chest tube insertion and died within 3 months. A patient with chronic empyema had a delayed diagnosis of esophagopleural fistula 2 years after a presumed intraoperative injury; he was managed with thoracoplasty and feeding gastrostomy and died 12 months later. Five patients had an attempt at curative treatment. A single patient underwent thoracoplasty and bipolar exclusion of the esophagus and had secondary reconstruction with a coloplasty; he died with postoperative peritonitis. Four patients underwent thoracoplasty and muscle flap repair of the esophagus. There was 1 operative death from pulmonary embolism, whereas 3 patients recovered and are well with follow-up of 18 months, 2 years, and 5 years, respectively. We conclude that the prognosis of esophagopleural fistula is ominous when associated with cancer recurrence. A curative approach should combine direct repair of the esophagus with a muscle flap and eradication of the associated empyema with thoracoplasty. This aggressive treatment is addressed to debilitated patients and carries high rates of mortality and morbidity.

Pleuropulmonary aspergilloma: clinical spectrum and results of surgical treatment.

From 1974 to 1991, 77 patients were admitted for pulmonary (55), pleural (16), or bronchial (6) aspergilloma. About 50% were asymptomatic. Sixty-three underwent operation. Pulmonary aspergillomas were operated on for therapeutic need in 26 and on principle in 18; the procedures were 28 lobar or segmental resections, 10 thoracoplasties, and 5 pleuropneumonectomies (1 patient had exploration only). Pleural aspergillosis was treated by operation on principle in 5 and for therapeutic need in 8 patients; 10 thoracoplasties, 1 attempt at pleuropneumonectomy, and 2 decortications were performed. All six bronchial lesions were operated on as a rule. Overall postoperative mortality was 9.5%. Major complications were bleeding (n = 37), pleural space problems (n = 24), respiratory failure (n = 6), and postpneumonectomy empyema (n = 4). All patients with pleural disease experienced complications. The outcome was better after lobar or segmental resection than after thoracoplasty (mortality, 6% versus 15%). Asymptomatic and nonsequellary pulmonary or bronchial aspergilloma also had an improved outcome. We conclude that operation is at low risk in pulmonary or bronchial locations in asymptomatic patients and in the absence of sequellae; the risk is high in symptomatic patients for whom operation is the only definite treatment. Pleuropneumonectomy should be avoided. Only symptomatic pleural aspergilloma should be operated on.

Bronchopulmonary aspergilloma: a reappraisal.

BACKGROUND: Classically, most complications observed after operations for aspergilloma occurred in patients with sequelae of tuberculosis. Because the incidence of tuberculosis has declined over the past two decades, aspergilloma is expected to develop with increasing frequency in patients without previous tuberculosis. Therefore, our hypothesis was that operative outcome should have improved during the most recent years in comparison with our previous experience. METHODS: Operative outcome of 12 recently accrued patients was evaluated and compared with a historic control group of 55 patients, previously reported by the same center. RESULTS: As expected, only 17% of patients of the present series had a history of tuberculosis, compared with 57% in the former series. Postoperatively, there was no mortality. Major morbidity has decreased, although this difference is not statistically significant: bleeding decreased from 44% to 9% of patients; space problems decreased from 47% to 18%; and prolonged hospital stay (>30 days) decreased from 32% to 9%. CONCLUSIONS: Our results support a trend toward improved postoperative outcome of operations for aspergilloma owing to a decreased incidence of aspergilloma growing in tuberculous cavitations.

Blood vessel invasion is a major prognostic factor in resected non-small cell lung cancer.

BACKGROUND: We examined the prognostic value of histologic indices in non-small cell lung cancer with particular interest in major blood vessel invasion. METHODS: We studied 593 patients who had curative resection between November 1983 and December 1988. We determined the histology, T and N status, peritumoral lung tissue invasion, tumor stroma, necrosis, mitotic rate, and blood vessel invasion. RESULTS: The median patient survival of the whole series was 3.2 years, with a 5-year survival of 38.9%. In univariate analysis, a high T stage, a high percentage of necrosis, blood vessel invasion, and N stage significantly worsened the survival. In multivariate analysis, only blood vessel invasion and, less significantly, T stage and lymph node metastasis remained independent prognostic factors. CONCLUSIONS: These results highlight the negative prognostic value of blood vessel invasion in non-small cell lung cancer and suggest that blood vessel invasion, T stage, and node metastasis are three unrelated and distinctive characteristics of resected non-small cell lung cancer.

Pneumonectomy for chronic infection is a high-risk procedure.

BACKGROUND: The purpose of this study was to estimate operative risk, and to identify indicators of adverse prognosis, in patients undergoing pneumonectomy for chronic infection. METHODS: Twenty-five patients aged 41 +/- 15 years underwent pneumonectomy (three completions) for chronic infection: sequelae of tuberculosis, 15; cystic bronchiectasis, 9; and radiation pneumonitis, 1. Eight patients had aspergilloma (7 after tuberculosis, 1 with radiation pneumonitis). RESULTS: Operative mortality was 4%. Operative blood loss was estimated at 1,983 +/- 1,424 mL, ranging from 150 to 5,600 mL. A single patient required reexploration. Eight patients (32%) had empyema, and a further 3 (12%) had bronchopleural fistula; thoracoplasty was required for 10 (40%). Sequelae of tuberculosis heralded increased operative bleeding (t = 2.884; p < 0.005). Incidence of empyema or bronchopleural fistula was increased in patients with sequelae of tuberculosis (chi 2 = 3.896; p < 0.05), patients with aspergilloma (chi 2 = 4.588; p < 0.05), patients in whom the parenchymal cavities were entered (chi 2 = 11.5; p < 0.001), and those in whom blood loss was in excess of 1,000 mL (chi 2 = 4.911; p < 0.05). CONCLUSIONS: We conclude that pneumonectomy is a high-risk procedure, especially in patients with sequelae of tuberculosis.

Are bilobectomies acceptable procedures?

BACKGROUND: Controversy about operative morbidity and oncologic value of bilobectomy has led to a review of our experience over the past 12 years. METHODS: The charts of 112 patients (100 men and 12 women with a mean age of 63 years) were reviewed for operative mortality and morbidity and long-term survival. Survival of patients with stage I or stage II disease was compared with that of stage-matched and age-matched groups having right pneumonectomy. RESULTS: Four patients (3.5%) died postoperatively. Nonfatal complications occurred in 55 patients (49%); the most frequent problem was pleural space disease (34%). Survival studies focused on the 96 patients with nonsmall cell bronchogenic cancer (44 in stage I, 32 in stage II, and 20 in stage IIIA). The overall 5-year survival rate was 40%; the 5-year survival rate was similar for stage I and stage II (41% for stage I, 50% for stage II, and 17% for stage IIIA). The incidence of local recurrence was significantly increased after bilobectomy for stage I cancer (chi 2 = 5.066; p < 0.05) compared with pneumonectomy but did not affect 5-year survival. Local recurrence and survival were similar after bilobectomy and pneumonectomy in stage II. CONCLUSIONS: These data demonstrate an increased morbidity after bilobectomy. Survival studies demonstrate an increased risk of local recurrence in patients with stage I disease, which might be partly explained by understaging.

Operative risk and prognostic factors of typical bronchial carcinoid tumors.

BACKGROUND: This study estimated operative risk and examined factors determining long-term survival after resection of typical carcinoid tumors. METHODS: From 1976 to 1996, 139 consecutive patients (66 male and 73 female patients with a mean age of 47 +/- 15 years) underwent thoracotomy for typical carcinoid tumor. The tumors were centrally located in 102 patients (73.4%). RESULTS: Radical resection was performed in 106 patients (7 pneumonectomies, 13 bilobectomies, and 86 lobectomies) and conservative resection in 33 (3 segmentectomies, 3 wedge resections, 20 sleeve lobectomies, and 7 sleeve bronchectomies). There were no postoperative deaths. Complications occurred in 19 patients (13.7%). The morbidity rate was not increased after bronchoplastic procedures (chi 2 = 0.033, not significant). Staging was pT1 in 107 patients (77.0%) and pT2 in 32 (23.0%); 13 patients (9.4%) had nodal metastases. Seventeen patients have died (12.2%), during follow-up, but only three deaths were related to the disease. The overall survival rate at 5, 10, and 15 years was estimated to be 92.4%, 88.3%, and 76.4%, respectively; estimated disease-free survival was 100% at 5 years and 91.4% at 10 and 15 years. Estimated survival of patients with lymph node metastasis was 100% at 5, 10, and 15 years. Univariate analysis failed to demonstrate any prognostic significance for sex, tumor size (T1 versus T2), tumor location (central versus peripheral), and type of resection. CONCLUSIONS: These data confirm an excellent prognosis after complete resection of typical carcinoid tumors, including those with lymph node metastases. Parenchyma-saving resections should be preferred.

Long-term complications of extraperiosteal plombage.

BACKGROUND: As soon as complications due to migration of extraperiosteal plombage material had been documented, early removal became the rule. Some patients who have escaped this rule may still present with long-term complications. METHODS: Since 1980, 14 patients aged 54 +/- 10 years were admitted 28 +/- 11 years after collapse therapy. Eight presented with signs of infection, 4 with hemoptysis, and 2 with periscapular pain. Vascular erosion, suspected in 3 patients, was demonstrated with angiograms in 1. RESULTS: Ablation of the material was combined with excision of the devitalized ribs in 13 patients. Femorofemoral bypass was used in 2 patients for repair of an aortic erosion. Single ablation of subcutaneously migrated material was performed in a poor-risk patient. Operative bleeding was moderate except in 2 patients; 1 of them died intraoperatively during repair of an aortic erosion. A second patient died postoperatively with a massive pulmonary embolus on day 11. Infection was diagnosed in 8 patients (Mycobacterium tuberculosis, 4; and pyogens, 4). Operative outcome was satisfactory in all 12 operative survivors. A single patient presented with an infected apical space at 1 year and underwent complementary resection of the first rib. CONCLUSIONS: We recommend routine ablation of any residual plombage material whenever operative risk is acceptable because of the high incidence of spontaneous complications.

Decortication is a valuable option for late empyema after collapse therapy.

BACKGROUND: Infection of previous collapse therapy spaces may raise challenging problems. This study evaluated a conservative surgical approach based on decortication. METHODS: Since 1979, 28 patients (mean age, 60 +/- 6 years) have presented at an average of 37 +/- 7 years after artificial pneumothorax for tuberculosis. Diagnosis of empyema was made on follow-up in 12 patients and on symptoms in 16 patients. Mean vital capacity was 66% +/- 16% of normal. Microorganisms were isolated in 13 patients (Aspergillus fumigatus in 5, Mycobacterium tuberculosis in 4, anaerobes in 4). Decortication was made in 24 patients, associated with thoracoplasty in 4, and with partial lung resection in 2 patients. Thoracoplasty alone was performed in 2 patients, and 2 patients underwent an extrapleural pneumonectomy. RESULTS: Both extrapleural pneumonectomies were complicated with empyema requiring thoracoplasty, resulting in one postoperative death. Operative mortality after decortication was nil. Mean intraoperative blood loss during decortication was 1,830 +/- 1,310 mL. All patients were extubated within 24 hours, except 1 patient who was ventilator-dependent preoperatively. Prolonged air leaks were common (mean duration of drainage, 16 +/- 11 days), but ultimately sealed. Existence of symptoms was predictive of prolonged air leaks (p < 0.01). CONCLUSIONS: We conclude that decortication may provide a one-stage cure avoiding the hazards of extrapleural pneumonectomy; the nonfunctioning remaining lung may resolve the space problem.

Tracheobronchial lacerations after intubation and tracheostomy.

BACKGROUND: Although long-term complications of intubation and tracheostomy are well documented, little has been reported on acute complications of airway access techniques. METHODS: Fourteen patients (1 male and 13 female patients) aged 15 to 80 years presented with tracheobronchial lacerations after single-lumen intubation (n = 9), double-lumen intubation (n = 1), or tracheostomy (n = 4). RESULTS: A left bronchial laceration after double-lumen intubation was discovered and repaired intraoperatively. A tracheal laceration after single-lumen intubation was recognized during induction of anesthesia. The remaining 12 were diagnosed within 6 to 126 hours (median, 24 hours) after injury. All patients had mediastinal and subcutaneous emphysema. At endoscopy, 12 injuries were located in the thoracic trachea and 1 in the cervical trachea. Twelve underwent primary repair through a right thoracotomy (n = 11) or left cervicotomy (n = 1), and 1 was treated conservatively. Two patients with tracheostomy injury died postoperatively. All repairs healed well but one. The latter was performed 5 days after the injury; a dehiscence occurred, but healed spontaneously. CONCLUSIONS: We conclude that prognosis of tracheal lacerations depends both on the general health of the patient and on the rapidity of diagnosis and treatment.