Jules M.M. van den Bosch

Surfactant Protein C Mutations Are the Basis of a Significant Portion of Adult Familial Pulmonary Fibrosis in a Dutch Cohort

RATIONALE Familial clustering of adult idiopathic interstitial pneumonias (IIP) suggests that genetic factors might play an important role in disease development. Mutations in the gene encoding surfactant protein C (SFTPC) have been found in children and families with idiopathic pneumonias, whereas cocarriage of a mutation in ATP-binding cassette subfamily A member 3 (ABCA3) was postulated to have a disease-modifying effect. OBJECTIVES To investigate the contribution of SFTPC mutations to adult familial pulmonary fibrosis (FPF) and the disease-modifying effect of mutations in ABCA3 within their families. METHODS Twenty-two unrelated patients with FPF (10%) were identified within our single-center cohort of 229 patients with IIP. SFTPC was sequenced in 20 patients with FPF and 20 patients with sporadic IIP. In patients with an SFTPC mutation, sequencing of ABCA3 was performed. Discovered variants were typed in more than 100 control subjects and 121 additional patients with sporadic IIP. MEASUREMENTS AND MAIN RESULTS In 5/20 unrelated patients with FPF (25%; confidence interval, 10-49) a mutation in SFTPC was detected: M71V, IVS4+2, and three times I73T. No mutations were detected in the sporadic or control cohort. Patients with SFTPC mutations presented with a histopathological pattern of usual interstitial pneumonia and nodular septa thickening and multiple lung cysts in combination with ground glass or diffuse lung involvement on chest high-resolution computed tomography. Two variants in ABCA3 were found in adult patients with FPF but not in affected children. CONCLUSIONS Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Primary sarcoma of the lung: A clinical study with long-term follow-up

Primary pulmonary sarcoma is an extremely rare tumor. In more than 30 years, only 22 patients with PPS were seen in our hospital; 18 patients (82%) underwent operation. Radical resection is the only curative treatment in patients with primary pulmonary sarcoma. All 4 patients (18%) who did not undergo operation died within 17 months. All 7 patients (32%) in whom no radical resection could be performed died between 10 months and 16 years after operation. Total resection of the tumor could be performed in 11 patients (50%). Of these, 7 are still alive (64%), and 1 patient died of an unrelated cause after 25 years (mean follow-up, 13.5 years). Histologic diagnosis in these patients was leiomyosarcoma in 4, malignant schwannoma in 2, and fibrosarcoma and undifferentiated sarcoma in 1 each. Median survival for all patients was 24 months. Actuarial 5-year survival was 44% for all patients. Small tumor diameter and low-grade malignancy are statistically significant favorable prognostic factors. No patient with grade 1 tumor died; the median survival was 60 months for grade 2 sarcomas, and 17 months for grade 3 sarcomas. No patient with a completely resected small primary pulmonary sarcoma had recurrence or metastasis.

Survival in resected stage I lung cancer with residual tumor at the bronchial resection margin

BACKGROUND Sometimes microscopic residual tumor is found at the bronchial resection margin despite an apparently complete resection of lung cancer. This may adversely affect the patients prognosis. Its impact on survival is unclear. METHODS The records of 834 patients with resected stage I non-small cell lung cancer were studied. Patients with complete resection were assigned to the complete resection group (n = 802); patients with microscopic residual tumor at the bronchial resection margin that was accepted were assigned to the residual tumor group (n = 23). Residual tumor was classified as carcinoma in situ, mucosal residual disease, or peribronchial residual disease. RESULTS The 5-year survival in the patients in the complete resection group was 54%; it was 58% in the residual tumor group with carcinoma in situ and 27.3% in the residual tumor group with invasive tumor (mucosal residual disease or peribronchial residual disease). The difference in survival between patients in the complete resection group and patients in the residual tumor group with invasive tumor was significant (p = 0.03). CONCLUSIONS The presence of mucosal or peribronchial residual disease, but not carcinoma in situ, at the bronchial resection margin in patients with stage I non-small cell lung cancer has an adverse effect on survival.

Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups

The HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We therefore typed HLA-DRB1 and DQB1 in 340 UK, 139 Dutch and 163 Japanese sarcoidosis patients and, respectively, 354, 218 and 168 healthy controls from these populations. We applied consistent phenotyping and genotyping and investigated associations between HLA class II alleles and distinct disease phenotypes within and between ethnic groups. DRB1*01 and DQB1*0501 are protective against all manifestations of sarcoidosis. Lung-predominant sarcoidosis is associated with DRB1*12 and *14. Löfgrens syndrome is a common sarcoidosis phenotype in the Dutch and is strongly associated with the DRB1*0301 allele. This phenotype is not seen among the Japanese in whom DRB1*0301 is absent. The same allele is protective for UK uveitis. Sarcoid uveitis is common in Japan. The DRB1*04-DQB1*0301 haplotype is a risk factor for this disease manifestation in Japanese and UK subjects but protective for sarcoidosis overall. We show that distinct sarcoidosis phenotypes have similar genetic associations across ethnic groups. The disease case mix differs between centres and may be explained by different ethnic allelic frequencies.

Long-term survival after bronchial sleeve resection: univariate and multivariate analyses.

BACKGROUND Long-term results after bronchial sleeve resection remain controversial, especially in relation to nodal involvement. In a previous report, there were no 10-year survivors among patients with N1 or N2 disease. METHODS From 1960 to 1989, 145 patients underwent bronchial sleeve resection for a bronchogenic tumor. Follow-up was updated until the end of 1994, so the minimum follow-up was 5 years for surviving patients. A univariate analysis and a multivariate analysis were performed. RESULTS For the whole group, 5-year, 10-year, and 15-year survival rates were 46%, 33%, and 22%, respectively. The median survival time was 53 months. Five-year and 10-year survival rates for the 71 patients with no disease were 62% and 51%, respectively; for the 58 patients with N1 disease, 31% and 10%; and for the 16 patients with N2 disease, 5-year and 7-year survival rates were 31% and 13%. There was a highly significant difference in survival between patients with no and N1 or N2 disease but not between those with N1 and N2 disease. Multivariate analysis showed only nodal stage and patient age to be significant factors in relation to survival. CONCLUSIONS Long-term results after bronchial sleeve resection are influenced chiefly by nodal stage. A significantly lower survival is found in patients with N1 and N2 disease, and most of these patients die of distant metastases.

Lymph node type as a prognostic factor for survival in T2 N1 M0 non-small cell lung carcinoma

BACKGROUND Patients with stage II non-small cell lung carcinoma represent a group with varying 5-year survival rates. The influence of specific types of lymph node involvement on survival was investigated. METHODS Of 2,009 patients operated on from 1977 through 1993, the cases of 391 patients with pathologic T2 N1 M0 disease were reviewed. The N1 status was refined into lymph node involvement by direct extension or by metastases in lobar or hilar lymph nodes. RESULTS The cumulative 5-year survival rate of all hospital survivors (n = 369) was 37.8%. The 5-year survival rate of patients with lobar metastases was superior to that of patients with hilar metastases (57.3% versus 30.3%; p = 0.0028) and that of patients with lymph node involvement by direct extension (57.3% versus 39.1%; p = 0.03). The survival rate did not differ between those with hilar metastases and those with direct extension. Survival was significantly poorer in patients with visceral pleural involvement, in patients with adenocarcinoma, and in patients older than 60 years. Survival was not related to sex, type of resection, central growth, or tumor size. CONCLUSIONS Survival differs according to the type of lymph node involvement: lobar lymph node metastasis seems to be an early stage of the disease, whereas hilar lymph node metastasis represents a more advanced form. However, in T2 N1 M0 disease, other factors besides nodal status also seem to play an important role in postoperative survival.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC)

OBJECTIVE The experiences on the treatment of seven consecutive patients with large-cell neuroendocrine carcinoma (LCNEC) were studied, observed over 6 years from 1992. Since LCNEC was recognized as a separate histological entity, only very few series have been reported. Together with the carcinoids (atypical and typical) and the small-cell lung carcinoma (SCLC), it forms the spectrum of neuroendocrine tumors. METHODS Between 1992 and 1997, seven patients who underwent surgical resection were diagnosed as LCNEC postoperatively. Mean age was 65 years (range 54-77 years), five patients were male, all patients were heavy smokers. One patient was staged as IA, four as IB, one as IIIB and one as IV. RESULTS In five patients, preoperative diagnosis was unknown, in one squamous cell carcinoma and in one adenocarcinoma was suspected. There were four lobectomies, two bilobectomies and one resection of the lingular division with a wedge resection of the upper division of the left upper lobe. Three patients received adjuvant chemotherapy and one, adjuvant radiotherapy. Survival ranged from 7 to 39 months. There are no patients currently alive. CONCLUSIONS LCNEC is a high-grade neuroendocrine tumor with a poor prognosis. In our patients, after surgical resection or multimodality treatment, all have developed widespread metastatic disease with a rapidly fatal course. Due to the rarity of this tumor, the incidence, prognosis and optimal treatment remain to be determined.

TNM Staging and Long-Term Follow-up After Sleeve Resection for Bronchogenic Tumors

From 1960 to 1989, 145 patients (132 men and 13 women) with a mean age of 60.3 years underwent sleeve lobectomy or sleeve resection of a main bronchus for a bronchogenic tumor. Squamous cell carcinoma was predominantly found (116 patients, 80.0%), followed by carcinoid tumor in 13 patients (9.0%). Postoperative staging was: stage I, 61 patients (42.1%); stage II, 47 (32.4%); stage IIIA, 33 (22.8%); and stage IIIB, 4 (2.7%). Thirty-day mortality was 4.8% (7 patients). Follow-up was complete except for 1 patient who was lost to follow-up 4 years after operation. For the whole group, 5-, 10-, and 15-year survival rates were 49%, 37%, and 18%, respectively. Better survival was noted in patients with carcinoid tumor and squamous cell carcinoma. Considering 112 patients with T2 and T3 squamous cell carcinoma, 5- and 10-year survival rates for N0 disease (52 patients) were 59% and 47%, for N1 disease (51 patients) 21% and 0%, and for N2 disease (9 patients) 44% and 0%. Differences between N1 and N2 disease were not statistically significant. Survival after sleeve resection is best for carcinoid tumors and squamous cell carcinoma with negative nodes. Presence of N1 or N2 disease significantly worsens prognosis, with no 10-year survivors and no difference between N1 and N2 status.

Results of surgical treatment of T4 non-small cell lung cancer

OBJECTIVE Because of location and invasion of surrounding structures, the role of surgical treatment for T4 tumors remains unclear. Extended resections carry a high mortality and should be restricted for selected patients. This study clarifies the selection process in non-small cell T4 tumors with invasion of the mediastinum, recurrent nerve, heart, great vessels, trachea, esophagus, vertebral body, and carina, or with malignant pleural effusion. METHODS From 1977 through 1993, 89 patients underwent resection for primary non-small cell T4 carcinomas. Resection was regarded as complete in 34 patients (38.2%) and incomplete in 55 patients (61.8%). Actuarial survival time was calculated and risk factors for late death were identified. RESULTS Overall hospital mortality was 19.1% (n=17). Mean 5-year survival was 23.6% for all hospital survivors, 46.2% for patients with complete resection and 10.9% for patients with incomplete resection (P=0.0009). In patients with complete resection, mean 5-year survival for patients with invasion of great vessels was 35.7%, whereas mean 5-year survival for invasion of other structures was 58.3% (P=0.05). Age, mediastinal lymph node involvement, type of operative procedure, and postoperative radiotherapy did not significantly influence survival. CONCLUSION In certain T4 tumors complete resection is possible, resulting in good mean 5-year survival especially for tumors with invasion of the trachea or carina. High hospital mortality makes careful patient selection imperative.

Completion pneumonectomy: analysis of operative mortality and survival.

BACKGROUND A single-institution experience with completion pneumonectomy was analyzed to assess operative mortality and late outcome. METHODS A consecutive series of 138 completion pneumonectomies from 1975 to 1995 was reviewed, and compared with single-stage pneumonectomies performed during the same period. RESULTS Hospital mortality was 13.8%, including 4 intraoperative and 15 postoperative deaths. Hospital mortality was the same for lung cancer (13.2%) as for benign disease (15.5%). It was 37.5% if an early complication of the primary operation was the indication (p = 0.01). If infection of the pleural space was the indication for completion pneumonectomy, hospital mortality was 23.3% (p > 0.05). In 760 single-stage pneumonectomies hospital mortality was 8.7% (p > 0.05). Five-year actuarial survival after completion pneumonectomy was 42.5% for all patients, 32.3% for those with lung cancer, and 58.8% for those with benign disease. CONCLUSIONS Hospital mortality for completion pneumonectomy was the same for malignant as for benign indications. It was significantly higher if completion pneumonectomy was done for an early complication of the primary operation. Results at long term of lung cancer patients were the same for single-stage pneumonectomy and completion pneumonectomy.