Structural basis for hyperpermeability of tumor vessels in advanced lung adenocarcinoma complicated by pleural effusion.

BACKGROUND: Malignant pleural effusion (MPE) has a profound impact on quality of life and survival in patients with lung cancer. Identification of the factors within the tumor and its environment that mediate MPE is still lacking. PATIENTS AND METHODS: Intratumoral microvessel density (MVD), endothelial cell and pericyte (PC) capillary coverage, endothelial cell (EC)-PC relationship, lymphatic endothelium integrity, and the expression of receptor tyrosine kinases were all assessed immunohistochemically in pleural tumor biopsy specimens from 24 patients with lung adenocarcinoma (ADC) with and without pleural disease, with the aim to evaluate the involvement with MPE. RESULTS: In the effusion-positive⁺ specimens, MVD values were found to be significantly higher, and a number of vessels were noted to lack immunoreactivity for ECs (CD31). Likewise, PC α-smooth muscle actin (αSMA) expression was also less extensive in the MPE⁺ cases. The observation of only sporadic staining of PCs can also explain the findings regarding platelet-derived growth factor receptors (PDGFRs), the expression of which, although more prominent in MPE⁺ samples, were almost exclusively detected on tumor stromal cells and not on vascular PCs. Conversely, vascular endothelial growth factor receptors (VEGFRs) appeared on both kinds of cells. With respect to lymphatic vessels, lymphatic intraluminal tumor cells were occasionally found in MPE⁺ specimens. CONCLUSION: Our study suggests that disturbed vessel wall integrity, as well as abnormalities of fluid clearance by the lymphatic system, together with overexpression of growth factors, may take part in the pleural fluid accumulation in lung ADCs. Results of the decreased PC capillary coverage and PDGFR expression in MPE are discussed.

Resection and heated pleural chemoperfusion in patients with thymic epithelial malignant disease and pleural spread: a single-institution experience.

OBJECTIVE: Our objective was to evaluate whether resection and heated pleural chemoperfusion (HPCP) is an effective treatment for de novo stage IVa thymoma (DNT) and thymic carcinoma (TC) and for thymoma with pleural relapse (TPR). METHODS: A retrospective study was conducted of patients undergoing resection and HPCP in 1 center. HPCP with cisplatinum ± doxorubicin (adriamycin) was performed for 60 minutes using a standard roller pump and a modified heat exchanger to a maximal intrapleural temperature of 43°C. Follow-up included at least 1 annual computed tomographic scan until death or March 2012. RESULTS: Thirty-five patients, 17 DNT, 14 TPR, and 4 TC, completed 42 intended treatments and were followed up for 4 to 202 months (median, 62 months). Seven patients had repeated HPCP at an interval of 2 to 12 years. There was no systemic toxicity. Ninety-day mortality was 2.5%. Major and minor morbidity occurred in 12% each. Five-, 10-, and 15-year overall survivals for DNT, TPR, and TC were 81%, 73%, 58% (DNT), 67%, 56%, 28% (TPR), and 0%, 0%, 0% (TC). Five- and 10-year progression-free survival was 61%, 43% for DNT and 48%, 18% for TPR. Presently, 11 of 17 DNT patients are alive (6, no evidence of disease), and 8 of 14 TPR are alive (6, no evidence of disease). Median survival for thymoma was 157 months. Overall survival was unrelated to any preoperative or intraoperative variable. Progression-free survival was improved in R0 compared with R1-2 resection (P < .001). Local control achieved in 21 (57%) of 37 procedures in thymoma patients was related only to completeness of resection (P = .015). CONCLUSIONS: (1) Lung-sparing resection and HPCP is feasible and safe. (2) In thymoma with pleural spread it offers excellent survival despite moderate pleural control. (3) Preliminary results with stage IVa TC are disappointing.

The expression of three genes in primary non-small cell lung cancer is associated with metastatic spread to the brain.

PURPOSE: Brain metastases affect 25% of patients with non-small cell lung cancer (NSCLC). We hypothesized that the expression of genes in primary NSCLC tumors could predict brain metastasis and be used for identification of high-risk patients, who may benefit from prophylactic therapy. EXPERIMENTAL DESIGN: The expression of 12 genes was measured by real-time quantitative reverse transcriptase PCR in 142 frozen NSCLC tissue samples. Univariate and multivariate Cox regression analysis was used to analyze the correlation between gene expression and the occurrence of brain metastasis. Immunohistochemistry on independent samples was used to verify the findings. RESULTS: A score based on the expression levels of three genes, CDH2 (N-cadherin), KIFC1, and FALZ, was highly predictive of brain metastasis in early and advanced lung cancer. The probability of remaining brain metastasis-free at 2 years after diagnosis was 90.0+/-9.5% for patients with stage I/stage II tumors and low score compared with 62.7+/-12% for patients with high score (P<0.01). In patients with more advanced lung cancer, the brain metastasis-free survival at 24 months was 89% for patients with low score compared with only 37% in patients with high score (P<0.02). These results were confirmed by immunohistochemical detection of N-cadherin in independent cohort of primary NSCLC. CONCLUSIONS: The expression levels of three genes in primary NSCLC tumors may be used to identify patients at high risk for brain metastasis who may benefit from prophylactic therapy to the central nervous system.

Adjuvant radiotherapy for thymic epithelial tumor: treatment results and prognostic factors.

OBJECTIVE: To determine whether the use of adjuvant radiation in the treatment of invasive thymic tumors affects survival and to identify prognostic factors. METHODS: The files of 47 patients with thymic tumors treated by adjuvant radiation in our institute from 1984 to 2003 were reviewed for data on prognosis and survival. All patients underwent thoracotomy followed by either total macroscopic resection (n = 42) or biopsy (n = 5). The radiation dose ranged from 26 to 60 Gy. RESULTS: Median duration of follow-up was 10.6 years. Overall 5-year survival was 73% (60%-88%): 77% for thymoma (n = 35/45) versus 33% for thymic carcinoma (n = 2/6) (P = 0.14). Better survival was associated with lower disease stage (II vs. III/IVA, P = 0.01), resection (P = 0.0004), myasthenia gravis at presentation (P = 0.04), and higher radiation dose (45 Gy, P = 0.02); sex, smoking, tumor size, pathology, and margin status had no effect. Locoregional relapse occurred in 11 patients and distant metastasis in 4. The 5-year disease-free survival was 67% (52%-86%), with a median time to recurrence of 8.3 years. The better overall survival and disease-free survival associated with higher doses of radiation were also true for stage II patients. On multivariate analyses after adjusting for age, higher disease stage and lower radiation dose were found to adversely affect overall survival and disease-free survival. Thymic carcinoma had an impact only on disease-free survival. CONCLUSION: Postoperative radiation therapy to doses above 45 Gy may improve the disease-free and overall survival of patients with invasive thymoma, especially stage II. Thymic carcinoma has a worse prognosis.

The sequence of vessel interruption during lobectomy: does it affect the amount of blood retained in the lobe?

OBJECTIVE: In a previous study, we have shown that the sequence of vessel interruption (SVI) during lobectomy has no impact on tumor recurrence. The aim of the present study was to determine whether SVI has an impact on the amount of blood retained in the resected lobe. PATIENTS AND METHODS: A non-randomized prospective study including 30 patients undergoing lobectomy for neoplasms. Group A-1'st had all lobar arteries ligated before interruption of the lobar vein and group V-1'st had a reverse sequence. Generous exclusion criteria were used, so as to include only patients with straightforward lobectomy, attempting to isolate SVI as the only factor that could affect blood loss. Lobar weight was recorded immediately after lobectomy. All ligatures and staplers were removed; blood drained from the lobe, collected and measured, and thereafter the lobe was weighed again. RESULTS: Sixteen patients entered group A-1'st and 14 group V-1'st. The groups were similar in age, sex, body surface, histology, prior therapy, stage, FEV1%, length of operation, and number of segments resected. The amount of blood drained from the lobe was 31.4+/-13 and 34.2+/-14.8ml in group A-1'st and V-1'st, respectively. The lobar weights before and after blood drainage were 177.6+/-56.9, 141.7+/-49.1g and 201.5+/-74.2, 161.6+/-69.7g, respectively. The amount of blood divided to the lobar weight was 0.178+/-0.052 in group A-1'st and 0.177+/-0.099 in group V-1'st. All of these figures did not differ statistically. No patient required blood transfusion during or after surgery. CONCLUSIONS: In straightforward lobectomy the amount of blood retained in the resected lobe is small. This amount is not affected by the sequence of hilar vessel interruption.

Genetic analyses of non-small cell lung cancer in Jewish Israeli patients.

BACKGROUND: The contribution of the abnormal DNA mismatch repair system to non-small cell lung cancer tumorigenesis is controversial and has not been reported in Jewish Israeli patients. Similarly, the involvement of 3p deletions in NSCLC in the same population has not been assessed. OBJECTIVES: To assess the contribution of the DNA-MMR system to NSCLC pathogenesis by analyzing microsatellite instability, and evaluate loss of heterozygosity at 3p rates in Israeli NSCLC patients. METHODS: Paired DNA from tumorous and non-tumorous tissue was extracted, and genotyping for MSI determination was carded out using the five Bethesda markers and for determining LOH two 3p markers were used. Genotyping was performed using polymerase chain reaction amplification and size separation on an ABI semiautomatic DNA sequencer, and the allelic patterns of tumorous and non-tumorous tissue were compared. RESULTS: Forty-four NSCLCs from 35 smokers and 9 non-smokers were analyzed, with 26 of the 44 (59%) at stage I disease. Using five microsatellite markers (D17S250, D5S346, D2S123, BAT-25, BAT-26) (known as Bethesda markers) for MSI determination, 6 of the 44 tumors (13.6%) exhibited MSI in at least one marker. Similarly, genotyping for LOH at chromosome 3p was performed using two markers (D3S4103, D3S1234) located at 3p14.2 I. With D3S4103, 33 of the 44 patients successfully analyzed were homozygous and therefore non-informative with respect to LOH. Using D3S1234, 33 of 36 patients (91.7%) were heterozygous, and 23 of these individuals' tumors (69.7%) displayed LOH. Unexpectedly, 4 of 33 tumors (12.1%) genotyped by D3S4103, and 16 of 36 tumors (44.5%) genotyped by D3S1234 showed a pattern of MSI, even though only one of these tumors showed a similar pattern when genotyped with the five consensus markers. Overall, 23 of 44 tumors (52.3%) demonstrated MSI on at least one marker, and 5 of these 23 tumors (21.7%) had MSI on two or more markers. CONCLUSIONS: MSI using 3p markers and not the Bethesda markers occurs at a high rate and in early stages in Jewish NSCLC patients.

Experience with somatostatin receptor scintigraphy in the management of pulmonary carcinoid tumors.

BACKGROUND: Somatostatin receptor scintigraphy has been used widely for the evaluation of neuroendocrine tumors in the gastrointestinal tract. Its use for detecting and staging thoracic carcinoids is only sporadically reported. OBJECTIVES: To evaluate the possible roles of SRS in the management of proven or suspected pulmonary carcinoids. METHODS: We conducted a retrospective study of all patients undergoing SRS for known or suspected pulmonary carcinoids in a tertiary referral center during a 10 year period. During this period 89 patients underwent resection of pulmonary carcinoids and SRS was used for detection, staging or localization purposes in 8 of them (9%). Scans were labeled true positive, true negative, false positive, or false negative in comparison with histologic or follow-up results. RESULTS: SRS was true positive in 6/6 lung locations; true positive in 2/8, true negative in 4/8 and false positive in 2/8 lymph node locations; and true positive in 1/8, true negative in 6/8 and false negative in 1/8 distant locations. The sensitivity, specificity, positive and negative predictive values and accuracy were 90%, 83%, 83%, 91% and 87% respectively. The scans were strongly positive in the tumors and involved lymph nodes. SRS correctly localized an occult secreting pulmonary carcinoid. Granulomatous and reactive lymph nodes showed increased uptake. SRS was accurate in ruling out distant metastases. CONCLUSIONS: SRS is effective for visualizing and localizing pulmonary carcinoids. It assists in the staging of these tumors by detecting lymph node involvement and confirming or ruling out distant metastases. Inflammatory areas in the lung or lymph nodes may be falsely positive.

The sequence of vessel interruption during lobectomy for non-small cell lung cancer: is it indeed important?

OBJECTIVE: During pulmonary resections for non-small cell lung cancer, the pulmonary vein is traditionally interrupted first to prevent seeding of malignant cells and consequently decrease metastatic implantation. This hypothesis was never confirmed scientifically. The aim of the present study was to determine whether the sequence of vessel interruption during lobectomy (lobar vein or lobar artery first) affects disease recurrence. METHODS: A historical prospective study was performed of 279 consecutive patients with complete follow-up, who survived lobectomy for non-small cell lung cancer during 1992 to 1998, in a single center. Pre-, intra-, and postoperative variables were collected from the medical records; recurrence and vital status were obtained from follow-up files, central population registry, and personal confirmation, updated to December 2000. Comparison of recurrence rates by sequence of ligation and other independent variables was assessed by univariate and multivariate logistic regression analyses. RESULTS: A total of 133 patients (48%) had vein interruption before the artery (V-first) and 146 (52%) had artery interruption first (A-first). The distribution of demographic, clinical, and other characteristics was similar between the 2 groups, except for the operated side and performing surgeons. The morbidity, blood requirement, and length of stay were equal for both groups. The total recurrence rate (A-first, 53%; V-first, 51%) was similar. Multivariate analysis (controlling for the effect of the performing surgeon) revealed elevated risk for recurrence among patients with high disease stage (odds ratio = 2.54), male gender (odds ratio = 1.59), intraoperative lung manipulation (odds ratio = 2.72), and blood transfusion (odds ratio = 1.49). Sequence of vessel interruption was not found as a risk factor for recurrence (odds ratio = 1.29; 95% 0.73 to 2.29, P =.4). CONCLUSIONS: Our results did not show that sequence of vessel interruption during lobectomy plays a role in tumor recurrence. A prospective study with randomization in selection of method as well as surgeons for each patient is needed to confirm these results.

Transsternal transpericardial closure of a postlobectomy bronchopleural fistula.

We report a case of chronic empyema and bronchopleural fistula after lobectomy for tuberculosis. The patient had undergone four different surgical procedures to correct his bronchopleural fistula during an interval of seven years. Finally, he had a successful closure of the fistula using the transsternal transpericardial approach.