Management of stage I and II thymoma.

With a knowledgeable assessment of the clinical presentation and demographic and radiologic characteristics, most thymomas can be reliably identified preoperatively without the need for a biopsy. Surgery is the mainstay of treatment for stage I and II thymoma. The rate of complete resection is essentially 100% by open techniques, and recurrences are rare. A complete thymectomy via a sternotomy is the standard approach. Adjuvant radiotherapy after a complete resection does not appear to be of benefit. In the rare event of a recurrence, an aggressive approach should be taken with re-resection whenever possible.

Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells.

Telomerase plays an important role in the maintenance of telomere ends in normal and tumor cells and ectopic expression can immortalize human bronchial epithelial (HBE) cells. We assessed telomerase activation, growth properties and methylation status in the hTERT promoter in a panel of HBE cell cultures in relation to smoking and previous lung cancer history. HBE cells were obtained from a total of 26 subjects, six of whom were lifelong non-smokers, while 20 subjects had a smoking history, including seven who had lung carcinoma. Telomerase activity was determined using the telomeric repeat amplification protocol (TRAP). Maximum passage number and time to senescence were also determined through extended culturing. The distribution of the telomerase activity between ever-smokers and never-smokers was significantly different (P=0.03, F-test), and there was a strong correlation between telomerase activity and the number of pack-years smoked (P=0.0012, F-test for slope). A small difference in telomerase activity was observed according to lung cancer status (P=0.02, F-test). Telomerase activity was not correlated with maximum passage number after extended culturing or with time to senescence. None of the HBE cultures demonstrated methylation of the hTERT promoter. Our results indicate an association between tobacco carcinogen exposure and telomerase activity in normal bronchial epithelium, although a causative role of tobacco smoking in the (re)activation of telomerase can not be proven. An increase in telomerase activity in normal bronchial epithelium might extend the lifespan of cells at risk for malignant transformation, and thus contribute to lung carcinogenesis.

Chromosomal abnormalities in bronchial epithelium from smokers, nonsmokers, and lung cancer patients.

The identification of individuals who are at greatest risk of developing lung cancer would greatly improve diagnosis and possibly lead to early treatment. To study the use of karyotypes for this purpose, we used short-term human bronchial epithelial (hBE) cell cultures from nonsmokers, smokers, and lung cancer patients. Twenty-five metaphases were scored for hBE cell cultures obtained from 32 patients: 8 were nonsmokers, and 24 had a history of smoking (of whom 11 had had lung cancer surgery). The number of abnormal metaphases ranged from 0 to 4 per cell culture. No overall differences in the number of abnormal metaphases were observed between nonsmokers and smokers or between lung cancer patients and non-lung cancer patients. The most commonly observed abnormalities were structural changes in chromosome 1 (six cultures), loss of chromosome 17 (six cultures), and trisomy of chromosome 20 (three cultures). These specific alterations were found almost exclusively in patients with a history of tobacco smoking. The results did not indicate that general chromosomal abnormalities are a useful marker for tobacco smoke exposure or cancer risk.

Multifocal right atrial myxoma and pulmonary embolism.

Multifocal cardiac myxoma with greater than two foci is rarely reported in the literature. We report a case of a 22-year-old woman who presented with profound right heart failure, and was found to have seven right atrial myxomas with bilateral pulmonary embolism, including near-complete occlusion of right pulmonary arterial flow. Multifocal atrial myxoma occurs most often in the familial setting, and often is associated with recurrence. Her disease was nonfamilial. She was successfully treated with surgical resection, and has had complete recovery with no evidence of recurrence over a 4-year period.

Thymic tumors.

Thymic tumors include thymic carcinoma, which exhibit aggressive behavior, and thymomas, which manifest a more indolent course. Complete resection is the mainstay of treatment, and there appears to be little benefit to partial resection. Postoperative radiotherapy may be useful in incompletely resected patients. Preoperative chemotherapy appears to increase the rate of complete resection and survival of patients with a stage III or IVa thymoma and should strongly be considered in such cases.

Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma.

BACKGROUND: Brain metastases are one of the most malignant complications of lung cancer and constitute a significant cause of cancer related morbidity and mortality worldwide. Recent years of investigation suggested a role of LKB1 in NSCLC development and progression, in synergy with KRAS alteration. In this study, we systematically analyzed how LKB1 and KRAS alteration, measured by mutation, gene expression (GE) and copy number (CN), are associated with brain metastasis in NSCLC. MATERIALS AND METHODS: Patients treated at University of North Carolina Hospital from 1990 to 2009 with NSCLC provided frozen, surgically extracted tumors for analysis. GE was measured using Agilent 44,000 custom-designed arrays, CN was assessed by Affymetrix GeneChip Human Mapping 250K Sty Array or the Genome-Wide Human SNP Array 6.0 and gene mutation was detected using ABI sequencing. Integrated analysis was conducted to assess the relationship between these genetic markers and brain metastasis. A model was proposed for brain metastasis prediction using these genetic measurements. RESULTS: 17 of the 174 patients developed brain metastasis. LKB1 wild type tumors had significantly higher LKB1 CN (p<0.001) and GE (p=0.002) than the LKB1 mutant group. KRAS wild type tumors had significantly lower KRAS GE (p<0.001) and lower CN, although the latter failed to be significant (p=0.295). Lower LKB1 CN (p=0.039) and KRAS mutation (p=0.007) were significantly associated with more brain metastasis. The predictive model based on nodal (N) stage, patient age, LKB1 CN and KRAS mutation had a good prediction accuracy, with area under the ROC curve of 0.832 (p<0.001). CONCLUSION: LKB1 CN in combination with KRAS mutation predicted brain metastasis in NSCLC.

Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation.

BACKGROUND: Lung adenocarcinoma (LAD) has extreme genetic variation among patients, which is currently not well understood, limiting progress in therapy development and research. LAD intrinsic molecular subtypes are a validated stratification of naturally-occurring gene expression patterns and encompass different functional pathways and patient outcomes. Patients may have incurred different mutations and alterations that led to the different subtypes. We hypothesized that the LAD molecular subtypes co-occur with distinct mutations and alterations in patient tumors. METHODOLOGY/PRINCIPAL FINDINGS: The LAD molecular subtypes (Bronchioid, Magnoid, and Squamoid) were tested for association with gene mutations and DNA copy number alterations using statistical methods and published cohorts (n = 504). A novel validation (n = 116) cohort was assayed and interrogated to confirm subtype-alteration associations. Gene mutation rates (EGFR, KRAS, STK11, TP53), chromosomal instability, regional copy number, and genomewide DNA methylation were significantly different among tumors of the molecular subtypes. Secondary analyses compared subtypes by integrated alterations and patient outcomes. Tumors having integrated alterations in the same gene associated with the subtypes, e.g. mutation, deletion and underexpression of STK11 with Magnoid, and mutation, amplification, and overexpression of EGFR with Bronchioid. The subtypes also associated with tumors having concurrent mutant genes, such as KRAS-STK11 with Magnoid. Patient overall survival, cisplatin plus vinorelbine therapy response and predicted gefitinib sensitivity were significantly different among the subtypes. CONCLUSIONS/ SIGNIFICANCE: The lung adenocarcinoma intrinsic molecular subtypes co-occur with grossly distinct genomic alterations and with patient therapy response. These results advance the understanding of lung adenocarcinoma etiology and nominate patient subgroups for future evaluation of treatment response.

Lung squamous cell carcinoma mRNA expression subtypes are reproducible, clinically important, and correspond to normal cell types.

PURPOSE: Lung squamous cell carcinoma (SCC) is clinically and genetically heterogeneous, and current diagnostic practices do not adequately substratify this heterogeneity. A robust, biologically based SCC subclassification may describe this variability and lead to more precise patient prognosis and management. We sought to determine if SCC mRNA expression subtypes exist, are reproducible across multiple patient cohorts, and are clinically relevant. EXPERIMENTAL DESIGN: Subtypes were detected by unsupervised consensus clustering in five published discovery cohorts of mRNA microarrays, totaling 382 SCC patients. An independent validation cohort of 56 SCC patients was collected and assayed by microarrays. A nearest-centroid subtype predictor was built using discovery cohorts. Validation cohort subtypes were predicted and evaluated for confirmation. Subtype survival outcome, clinical covariates, and biological processes were compared by statistical and bioinformatic methods. RESULTS: Four lung SCC mRNA expression subtypes, named primitive, classical, secretory, and basal, were detected and independently validated (P < 0.001). The primitive subtype had the worst survival outcome (P < 0.05) and is an independent predictor of survival (P < 0.05). Tumor differentiation and patient sex were associated with subtype. The expression profiles of the subtypes contained distinct biological processes (primitive: proliferation; classical: xenobiotic metabolism; secretory: immune response; basal: cell adhesion) and suggested distinct pharmacologic interventions. Comparison with lung model systems revealed distinct subtype to cell type correspondence. CONCLUSIONS: Lung SCC consists of four mRNA expression subtypes that have different survival outcomes, patient populations, and biological processes. The subtypes stratify patients for more precise prognosis and targeted research.

Helical computed tomography inaccuracy in the detection of pulmonary metastases: can it be improved?

BACKGROUND: In thoracic surgery, manual lung palpation for detection of pulmonary metastases during resection is the standard of care, despite improvements in computed tomography (CT) imaging. In our previous study based on chart review alone, the accuracy of helical CT in the detection of pulmonary metastases was surprisingly low, with a sensitivity of 78%. We hypothesized that this may be improved by scan interpretation with adequate clinical history and focused documentation of all pulmonary lesions, and may be influenced by the training of the reader. METHODS: Preoperative CT scans of 53 patients undergoing 60 cases of pulmonary metastasectomy at our center from 1996 to 2004 were retrospectively reviewed by a dedicated chest radiologist and a non-chest radiologist. Nodules detected on preoperative helical CT were compared with pathologically confirmed metastases. RESULTS: In 27 of 59 (46%) cases read by radiologist 1, and 27 of 58 (47%) cases read by radiologist 2, metastases found by lung palpation were not seen on preoperative CT. Preoperative CT was entirely correct (no missed metastases or false-positive lesions) in only 11 of 59 (19%) of cases read by radiologist 1, and 11 of 58 (19%) of cases read by radiologist 2. CONCLUSIONS: Helical CT misses metastases in 46% to 47% of cases. Accuracy of preoperative CT scanning for detection of pulmonary metastases was not improved with the provision of clinical history to the reader, nor was it influenced by the interpreter's training. A combined approach to pulmonary metastasectomy including preoperative and postoperative CT as well as manual lung palpation is necessary to render the patient disease-free.

Of buffaloes, horseshoes, and having no connections.

We report a patient with multiple congenital pulmonary anomalies, including unilateral pulmonary artery agenesis with an atretic left lung, "buffalo chest," and a variant of the anatomic anomaly "horseshoe lung," discovered during double lung transplantation. Both hemithoraces were filled by the right lung. The right chest was occupied primarily by the anatomic right lower lobe, and the left chest by the right middle lobe at the apex and the anatomic right upper lobe at the base.

Accuracy of helical CT in the detection of pulmonary metastases: is intraoperative palpation still necessary?

BACKGROUND: Pulmonary metastasectomy is well accepted in patients with isolated metastases from an extrathoracic malignancy. The standard approach involves careful intraoperative palpation of the lungs because more metastases are frequently found than were seen by preoperative conventional computed tomography (CT). Helical CT detects more nodules than conventional CT, raising the question of whether palpation of the lungs is still necessary if helical CT is used. METHODS: Retrospective review was done of medical records of patients undergoing metastasectomy with curative intent at the University of North Carolina (UNC) from 1999 to 2003. During this time at UNC, helical CT was routinely performed using a standardized technique, and all metastasectomy patients underwent manual lung palpation. The primary outcome measure of this study was whether malignant nodules (palpated, resected, and proven histologically) were reliably detected preoperatively by helical CT. RESULTS: Thirty-four patients were identified who underwent 41 cases of pulmonary metastasectomy with lung palpation. Our analysis revealed that in 22% (9/41), more malignant nodules were found intraoperatively than were detected by helical CT. Of 88 malignant intraparenchymal nodules, 69 were detected by helical CT (sensitivity 78%). Subset analyses of tumor histology, disease-free interval, the presence of a single lesion versus multiple lesions, the interval between the CT and metastasectomy, and the size of the largest lesion were unable to identify a cohort in which lung palpation was no longer needed after preoperative helical CT. CONCLUSIONS: Despite the advent of helical CT, palpation of the lung is necessary if the goal is to resect all detectable disease.