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Raphael Bueno

Publications and source records attributed to Raphael Bueno.

At least 37 records · Page 2Linked to original sources
PubMed2004

Gene expression profiles predict survival and progression of pleural mesothelioma.

PURPOSE: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages. EXPERIMENTAL DESIGN: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip. Using both dChip and SAM, neural networks constructed a common 27 gene classifier, which was associated with either the high-risk and low-risk group of patients. Data were validated using real-time PCR and immunohistochemical staining. The 27 gene classifier was also used for validation in a separate set of 17 MPM patients from another institution. RESULTS: The groups predicted by the gene classifier recapitulated the actual time to progression and survival of the test set with 95.2% accuracy using 10-fold cross-validation. Clinical outcomes were independent of histology, and heterogeneity of progression and survival in early stage patients was defined by the classifier. The gene classifier had a 76% accuracy in the separate validation set of MPMs. CONCLUSIONS: These data suggest that pretherapy gene expression analysis of mesothelioma biopsies may predict which patients may benefit from a surgical approach.

Disease Progression↗
PubMed2004

Integrin-dependent protein tyrosine phosphorylation is a key regulatory event in collagen-IV-mediated adhesion and proliferation of human lung tumor cell line, Calu-1.

BACKGROUND: The clinical phenomenon of lung cancer metastasis to specific target organs is believed to be a direct interaction between tumor cells and extracellular matrix components. During invasion, tumor cells attach to the basement membrane protein, collagen type IV, degrade it, migrate through blood vessels, and adhere to extracellular matrix proteins. METHODS: Four nonsmall-cell lung cancer cells were tested for adhesion, proliferation, migration and morphologic alterations on collagen type IV matrix by immunoprecipitation, Western blotting, phase contrast and time lapse video microscopy. RESULTS: Collagen type IV promoted Calu-1 cell adhesion (< 15 minutes) and motility (< 6 hours) without any significant effect on proliferation. beta(1)-integrin is essential for collagen type IV adhesion and 8 to 10 fold higher expression of beta1-integrin on the surface of Calu-1 cells was identified. A protein tyrosine phosphatase inhibitor, peroxyvanadate, caused 50% inhibition in the adhesion process within 5 minutes but exposure to 60 micromol/L genistein for 72 hours, a protein tyrosine kinase inhibitor, drastically inhibits Calu-1 cell proliferation (> 70%). We examined the influence of beta1-integrin, peroxyvanadate and genistein on the spreading morphogenesis of Calu-1 cells on Collagen type IV. Use of either 1 microg of anti beta1-integrin inhibitory antibody (P5D2), 100 micromol/L peroxyvanadate or 60 micromol/L genistein had dramatic influence on the spreading of Calu-1 cells. Finally, Focal adhesion kinase was identified as a phosphoprotein target. CONCLUSIONS: We have characterized an in vitro model of matrix-specific binding of a lung cancer cell line, Calu-1 to Coll IV. Calu-1 cells use primarily a beta1-integrin mediated intracellular tyrosine phosphorylation phenomenon as the key regulatory mechanism for its binding advantage to Coll IV matrix.

Carcinoma, Non-Small-Cell Lung↗
PubMed2004

Pleural biopsy: a reliable method for determining the diagnosis but not subtype in mesothelioma.

BACKGROUND: Survival after tri-modality therapy with extrapleural pneumonectomy (EPP) and postoperative chemoradiotherapy is longer for patients with epithelial MPM versus mixed or sarcomatoid subtypes, leading some to decline aggressive therapy for patients with nonepithelial histology. However, pathologic diagnosis of malignant pleural mesothelioma (MPM) and subclassification into one of the three histologic subtypes (epithelial, mixed, sarcomatoid) can be challenging. Pleural biopsy has been proposed as the diagnostic gold standard. We investigated the accuracy of open pleural biopsy for diagnosis and subtype identification in MPM. METHODS: Patients with suspected MPM routinely undergo open pleural biopsy to establish diagnosis. Those diagnosed definitively by pleural biopsy or cytology are offered pleurectomy or EPP dependent on stage and cardiorespiratory status. We reviewed medical records for all patients undergoing EPP at our institution, comparing tissue and subtype diagnosis at initial diagnostic biopsy versus definitive resection. RESULTS: Between 1988 and 2000, 305 of 332 consecutive patients undergoing EPP had MPM. One patient diagnosed with MPM at pleural biopsy was misclassified. Subtype analysis at pleural biopsy proved correct in 80% (226/282). Most patients (174/192) with epithelial subtype at final diagnosis were diagnosed correctly at pleural biopsy. However, 44% (45/103) with pathologic diagnosis of nonepithelial subtype at resection were initially misdiagnosed with the epithelial subtype. The sensitivity of pleural biopsy for epithelial MPM was 97% with a specificity of 56%. CONCLUSIONS: Open pleural biopsy is accurate and should be considered the gold standard diagnostic method for MPM. It is less sensitive for determining histologic subclass, particularly with nonepithelial subtypes.

Biopsy↗
PubMed2004

Thoracoscopic surgery in elderly lung cancer patients.

Age is a recognized risk factor for death after thoracotomy in elderly patients with lung cancer. Among other factors, the genesis of this risk is the physiologic debilitation that occurs after division of the intrathoracic respiratory muscles during thoracotomy, as well as the loss of lung tissue after lung resection. Recent advances in video-assisted thoracic surgery (VATS) techniques provide an alternative to standard thoracotomy in elderly lung cancer patients, resulting in decreased recovery times and fewer perioperative complications. Likewise, smaller lung resections (VATS-guided limited wedge resection versus lobectomy with thoracotomy) can be adequate oncologic procedures in patients with a limited life expectancy but resectable disease. We studied these alternative procedures in a cohort of thoracic surgical patients at the Brigham and Women's Hospital in Boston, MA. Proposed investigations of the psychosocial implications of thoracic surgery in the elderly, irrespective of the safety of these maneuvers, are addressed.

Age Factors↗
PubMed2004

Adenocarcinoma of the gastric cardia: what is the optimal surgical approach?

BACKGROUND: The incidence of adenocarcinoma of the gastric cardia is rising in Western countries. This study evaluates prognostic factors associated with surgical management of this cancer. STUDY DESIGN: Medical records of consecutive patients with gastric cardial cancer treated by surgical resection from 1991 through 2001 were reviewed. Survival was analyzed using the Kaplan-Meier method. Prognostic factors were evaluated using log-rank test and Cox regression. Mean followup period was 34 months. RESULTS: Eighty-two patients met study inclusion criteria. Median patient age was 65 years (range 86 to 22). Fifty-nine (72%) patients had type II tumors and 23 (28%) patients had type III tumors, according to the Siewert classification for gastroesophageal junction tumors. Twenty-seven (33%) patients underwent total esophagectomy, 24 (29%) patients underwent extended gastrectomy with thoracotomy, and 31 (38%) patients underwent extended gastrectomy without thoracotomy. Overall postoperative 5-year survival rate was 30%. On multivariate analysis, patient age 65 years and older, absence of lymph node metastasis, and R0 resection emerged as factors independently associated with improved postoperative survival. Frequency with which proximal resection margin was infiltrated with cancer was a function of gross margin length and T stage. Proximal gross margin length of at least 6 cm was required to achieve a microscopically negative proximal margin for T3 and T4 cancers. CONCLUSIONS: Achieving R0 resection should be the goal of surgical therapy for the gastric cardial cancer. The surgical approach should be tailored to individual patients to achieve this goal.

Adenocarcinoma↗
PubMed2004

Prevention, early detection, and management of complications after 328 consecutive extrapleural pneumonectomies.

OBJECTIVE: Extrapleural pneumonectomy for therapy of mesothelioma has been associated with significant perioperative mortality and morbidity. Postoperative complications of this procedure require a unique management approach. We developed treatment algorithms for most of the common complications of extrapleural pneumonectomy resulting in reduced mortality and hospital stay. Complications after extrapleural pneumonectomy were further analyzed to elucidate means of prevention, early detection, and treatment. METHODS: A total of 496 patients undergoing extrapleural pneumonectomy were reviewed for mortality rates, with a subset of 328 consecutive patients between 1980 and 2000 who were examined for detailed morbidity data by using a prospective clinical database. RESULTS: Median age was 58 years (range, 28-77 years), with a 10-day (range, 4-101 days) median length of stay. One hundred ninety-eight (60.4%) of 328 patients experienced minor and major complications, and 11 of 328 patients died, for an overall mortality rate of 3.4%. Complications included the following: atrial fibrillation (145 [44.2%]), prolonged intubation (26 [7.9%]), vocal cord paralysis (22 [6.7%]), deep vein thrombosis (21 [6.4%]), technical complications (patch dehiscence, hemorrhage, or both; 20 [6.1%]), tamponade (12 [3.6%]), acute respiratory distress syndrome (12 [3.6%]), cardiac arrest (10 [3%]), constrictive physiology (9 [2.7%]), aspiration (9 [2.7%]), renal failure (9 [2.7%]), empyema (8 [2.4%]), tracheostomy (6 [1.8%]), myocardial infarction (5 [1.5%]), pulmonary embolus (5 [1.5%]), and bronchopleural fistula (2 [0.6%]). Clinical data demonstrated the following: (1) prophylaxis for atrial fibrillation is recommended; (2) early ambulation, aspiration precautions, endoscopic assessment of the vocal cords, and avoidance of fluid overload are crucial; (3) perioperative diagnosis and aggressive management of deep vein thrombosis are important; (4) immediate reoperation and open cardiac massage are essential for relief of cardiac herniation and tamponade from cardiac patch dysfunction; (5) diaphragmatic patch dehiscence, hemorrhage, or both require immediate reoperation; (6) early signs of infection might indicate bronchopleural fistula or empyema and should be treated with thoracoscopic or open drainage and staged removal of patch material; and (7) excessive perioperative mediastinal shift is treated with a catheter placed intraoperatively. CONCLUSION: Complications after extrapleural pneumonectomy require a unique approach to management, and mortality can be minimized by early detection and aggressive treatment.

Adult↗
PubMed2004

Genetics of malignant pleural mesothelioma: molecular markers and biologic targets.

MPM is a poorly understood lethal malignancy. Although the pathobiology of MPM is not completely elucidated, new genomic technology is likely to help shed light on the mechanisms of carcinogenesis through genome-wide screening of tumor-specific gene expression. Related efforts to identify the molecular markers of mesothelioma are pursued with the aim of refining current diagnostic capabilities, predicting prognosis, and designing appropriate trimodality programs. These new genomic tools also will assist efforts to tailor current adjuvant and neoadjuvant therapies, optimizing their effect and furthering research that may lead to new therapeutic options.

Apoptosis↗
PubMed2004

A diagnostic test for prostate cancer from gene expression profiling data.

PURPOSE: Multiple recent studies show excellent classification accuracy using bioinformatics tools applied to expression profiling data on various tumors. However, the clinical applicability of these techniques remains unfulfilled because of difficulty in translating complex multigene mathematical algorithms into reproducible, platform independent tests. We recently developed a broadly applicable platform independent method based on simple ratios of gene expression to diagnose and predict outcome in cancer. In the current study we applied this technique to the diagnosis of prostate cancer. MATERIALS AND METHODS: We developed a ratio based predictive model using a training set of 32 samples with previously published gene profiling data. We then tested and refined the model using additional independent samples with previously published microarray data from another source (that is the test set of 34 samples). Finally, the optimal ratio based test was examined with quantitative reverse transcriptase-polymerase chain reaction for data acquisition in a third cohort of samples consisting of 10 frozen normal and 10 tumor prostate tissues. RESULTS: A 3-ratio test using 4 genes was 90% accurate (18 of 20 samples) for distinguishing normal prostate and prostate cancer samples obtained at surgery (Fisher's exact test p = 0.0007). This test did not result in any false-negative findings. CONCLUSIONS: We describe and validate a new gene ratio based test for the diagnosis of prostate cancer, which was developed from the analysis of extensive gene profiling data for the diagnosis of prostate cancer. This test can be easily adapted to the clinical arena without the need for complex computer software or hardware. We anticipate that the gene ratio based diagnosis of prostate cancer using fine needle aspirations could serve as a useful adjunct to standard histopathological techniques.

Gene Expression Profiling↗
PubMed2004

The use of cardiopulmonary bypass during resection of locally advanced thoracic malignancies: a 10-year two-center experience.

The use of cardiopulmonary bypass (CPB) for locally advanced thoracic malignancies is highly controversial. The purpose of this study was to document the techniques and results of CPB to facilitate the resection of complex thoracic malignancies and to identify common themes that provided for successful outcomes. This was a retrospective study that took place from January 1992 to September 2002. Fourteen consecutive patients (median age, 59 years; age range, 18 to 69 years; seven men and seven women) underwent CPB during the resection of locally advanced thoracic malignancies at two Boston hospitals. CPB was planned in 8 of 14 patients (57%) with centrally located tumors, while 6 of 14 patients (43%) required emergent institution of CPB due to injury of the superior vena cava (2 patients), inferior vena cava (2 patients), or pulmonary artery (2 patients). Complete microscopic resection was achieved in 12 of 14 patients (86%). The operative mortality rate was 1 of 14 patients (7%) due to pulmonary embolism (ie, the elective group). The median ICU and hospital lengths of stay were 5 and 9 days, respectively. The overall 1-year, 3-year, and 5-year survival rates were 57%, 36%, and 21%, respectively. The planned use of CPB to facilitate complete resection of thoracic malignancies should be considered only after careful patient selection. The availability of CPB also provides a safety net in the event of injury to vascular structures during tumor resection.

Adolescent↗
PubMed2004

Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule.

STUDY OBJECTIVES: To determine the probability of malignancy for a solitary pulmonary nodule (SPN) as a function of cancer history. SETTING AND DESIGN: Patients who had undergone resection of SPNs at Brigham and Women's Hospital between August 1989 and October 1998 were analyzed. The cohort was split into the following three groups: no history of cancer; history of lung cancer; and history of extrapulmonary malignancy. The histology of the SPN was determined after excision. Logistic regression was used to evaluate the effect of covariates on the probability of malignancy. MEASUREMENTS AND RESULTS: A total of 1,104 patients (55% women; median age, 64 years; age range, 17 to 88 years) underwent removal of 353 benign lesions (32%), 638 non-small cell lung cancers (NSCLCs) [58%], and 113 metastases (10%). Antecedent cancer history was significantly associated with final diagnosis (p < 0.0001), with SPNs being malignant in 63% of patients with no previous cancer, 82% of those with a history of lung cancer (NSCLC, 80%; metastases, 2%), and 79% of patients with history of extrapulmonary cancer (NSCLC, 41%; metastases, 38%). There was no difference in the cause of SPNs between patients with a history of a single cancer and those with a history of multiple cancers. The probability of a benign cause ranged between 62% for nodules < 1 cm to 17% when nodules were > 3 cm, if the patient had no history of cancer (p < 0.0001). The probability of an SPN being benign was cut in half if there was a history of cancer. Among patients with previous extrapulmonary malignancy, age, smoking history, and histology were predictors of diagnosis (p < 0.0001). These variables were used to construct a clinical score to predict the probability of an SPN being a NSCLC or metastasis in these patients. CONCLUSIONS: A history of cancer is an important predictor of the probability of malignancy in new SPNs. Metastases from previous cancer account for almost half of SPNs seen among patients in this subgroup. Diagnosis depends on the histology of previous malignancies, smoking history, age, and size of the SPN.

Adolescent↗
PubMed2003

Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

PURPOSE: Vaccination with irradiated, autologous melanoma cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) by retroviral-mediated gene transfer generates potent antitumor immunity in patients with metastatic melanoma. Further clinical development of this immunization scheme requires simplification of vaccine manufacture. We conducted a phase I clinical trial testing the biologic activity of vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer. PATIENTS AND METHODS: Excised metastases were processed to single cells, transduced with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1 x 10(6), 4 x 10(6), or 1 x 10(7) tumor cells, depending on overall yield, and were injected intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 745 ng/106 cells/24 hours. Toxicities were restricted to grade 1 to 2 local skin reactions. Eight patients were withdrawn early because of rapid disease progression. Vaccination elicited dense dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates at injection sites in 19 of 26 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransduced tumor cells in 17 of 25 patients. Metastatic lesions that were resected after vaccination showed brisk or focal T-lymphocyte and plasma cell infiltrates with tumor necrosis in 10 of 16 patients. One complete, one partial, and one mixed response were noted. Ten patients (29%) are alive, with a minimum follow-up of 36 months; four of these patients have no evidence of disease. CONCLUSION: Vaccination with irradiated, autologous melanoma cells engineered to secrete GM-CSF by adenoviral-mediated gene transfer augments antitumor immunity in patients with metastatic melanoma.

Adenoviridae↗
PubMed2003

Using gene expression ratios to predict outcome among patients with mesothelioma.

BACKGROUND: We have recently demonstrated that simple ratios of the expression levels of selected genes in tumor samples can be used to distinguish among types of thoracic malignancies. We examined whether this technique could predict treatment-related outcome for patients with mesothelioma. METHODS: We used gene expression profiling data previously collected from 17 mesothelioma patients with different overall survival times to define two outcome-related groups of patients and to train an expression ratio-based outcome predictor model. A Student's t test was used to identify genes among the two outcome groups that had statistically significant, inversely correlated expression levels; those genes were used to form prognostic expression ratios. We used a combination of several highly accurate expression ratios and cross-validation techniques to assess the internal consistency of this predictor model, quantitative reverse transcription-polymerase chain reaction of tumor RNA to confirm the microarray data, and Kaplan-Meier survival analysis to validate the model among an independent set of 29 mesothelioma tumors. All statistical tests were two-sided. RESULTS: We developed an expression ratio-based test capable of identifying 100% (17/17) of the samples used to train the model. This test remained highly accurate (88%, 15/17) after cross-validation. A four-gene expression ratio test statistically significantly (P =.0035) predicted treatment-related patient outcome in mesothelioma independent of the histologic subtype of the tumor. CONCLUSIONS: Gene expression ratio-based analysis accurately predicts treatment-related outcome in mesothelioma samples. This technique could impact the clinical treatment of mesothelioma by allowing the preoperative identification of patients with widely divergent prognoses.

Adult↗
PubMed2003

Gene expression in lung adenocarcinomas of smokers and nonsmokers.

Adenocarcinoma (AC) has become the most frequent type of lung cancer in men and women, and is the major form of lung cancer in nonsmokers. Our goal in this paper was to determine if AC in smokers and nonsmokers represents the same genetic disease. We compared gene expression profiles in resected samples of nonmalignant lung tissue and tumor tissue in six never-smokers with AC and in six smokers with AC, who were matched for clinical staging and histologic criteria of cell differentiation. Results were analyzed using a variety of bioinformatic tools. Four times as many genes changed expression in the transition from noninvolved lung to tumor in nonsmokers as in smokers, suggesting that AC in nonsmokers evolves locally, whereas AC in smokers evolves in a field of genetically altered tissue. There were some similarities in gene expression in smokers and nonsmokers, but many differences, suggesting different pathways of cell transformation and tumor formation. Gene expression in the noninvolved lungs of smokers differed from that of nonsmokers, and multidimensional scaling showed that noninvolved lungs of smokers groups with tumors rather than noninvolved lungs of nonsmokers. In addition, expression of a number of genes correlated with smoking intensity. Our findings, although limited by small sample size, suggest that additional studies comparing noninvolved to tumor tissue may identify pathogenetic mechanisms and therapeutic targets that differ in AC of smokers and nonsmokers.

Adenocarcinoma↗
PubMed2003

Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma.

PURPOSE: We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS: Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS: Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION: Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Adult↗
PubMed2003

Menopausal effects on presentation, treatment, and survival of women with non-small cell lung cancer.

BACKGROUND: Small population studies have reported higher survival rates for women than men with non-small cell lung carcinoma (NSCLC). Because human NSCLC cells express estrogen receptors, we evaluated hormonally active and inactive women to identify biologically mediated differences. METHODS: A total of 14,676 US women with stage I through IV primary non-small cell lung cancer (NSCLC) from the 1992 to 1997 Surveillance, Epidemiology, and End Results database were grouped into two categories based on the average menopausal age of 51 years as defined by the American College of Obstetricians and Gynecologists: ages 31 to 50 premenopausal (n = 2,230, 15%) and ages 51 to 70 postmenopausal (n = 12,446, 85%). Extreme ages were excluded. Statistics were calculated with chi(2) or Mann-Whitney tests, Kaplan-Meier estimates with log-rank tests, and Cox proportional hazards models. RESULTS: Premenopausal women more commonly presented with advanced clinical stage, less favorable histology (adenocarcinoma), and poorly differentiated tumors, and more often underwent pneumonectomies. Surgery with curative intent was performed in 31% premenopausal and 33% postmenopausal women (p = 0.03). Overall survival for premenopausal and postmenopausal women was not significantly different (median 10 and 9 months, all stages; 70 and 71 months, stages I and II). Adjusting for significant covariates (stage, histology, size, grade, extent of surgery), postmenopausal women had higher lung-cancer-related deaths (hazard ratio, 1.14; 95% confidence interval, 1.03 to 1.27). CONCLUSIONS: Premenopausal women presented more often with advanced disease and underwent more extensive resection, yet had survival advantage after covariate adjustment. Additionally, postmenopausal women had a survival advantage compared with their male counterparts. Results suggest that estrogen exposure creates a milieu that may confer a protective effect through some yet unknown mechanisms that determine outcome of the neoplastic process and warrant further investigation.

Adenocarcinoma↗
PubMed2003

Patterns of allelic loss differ in lung adenocarcinomas of smokers and nonsmokers.

Cigarette smoking is the most important cause of lung cancer, however approximately 10% of patients with lung cancer have no history of smoking. While the molecular pathogenesis of smoking associated lung carcinogenesis is becoming well characterized, the pathogenesis of lung cancer in nonsmokers is not. We designed a study to examine the pathogenesis of adenocarcinoma in nonsmokers by determining if loss of heterozygosity (LOH) in tumors of nonsmokers differs from those of smokers. We evaluated six cases of primary adenocarcinoma in never smokers and six selected cases in smokers, matched by clinical and histological criteria. LOH in tumor DNA relative to nonmalignant lung DNA was determined at 52 microsatellites located on ten chromosomal loci. The extent of allelic loss in smokers, as measured by fractional allelic loss (FAL), was compared with nonsmokers. LOH was more frequent in the tumors of nonsmokers than of smokers with mean FAL of 46% in nonsmokers and 28% in smokers (P<0.05). Increased LOH in nonsmokers was most pronounced at chromosomes: 3p, 8p, 9p, 10p, and 18q. Since this study compared allelic loss between lung and tumor-bearing lung, less frequent LOH in smokers' tumors can be interpreted to suggest LOH was already present in the nonmalignant lung of smokers and fewer additional instances of allelic loss were present in the tumors of smokers. Our results suggest that the early steps of lung carcinogenesis differ in nonsmokers compared with smokers. In addition, the chromosomal sites of LOH may identify genes important for lung carcinogenesis in nonsmokers.

Adenocarcinoma↗
PubMed2003

The burned trachea.

Tracheal burns caused by thermal or chemical injuries are uncommon, but they can be difficult to manage. A high index of suspicion is required for early detection of these injuries. Acutely, they are often life threatening unless they are diagnosed quickly and managed properly. Tracheal burn injuries can lead to long-term stenoses, which require specialized surgical techniques and chronic therapy--often with Montgomery T-tubes--for their proper management.

Bronchoscopy↗