Association between diabetes and esophageal cancer, independent of obesity, in the United States Veterans Affairs population.

In the past 30 years, the incidence of esophageal adenocarcinoma (EAC) has increased more rapidly than any other cancer in the United States. The prevalence of obesity and diabetes mellitus has drastically increased as well. We explored the potential association between obesity, diabetes mellitus, and EAC. By means of retrospective interrogation of an administrative database from fiscal year 2005-2009, we identified two cohorts. The cancer cohort was defined as patients with adenocarcinoma of the distal esophagus or gastric cardia. The comparison cohort contained patients with gastroesophageal reflux disorder (GERD; diagnosis coupled with a procedure code for fundoplication). Patient data, including demographic measures, diagnoses of obesity, diabetes mellitus, dyslipidemia, alcohol abuse, and nicotine dependence were examined. A logistic regression model identified risk factors for development of EAC. The sample included 2,836 patients identified as having either EAC (1,704) or fundoplication with GERD (1,132). Although slightly higher percentages of the benign cohort were obese, the cancer cohort had more diabetics (30.8% vs. 14.8%; chi-square = 94.5; P < 0.0001). In a logistic regression analysis adjusting for comorbidity and lifestyle factors, diagnosis of diabetes mellitus was significantly associated with esophageal cancer as opposed to GERD without cancer (OR = 2.2; 95% confidence interval [CI] 1.7-2.8). Nicotine dependence was also identified as a risk factor (OR = 1.7; 95% CI 1.4-2.0). We identified a potential association between diabetes mellitus and adenocarcinoma of the esophagus or gastric cardia. This association appears to be independent of obesity. Additionally, nicotine dependence was identified as a risk factor for EAC.

Risk factors associated with atrial fibrillation after noncardiac thoracic surgery: analysis of 2588 patients.

OBJECTIVE: The purpose of this study was to identify risk factors associated with the onset of atrial fibrillation after thoracic surgery to allow more targeted interventions in patients with the highest risk. METHODS: A comprehensive prospective database was used to identify patients undergoing major thoracic surgery from January 1, 1998, through December 31, 2002. Data collection was performed at point of contact: at preoperative evaluation, the time of the operation, discharge, and postoperative visits. All patients undergoing resection of a lung, the esophagus, the chest wall, or a mediastinal mass were included in this study. Univariate and multivariate analyses of factors associated with the development of atrial fibrillation were analyzed. RESULTS: There were 2588 patients who met the inclusion criteria. The overall incidence of atrial fibrillation was 12.3% (n = 319). Categories of disease were primary lung cancer, pulmonary metastasis, esophageal cancer, intrathoracic metastasis, benign lung disease, other mediastinal tumors, mesothelioma, chest wall tumors, benign esophagus, and "other." Patients with atrial fibrillation had increased mean lengths of hospital stay, mortality rates, and mean hospital charges. Univariate analysis evaluated age, sex, disease category, comorbidities, preoperative therapy, and procedure, and significant variables were entered into the multivariate analysis. Significant variables (relative risk; 95% confidence interval) in the multivariate analysis were male sex (1.72; 1.29-2.28), age 50 to 59 years (1.70; 1.01-2.88), age 60 to 69 years (4.49; 2.79-7.22), age 70 years or greater (5.30; 3.28-8.59), history of congestive heart failure (2.51; 1.06-6.24), history of arrhythmias (1.92; 1.22-3.02), history of peripheral vascular disease (1.65; 0.93-2.92), resection of mediastinal tumor or thymectomy (2.36; 0.95-5.88), lobectomy (3.89; 2.19-6.91), bilobectomy (7.16; 3.02-16.96), pneumonectomy (8.91; 4.59-17.28), esophagectomy (2.95; 1.55-5.62), and intraoperative transfusions (1.39; 0.98-1.98). CONCLUSIONS: The significant variables identified by means of multivariate analysis were associated with the occurrence of atrial fibrillation. Preventive therapies in selected populations might reduce the incidence of atrial fibrillation.

Histone deacetylase inhibitor downregulation of bcl-xl gene expression leads to apoptotic cell death in mesothelioma.

It has been shown that mesothelioma expresses the antiapoptotic protein BCL-XL, but not BCL-2, rendering bcl-xl gene expression a potential therapeutic target. Sodium butyrate (NaB) is a histone deacetylase inhibitor capable of alteration of bcl-2 family protein expression in other tumor types. Mesothelioma cell lines (REN, I-45) were exposed to NaB, and viability (colorimetric assay) and apoptosis (TUNEL, Hoescht staining, flow cytometry) were evaluated. Effects on bcl-2 family protein, fas-fas ligand, and caspases were examined by Western blot analysis and functional assay. An RNase assay evaluated bcl-2 family messenger RNA (mRNA) expression. Overexpressing BCL-XL mesothelioma clones were created by plasmid transfer. Cells were sensitive to NaB at low IC(50) (REN, 0.3 mM; I-45, 1 mM) and demonstrated apoptosis (percentage of cells below G1 phase by flow cytometry [sub-G1]: REN, 38.5%; I-45, 30.9%). A significant decrease in BCL-XL protein expression was noted with BAK, BAX, and BCL-2 unchanged, and this was corroborated at the transcriptional level with selectively decreased bcl-xl mRNA production after sodium butyrate exposure. Fas expression and fas-fas ligand sensitivity were unchanged. Caspases demonstrated low-level activation. Stable overexpressing BCL-XL clones were proportionally resistant to the NaB effect. This study suggests that mesothelioma cells are sensitive to the induction of apoptosis related to the attenuation of antiapoptotic bcl-xl gene and protein expression. Additional study of the therapeutic benefit of targeting bcl-xl gene expression in mesothelioma is warranted.

Significant augmentation of pro-apoptotic gene therapy by pharmacologic bcl-xl down-regulation in mesothelioma.

The ratio of pro-apoptotic (PAP) and anti-apoptotic (AAP) bcl-2 proteins is important in apoptosis regulation. We sought to determine if inhibition of the AAP bcl-xl by sodium butyrate (SB) would augment apoptotic cellular death in mesothelioma when combined with adenoviral pro-apoptotic gene therapy (PAGT) by simultaneously increasing PAP and decreasing AAP in these cells. Human mesothelioma cell lines were exposed to AdBax, AdBak, Adp53, and SB alone as well as all vectors combined with SB at varying doses and time points. Cell death was assessed, and apoptosis evaluated by morphology and FACS. Isobologram analysis evaluated additive or synergistic effect. Cellular death and apoptosis were augmented by PAGT/SB combinations compared to monotherapy. Following AdBax/SB and AdBak/SB, a decrease of the AAP bcl-xl was noted in combination with increases in PAP bax and bak. By isobologram analysis, additive or synergistic cell killing was noted with both combinations. SB treatment did not significantly augment cell killing or apoptosis in combination with Adp53. PAGT/SB was more effective than monotherapy in induction of apoptotic cell death. Synergy may be due to the ability of SB to decrease bcl-xl with marked increases in PAP engendered by PAGT. Combination therapy with agents that down-regulate AAP in addition to PAGT may prove useful clinically.

Pulmonary granuloma caused by Pseudomonas andersonii sp nov.

Pulmonary granuloma is a common lesion for which gram-negative bacteria are rarely implicated as a cause. Hence, most physicians are unaware of this etiology. We isolated a gram-negative bacterium from a surgically resected pulmonary granuloma in a 42-year-old, nonimmunocompromised woman. Within the necrotizing granuloma, numerous organisms also were demonstrated by Gram stain, suggesting a cause-disease relationship. Characterization of the bacterium by sequence analysis of the 16S ribosomal gene, cellular fatty acid profiling, and microbiologic studies revealed a novel bacterium with a close relationship to Pseudomonas. We propose a new species for the bacterium, Pseudomonas andersonii. These results suggest that the differential diagnosis of a lung granuloma also should include this gram-negative bacterium as a potential causative agent, in addition to the more common infections caused by acid-fast bacilli and fungi. This bacterium was shown to be susceptible to most antibiotics that are active against gram-negative bacteria.

Treatment of stage I and II non-small-cell lung cancer.

BACKGROUND: The appropriate staging and treatment of patients with stage I and II non-small-cell lung cancer (NSCLC) are important in that the potential for a lost curative opportunity in this population is greater than for those presenting with advanced NSCLC. METHODS: Treatment options -- surgery, radiation therapy, and chemotherapy -- for stage I and II NSCLC are reviewed, and the impact of newer staging modalities on patient survival is discussed, including altering both the lead-time and clinicopathologic stage biases that exist in the diagnosis and treatment of NSCLC. Some predictions are also made regarding how that standard may change for clinicians in the near future, and methods for further improvements in posttreatment survival in this group are discussed. RESULTS: Whenever possible, patients with early-stage NSCLC should be treated with surgical resection. Patients for whom resection is not an option may benefit from radiation as definitive therapy. Positive results with neoadjuvant chemotherapy have led to an ongoing randomized trial (Intergroup S9900) to compare surgery alone to neoadjuvant chemotherapy plus surgery. CONCLUSIONS: Staging bias may affect the overall low survival of early-stage NSCLC. However, true stage-specific survival may improve with newer imaging modalities. Future advances, including closed transthoracic radiation, thermal ablative therapy techniques, and gene therapy, may supplant the need to surgically resect these tumors to achieve local control.

Preoperative chemotherapy for lung cancer does not increase surgical morbidity.

BACKGROUND: Preoperative chemotherapy (C+S) for non-small cell lung cancer (NSCLC) has increased in an attempt to improve survival. Patients receiving C+S potentially may have an increase in postoperative morbidity and mortality compared with surgery alone (S). We reviewed our experience with C+S and S in a tertiary referral center. METHODS: Three hundred eighty consecutive patients underwent lobectomy or greater resection for NSCLC between August 1, 1996, and April 30, 1999: 335 patients (259 S; 76 C+S) were analyzed; 45 additional patients were excluded for prior NSCLC, other chemotherapy for other malignancy, or radiation. We compared morbidity and mortality overall, and by subset analysis (clinical stage, pathological stage, procedure, and by protocol use) for both C+S and S patients. RESULTS: Demographics, comorbidities, and spirometry were similar. We noted no significant difference in overall or subset mortality or morbidity including pneumonia, acute respiratory distress syndrome, reintubation, tracheostomy, wound complications, or length of hospitalization. CONCLUSIONS: C+S did not significantly affect morbidity or mortality overall, based on clinical stage, postoperative stage, or extent of resection. The potential for enhanced survival in resectable NSCLC justifies continued study of C+S.

Surgical resection of non-small cell carcinoma after treatment for small cell carcinoma.

BACKGROUND: Development of non-small cell lung carcinoma (NSCLC) in patients previously treated for small cell carcinoma (SCLC/NSCLC) is well described; however, little is known about clinical outcome. METHODS: A single-institution 20-year review was performed. Patient characteristics and survival for SCLC/ NSCLC patients were compared with those for control patients matched for stage, resection, and previous malignancy. RESULTS: One thousand four hundred four patients with small cell carcinoma were identified, and 29 underwent therapy for metachronous NSCLC: 11 of 29 patients underwent surgical resection, 10 of these 11 (90%) were stage I. Compared with surgically treated stage I NSCLC patients, SCLC/NSCLC patients were more likely to have squamous histology (70% versus 35%, p = 0.026); and subanatomic resection (90% versus 17.4%, p < 0.0005). The SCLC/NSCLC patients had significantly poorer survival when compared with stage I NSCLC patients undergoing any resection (24.53 versus 74.43 months, p = 0.003) and stage I NSCLC patients receiving wedge resection (24.53 versus 58.39 months, p = 0.006). Survival was similar to NSCLC patients with a history of previous treated extrathoracic solid malignancy. CONCLUSIONS: Surgical resection for SCLC/NSCLC patients is feasible, but poorer prognosis is noted when compared with stage-matched control patients. Surgical candidates should be carefully chosen, and alternative local control modalities considered.

A single-institutional, multidisciplinary approach to primary sarcomas involving the chest wall requiring full-thickness resections.

OBJECTIVE: Primary sarcomas involving the chest wall requiring full-thickness excision are rare. We reviewed our experience with these lesions in a tertiary referral cancer center by using multidisciplinary approaches. METHODS: A 10-year retrospective study identified 51 patients referred with primary sarcomas of the chest wall: 40 for initial treatment and 11 after previous unsuccessful surgical excisions elsewhere (secondary referral). Presenting symptoms were pain alone in 23 (45%) of 51 patients, pain with an associated mass in 8 (16%) patients, and an asymptomatic mass alone in 13 (25%) patients. Median symptom duration was 241 days in the primary group and 225 days in the recurrent group. Tumor locations were the sternum (n = 11), the rib alone (n = 36), and the posterior rib with extension into vertebral bodies (n = 4). Histologic types included the following: chondrosarcomas (n = 15), malignant fibrous histiocytomas (n = 9), osteosarcomas (n = 4), Ewing sarcomas (n = 3), desmoid tumors (n = 7), and other types (n = 13). The median tumor volume of those referred initially was 311 cm(3) compared with 84 cm(3) in patients with recurrent lesions. RESULTS: Twenty-six (51%) of 51 patients received treatment before resection, including chemotherapy alone (n = 22), radiation alone (n = 3), and combined chemotherapy and radiation therapy (n = 1). The complete sternum was removed in 6 of 11 patients, and the average number of ribs requiring resection was 3.8. Four patients had vertebral body resections. Prosthetic meshes alone were required in 16 of 51 patients, and meshes with methylmethacrylate were required in 18 of 51 patients. Muscle flap reconstructions by plastic surgery were required in 24 patients. Negative margins were obtained in 47 of 51 patients. There were no perioperative deaths with morbidities occurring in 12 (24%) of 51 patients (wound [n = 3], prolonged air leak [n = 1], prolonged ventilator requirement [n = 1], arrhythmias [n = 3], doxorubicin (Adriamycin)-induced cardiomyopathy [n = 1], and other [n = 3]). Postoperative treatment was administered to 13 patients (chemotherapy alone, n = 9; chemotherapy with radiation therapy, n = 4). The cumulative 5-year survival of all patients was 64% (initial referral, 61.3%; secondary referral, 72.7%). The average follow-up is 44.7 months. CONCLUSIONS: A combined aggressive multidisciplinary approach to primary sarcomas of the chest wall resulted in no treatment-related deaths and a cumulative 5-year survival of 64% in patients referred to our tertiary care cancer center.

Adenovirus-mediated Bak gene transfer induces apoptosis in mesothelioma cell lines.

OBJECTIVE: Conventional treatment for mesothelioma is largely ineffective. We therefore evaluated the novel approach of adenoviral gene transfer of the proapoptotic Bcl-2 family member Bak in mesothelioma cancer cell lines, which are sensitive and resistant to adenoviral p53. METHODS: Binary adenoviral Bak (Ad/GT-Bak and Ad/GV16) and LacZ (Ad/GT-LacZ and Ad/GV16) vectors were used for transduction of the mesothelioma cell lines I-45 (p53 resistant) and REN (p53 sensitive). Protein levels were determined by Western blotting. Apoptosis was assessed by morphologic changes, caspase-3 cleavage, and fluorescence-activated cell sorter analysis of subdiploid populations. Cell viability was determined with the XTT assay. Statistical analysis was performed with analysis of variance and the Student t test. RESULTS: High levels of Bak gene transfer were seen after coadministration of Ad/GT-Bak and Ad/GV16 in both mesothelioma cell lines. Apoptosis was induced 24 hours after Bak but not LacZ gene transfer ([Bak: I-45, 36%; REN, 25%] vs [LacZ: I-45, 1%; REN, 3%], P <.05]) in p53-sensitive (REN) and p53-resistant (I-45) cell lines. Cellular viability was significantly decreased 48 to 72 hours after Bak gene transfer compared with control vector in both cell lines (72 hours: Bak I-45, 1.4% +/- 1.0%, and Bak REN, 4.7% +/- 1%, vs Lac-Z I-45, 83% +/- 3%, and Lac-Z REN, 100% +/- 1%; P <.05). CONCLUSIONS: Adenovirus-mediated overexpression of the Bak gene induces apoptosis and decreased cellular viability in p53-sensitive and p53-resistant mesothelioma cells. These data suggest that the gene transfer of proapoptotic Bcl-2 family members may represent a novel gene therapy strategy to treat mesothelioma.

Prodrug/drug sensitivity gene therapy: current status.

The prodrug strategy has its own particular real and theoretic obstacles. Clinical strategies and research efforts have tried to approach these problems. The bystander effect, whereby nontransduced cells are affected by simple proximity to those that have received the novel gene, has enabled many prodrug systems to be more efficient than anticipated. Several prodrug gene therapy systems have been developed, including the HSVtk/GCV and CD/5-FC systems. Preclinical work serves as the foundation for clinical trials examining the use of prodrug gene therapy systems. At least 21 prodrug gene therapy trials have been approved for patient enrollment in the United States and Europe. Recent work has demonstrated the success of prodrug gene therapy, which might lead to combination therapies using vector transfer of both prodrug/suicide as well as immune-enhancing genes to tumors.

Bilateral sequential lung transplant for ectodermal dysplasia.

A case of bilateral sequential lung transplantation for anhidrotic ectodermal dysplasia is presented. The patient was a 16-year-old male with end-stage lung disease secondary to chronic severe respiratory infection. Although a relatively rare disease, the common association of fatal pulmonary compromise in those affected with this disorder warrants consideration of lung transplantation as a viable therapeutic option.

Outpatient management of malignant pleural effusion by a chronic indwelling pleural catheter.

BACKGROUND: Previous studies have shown that a chronic indwelling pleural catheter (PC) safely and effectively relieved dyspnea, maintained quality of life, and reduced hospitalization in patients with malignant pleural effusions. Outpatient management of malignant pleural effusion with a PC may reduce length of stay and early (7-day) charges compared with inpatient management with chest tube and sclerosis. METHODS: A retrospective review of consecutive PC patients (n = 100; 60 outpatient, 40 inpatient) were treated from July 1, 1994 to September 2, 1998 and compared with 68 consecutive inpatients treated with chest tube and sclerosis between January 1, 1994 and December 31, 1997. Hospital charges were obtained from date of insertion (day 0) through day 7. RESULTS: Demographics were similar in both groups. Pretreatment cytology was positive in 126 of 168 patients (75%), negative in 21 (12.5%), and unknown in 21 (12.5%). Primary histology included lung (n = 61, 36%), breast (n = 39, 23%), lymphoma (n = 12, 7%), or other (n = 56, 34%). Median survival was 3.4 months and did not differ significantly between treatment groups. Overall median length of stay was 7.0 days for inpatient chest tube and inpatient PC versus 0.0 days for outpatient Pleurx. No mortality occurred related to the PC. Eighty-one percent (81/100) of PC patients had no complications. One or more complications occurred in 19 patients (19%). Patients treated with outpatient PC (n = 60) had early (7-day) mean charges of $3,391 +/- $1,753 compared with inpatient PC (n = 40, $11,188 +/- $7,964) or inpatient chest tube (n = 68, $7,830 +/- $4,497, SD) (p < 0.001). CONCLUSIONS: Outpatient PC may be used effectively and safely to treat malignant pleural effusions. Hospitalization is not required in selected patients. Early (7-day) charges for malignant pleural effusion are reduced in outpatient PC patients compared with inpatient PC patients or chest tube plus sclerosis patients.

Cadherin and catenin expression in normal human bronchial epithelium and non-small cell lung cancer.

Cadherins are transmembrane cell adhesion molecules (CAMS) that mediate cell-cell interactions and are important for maintenance of epithelial cell integrity. This function is dependent on an indirect interaction between the cytoplasmic domain of the cadherin molecule with three cytoplasmic proteins known as alpha-, beta-, and gamma-catenin (-cat). Growing evidence suggests that alterations in cadherin or catenin expression or function may be important to the development of an invasive or metastatic phenotype. Immunohistochemical techniques were used to study the expression of the two major epithelial cadherins, E-cadherin (E-cad) and P-cadherin (P-cad) as well as alpha- and gamma-cat in normal bronchial epithelium and in a series of carefully TMN-staged pulmonary adenocarcinomas (n = 21) and squamous cell carcinomas (n = 7). The cadherin profile of normal pseudostratified bronchial epithelium was heterogeneous. Basilar cells strongly expressed P-cad, alpha- and gamma-cat, while columnar cells moderately expressed E-cad, alpha- and gamma-cat. In contrast to other epithelial tumors, E-cad on non-small cell lung carcinomas was actually upregulated, however, a decrease in P-cad expression was noted in 68%. At least one cadherin or catenin was downregulated, compared to normal bronchial epithelium, in 82% of tumors examined. With the exception of an association between loss of P-cad expression and poorly differentiated state, changes in cadherin and catenin expression levels were not significantly correlated to tumor stage, cell type, or nodal status. These findings illustrate that alteration of expression of cadherins and catenins are often found in non-small cell lung carcinoma when compared to the progenitor bronchial epithelium, and may play a role in the development of the malignant phenotype.

Management of exsanguinating hemoptysis during cardiopulmonary bypass.

BACKGROUND: Large-volume hemoptysis during cardiopulmonary bypass is an infrequent, but life-threatening event. Rapid airway clearance and control are the primary prerequisites for successful management. METHODS: The cases of 3 patients with different sources of exsanguinating hemoptysis during cardiopulmonary bypass managed initially with rigid bronchoscopy were reviewed. RESULTS: In all patients, airway control was rapidly established and weaning from cardiopulmonary bypass CPB was accomplished. Two patients survived the operative procedure. The other patient died in the operating room of unremitting bilateral pulmonary hemorrhage. CONCLUSIONS: Major hemoptysis during cardiopulmonary bypass is best dealt with initially by rapid airway control and cessation of bypass in an expeditious manner. An algorithm for suggested management is provided. The rigid bronchoscope is the optimal tool for initial management and it should always be available. Definitive treatment is determined by the cause and the persistence of hemorrhage once these maneuvers have been performed.

Diffuse airway narrowing from carcinoma metastatic to the bronchial submucosa: identification by chest CT.

The differential diagnosis of dyspnea in patients with prior malignancy and nondiagnostic chest radiographs is broad. We report a case of breast carcinoma diffusely metastatic to the bronchial submucosa presenting as obstructive airway disease. Chest radiographs failed to suggest metastatic disease as the cause of dyspnea. CT, however, revealed the unusual finding of diffusely thickened and narrowed airways. Carcinoma confined to airway submucosa was identified using bronchial biopsy. We suggest that diffuse airway narrowing from submucosal metastasis can be demonstrated by CT and should be added to the differential diagnosis of dyspnea in cancer patients with nondiagnostic chest radiographs and evidence of airflow obstruction.

Mediastinoscopic subtotal removal of mediastinal cysts.

STUDY OBJECTIVE: Evaluate the use of mediastinoscopy in the surgical diagnosis and treatment of mediastinal cystic masses in adults. DESIGN: Case reports and literature review. SETTING: Academic department of surgery. PATIENTS: Three consecutive adults with mediastinal masses identified on plain radiographs and CT. INTERVENTIONS: Operative mediastinoscopy. MEASUREMENTS AND RESULTS: All patients were successfully treated with removal of cyst wall, establishment of diagnosis, and same-day hospital discharge. CONCLUSIONS: Simple mediastinoscopic removal of mediastinal cysts offers the same potential for diagnosis and treatment as more conventional methods, with a potential for less morbid and more cost-effective care.

Severe acute extrinsic airway compression by mediastinal tumor successfully managed with extracorporeal membrane oxygenation.

The successful use of femoral venoarterial extracorporeal membrane oxygenation to support an adult patient with extrinsic airway compression secondary to a large mediastinal tumor is presented. Extracorporeal membrane oxygenation was continued until a combination of chemotherapy and radiation therapy allowed sufficient tumor shrinkage to permit decannulation. This method should be considered and available before manipulation of the airway in similar patients.