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.

Presence and formation of cobalamin analogues in multivitamin-mineral pills.

Because the origin of cobalamin (vitamin B12) analogues in animal chows and animal and human blood and tissues is unknown, we investigated the possibility that multivitamin interactions might convert cobalamin to cobalamin analogues. We homogenized three popular multivitamin-mineral pills in water, incubated them at 37 degrees C for 2 h, and isolated the cobalamin. Using paper chromatography we observed that 20-90% of the cobalamin was present as cobalamin analogues. Studies using CN-[57Co]cobalamin showed that these analogues were formed due to the concerted action of vitamin C, thiamine, and copper on CN-cobalamin. These cobalamin analogues are absorbed from the gastrointestinal tract of mice and either fail to stimulate or actually inhibit cobalamin-dependent enzymes when injected parenterally. We conclude that CN-cobalamin can be converted to potentially harmful cobalamin analogues by multivitamin-mineral interactions and that these interactions may be responsible for the presence of cobalamin analogues in animal chows and animal and human blood and tissues.

Use of recombinant adenovirus to transfer the herpes simplex virus thymidine kinase (HSVtk) gene to thoracic neoplasms: an effective in vitro drug sensitization system.

Transfer of the herpes simplex virus thymidine kinase (HSVtk) gene into tumor cells using retroviral vectors followed by administration of ganciclovir provides a potential strategy for the treatment of malignancy. Because of the limitations of using retroviral vectors for clinical application, the feasibility of using a recombinant adenovirus containing HSVtk was examined. Cell lines derived from human malignant mesotheliomas and non-small cell lung cancers infected with a recombinant adenovirus containing HSVtk showed strong expression of HSVtk protein as determined by immunohistochemical staining. Infection with a recombinant adenovirus containing HSVtk rendered cells sensitive to doses of ganciclovir that were 2-3 logs lower than uninfected cells or those infected with a control virus. A strong "bystander effect" was noted in mesothelioma lines; there was no diminution in the efficacy of ganciclovir treatment until the ratio of infected:uninfected cells fell below 1:10. This study thus demonstrates in vitro efficacy of an adenovirus-transduced HSVtk drug sensitization gene therapy system in thoracic malignancies. Recombinant adenovirus transfer of the HSVtk gene followed by ganciclovir may have promise as an in situ treatment for tumors.

Treatment of pleural mesothelioma in an immunocompetent rat model utilizing adenoviral transfer of the herpes simplex virus thymidine kinase gene.

Previously, we have treated malignant mesothelioma (MM) growing in the peritoneal cavity of immunodeficient mice utilizing a recombinant adenovirus vector carrying the herpes simplex virus-thymidine kinase gene (Ad.RSVtk) followed by administration of the anti-viral drug ganciclovir (GCV). To mimic more closely the clinical situation in human MM, a syngeneic model of pleural MM was developed in immunocompetent Fischer rats. Administration of Ad.RSVtk into the pleural space of animals with established multifocal tumor followed by systemic GCV therapy resulted in significant tumor regression at 20 days in HSVtk/GCV-treated animals (average tumor weight 0.6 +/- 0.2 gram; n = 12) versus control animals (average weight 5.4 +/- 0.2 grams; n = 21; p < 0.001). In additional studies, Ad.RSVtk/GCV-treated animals had a mean survival of 34 days (average tumor weight 1.0 +/- 0.3 gram at death) versus 26 days in control animals (average tumor weight 6.2 +/- 0.6 grams at death). A significant reduction in tumor burden was also seen when more advanced, bulkier disease was treated. These studies demonstrate the Ad.RSVtk/GCV system is effective in the treatment of pleural-based tumors in an immunocompetent host. However, there are limitations to this treatment approach that result in only small increments in survival.

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.

Tetracycline pleurodesis--associated acute renal failure.

Chemical pleurodesis is a frequently performed procedure for pneumothorax and effusion and significant adverse effects are unusual. We present a previously unreported case of acute renal failure associated with tetracycline pleurodesis. Recent studies have shown that intrapleural drug administration may lead to therapeutic serum levels. Systemic toxic drug effects may therefore be noted with chemical pleurodesants such as tetracycline. Alternative methods of pleurodesis should always be considered if a sensitivity or metabolic abnormality is suspected.

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.

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.

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.

Differential sensitivity of thoracic malignant tumors to adenovirus-mediated drug sensitization gene therapy.

Malignant mesothelioma may prove to be an attractive candidate for somatic gene therapy with replication-deficient recombinant adenovirus transfer of a toxic, or drug sensitization gene. Transfer of the herpes simplex thymidine kinase type I gene (HSVtk), followed by exposure to the acyclic nucleoside drug ganciclovir, has been shown to be an effective tumor cell killing system. To study generalized applicability, we tested a number of thoracic malignant cell lines for their sensitivity to gancyclovir after infection with an adenoviral vector containing the HSVtk gene (Ad.RSVtk). Using the concentration of gancyclovir required to kill 50% of the cells (IC50) as a measure of sensitivity, we detected variable sensitivity among cell lines, with mesothelioma most sensitive (IC50 = 0.075 to 2.8 mumol/L gancyclovir), and non-small-cell carcinoma lines having an intermediate sensitivity (IC50 = 1.5 to 100 mumol/L). In contrast, an ovarian carcinoma line was extremely resistant (IC50 > 2000 mumol/L). To study the possible mechanisms for these differences, we studied cell lines with regard to their ability to be infected with an adenoviral vector containing a marker gene (Ad.CMVlacZ) and expression of the vitronectin receptor alpha v (an integrin cell adhesion molecule shown to be required for adenovirus internalization after initial binding). We found that the degree of lacZ transduction correlated with HSVtk sensitivity, whereas vitronectin receptor expression did not, suggesting that differences in initial viral binding ability, rather than internalization, may explain the sensitivity differences seen in vitro.

Thoracoscopic management of descending necrotizing mediastinitis.

Descending necrotizing mediastinitis (DNM) is a lethal process originating from odontogenic, pharyngeal, or cervical infectious sources that descends along fascial planes into the mediastinum. Despite earlier use of antibiotics and surgical drainage, the mortality (>50%) has changed little since the first large series reported in the preantibiotic era. The surgical management remains controversial, with support ranging from cervical drainage alone to cervical drainage and routine thoracotomy. We report a case of thoracoscopic drainage and debridement of a mediastinal abscess resulting from descending necrotizing mediastinitis. The decreased morbidity of this approach compared with posterolateral thoracotomy and the improved drainage of the mediastinum compared with cervical drainage support this method as an attractive management of patients with DNM.

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.

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.

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.

Prophylaxis of serious cytomegalovirus infection in renal transplant candidates using live human cytomegalovirus vaccine. Interim results of a randomized controlled trial.

We report the interim results of a randomized, double-blind, placebo-controlled, clinical trial of prophylactic, live, attenuated cytomegalovirus (CMV) vaccination (Towne strain of CMV) of renal transplant candidates (RTCs). One hundred seventy-two RTCs were treated and subsequently underwent transplantation and followed up for at least one year and up to five years after transplantation. Eighty-eight RTCs received vaccine, and 84 received placebo. Results were analyzed according to the prevaccination serologic status (anti-CMV antibody titer) of the recipient (R- or R+) and the donor (D- or D+). The overall incidence of CMV disease was highest in the R-D+ group and almost absent in the R-D- group. There was no difference in the incidence of CMV infection or disease between vaccinated and respective placebo control recipients in either the R-D+, R+D+, R+D-, or R-D- groups. In contrast, the severity of CMV disease was significantly decreased in R-D+ vaccinees vs R-D+ placebo-treated recipients. Moreover, in the R-D+ group, one- and five-year cadaver renal allograft actuarial survival rates were 73% and 62%, respectively, for CMV vaccinees vs 40% and 25%, respectively, for control placebo patients. We conclude that seronegative cadaver RTCs may benefit from vaccination with live, attenuated, Towne strain CMV vaccine before transplantation.

Thoracoscopic removal of mediastinal parathyroid adenoma.

Mediastinal parathyroid tissue hyperfunctions in as much as 25% of the patients with primary hyperparathyroidism, and this may be responsible for causing conventional operative procedures to fail in as much as one-third of the cases. When lesions prove to not be accessible through a cervical incision, or when a mediastinal adenoma is diagnosed before cervical procedures, median sternotomy and angiographic ablation have been considered the only options for removal. However, thoracoscopy has theoretic advantages over both. Two patients underwent successful thoracoscopic removal of a hyperfunctioning ectopic mediastinal parathyroid adenoma and their cases are presented here.

Loss of alpha-v integrin expression and recurrence in node-negative lung carcinoma.

BACKGROUND: Despite "curative" resection, metastases develop in many patients with node-negative (N0) non-small cell lung carcinoma. Alternative biologic markers for this tumor would be useful. Integrins are cell adhesion molecules that are thought to be important in tumor progression, and expression of these molecules previously has been shown to be altered in non-small cell lung carcinoma. We evaluated alterations in integrin expression and clinical outcome. METHODS: Immunohistochemical staining of tumor specimens was performed, and clinical data were reviewed retrospectively. RESULTS: Data were complete for 42 patients. Half of all patients (21/42) and 9 of 26 patients with negative nodes experienced tumor recurrence during follow-up. Neither histologic type nor tumor differentiation status correlated with recurrence. However, loss of the alpha v integrin subunit was associated significantly with recurrence in the N0 group. Seventy-five percent of patients with negative nodes who exhibited recurrence lost alpha v expression, compared with only 10% of patients with negative nodes who did not exhibit recurrence (p = 0.012). Alterations of other integrin subunits did not correlate significantly with prognostic follow-up variables. CONCLUSIONS: Loss of alpha v expression may serve as a marker for patients with node-negative non-small cell lung carcinoma who are at high risk for recurrence, potentially directing additional therapies.

Resection of a pulmonary malignancy invading the intrapericardial inferior vena cava.

Resection of extensive lung cancers invading thoracic vascular structures (T4 lesions) can yield long-term survival provided the margins and nodes are free of tumor. We report the resection of the suprahepatic inferior vena cava for direct tumor involvement by a pulmonary malignancy. The resection was performed without bypass, and the cava was subsequently reconstructed with a 22-mm-diameter Dacron graft. Patency was documented on postoperative magnetic resonance angiograms. The patient was discharged home on postoperative day 10 without complications and remains well 8 months after the operation. Potentially curative resections and reconstructions of suprahepatic inferior vena cava involved with pulmonary malignancies are possible and can be done without cardiopulmonary bypass.

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.