Protection of human muscle acetylcholinesterase from soman by pyridostigmine bromide.

INTRODUCTION: Pretreatment with pyridostigmine bromide (PB) of human intercostal muscle fibers exposed to the irreversible acetylcholinesterase (AChE) inhibitor soman was investigated. METHODS: Muscles were pretreated with 3 × 10(-6) M PB or saline for 20 minutes, then exposed to 10(-7) M soman for 10 minutes. RESULTS: AChE of muscles treated with soman alone was inhibited >95%. In contrast, PB pretreatment of soman-exposed bundles protected 20% of AChE activity. AChE of bundles exposed to PB alone recovered after 4 hours, but bundles exposed to both PB and soman did not. Soman-induced reduction of resting membrane potentials and increment of amplitudes and decay times of miniature endplate potentials (MEPPs) were partially corrected by PB pretreatment. CONCLUSIONS: In vitro pretreatment of human muscles with PB protected up to 20% of muscle AChE and ameliorated some deleterious effects on endplate physiology induced by soman.

Mediastinoscopy might not be necessary in patients with non-small cell lung cancer with mediastinal lymph nodes having a maximum standardized uptake value of less than 5.3.

OBJECTIVE: Accurate pretreatment staging in non-small cell lung cancer remains tantamount in formulating an appropriate treatment plan. The maximum standardized uptake value obtained with integrated fluorodeoxyglucose-positron emission tomography/computed tomography has been proposed to be a predictor of malignancy in mediastinal lymph nodes. A recent study has also suggested that accuracy of integrated fluorodeoxyglucose-positron emission tomography/computed tomography might be improved by increasing the maximum standardized uptake value used for calling a lymph node positive from 2.5 to 5.3. We tested the hypotheses that the maximum standardized uptake value is a predictor of individual lymph node metastasis in non-small cell lung cancer and that pathologic staging with mediastinoscopy might not be necessary in patients with a maximum standardized uptake value of less than 5.3 in their mediastinal lymph nodes. METHODS: This is a retrospective review of 765 lymph nodes sampled from 110 patients in a single institution with biopsy-proved non-small cell lung cancer. All patients underwent integrated fluorodeoxyglucose-positron emission tomography/computed tomography before biopsy or resection of their mediastinal lymph nodes. Surgical staging was the reference standard. All N2 lymph nodes were individually assessed according to station. Data were analyzed by using the Pearson chi(2) test. RESULTS: Twenty-one (19%) of 110 patients had N2 disease, and a total of 765 N2 lymph nodes were pathologically examined. The mean and median maximum standardized uptake values for N2 nodes with metastatic disease were 9.2 (95% confidence interval, 7.0-11.4) and 7.2 (range, 2.2-25.8), respectively. For benign N2 nodes, the mean and median maximum standardized uptake values were 1.5 (95% confidence interval, 1.4-1.6) and 1.0 (range, 1.0-9.6), respectively (P < .05). When integrated fluorodeoxyglucose-positron emission tomographic/computed tomographic scans were reinterpreted by using a maximum standardized uptake value of 5.3 as a cutoff for malignancy, sensitivity decreased from 93% to 81% (P = .15), specificity increased from 86% to 98% (P < .01), positive predictive value increased from 22% to 64% (P < .01), negative predictive value was unchanged at 99%, and overall accuracy of integrated positron emission tomography/computed tomography increased from 87% to 97% (P < .01). CONCLUSIONS: The maximum standardized uptake value is a predictor of individual lymph node metastasis in non-small cell lung cancer. Accuracy of integrated positron emission tomography/computed tomography is significantly improved by using a maximum standardized uptake value of 5.3 to assign malignancy, thereby dramatically decreasing the number of false-positive results. More importantly, these results suggest that some patients with non-small cell lung cancer with a maximum standardized uptake value less than 5.3 in their N2 lymph nodes might be able to forego mediastinoscopy and proceed directly to thoracotomy. This represents a significant change in the current management of standardized uptake value-positive mediastinal lymph nodes in non-small cell lung cancer.

A phase II study of paclitaxel, carboplatin, and radiation with or without surgery for esophageal cancer.

BACKGROUND: Cisplatin-based chemoradiotherapy (CRT) has been a standard treatment for patients with locally advanced esophageal cancer. However, cisplatin is associated with significant toxicity. We conducted a phase II clinical trial of concurrent paclitaxel, carboplatin, and radiation with or without surgery as an alternative to the standard cisplatin-based CRT for localized and metastatic esophageal cancer. METHODS: Fifty patients with esophageal cancer were enrolled: 16 patients with stage II, eight patients with stage III, and 26 patients with stage IV disease. Two thirds (67%) of patients had adenocarcinoma and one third (33%) with squamous histology. Patients with resectable disease were treated with paclitaxel 30 mg/m, twice weekly for 10 doses, carboplatin AUC (area under the curve) 1.5 weekly for five doses; and concurrent radiation, 1.8 Gy/day, for a total of 45 Gy, followed by esophagectomy. Without surgery, patients received an additional dose each of paclitaxel and carboplatin with concurrent radiation for a total of 50.4 Gy, followed by two consolidation cycles of paclitaxel (200 mg/m) and carboplatin (AUC 6). RESULTS: During CRT, common stage III/IV toxicities included nausea/emesis (19%), esophagitis (9%), and neutropenia (4%). For consolidation chemotherapy, neutropenia (23%), neuropathy (8%) and nausea/emesis (4%) were the most common stage III/IV side effects. After CRT, 26% had a complete response, 17% had a partial response, and 41% had stable disease. Ninety-one percent of patients had clinical improvement of dysphagia. With a median follow-up of 32 months, the median survival was 12 months for patients with metastatic disease, 44 months for localized disease treated with esophagectomy, and >44 months for localized disease treated with definitive CRT. CONCLUSIONS: The regimen of paclitaxel, carboplatin, and radiation with or without surgery is well tolerated with promising efficacy for patients with esophageal cancer.

Advances in positron emission tomography technology have increased the need for surgical staging in non-small cell lung cancer.

OBJECTIVES: Pretreatment staging of patients with non-small cell lung cancer is critically important in determining an appropriate treatment plan. As positron emission tomography (PET) and computed tomography (CT) are proven complementary modalities in clinical staging, recent advances in PET technology have brought forth integrated PET/CT as the new standard. We tested the hypothesis that improvements in PET technology have not increased the sensitivity or specificity of PET in the staging of non-small cell lung cancer to an extent that surgical staging is no longer required. METHODS: This is a retrospective, single-institution review of 336 patients from 1995 to 2005 with biopsy-proven non-small cell lung cancer who underwent [18F] fluoro-2-deoxy-D-glucose-PET before mediastinal lymph node sampling by cervical mediastinoscopy or thoracotomy. Clinical records, histopathologic reports, and PET findings were reviewed. Data were analyzed by the Pearson chi2 test. RESULTS: Within the study population, 210 patients had routine PET and 126 had integrated PET/CT. For detecting mediastinal metastases the sensitivities of PET versus integrated PET/CT were 61.1% versus 85.7% (P < .05), specificities were 94.3% versus 80.6% (P < .001), positive predictive values were 68.8% versus 55.8%, negative predictive values were 92.1% versus 95.2%, and overall accuracy was 88.6% versus 81.7%. CONCLUSIONS: Improvements in PET technology have increased integrated PET/CT sensitivity at the cost of significantly decreased specificity. Although it may appear that integrated PET/CT incurs fewer false negative results, the dramatic increase in false positive results reinforces the notion that integrated PET/CT should be used only as an adjunct to clinical staging and that surgical staging remains the gold standard in non-small cell lung cancer.

Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved.

OBJECTIVE: Bronchioloalveolar lung cancer is commonly multifocal and can also present with other non-small cell types. The staging and treatment of multifocal non-small cell cancer are controversial. We evaluated the current staging of multifocal bronchioloalveolar carcinoma and the therapeutic effectiveness of resection when this tumor type is involved. METHODS: We reviewed our experience between 1992 and 2000 with complete pulmonary resections for bronchioloalveolar carcinoma. Kaplan-Meier survival curves were calculated from the dates of pulmonary resection. RESULTS: Among 73 patients with bronchioloalveolar carcinoma, 14 patients, 7 male and 7 female with a mean age of 65 years (51-87 years), had multifocal lesions without lymph node metastases. Follow-up was 100% for a median of 5 years (range 2.6-8.5 years). Tumor distribution was unilateral in 9 patients and bilateral in 5 patients. The multifocal nature of the disease was discovered intraoperatively in 4 patients. Nine patients had 2 lesions, 4 patients had 3 lesions, and 1 patient had innumerable discrete foci in a single lobe. Operative mortality was 0. Postoperatively, 10 patients were staged pIIIB or pIV on the basis of multiple foci of similar morphology; 4 patients had some differences in histology (implying multiple stage 1 primaries). The median survival time to death from cancer was 14 months (141 days-5.6 years). The overall 5-year survival after resection of multifocal bronchioloalveolar carcinoma was 64%. Unilateral or bilateral distribution had no impact on survival. CONCLUSIONS: The current staging system is not prognostic for multifocal bronchioloalveolar carcinoma without lymph node metastases. Complete resection of multifocal non-small cell lung cancer when bronchioloalveolar carcinoma is a component may achieve survivals similar to that of stage I and II unifocal non-small cell lung cancer. When bronchioloalveolar carcinoma is believed to be one of the cell types in multifocal disease without lymph node metastases, consideration should be given to surgical resection.

Thoracoscopic and laparoscopic esophagectomy for benign and malignant disease: lessons learned from 46 consecutive procedures.

BACKGROUND: Transhiatal and transthoracic esophagectomy are common approaches for esophageal resection. The literature is limited regarding the combined thoracoscopic and laparoscopic approach to esophagectomy. The aim of this study was to evaluate the outcomes of combined thoracoscopic and laparoscopic esophagectomy for the treatment of benign and malignant esophageal disease. STUDY DESIGN: We performed a retrospective chart review of 46 consecutive minimally invasive esophagectomies performed between August 1998 and September 2002. Indications for esophagectomy were carcinoma (n = 38), Barrett's esophagus with high-grade dysplasia (n = 3), and recalcitrant stricture (n = 5). Of 38 patients with carcinoma 23 (61%) had neoadjuvant therapy. The main outcome measures were operative time, blood loss, length of intensive care unit and hospital stay, conversion rate, morbidity, mortality, pathology, disease recurrence, and survival. RESULTS: Approaches to esophagectomy were thoracoscopic and laparoscopic esophagectomy (n = 41), thoracoscopic and laparoscopic Ivor Lewis resection (n = 3), abdominal only laparoscopic esophagogastrectomy (n = 1), and hand-assisted laparoscopic transhiatal esophagectomy (n = 1). Minimally invasive esophagectomy was successfully completed in 45 (97.8%) of 46 patients. The mean operative time was 350 +/- 75 minutes and the mean blood loss was 279 +/- 184 mL. The median length of intensive care unit stay was 2 days and median length of stay was 8 days. Major complications occurred in 17.4% of patients and minor complications occurred in 10.8%. Late complications were seen in 26.1% of patients. The overall mortality was 4.3%. Among the 38 patients who underwent esophagectomy for cancer the 3-year survival was 57%. In a mean followup of 26 months there was no trocar site or neck wound recurrences. CONCLUSIONS: A thoracoscopic and laparoscopic approach to esophagectomy is technically feasible and safe for the treatment of benign and malignant esophageal disease. With a mean followup of 26 months thoracoscopic and laparoscopic esophagectomy appears to be an oncologically acceptable surgical approach for the treatment of esophageal cancer.

Aggressive management of lung donors classified as unacceptable: excellent recipient survival one year after transplantation.

OBJECTIVE: A dire shortage of lungs for transplantation exists. We hypothesized that aggressive organ procurement organization management of lungs usually rated as unacceptable (ratio of Pao(2) to inspired oxygen fraction <150) might make them acceptable for transplantation. We also hypothesized that lungs from donors who died of trauma could be used for transplantation with recipient survival comparable with that seen with lungs from donors who died of nontraumatic causes. METHODS: From January, 1, 1995, through August 31, 2000, a total of 194 donors resulted in 228 lung transplants. Of these, 27 donors were deemed unacceptable for lung transplantation according to organ procurement organization protocol. We used the California Transplant Donor Network database to conduct a retrospective review of all 194 donors, including the 27 supposedly unacceptable donors who were treated with invasive monitoring (central venous pressure), methylprednisolone, fluid restriction, inotropic agents, bronchoscopy, and diuresis. We evaluated survivals at 30 days and 1 year of patients who received lungs rated as unacceptable and acceptable. In addition, we compiled data on recipient survival for a subgroup of 122 recipients with lungs from donors who died of trauma and compared these data with those of recipients who received lungs from donors who died of nontraumatic causes to see whether the donor's death by trauma resulted in higher recipient mortality. RESULTS: After aggressive organ procurement organization management, ratios of Pao(2) to inspired oxygen fraction, central venous pressures, fluid balances, dopamine requirements, and chest radiographs of unacceptable donors according to organ procurement organization criteria were comparable with those of acceptable donors. There were no significant differences in recipient mortality between groups at 30 days or 1 year after transplantation. Moreover, no significant difference was found in mortalities of recipients who received lungs from donors who died of traumatic and nontraumatic causes. CONCLUSION: Aggressive organ procurement organization management of donors initially considered unacceptable may increase the number of lungs available for transplantation.

Selective overexpression of inflammatory molecules in hearts from brain-dead rats.

BACKGROUND: Inflammatory processes that occur before, during, and after surgery may contribute to damage of transplanted hearts and their ability to withstand acute and chronic rejection. METHODS: We determined the expression of mRNA for 10 inflammatory indicator molecules in hearts from brain-dead animals in which stable circulation was maintained. To produce brain death in male rats (n = 11), we inflated an intracranial balloon with saline (245 microl +/- 27 microl) to produce apnea and areflexia. Mean arterial pressure was maintained at 80 +/- 2 mm Hg for 6 hours. Controls (n = 11) received a burr hole but no balloon (mean arterial pressure, 94 +/- 1 mm Hg). We measured expression of each indicator molecule mRNA relative to expression of glyceraldehyde-3-phosphate dehydrogenase mRNA using reverse-transcriptase polymerase chain reaction. RESULTS: Relative expression of intercellular adhesion molecule-1, vascular adhesion molecule-1, interleukin-1beta, and interleukin-6 mRNAs differed significantly (2.4 -4.6 times higher) between brain-dead and control hearts (p < 0.05; group t-test). CONCLUSION: Increases in the inflammatory cytokine, interleukin-1beta, whose mRNA also increased, may mediate the overexpression of the adhesion molecule and interleukin-6 mRNAs. The data suggest that endothelial cells become inflamed during brain death, even when the circulation is stable, which may lead to leukocyte-endothelial interactions during brain death or after graft transplantation.

Advantages of positron emission tomography over computed tomography in mediastinal staging of non-small cell lung cancer.

BACKGROUND: New treatment algorithms in early stage non-small cell lung cancer (NSCLC) involving preoperative chemotherapy require accurate clinical staging of the mediastinum. This study compares the accuracy of 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) scanning with that of computed tomography (CT) scanning in the clinical staging of non-small cell lung cancer. MATERIALS AND METHODS: A retrospective review was performed on 52 patients with NSCLC who were evaluated with both CT and PET scans. All patients had their mediastinal lymph nodes sampled by mediastinoscopy or at the time of thoracotomy for pulmonary resection. Each imaging study was evaluated separately and correlated with histopathologic results. RESULTS: For detecting mediastinal metastases the sensitivities of PET and CT scans were 67 and 50%, respectively; specificities were 91 and 65%, respectively; accuracies were 88 and 63%, respectively; positive predictive values were 50 and 16%, respectively; negative predictive values were 95 and 88%, respectively. PET scans were significantly better than CT scans at detecting mediastinal metastases (PET, 4/8; CT, 3/19) (P = 0.01). CONCLUSIONS: PET scanning is superior to CT scanning for clinical staging of the mediastinum in NSCLC. A more confident decision regarding stratification of patients into current treatment algorithms can be made when the decision is based on PET scanning rather than the current "gold standard" of CT scanning.