Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy.

PURPOSE: To determine the prognostic and predictive significance of p53 and K-ras mutations in patients with completely resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized preoperatively to receive adjuvant postoperative radiotherapy (Arm A) or radiotherapy plus concurrent chemotherapy (Arm B). p53 protein expression was studied by immunohistochemistry (IHC) and p53 mutations in exons 5 to 8 were evaluated by single-strand conformational analysis. K-ras mutations in codons 12, 13, and 61 were determined using engineered restriction fragment length polymorphisms. RESULTS: Four hundred eighty-eight patients were entered onto E3590; 197 tumors were assessable for analysis. Neither presence nor absence of p53 mutations, p53 protein expression, or K-ras mutations correlated with survival or progression-free survival. There was a trend toward improved survival for patients with wildtype K-ras (median, 42 months) compared with survival of patients with mutant K-ras who were randomized to chemotherapy plus radiotherapy (median, 25 months; P = .09). Multivariate analysis revealed only age and tumor stage to be significant prognostic factors, although there was a trend bordering on statistical significance for K-ras (P = .066). Analysis of survival difference by p53 by single-stranded conformational polymorphism and IHC, interaction of p53 and K-ras, interaction of p53 and treatment arm, nodal station, extent of surgery, weight loss, and histology did not reach statistical significance. CONCLUSION: p53 mutations and protein overexpression are not significant prognostic or predictive factors in resected stage II or IIIA NSCLC. K-ras mutations may be a weak prognostic marker. p53 or K-ras should not be routinely used in the clinical management of these patients.

Obliteration of empyema tract with deepithelialized unipedicle transverse rectus abdominis myocutaneous flap.

Four patients with chronic empyema after pneumonectomy have undergone successful obliteration of the empyema tract with a deepithelialized transverse rectus abdominis myocutaneous flap. The deepithelialized skin island has provided sufficient bulk for tract obliteration. Rotation of the skin island into the long axis of the rectus muscle has added considerable length to this flap, allowing it to reach the apex of the thoracic cavity. A recurrent loculation developed 4 months after the obliteration procedure in one patient. This was successfully treated with open pleural drainage and a second Clagett procedure. Over a mean follow-up period of 35 months, all four patients are free of further infectious sequelae. Chest roentgenograms have confirmed eradication of the tracts in all four patients.

Platelet aggregation inhibition in human umbilical vein grafts and negatively charged bovine heterografts.

Glutaraldehye-tanned human umbilical vein grafts (4 mm) and negatively charged bovine heterografts (4 mm) were placed as bypasses in the femoral arteries of 20 dogs randomized into 10 treated with aspirin and dipyridamole and 10 were not treated. Autogenous vein grafts were placed as controls. Platelet aggregation inhibition by aspirin and dipyridamole significantly improved the patency of human umbilical vein grafts from 10% to 60%. It had no effect on patencies of autogenous veins (100%) or on negatively charged bovine heterografts (0% patency). Inherent graft properties continue to play an important and sometimes overriding role in long-term graft patency in small vessel bypasses. Neointimal fibrous hyperplasia at both proximal and distal anastomoses again was shown to be intimately associated with late graft occlusions.

Predicted hyperemic angiography: a technique of distal arteriography in the severely ischemic leg.

A technique of distal arteriography in the severely ischemic leg has been developed by modifying hyperemic angiography. The postischemic hyperemic response can be measured for a given patient and the time fo maximum glow predicted. A study of 35 patients with severe ischemia has shown the maximum hyperemic response time (MHRT) to vary greatly among patients. Knowing the specific MHRT in advance has enabled us to inject contrast during maximum flow periods. The resulting predicted hyperemic angiograms provided visualization of the pedal arch in four extremities not visualized by conventional angiography. Predicted hyperemic angiography appears to provide a means of evaluating calf and pedal circulations in severely ischemic legs prior to surgery.

The role of thoracoscopy in the AIDS/immunocompromised patient.

A review of the thoracic complications associated with the immunosuppression seen in the setting of the acquired immunodeficiency syndrome (AIDS), transplantation, and cancer chemotherapy was undertaken to define the role of thoracoscopy and video-assisted thoracic surgery in this context. Pulmonary parenchymal disease, pleural effusions, pneumothorax, and pericardial effusions are the primary conditions in which thoracoscopy can be helpful. Thoracoscopic wedge biopsy can be used in patients with parenchymal disease when bronchoalveolar lavage, transbronchial biopsy, or an empiric trial of antibiotics fail to yield a diagnosis. If pleural effusions are loculated and highly fibrinous, effective drainage can be achieved thoracoscopically. Early bleb stapling and apical pleurectomy are often necessary in the management of AIDS-related pneumothorax and can be readily done using video-assisted thoracic surgical techniques. Successful thoracoscopy in the immunocompromised patient requires the ability to tolerate one-lung anesthesia, a manageable lung parenchyma, and a satisfactory coagulation profile.

Summary of current cooperative group clinical trials in thoracic malignancies. The Thoracic Intergroup.

Historically, thoracic surgeons have played a pivotal role in the success of clinical trials for early-stage thoracic malignancies. This is illustrated by the experience of the Veterans Administration Surgical Oncology Group and by the Lung Cancer Study Group. Since the dissolution of the Lung Cancer Study Group, the other cooperative groups have been unable to complete any large randomized trials because of a lack of surgical participation. A group of thoracic surgeons is now addressing this problem by unifying research efforts across the cooperative groups. The aim of this summary is to disseminate information about those efforts, and to encourage the involvement of North American thoracic surgeons in current clinical trials.

Reinfusion of shed blood after coronary operation causes elevation of cardiac enzyme levels.

We studied the effect of reinfusing mediastinal and chest tube drainage (autotransfusion) after coronary artery bypass grafting on circulating levels of creatine kinase, lactate dehydrogenase, and serum glutamic-oxaloacetic transaminase in 20 patients. Reinfusion of 469 +/- 171 mL (mean +/- standard deviation) of drainage caused enzyme levels to rise to 372% (creatine kinase), 159% (serum glutamic-oxaloacetic transaminase), and 143% (lactate dehydrogenase) of their levels before autotransfusion. The MB fraction of the circulating creatine kinase was not elevated. Enzyme changes caused by autotransfusion can potentially mimic or mask the presence of perioperative myocardial infarction. Enzyme determinations after coronary artery bypass grafting must be carefully interpreted when reinfusion of shed blood is used as a blood salvage technique. Routine measurement of these enzymes after operation may not be warranted.

Palliation of inoperable esophageal carcinoma with the Wallstent endoprosthesis.

BACKGROUND: Palliation of malignant dysphagia can be achieved by insertion of an endoprosthesis. Recently, metallic self-expanding prostheses have been introduced that offer the advantage of a lower complication rate over their plastic counterpart. METHODS: Thirteen patients with dysphagia due to inoperable carcinoma of the esophagus were treated with coated Wallstent (Schneider (USA) Inc, Minneapolis, MN) endoprostheses, which were placed under fluoroscopic control. All patients were given general anesthesia during the procedure. RESULTS: After successful insertion of all endoprostheses, the dysphagia of 12 of the patients improved while in the hospital. Average length of stay was 4.4 days. Two patients required a second stent because of migration or tumor overgrowth. Seven patients died with a mean survival of 54 days (range, 14 to 144 days), and 6 are alive a mean of 112 days (range, 32 to 263 days) after treatment. CONCLUSIONS: Coated Wallstent insertion is an effective, single treatment that quickly improves the patients' quality of life. Its effect on survival is yet to be established when used as a last resort in patients with inoperable esophageal carcinoma and poor general condition.

Trial of a novel synthetic sealant in preventing air leaks after lung resection.

BACKGROUND: Postoperative air leaks are a major cause of morbidity after lung resections. This study was designed to evaluate the efficacy and safety of a new synthetic, bioresorbable surgical sealant in preventing air leaks after pulmonary resection. METHODS: In a multicenter trial, 172 patients undergoing thoracotomy were randomized intraoperatively in a 2:1 ratio to receive surgical sealant applied to sites at risk for air leak after standard methods of lung closure (treatment group) or to have standard lung closure only (control group). The primary outcome variable was the percentage of patients free of air leakage throughout hospitalization. Secondary outcome variables were the control of air leaks intraoperatively and the time to postoperative air leak cessation. Time to chest tube removal, time to hospital discharge, and safety outcomes were also evaluated. RESULTS: Air leaks were identified before randomization in 89 of 117 patients in the treatment group and in 39 of 55 patients in the control group. Application of the sealant resulted in control of air leaks in 92% of treated patients (p < or = 0.001). A significantly higher percentage of treated patients than control patients remained free of air leaks during hospitalization (39% versus 11%, p < or =0.001). The mean times to last observable air leak were 30.9 hours in the treatment group and 52.3 hours in the control group (p = 0.006). In the treatment group, trends were observed for reduced time to chest tube removal and earlier discharge. No significant difference was identified in postoperative morbidity and mortality between the two groups. CONCLUSIONS: Air leaks after lung resection occur in most patients. The application of this novel surgical sealant appears to be effective and safe in preventing postoperative air leaks.

Comparison of platelet adherence and aggregation in modified human umbilical vein and autogenous vein grafts.

The use of glutaraldehyde-tanned human umbilical vein as a vascular conduit has recently become popular. In previous studies in our laboratory, neointimal fibrous hyperplasia was responsible for poor long-term patency of this material in a canine model. The present study was undertaken to compare the platelet-adhering characteristics of autogenous vein and modified human umbilical vein. After platelets were labelled with chromium-51, 10 mongrel dogs underwent bilateral end-to-side femoral artery bypass grafts. Human umbilical vein and autogenous jugular vein were placed in opposing groins of each dog. Two hours after graft implantation, the animals were killed and the grafts retrieved along with 1 cm of the host artery at each anastomosis. These specimens and an aliquot of blood were placed in a scintillation counter and radioactivity levels were determined. The human umbilical vein had significantly more platelet adherence than the autogenous veins as determined by counts per gram per 10 minutes. The handling characteristics of human umbilical vein were also suboptimal. Separation of the graft layers was occasionally observed, sometimes resulting in intramural hematomas and graft dissection. The previously reported poor performance of human umbilical vein in the canine model is most likely a result of its platelet-adhering surface and poor handling characteristics.

Neurologic complications in thoracic surgery.

In this article, a significant number of neurologic conditions have been presented that have importance to the thoracic surgeon. The most important point, however, is that most of the neurologic complications are avoidable by careful surgical technique and preoperative and postoperative care.

Chylothorax.

The management of chylothorax requires a thorough understanding of the anatomy and pathophysiology of the major thoracic lymphatics, prompt diagnosis, and (with rare exception) conservative management, including evacuation of the pleural space, nutritional support, and measures to reduce chyle production. A minority of chylothoraces will fail to resolve with these measures. Surgical intervention is then required to prevent chronic metabolic deterioration and death.

Photodynamic therapy for human malignant mesothelioma in the nude mouse.

Photodynamic therapy (PDT) utilizes a photoactivatable preparation, Photofrin II, which selectively localizes in cancerous tissue and produces substances toxic to that tissue when activated by light. Whether PDT would be able to selectively destroy human malignant mesothelioma was investigated by using a human-derived malignant mesothelioma tumor subcutaneously implanted in nude mice. Human malignant mesothelioma was grown subcutaneously to a size of 0.2-0.4 cm3. Selective retention of Photofrin II was studied by measuring light-induced inhibition of cytochrome c oxidase activity in tumor, heart, and lung. Photofrin II was retained in greater quantities in tumor than in heart or lung at 24 hr after injection. Using laser light at 630 nm under varying conditions, tumor growth was measured every 2 days following PDT for 18 days. All PDT regimens were successful in destroying malignant mesothelioma. Photofrin II at 5 mg/kg was superior to 2 mg/kg (P less than 0.005), light delivered at 50 mW/cm2 x 2 hr was superior to that delivered at 200 mW/cm2 x 30 min (P less than 0.05), and a total fluence of 180 J/cm2 was equivalent to 360 J/cm2 in affecting tumor growth. Ten of 12 mice treated at 50 mW/cm2 became tumor-free and remained so for 30 days following treatment. We concluded that PDT was effective against human malignant mesothelioma in a nude mouse model without adversely affecting the animal. A role for PDT in treating patients with malignant mesothelioma may exist.

The use of fiberoptic endoscopy in anesthesia.

The fiberoptic bronchoscope has contributed greatly to the practice of anesthesiology over the past 30 years. It has become an indispensable tool in the approach to the difficult airway, as well as the placement and positioning of double-lumen tubes for thoracic surgery. The equipment, preparation, and methods for using the endoscope in anesthesia, are presented here.

Effects of photodynamic therapy on xenografts of human mesothelioma and rat mammary carcinoma in nude mice.

We have examined the effectiveness of photodynamic therapy against R3230AC rat mammary adenocarcinoma and human mesothelioma as xenografts in the same host. The results demonstrate that the xenografted human tumour is significantly more responsive to photodynamic treatment than the rodent mammary tumour. Studies also showed that the mesothelioma xenograft was fluence rate- and fluence-dependent while the rat tumour exposed to the same conditions demonstrated neither of these dependencies. This disparity in response was not attributable to a difference in either whole-tumour uptake or subcellular distribution of the porphyrin photosensitiser. Analysis of the effects of visible irradiation on cytochrome c oxidase activity, measured in mitochondria prepared from tumours borne on hosts injected with photosensitiser, demonstrated that photoradiation-induced enzyme inhibition was significantly greater in mesothelioma than in R3230AC mammary tumour preparations. However, in parallel studies conducted in vitro, when photosensitiser and light were delivered to previously unperturbed mitochondria, rates of enzyme inhibition were not significantly different. Both tumours were established in long-term cell culture. While the uptake of porphyrin photosensitiser was equivalent in both cell lines, the R3230AC cells displayed a significantly greater photosensitivity than the mesothelioma cells. The data presented here demonstrate that the mechanisms that govern response to photodynamic therapy are complex, but in the case of these two xenografted tumours host response to therapy is not likely to play a significant role.

The effects of low-dose radiation on neointimal hyperplasia.

PURPOSE: We sought to determine whether low-dose radiation can inhibit neointimal hyperplasia immediately after balloon injury to the common carotid artery and to assess the extent of endothelial regeneration after treatment. METHODS: Sprague-Dawley rats were subjected to balloon injury to the common carotid artery. Immediately after injury rats were treated with a single dose of iridium 192 radiation at 5 gy, 10 gy, and 15 gy or received no radiation (control). Three weeks after injury and treatment, vessels were harvested and compartment areas were measured on fixed specimens. Scanning and transmission electron microscopy, along with Evans blue dye uptake into injured vessels, was used to assess the effect radiation had on endothelial regeneration. RESULTS: Rats receiving radiation at all three doses demonstrated no intimal thickening when compared with rats that were not treated (at 5 Gy 0.01 +/- 0.01 mm2; at 10 Gy 0.02 +/- 0.01 mm2; at 15 Gy 0.05 +/- 0.02 mm2; with balloon injury/no radiation 0.12 +/- 0.02 mm2; p < 0.01). In addition, the groups that were irradiated had no medial thickening when compared with control rats (at 5 Gy 0.22 +/- 0.02 mm2; at 10 Gy 0.21 +/- 0.02 mm2; at 15 Gy 0.22 +/- 0.07 mm2; with balloon injury/no radiation 0.37 +/- 0.03 mm2; p < 0.01). Endothelial regeneration, evaluated by transmission and scanning electron micrographs along with uptake of Evans blue dye, was significantly greater in animals that received radiation compared with controls. CONCLUSIONS: Low-dose radiation prevents the occurrence of neointimal hyperplasia after balloon injury and may have a future role in vascular grafting.