Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.

Alterations of p14ARF, p53, and p73 genes involved in the E2F-1-mediated apoptotic pathways in non-small cell lung carcinoma.

Overexpression of E2F-1 induces apoptosis by both a p14ARF-p53- and a p73-mediated pathway. p14ARF is the alternate tumor suppressor product of the INK4a/ARF locus that is inactivated frequently in lung carcinogenesis. Because p14ARF stabilizes p53, it has been proposed that the loss of p14ARF is functionally equivalent to a p53 mutation. We have tested this hypothesis by examining the genomic status of the unique exon 1beta of p14ARF in 53 human cell lines and 86 primary non-small cell lung carcinomas and correlated this with previously characterized alterations of p53. Homozygous deletions of p14ARF were detected in 12 of 53 (23%) cell lines and 16 of 86 (19%) primary tumors. A single cell line, but no primary tumors, harbored an intragenic mutation. The deletion of p14ARF was inversely correlated with the loss of p53 in the majority of cell lines (P = 0.02), but this relationship was not maintained among primary tumors (P = 0.5). E2F-1 can also induce p73 via a p53-independent apoptotic pathway. Although we did not observe inactivation of p73 by either mutation or DNA methylation, haploinsufficiency of p73 correlated positively with either p14ARF or p53 mutation or both (P = 0.01) in primary non-small cell lung carcinomas. These data are consistent with the current model of p14ARF and p53 interaction as a complex network rather than a simple linear pathway and indicate a possible role for an E2F-1-mediated failsafe, p53-independent, apoptotic pathway involving p73 in human lung carcinogenesis.

Nitric oxide synthase, cyclooxygenase 2, and vascular endothelial growth factor in the angiogenesis of non-small cell lung carcinoma.

We have investigated the hypothesis that nitric oxide synthase (NOS2), cyclooxygenase-2 (COX2), and vascular endothelial growth factor (VEGF) protein levels individually demonstrate a direct correlation with microvessel density (MVD) and clinical outcome in human non-small cell lung cancer (NSCLC). Furthermore, we hypothesized that MVD may explain the propensity of certain histological lung cancer subtypes for early metastasis via a hematological route. Immunohistochemically, we studied the protein expression levels of NOS2, COX2, and VEGF and MVD by counting CD31-reactive blood vessels (BVs) in 106 surgically resected NSCLC specimens. NOS2, COX2, and VEGF immunoreactivity were observed in 48, 48, and 58%, respectively, of the study subjects, and their levels correlated with MVD at the tumor-stromal interphase (P < or = 0.001). More adenocarcindmas and large cell carcinomas displayed overexpression of NOS2 when compared with squamous cell carcinoma (SCC; r = 0.44; P < 0.001). NOS2 and COX2 levels were found to correlate positively with VEGF status (r = 0.44; P < 0.001, 0.01, and 0.03, respectively). These results attest to the significant interaction of these factors in the angiogenesis of NSCLC. Although neither angiogenic factors nor MVD correlated with patient survival, the latter correlated with tumor clinical stage in both squamous (SCC; 73 BVs/mm2) and non-SCC (78 BVs/mm2) tumors. These results indicate that angiogenesis is a complex process that involves multiple factors including NOS2, COX2, and VEGF. Furthermore, the role of angiogenesis in the biology of various histological lung cancer types may be different. The complexity of angiogenesis may explain the modest results observed in antiangiogenesis therapy that target a single protein.

Anti-p53 antibodies in sera from patients with chronic obstructive pulmonary disease can predate a diagnosis of cancer.

Serum anti-p53 antibodies (p53-Abs) may be surrogate markers for both p53 alterations and preclinical cancer. Ancillary to a prospective trial to abate progressive development of clinical stages of chronic obstructive pulmonary disease, we conducted a retrospective, nested case-control study. Twenty-three cases were diagnosed with cancer during the trial. Enzyme immunoassay, immunoblotting, and immunoprecipitation were used to detect p53-Abs in serum, immunohistochemistry (IHC) to detect p53 accumulation, and single-strand conformation polymorphism and DNA sequencing to detect p53 mutations in tumor samples. p53-Abs were detected by three types of assays in five (23%) of the cancer patients, 80% of whom had detectable p53-Abs before diagnosis: 2 lung cancers (7 and 6 months before), 1 prostate cancer (11 months), and 1 breast cancer (5 months). Four Ab-positive patients had IHC-positive tumors. Two of 4 Ab-positive patients and 2 of 14 Ab-negative had p53 missense mutations or base pair deletion and IHC-positive tumors. The 44 noncancer COPD controls, matched with the cancer cases for age, gender, and smoking habits, were negative for p53-Abs. These results indicate that p53-Abs may facilitate the early diagnosis of cancer in a subset of smokers with chronic obstructive pulmonary disease who are at an increased cancer risk.

p21waf1/cip1 and transforming growth factor beta 1 protein expression correlate with survival in non-small cell lung cancer.

p21waf1/cip1 encodes a cyclin-dependent kinase inhibitor that is transcriptionally activated by the p53 tumor suppressor gene, transforming growth factor beta 1 (TGF-beta 1), AP2, and other pathways. Because p21waf1/cip1, p53, and TGF-beta 1 all regulate apoptosis and the cell cycle, we tested the hypothesis that their relative protein levels would correlate with biological features including the survival of non-small cell lung cancer (NSCLC) patients. We conducted an immunohistochemical analysis of p21waf1/cip1 and TGF-beta 1 and identified four patient groups with distinct survival outcomes. Concordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and high TGF-beta 1 expression or low p21waf1/cip1 and low TGF-beta 1 expression) predicted 70% disease-free survival at 2000 days of follow-up. Discordant p21waf1/cip1 and TGF-beta 1 expression (i.e., either high p21waf1/cip1 and low TGF-beta 1 expression or low p21waf1/cip1 and high TGF-beta 1 expression) predicted 35% disease-free survival (P = 0.0003; log-rank test). These survival relationships were not attributable to differences in grade, stage, or p53 status. Although current models do not fully explain these complex interactions, most of these data fit a paradigm whereby TGF-beta 1 regulation determines NSCLC survival. In addition to the survival correlation, we found that high p21waf1/cip1 protein expression correlated with high tumor grade (P = 0.014). There is little evidence that p21waf1/cip1 protein levels accurately predict p53 mutation status in NSCLC; specifically, 20 of 48 (42%) tumors with p53 mutations contained high levels of p21waf1/cip1 protein. These findings indicate that p21waf1/cip1 immunohistochemical analysis may provide useful information concerning the biological properties of NSCLC.

p53 mutation spectrum in relation to GSTM1, CYP1A1 and CYP2E1 in surgically treated patients with non-small cell lung cancer.

p53 mutation status was analysed in relation to DNA polymorphisms of GSTM1, CYP1A1 and CYP2E1 from 105 surgically resected non-small cell lung cancer cases. Demographic factors, smoking, occupation, family history, tumour histology, grade and stage were taken into account. p53 mutations, detected either directly by DNA sequencing (P = 0.04, adjusted for smoking) or indirectly by immunostaining (P = 0.06), were overrepresented among CYP1A1 variants. Mutations in exon 8 and transitions at CpG sites in the p53 gene were favoured in this subset. There was no relation between the individual gene polymorphisms or p53 mutations and disease-free survival by Kaplan-Meier analysis. The finding of excess CYP1A1 heterozygotes in individuals with p53 mutations after adjustment for smoking suggests that CYP1A1 activation contributes to lung cancer via p53 inactivation.

p53 mutations and occupational exposures in a surgical series of lung cancers.

p53 mutations are frequent in malignant lung tumors. Of 88 surgically treated lung cancers from cigarette smokers previously evaluated for p53 mutations, 45 tumors (51.1%) had mutations in exons 5-8 (D. G. Guinee, Jr. et al., Carcinogenesis (Lond.), 16: 993-1002, 1995). We report here the examination of 13 occupational exposures and 13 high-risk occupations in relation to these p53 mutations. Two molecular abnormalities were associated with occupational exposures: (a) G:C-->T:A transversions on the coding (nontranscribed) strand (n = 13) were associated with chromate exposure and employment in the metal industry (P < 0.05) and marginally associated with nickel exposure (P = 0.056); and (b) G:C-->A:T transitions at non-CpG sites (n = 9) were associated with work in the petrochemical industry (P = 0.05). No association was found between p53 mutations and gender, cigarette pack-years, tumor histology, age at diagnosis, or family history of lung cancer. Because all three chromate-exposed subjects had large cell carcinomas exhibiting G: C-->T:A coding-strand transversions, follow-up of a cohort with this exposure should clarify the association with the p53 gene.

Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone, metyrapone, and corticotropin-releasing factor.

Cushing's syndrome due to bronchial carcinoid tumors that secrete adrenocorticotropin (ACTH) may be difficult to distinguish from pituitary Cushing's disease, since the responses to dexamethasone and metyrapone are sometimes similar. Recently, the ACTH and cortisol responses to ovine corticotropin-releasing factor (oCRF) have been shown to be different in pituitary Cushing's disease than in Cushing's syndrome due to other causes. It is not known if the response to oCRF can distinguish pituitary Cushing's disease from those ACTH-secreting bronchial carcinoid tumors that respond to dexamethasone and metyrapone. A case of Cushing's syndrome due to an ACTH-secreting bronchial carcinoid is described in which the responses to dexamethasone, metyrapone, and oCRF were indistinguishable from the responses observed in pituitary Cushing's disease. A bronchial carcinoid tumor should be considered even when responses to dexamethasone, metyrapone, and oCRF suggest pituitary Cushing's disease.

In vivo quantitation of platelet deposition on human peripheral arterial bypass grafts using indium-111-labeled platelets. Effect of dipyridamole and aspirin.

Indium-111-labeled autologous platelets, injected 48 hours after operation, were used to evaluate the thrombogenicity of prosthetic material and the effect of platelet inhibitor therapy in vivo. Dacron double-velour (Microvel) aortofemoral artery bifurcation grafts were placed in 16 patients and unilateral polytetrafluoroethylene femoropopliteal grafts were placed in 10 patients. Half the patients in each group received platelet inhibitors before operation (dipyridamole, 100 mg 4 times a day) and after operation (dipyridamole, 75 mg, and acetylsalicylic acid, 325 mg 3 times a day); the rest of the patients served as control subjects. Five-minute scintigrams of the graft region were taken with a gamma camera interfaced with a computer 48, 72, and 96 hours after injection of the labeled platelets. Platelet deposition was estimated from the radioactivities of the grafts and expressed as counts per 100 pixels per microcurie injected. Dipyridamole and aspirin therapy significantly reduced the number of platelets deposited on Dacron grafts and prevented platelet accumulation over 3 days. With the small amount of platelet deposition on polytetrafluoroethylene femoropopliteal artery grafts even in control patients, platelet inhibitor therapy had no demonstrable effect on platelet deposition on these grafts. It is concluded that (1) platelet deposition on vascular grafts in vivo can be quantitated by noninvasive methods, and (2) dipyridamole and aspirin therapy reduced platelet deposition on Dacron aortofemoral artery grafts.

Thoracic wall defects: surgical management of 205 consecutive patients.

In this article, we review our experience during the past 9 years with 205 consecutive thoracic wall reconstructions. The 100 female and 105 male patients ranged in age from 12 to 85 years (mean, 53.4 years). One hundred fourteen patients had thoracic wall tumors, 56 had radiation necrosis, 56 had infected median sternotomy wounds, and 8 had costochondritis. Twenty-nine of these patients had combinations of the aforementioned conditions. One hundred seventy-eight patients underwent skeletal resection. A mean of 5.4 ribs were resected in 142 patients. Total or partial sternectomies were performed in 60. Skeletal defects were closed with prosthetic material in 66 patients and with autogenous ribs in 12. One hundred sixty-eight patients underwent 244 muscle flap procedures: 149 pectoralis major, 56 latissimus dorsi, 14 rectus abdominis, 13 serratus anterior, 8 external oblique, 2 trapezius, and 2 advancement of diaphragm. The omentum was transposed in 20 patients. The mean number of operations per patient was 1.9 (range, 1 to 8). The mean duration of hospitalization was 16.5 days. One perioperative death occurred (at 29 days). Four patients required tracheostomy. During a mean follow-up of 32.4 months, there were 49 late deaths, predominantly due to malignant disease. All 204 patients who were alive 30 days after operation had excellent surgical results at last follow-up examination or at the time of death due to causes unrelated to the reconstructive procedure.

Chondrosarcoma of the manubrium. Resection and reconstruction with pectoralis major muscle.

Chondrosarcomas of the sternum are best treated by resection with tumor-free margins. Reconstruction of the manubrium and superior aspect of the sternum is one of the most difficult challenges for the reconstructive surgeon. In the past, most of the structural stability following resection of this area has depended on the formation of dense fibrous tissue and scar. We presented a case of reconstruction of the bony defect with autogenous bone grafting in conjunction with transposition of the pectoralis major muscle for increased protection and stability of the chest wall as well as for nourishment for the bone graft.

Bronchial carcinoid tumors.

Bronchial carcinoid tumors, termed (incorrectly) "bronchial adenomas" in the past, are uncommon pulmonary neoplasms. These tumors are currently classified as neuroendocrine in origin because of their potential to form and sometimes secrete a variety of chemical substances. Overall, approximately 75% of bronchial carcinoid tumors arise in the lobar bronchi, 10% occur in the main-stem bronchi, and 15% originate in the periphery of the lung. Well-differentiated carcinoid tumors constitute almost 90% of all bronchial carcinoids. Atypical carcinoid tumors have a higher malignant potential than do typical bronchial carcinoids. The carcinoid syndrome is rarely, if ever, associated with carcinoids limited to the tracheobronchial tree. Occasionally, Cushing's syndrome due to ectopic hormone production is caused by bronchial carcinoid tumors. More than 75% of bronchial carcinoids are detected on conventional posteroanterior chest roentgenograms. Computed tomography may help disclose small neoplasms that are occult on conventional roentgenography, particularly in the assessment of patients who have Cushing's syndrome due to ectopic hormone production. Pulmonary resection is the treatment of choice for bronchial carcinoids. The prognosis is related to the pathologic grade and stage of the tumor.

Mediastinal parathyroid cysts.

OBJECTIVE: To present our experience with mediastinal parathyroid cysts and summarize previously reported cases. DESIGN: We retrospectively reviewed medical records and reviewed the pertinent literature. MATERIAL AND METHODS: The clinical, operative, and pathologic findings in 7 cases of mediastinal parathyroid cysts encountered at one institution and 31 cases previously reported in the literature are described. RESULTS: Rarely, cysts may arise from an aberrant mediastinal parathyroid gland. Such cysts may manifest as a symptomatic mass, as an asymptomatic finding on roentgenography, or during the assessment of a patient with hyperparathyroidism. The diagnosis may be made by fine-needle aspiration or by excision and pathologic examination. CONCLUSION: Functioning parathyroid cysts represent degeneration of a hyperfunctioning gland, such as an adenoma, and are usually removed through a cervical approach. Nonfunctioning cysts in asymptomatic patients with normal serum calcium levels are considered indeterminate and should be managed accordingly. Excision is usually recommended.

Video-assisted thoracic surgical procedure: management of a solitary pulmonary nodule.

Solitary pulmonary nodules continue to challenge all diagnostic skills. Herein we describe video-assisted thoracic surgical intervention, a new, minimally invasive technique that aids physicians in obtaining a definitive histologic diagnosis in a select group of patients with an indeterminate solitary pulmonary nodule.

Dirofilaria immitis: a rare, increasing cause of pulmonary nodules.

Dirofilariasis is an unusual but increasing cause of solitary pulmonary nodules. In this study, we reviewed the entire experience with dirofilariasis at our institution. Five such patients were identified. In all patients, the Dirofilaria immitis infection manifested as a solitary pulmonary nodule, and all patients underwent thoracotomy for diagnosis. None required systemic treatment. D. immitis is found in dog, cat, wolf, coyote, and fox populations throughout the United States, but the highest concentrations have been noted in the eastern, southeastern, and southern coastal states. The distribution of human cases of D. immitis infection has a similar pattern. Pulmonary dirofilariasis should be included in the differential diagnosis of peripheral noncalcified pulmonary nodules, especially in endemic areas.

Carcinosarcoma of the lung: Mayo Clinic experience and response to chemotherapy.

The clinical presentation, clinical course, and results of various treatment modalities of 17 patients with carcinosarcoma of the lung were reviewed. This group of patients was 0.2% of all Mayo Clinic patients with lung cancer who had been treated between 1971 and 1982. Most patients were men in the sixth decade of life who had a history of smoking. Ten of 17 neoplasms were located in the upper lobes. Noninvasive diagnostic tests had a low yield in detecting carcinosarcomas. Pulmonary resection with curative intent was performed in 15 of 17 patients; however, only 4 patients were alive at 6, 8, 28, and 39 months, respectively, postoperatively. The median survival was 1 year. Doxorubicin-based chemotherapeutic programs produced an objective response in two of four patients.

Aortic graft-enteric fistula.

Fifteen years' experience with 20 patients undergoing 24 operations for intestinal bleeding from aortic graft-enteric fistula at the Mayo Clinic has been reviewed. A review of the English language literature permits analysis of an additional 127 patients who underwent surgical intervention for this condition. Associated operative mortality in our experience and in that of others has been high--55% and 46%, respectively. Long-term survival in both groups remains low--approximately 15%. Consideration has therefore been given to aspects of prophylaxis, diagnosis, and intervention which may minimize future morbidity and mortality.

Horseshoe kidney associated with surgery of the abdominal aorta.

Of 53 patients with horseshoe kidney (9 in the present series), 45 underwent operation for an abdominal aortic aneurysm: 40 electively and 5 on an emergency basis. The remaining eight patients underwent revascularization for arteriosclerosis obliterans. Of the 53 patients, 35 (66%) had renal artery anomalies. The anomalous arteries prevented aortic repair in 6 patients (17%), were left undisturbed in 9 (26%), were revascularized in 7 (20%), and were ligated in 13 (37%). Partial nephrectomy was required in 2 of the 13 patients undergoing arterial ligation. Symphysiotomy was performed in 16 (30%) of the 53 patients. The following approach to management of horseshoe kidney associated with disease of the abdominal aorta is suggested. 1. Whenever a horshoe kidney is suspected, excretory urography, aortography, and, if necessary, selective renal arteriography should be obtained preoperatively. 2. Anomalous renal arteries arising from resected segments of the aorta should be revascularized whenever technically possible, usually by reimplantation of the renal artery into the aortic graft. 3. If an anomalous renal artery is ligated, the kidney should be inspected for signs of ischemia, and partial nephrectomy should be performed if ischemia occurs. 4. Symphysiotomy should be avoided. If division is necessary, symphysiectomy is preferable to symphysiotomy. In either circumstance, care need be taken lest there be fusion of the urinary collecting system and the renal parenchyma. In most patients with horseshoe kidney, aortic surgery has been accomplished without complication and with only minor alteration in surgical technique, even when the renal anomaly is first detected at surgical exploration.

Differential mechanical ventilation in respiratory failure due to severe unilateral lung disease.

Severe unilateral lung disease that produces respiratory failure may necessitate mechanical ventilatory support to sustain gas exchange. This article describes the successful use of differential lung ventilation in the management of one patient with diffuse unilateral pneumonia and another with a postoperative bronchopleural fistula after standard methods of mechanical ventilation failed to provide adequate gas exchange for these patients.

Abdominal angina and neurofibromatosis.

A young man with severe abdominal pain and weight loss due to intestinal ischemia was examined. At operation, the origins of the celiac and superior mesenteric arteries were found to be compressed by plexiform neurofibromatosis. Symptoms were relieved by reconstructive arterial surgery.