Comparison of DNA adducts and sister chromatid exchange in lung cancer cases and controls.

In a molecular epidemiological study of lung cancer cases (n = 81) and noncancer controls (n = 67), polycyclic aromatic hydrocarbon (PAH)-DNA adducts were evaluated in peripheral blood leukocytes from all subjects and in a smaller number of lung tissue specimens collected prior to or at surgery. Sister chromatid exchanges (SCE) in lymphocytes were also studied in a subset of cases and controls. Questionnaire, medical record, or tumor registry data provided a family history of cancer, as well as information on cigarette smoking, dietary and occupational exposure to PAHs, and other factors related to SCEs. In both cases and controls PAH-DNA adducts in leukocytes measured by an enzyme-linked immunosorbent assay were not significantly related to age, sex, ethnicity, amount of cigarette smoking, passive smoking, dietary charcoal, or caffeine consumption. Nor did family history of cancer or histological type of cancer significantly affect adduct levels. However, when subjects were stratified by smoking status (current, former, and nonsmoker), lung cancer cases who were current smokers had significantly higher levels of covalent adducts than current smoker controls. A seasonal variation was observed in PAH-DNA binding, with a peak in adduct levels during July-October. This peak corresponds to that seen in a prior study of aryl hydrocarbon hydroxylase inducibility by other investigators. The finding of significant levels of PAH-DNA adducts in former smokers and non-smokers supports an earlier observation that this marker is not smoking specific but reflects a pervasive and variable "background" exposure to PAH. These results are consistent with a genetically determined enhancement of PAH-DNA adduct formation in leukocytes of lung cancer cases which is evident in current smokers. The results in lung tissue are limited by the small number of samples. Adduct levels were not significantly increased in lung tissue of smokers compared with nonsmokers. An inverse linear correlation was seen between adduct values in lung tissue and age of the donors. SCEs were significantly related to pack years of smoking. However, there was no difference in the frequency of SCE between cases and controls; nor were SCE and DNA adducts significantly correlated in this small sample.

A molecular epidemiological case-control study of lung cancer.

Polycyclic aromatic hydrocarbon-DNA adducts were measured by ELISA in peripheral leukocytes from 119 non-small cell lung cancer patients and 98 controls at the Columbia-Presbyterian Medical Center. Thirty-one cases had adduct measurements in leukocytes, lung tumor, and nontumor specimens collected at surgery, and 34 had paired leukocyte and tumor specimens. Information on smoking, diet, and occupational exposure was collected. After adjustment for age, gender, ethnicity, season, and smoking, adducts in leukocytes were significantly higher in cases (P < 0.01) than controls; the odds ratio was 7.7 (95% confidence interval = 1.7-34; P < 0.01). Adducts in leukocytes were increased significantly in smokers and ex-smokers compared to nonsmokers among cases and controls (separately and combined) after adjusting for age, gender, ethnicity, and season (P < 0.05). The cases and controls differed in several respects: (a) adducts increased with the number of cigarettes smoked among the 51 cases who were current smokers (P = 0.05) but not among the current smokers in the controls; and (b) a seasonal variation in DNA binding, corresponding to that reported for aryl hydrocarbon hydroxylase inducibility, was observed in cases but not in controls. Among the cases, adducts in leukocytes were correlated more strongly with adducts in the lung tumor tissue than with those in nontumor lung tissue. The results in leukocytes are consistent with a constitutional susceptibility to lung cancer, which results in greater DNA damage from carcinogens in cigarette smoke. They suggested that it may ultimately be possible to use biomarkers such as adducts to identify individuals who would benefit most from early intervention.

Myasthenia gravis: determinants for independent ventilation after transsternal thymectomy.

We evaluated the respiratory function of 32 patients with myasthenia gravis who had transsternal thymectomy. Preoperative clinical, pulmonary function, and respiratory muscle pressure data were submitted to stepwise logistic regression analysis to identify preoperative factors that correlated with duration of supported ventilation after surgery. Ten patients (31%) had postoperative supported ventilation for more than 3 days. The duration of ventilatory support correlated most closely with maximal static expiratory pressure (r = 0.714, p less than 0.001). Expiratory weakness, by reducing cough efficacy, seems to be the main determinant that predicts need for longer postoperative supported ventilation.

Seronegative myasthenia gravis.

Of 221 patients with myasthenia gravis, 18.5% had no detectable antibodies to acetylcholine receptor. Seven of 14 patients (50%) with only ocular symptoms for more than 2 years were seronegative, and 25 of 145 (17%) patients with generalized myasthenia were seronegative. The clinical characteristics of seronegative patients did not differ from patients with high antibody titers. No seronegative patient had a thymoma, but that difference did not reach statistical significance. Lack of serum antibodies did not preclude favorable response to thymectomy or plasmapheresis.

Restriction fragment length polymorphism of chromosome 3 (3p) and the epidermal growth factor receptor gene in human non-small cell lung carcinomas.

We have examined the possible loss of 3p alleles in lung tumor samples from 28 patients with non-small cell lung cancers (non-SCLC), using tumor adjacent lung tissue from the same patients as controls. Of the 14 patients with squamous cell carcinoma only 2 (14%) displayed constitutional heterozygosity at the 3p locus and the tumors of both of these cases did not show reduction to homozygosity. Of the 14 patients with adenocarcinomas, 50% had constitutional heterozygosity, and two of the tumors displayed a loss of heterozygosity. We have also examined restriction fragment length polymorphisms (RFLPs) of the epidermal growth factor (EGF) receptor gene in 29 non-SCLC tumor samples and in the tumor adjacent lung tissue samples obtained from the same cases. Digestion of the DNA samples with the BstEII enzyme and hybridization to a HER-A64-3 probe revealed four different types of polymorphic patterns. We did not, however, detect significant differences in the specific polymorphic bands between tumor and paired non-tumor lung tissues or between the different types of carcinomas.

"Maximal" thymectomy for myasthenia gravis. Surgical anatomy and operative technique.

Removal of all thymic tissue is the goal of surgical treatment of myasthenia gravis. In this report we describe an operation that predictably achieves that goal in most patients. The results of surgical-anatomic studies in 50 consecutive specimens obtained by this technique indicate that an en bloc transcervical-transsternal "maximal" thymectomy is required to ensure removal of all available thymus in all patients. This procedure is recommended for all patients undergoing thymectomy in the treatment of myasthenia gravis with or without thymoma and in the treatment of thymoma with or without myasthenia gravis.

Pectus excavatum. Late results with and without operation.

The records were reviewed of 334 patients with a diagnosis of pectus excavatum at Presbyterian Hospital in New York, New York, from 1948 through 1977. No operation was done on 168; 174 operations were done on 166. In those not operated upon 18% of infants died of associated anomalies. The deformity improved or disappeared in half of the surviving infants and in some children up to the age of 6 years. Thereafter, it remained the same or worsened. Mild deformities were compatible with long life without symptoms; severe deformities were associated with chronic disability. In those operated upon, there was no surgical mortality. Results were satisfactory 5 plus years after operation in 68 of 102 patients. Late results deteriorated through adolescence and were more clearly related to method of correction than to sex, severity, age at operation, or time after operation. It is concluded that (1) operation is justified in appropriate cases; (2) it is seldom indicated before the age of 3 years; (3) results are best following operations between ages 3 and 6 years, although they may be satisfactory at any age; (4) results of radical operations are superior to results of simpler ones; and (5) better objective methods of evaluation over many years are needed to judge the value of any procedure.

"Maximal" thymectomy for myasthenia gravis. Results.

Thymectomy has been shown to be effective in the treatment of myasthenia gravis. The logical goal of operation has been complete removal of the thymus, but there has been controversy about the surgical technique and its relation to results. Surgical-anatomic studies have shown gross and microscopic thymus widely distributed in the neck and mediastinum. We believe that an en bloc transcervical-transsternal "maximal" thymectomy is required to remove all thymic tissue predictably. Ninety-five patients with generalized myasthenia gravis underwent "maximal" thymectomy consecutively between 1977 and 1985 and were evaluated 6 months to 89 months after operation. In Group A (N = 72), myasthenia gravis without thymoma, the uncorrected data revealed that 96% (69) had benefited from operation: 79% (57) had no symptoms; 46% (33) were in remission; 33% (24) were symptom free when receiving minimal doses of pyridostigmine; and none were worse. Life table analysis yielded a remission rate of 81% at 89 months. In group B (N = 8), myasthenia gravis without thymoma for which patients underwent reexploration for incapacitating weakness after earlier transcervical or transsternal operations, residual thymus was found in all. One patient was in remission, two were symptom free when receiving medication, one was unchanged, and none were worse. In group C (N 15), myasthenia gravis and thymoma, two patients were in remission and nine were symptom free when receiving medication. Two patients in this group died 2 and 4 years postoperatively in crisis. Response to thymectomy in group A was greater in patients with mild myasthenia gravis and may have been better in patients who had symptoms for less than 60 months preoperatively, but the response did not depend on age, sex, presence or absence of thymic hyperplasia or involution, or titers of acetylcholine receptor antibodies. The response to thymectomy in group B was striking but slower than in group A, perhaps because symptoms were more severe and of longer duration. The response in group C was also less good than in group A and proportionately fewer benefited. These results support the recommendation for thymectomy in the treatment of patients with generalized myasthenia gravis and indicate the desirability of a maximal procedure. For persistent or recurrent severe symptoms after previous transcervical or submaximal transsternal resections, reoperation by this technique is also recommended.

Thymic abnormalities: antigen or antibody? Response to thymectomy in myasthenia gravis.

The therapeutic value of thymectomy for myasthenia is still questioned although it retains an important place among management modalities that strive for sustained remission. Questions derive from uncertainty as to appropriate timing, variable extent of resection and quantitation of response. Forty-seven patients, followed one to seven years, underwent an extended transsternal or combined transcervical-transsternal procedure with anterior mediastinal exenteration. Sixteen have been in complete remission from six months to six years, four are asymptomatic on occasional pyridostigmine and eight are significantly improved. Evaluation of thymic pathology (hyperplasic, involuted areas, and thymoma) included a search for thymic myoid cells by fluorescence cytochemistry. Antibodies to acetylcholine receptor present in 38 of 43, decreased post-operatively to normal in four, by 50% to 80% in 14, by 20 to 50% in three and were unchanged in 14. Most remissions occurred in young women with noninvoluted hyperplastic glands and variably high anti-AChR titers which dropped toward normal in seven of 15. These results encourage us to utilize this procedure routinely.

A rational approach to total thymectomy in the treatment of myasthenia gravis.

Thymectomy is important in the treatment of myasthenia gravis. Total removal of the gland is considered indicated. Although median sternotomy has been the accepted surgical procedure, the transcervical approach has been advocated as a safer method of achieving total thymectomy. A surgical-anatomical study of the thymus was made in 22 patients. A high incidence of surgically important variations in thymic anatomy was found in the neck and in the mediastinum. We believe wide exposure by way of median sternotomy with direct vision is required to remove all of the extracapsular mediastinal thymus in many patients, and good cervical exposure is required to remove the anomalous tissue in the neck. If a total thymectomy is to be achieved, we recommend a median sternotomy and a cervical incision, using the meticulous dissection described.