Thymectomy in the treatment of ocular myasthenia gravis.

BACKGROUND: Thymectomy is an effective and accepted treatment for myasthenia gravis, but thymectomy for ocular myasthenia gravis (Osserman stage I) is controversial. OBJECTIVE: To assess the efficacy and propriety of thymectomy for the treatment of ocular myasthenia gravis. METHODS: We conducted a review and follow-up of all patients who had thymectomy for the treatment of ocular myasthenia gravis between 1970 and 1998 at the University of California, Davis, Medical Center, and the University of Rome, "La Sapienza," Rome, Italy. Patient response to thymectomy was categorized as follows: cured, patients who became symptom-free and required no further medication; improved, patients who required less medication and whose symptoms were less severe; unchanged, patients whose symptoms and medications were the same; worse, patients who had more severe symptoms, needed more medication, or died. RESULTS: Sixty-one patients (mean age 37 years; range 14-73 years) were followed up for a mean duration of 9 years (range 0.5-29 years). Ocular myasthenia gravis with mixed and cortical thymomas, stages I to IV, occurred in 12 patients, and ocular myasthenia without thymomas occurred in 49 patients. Transsternal thymectomy (n = 55) and transcervical thymectomy (n = 6) resulted in cure in 31 (51%) patients, improvement in 12 (20%) patients, no change in 16 (26%) patients, and worsening of symptoms (including 1 postoperative death) in 2 patients. Patient outcomes were statistically independent of the duration of preoperative symptoms (mean 9.5 months), patient age, or the presence or absence of thymoma. In patients with ocular myasthenia, 70% were cured or improved after thymectomy; in the subgroup of patients with ocular myasthenia and thymoma, 67% were cured or improved. CONCLUSION: Thymectomy is an effective and safe treatment for patients with ocular myasthenia gravis.

The history of lung transplantation.

Experimental lung transplantation began in the former Soviet Union in 1946. Experiments in the 1950s sought to understand the physiology and to master the technique of reimplantation. Study of the immunology of allografting in the 1960s lead to the first lung transplantation in a human in 1963 in the United States. Palliative lung transplantation was first reported from Canada in 1986 after the advent of effective and tolerable immunosuppressive regimens. Lung transplantation in centers of excellence is now an effective palliative method for more than 80% of carefully selected recipients. Widespread transplantation to treat end stage pulmonary dysfunction is impossible because of too few organ donors and imperfect management of rejection and infection.

Role of bronchial artery embolization in the management of hemoptysis.

OBJECTIVE: To assess the modern morbidity of hemoptysis and the contribution of therapeutic bronchial artery embolization to its management. METHODS: Medical record review of patients admitted for the treatment of hemoptysis from January 1991 to November 1995 and of patients who had therapeutic bronchial artery embolization from June 1986 to August 1995. Hemoptysis was labeled major or minor. RESULTS: A total of 138 patients were admitted with hemoptysis, 31 with major and 107 with minor hemoptysis. No emergency pulmonary resections were required. Mean follow-up was 13.5 months. Mortality was 29.7% (41/138) but was caused by bronchial bleeding in only 4.3% (6/138). Twenty-six patients underwent therapeutic bronchial artery embolization (mean follow-up [range], 14 months [0.3-69.0 months]). The initial success rate (no further bleeding during the initial admission) was 85% (22/26). The long-term success rate (no further bleeding during follow-up) was 58% (15/26). Only 2 patients with therapeutic bronchial artery embolization died of further hemoptysis. CONCLUSIONS: Hemoptysis signals life-threatening diseases. Therapeutic bronchial artery embolization is a good treatment adjunct to control bronchial bleeding and reduces the need for high-risk emergency lung resections.

Clonal origin of multiple lung cancers: K-ras and p53 mutations determined by nonradioisotopic single-strand conformation polymorphism analysis.

Disease stage is the most important factor in determining prognosis and treatment of lung cancer. Staging of lung cancer is complicated by presentation of multiple pulmonary malignant lesions with a similar histology. It is a dilemma to decide if these lesions are synchronous primaries arising from different malignant clones or metastases from a single clone. Lung cancer is associated with multiple genetic abnormalities including mutations of K-ras and p53, which are believed to occur prior to onset of metastasis. To determine the clonal origin of multiple pulmonary malginant nodules, we analyzed point-mutations of K-ras and p53 by microdissection, polymerase chain reactions (PCR), nonradioisotopic single-strand conformation polymorphism (SSCP) analysis, and DNA sequencing. Each pulmonary lesion was microdissected from paraffin slides. Genomic DNA was amplified by two sequential PCRs followed by electrophoresis in a minigel and silver staining. Deoxyribonucleic acid sequencing was performed if necessary to confirm a mutation found upon SSCP analysis. Applying this molecular approach, we were able to differentiate the clonal origins of multiple malignant nodules of the lung as exemplified by the two cases presented.

The alveolar type II cell is a pluripotential stem cell in the genesis of human adenocarcinomas and squamous cell carcinomas.

Studies in a canine bronchogenic carcinoma model indicate that alveolar type II cells may differentiate from carcinogen-exposed epithelium of larger bronchi and generate adenocarcinomas with bronchioloalveolar and other growth patterns. In this study, we investigated whether type II cells are one of the major proliferating cells (= stem cells) in the genesis of two major subsets of bronchogenic carcinoma in humans. Adenocarcinomas (17 bronchioloalveolar; 3 papillary; and 10 other) and squamous cell carcinomas (n = 27) as well as (pre)neoplastic lesions in adjacent bronchi and bronchioles were examined for the presence of type II cell markers and cellular proliferation markers (PCNA; Ki-67) using light and electron microscopy and immunohistochemistry. Distinctive features of type II cells, which do not depend upon the degree of cell maturity, are the approximately cuboid shape, large and roundish nucleus, cytoplasmic staining for surfactant protein A (SP-A), and presence of multilamellar bodies or their precursory forms. Cells with this phenotype were found in early progressive (i.e., dysplastic, in situ, microinvasive) lesions in conducting airways and in all the carcinomas investigated, although with a much greater abundance among glandular lesions compared to squamous lesions. The most consistent sites of type II cells were the basal and adjacent epithelial layers. Nuclear PCNA (Ki-67) expression usually predominated in the same region. None of the lesions displayed specific Clara cell features. Our findings strongly suggest that the type II cell is a pluripotential stem cell in human lung carcinogenesis. Based on our findings in humans and dogs, we postulate that type II tumor stem cells may originate from one of two sources: (1) normal bronchial epithelium (by an oncofetal mechanism of differentiation); and (2) normal alveolar type II cells.

Bronchial carcinogenesis in syngeneic hamsters.

Endobronchial sustained release implants of carcinogen were placed in males (m) and females (f) of four varieties of syngeneic hamsters: BIOF1D; BIO87.20; BIO1.5; BIO15.16. The sequential progression of carcinogenesis that occurred was faster for 1.5m than for 1.5f (P = 0.01) and less rapid for 15.16m than for 87.20m and F1Dm (P < 0.05). Fewer invasive cancers occurred in 15.16m than in the other male varieties (P < 0.01), in 1.5m than in 87.20m (P < 0.05), and in 87.20f than in 87.20m (P < 0.05). Adenocarcinoma occurred with greater frequency in the 1.5 variety than in the F1D variety (P < 0.05). Significant variability in susceptibility, incidence, and types of invasive cancers formed exists, providing new opportunities for further study of bronchial carcinogenesis.

Surgical management and treatment of esophageal fistula.

Esophageal fistula may involve the respiratory or cardiovascular system. Fistulas involving the respiratory system which originate from esophageal cancers are the most common. Diagnosis is best made with barium esophagogram. ERF of any cause usually leads to repetitive contamination of the respiratory tract, resulting in sepsis and death of the patient if untreated. In the case of MERF, whether from esophageal or lung cancer, only palliative treatment is usually possible. Better results, including cure, may be expected when a MERF is caused by lymphoma. Curative operation with closure of the fistula is usually possible for BERF if the fistula is identified and treated before irreversible damage has been done by infection, sepsis, and malnutrition. Esophagocardiovascular fistulas occur infrequently in comparison with ERF. These may involve the aorta, usually as a result of a thoracic aneurysm. Rarely one may encounter esophageal fistula to the pericardium or heart. Few survivors have been reported, but successful management is possible if early diagnosis is made and prompt surgical management is undertaken.

Comparison of DNA topoisomerase II alpha expression in small cell and nonsmall cell carcinoma of the lung. In search of a mechanism of chemotherapeutic response.

BACKGROUND: Small cell carcinoma of the lung (SCLC) is distinguished from nonsmall cell carcinoma (NSCLC) by its exquisite initial sensitivity to chemotherapy. Antineoplastic drugs effective against SCLC include doxorubicin, etoposide, and others. Recently, the molecular target of these drugs has been identified as the alpha form of DNA topoisomerase II, which is important in DNA replication and in the separation of chromosomes during normal cellular division. In this study we compared DNA topoisomerase II alpha expression in SCLC and NSCLC by immunohistochemistry. We hypothesized that the sensitivity of SCLC and relative insensitivity of NSCLC to these chemotherapeutic agents stem from different frequencies of DNA topoisomerase II alpha expression. METHODS: DNA topoisomerase II alpha expression was analyzed in 17 cases of SCLC and 24 cases of NSCLC by immunohistochemistry utilizing a monoclonal antibody recognizing the alpha isoform of DNA topoisomerase II. A topo II index was determined by dividing the number of tumor nuclei expressing DNA topoisomerase II by the total number of tumor nuclei counted. RESULTS: A significantly higher frequency of DNA topoisomerase II alpha expression was identified in SCLC (P < 0.001). The average topo II index for SCLC was 0.60 (range: 0.45-0.76) compared with NSCLC, 0.31 (range: 0.05-0.75). CONCLUSIONS: We conclude that DNA topoisomerase II alpha is expressed at a higher frequency in SCLC than in NSCLC, and that this expression is possibly involved in the response of SCLC to chemotherapeutic agents.

Multimodality therapy in stage III non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer commonly presents as locally advanced disease. This category of tumors is heterogeneous. Although some patients clearly benefit from operative management alone, the vast majority (more than 90%) will succumb to their disease within 5 years. In the past decade a large clinical research effort has been undertaken in an attempt to improve on this outcome using a combination of chemotherapy, radiotherapy, and operation. METHODS: The English-language literature was reviewed using the headings for lung neoplasms and text words combined modality therapy and multimodality therapy. In addition, the bibliographies of relevant articles were reviewed. Emphasis was placed on prospective randomized trials and large phase II studies. We review the rationale, design, and outcome of these trials, including both operative and nonoperative approaches. RESULTS: Several prospective, randomized trials now demonstrate an advantage to combined modality management over radiotherapy or operation alone when a cisplatin-based chemotherapy regimen is incorporated into the treatment plan. This advantage was seen using both operative and nonoperative approaches. CONCLUSIONS: Combined modality therapy offers an improved outcome for patients with stage III non-small cell lung cancer. Whether both operation and radiotherapy are needed for local control, the best sequence of treatment and the optimal chemotherapy regimen remain to be defined.

Alveolar stem cells in canine bronchial carcinogenesis.

Alveolar type II cells are not present in normal epithelium of canine segmental bronchi but after carcinogen exposure they do occur in intra-epithelial lesions with all degrees of atypia and in invasive lesions with different glandular growth patterns. Immunohistochemistry for proliferation markers (PCNA; Ki-67) strongly suggest that such novel type II cells are pluripotential stem cells in canine bronchial carcinogenesis. Very likely, bronchial carcinogenesis is subject to an oncofetal mechanism of differentiation: bronchial epithelial retrodifferentiation followed by novel differentiation of alveolar tumor stem cells.

Loss of nm23 and Alu DNA in human lung cancer propagated in nude mice.

Freshly resected human non-small cell lung cancer (NSCLC) has been successfully transplanted and propagated subcutaneously in nude mice (Cancer Letters 61 (1991) 53-60). We used this model to study the changes of the human metastasis suppressor genes, nm23-H1 and nm23-H2, through the process of propagation and metastasis of human NSCLC. Using a non-radioisotopic Southern analysis, the nm23-H1 and nm23-H2 genes were detected without evidence of deletion in the early generations of the tumor grafts. These genes, however, were absent from the tumor grafts sampled past 4 generations of propagation and from all the propagated metastases originated from the subcutaneous grafts. Further restriction analysis revealed that only mouse DNA, but no human Alu DNA, was present in the tumor specimens which lacked the human nm23 genes. Thus, there is a loss of human DNA but a gain of mouse DNA in the propagated tumors originated from the transplanted human NSCLC. The mechanisms of loss of human DNA in these propagated tumors in nude mice have yet to be delineated.

Histogenesis of adenosquamous bronchogenic carcinoma.

In our hamster lung cancer model studies, among 463 non-small-cell lung cancers (NSCLC), there were 47 adenosquamous neoplasms. In 24 of 27 lesions with diameters of less than 3.0 mm, the adenocarcinoma and the squamous cell carcinoma components arose as separate, spatially discrete lesions, but these were separate in only 7 of 20 lesions with diameters of 30 mm or greater. Co-infiltration of the components became more frequent as tumor size increased. The usual adenosquamous variety of NSCLC is likely a collision tumor, with each component possessing separate biological characteristics. Thus, future prognostically directed studies of this variety of NSCLC must recognize that these neoplasms have two components, each of which needs to assessed.

Successful xenotransplantation of human lung cancer correlates with the metastatic phenotype.

BACKGROUND: Occult micrometastases could explain deaths from stage I non-small cell lung cancer (NSCLC) after complete resections. If patients who have occult metastases could be identified, systemic therapy might be beneficial. METHODS: Non-small cell lung cancers from 81 patients in stages I, II, and III were transplanted to nude beige mice. Mean follow-up was 22.5 months (2 to 61 months). RESULTS: Twenty-one xenotransplants successfully took, and seven metastasized in the nude mice. Neither the predominant cell type nor the incidence of lymph node metastases correlated with the results of xenotransplantation. Of the 21 patients whose NSCLCs took in xenotransplantation, 13 (61.9%) have had development of metastases, and 9 (42.9%) have died of the cancer. Among the 57 patients whose NSCLCs did not take, 14 (24.6%) have had development of metastases, and 9 (15.8%) have died of their cancer. The higher incidence of metastases in association with xenotransplant take is significant (p = 0.0032). CONCLUSIONS: Patients whose NSCLCs take in xenotransplantation are at high risk for metastases. The xenotransplantation model is a step toward facilitating precise cellular biologic definition of the metastatic propensity of human NSCLC: