Biomedical subjects
Publications and source records attributed to D J Sugarbaker.
In patients who can tolerate single-lung ventilation and who have a long life expectancy, VATS offers definitive and durable treatment without the morbidity of an open thoracotomy. The patients who may benefit most from this technique include those with benign effusive disease, patients with malignant pericardial effusions with a good prognosis, and patients with concurrent pulmonary pathology.
BACKGROUND: Effusions in patients with esophageal carcinoma have only been reported rarely, and the cytologic findings in these specimens have not been well described. METHODS: The authors reviewed 70 effusion specimens from 45 patients with known esophageal carcinoma, 37 of whom underwent resection. RESULTS: Seventeen specimens were from 10 patients with squamous cell carcinoma; only 1 specimen contained malignant cells. Fifty-three specimens were from 35 patients with adenocarcinoma. Twenty-one specimens from 10 patients with adenocarcinoma contained malignant cells; these included 17 pleural, 2 pericardial, and 2 peritoneal fluids. Lymph node involvement at the time of resection was a significant risk factor for the development of a malignant effusion. The cytologic features were similar to those of other adenocarcinomas, but >50% of the specimens were hypocellular and neoplastic cells were rare. Three of 48 negative specimens contained markedly atypical mesothelial cells that were misinterpreted as possibly malignant; in each case the findings resolved over time. These cells were smaller and the chromatin more smudgy than in the neoplastic cells. Patients with positive effusions were significantly more likely to die of disease than those with a negative effusion, and the average time to death was shorter (5.3 months vs. 17 months). CONCLUSIONS: Malignant effusions are more common in patients with esophageal adenocarcinoma than those with squamous cell carcinoma. Markedly atypical mesothelial cells are a diagnostic pitfall in patients who undergo resection.
Transient pulmonary neuroendocrine cell hyperplasia and non-neuroendocrine lung tumors develop in nitrosaminetreated hamsters, which we hypothesized might modulate epithelial cell phenotype by expressing gene(s) homologous to human chromosome 3p gene(s) deleted in small cell carcinoma of the lung (SCLC). We differentially screened a chromosome 3 library using nitrosamine-treated versus normal hamster lung cDNAs and identified hepatocyte growth factor-like/macrophage-stimulating protein (HGFL/MSP) in injured lung. HGFL/MSP mRNA is low to undetectable in human SCLC and carcinoid tumors, but the HGFL/MSP tyrosine kinase receptor, RON, is present and functional on many of these neuroendocrine tumors. In H835, a pulmonary carcinoid cell line, and H187, a SCLC cell line, HGFL/ MSP induced adhesion/flattening and apoptosis. Using viable cell counts to assess proliferation after 14 d of treatment with HGFL/MSP, there is growth inhibition of H835 but not H187. Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia. These observations suggest that HGFL/MSP might regulate neuroendocrine cell survival during preneoplastic lung injury, which could influence the ultimate tumor cell phenotype.
BACKGROUND: Malignant pleural mesothelioma is uncommon, and presently, no standard treatment of this disease exists. The objective of our analysis was to study the patterns of failure for malignant pleural mesothelioma after trimodality treatment consisting of extrapleural pneumonectomy, chemotherapy, and radiation therapy. METHODS: Between 1987 and 1993, 49 patients with malignant pleural mesothelioma underwent extrapleural pneumonectomy. There were two perioperative deaths, and 1 patient died 5 weeks after extrapleural pneumonectomy. Thirty-five of the surviving patients received adjuvant chemotherapy (32/35 received cyclophosphamide, doxorubicin, and cisplatin) followed by hemithorax radiation therapy. Ten patients received chemotherapy but no radiation therapy, and 1 patient received no adjuvant therapy. Median follow-up time for the 23 living patients from the date of operation was 18 months. RESULTS: Of the 46 evaluable patients, 25 had recurrence (54%), with a median time to first failure of 19 months (range, 5 to 51 months). The sites of first recurrence were local in 35% of patients, abdominal in 26%, the contralateral thorax in 17%, and other distant sites in 8%. (Some patients had recurrence in multiple sites simultaneously.) CONCLUSIONS: The most common site of failure after trimodality therapy was the ipsilateral hemithorax. Isolated distant failures were uncommon. Future strategies should investigate methods of enhancing local tumor control.
BACKGROUND: The role of nonanatomic wedge resection in the management of stage I (T1 N0 M0) non-small-cell lung cancer continues to be debated against the present gold standard of care--anatomic lobectomy. METHODS: We analyzed the results of 219 consecutive patients with pathologic stage I (T1 N0 M0) non-small-cell lung cancer who underwent open wedge resection (n = 42), video-assisted wedge resection (n = 60), and lobectomy (n = 117) to assess morbidity, recurrence, and survival differences between these approaches. RESULTS: There were no differences among the three groups with regard to histologic tumor type. Analysis demonstrated the wedge resection groups to be significantly older and to have reduced pulmonary function despite a higher incidence of treatment for chronic obstructive pulmonary disease when compared with patients having lobectomy. The mean hospital stay was significantly less in the wedge resection groups. There were no operative deaths among patients having wedge resection; however, a 3% operative mortality occurred among patients having lobectomy (p = 0.20). Kaplan-Meier survival curves were nearly identical at 1 year (open wedge resection, 94%; video-assisted wedge resection, 95%; lobectomy, 91%). At 5 years survival was 58% for patients having open wedge resection, 65% for those having video-assisted wedge resection, and 70% for those having lobectomy. Log rank testing demonstrated significant differences between the survival curves during the 5-year period of study (p = 0.02). This difference was a result of a significantly greater non-cancer-related death rate by 5 years among patients having wedge resection (38% vs 18% for those having lobectomy; p = 0.014). CONCLUSION: Wedge resection, done by open thoracotomy or video-assisted techniques, appears to be a viable "compromise" surgical treatment of stage I (T1 N0 M0) non-small-cell lung cancer for patients with cardiopulmonary physiologic impairment. Because of the increased risk for local recurrence, anatomic lobectomy remains the surgical treatment of choice for patients with stage I non-small-cell lung cancer who have adequate physiologic reserve.
INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.
BACKGROUND: Lung volume reduction surgery (LVRS) using a linear cutting stapler or laser ablation via median sternotomy or thoracoscopy is a current therapy for symptomatic emphysema. The primary causes of morbidity and mortality (as high as 20%) are existing comorbidities and prolonged air leaks secondary to visceral pleural division. We report a novel technique using minimally invasive techniques designed to achieve volume reduction while preserving the visceral pleura. A novel lung grasper and a knifeless stapler are used to permanently plicate lung tissue without cutting visceral pleura. STUDY DESIGN: This prospective analysis involves a consecutive series of patients who had LVRS using this method. Between May 1995 and September 1996, 32 patients underwent 50 unilateral, staged bilateral, or bilateral thoracoscopic lung plication procedures. The indications for LVRS were standard; they included severe limiting dyspnea (forced expiratory volume in one second [FEV1] = 0.68 +/- 0.05), hyperinflated lungs with flattened diaphragms on chest x-ray, and diffuse emphysema seen on chest computed tomography scan. Ventilation and perfusion scanning was used to identify potential ventilation and perfusion mismatch target areas of lung for plication. RESULTS: The right lung was plicated first in 25 of 32 patients (78%), and upper lobe plications predominated (77%). A mean of 9.3 +/- 0.8 staple firings were used for each unilateral plication procedure. There were no perioperative deaths. Two patients (4%) required axillary thoracotomies to repair air leaks. Mean chest tube duration was 6.3 +/- 0.5 days. Median hospital stay was 7 days (range 3-15). An Intensive Care Unit stay was required following 8 procedures (17%). Postoperative morbidity occurred in 18 (39%) of 46 procedures, including 5 cases of atrial fibrillation and 4 persistent (> 7 days) air leaks. A minimum 2 month followup was available for 22 patients (32 of 46 procedures), demonstrating a clear chest x-ray with significant improvement in ipsilateral diaphragmatic contour. Twelve patients had unilateral reduction, and 10 patients had bilateral reduction in either a staged (n = 7) or sequential at one operation (n = 3) fashion. Twenty-five (78%) of 32 procedures were associated with improved pulmonary function, with a mean increase in FEV1, in patients in this subgroup of procedures, of 43 +/- 7% for each ipsilateral plication at a mean followup of 3.8 +/- 0.5 months. For the entire group of 32 procedures, the mean improvement in measured FEV1 was 29 +/- 7%. Supplemental oxygen requirement was significantly reduced in 9 of 16 patients following plication. CONCLUSION: These data suggest that minimally invasive surgical techniques coupled with a no-cut lung plication can achieve significant lung volume reduction with favorable postoperative morbidity and mortality. Lung plication appears to hold promise as an alternative technique of LVRS.
OBJECTIVE: To examine the responsiveness of the 36-Item Short Form Health Survey (SF-36) to clinical changes in three surgical groups and to study how health-related quality of life (HRQL) changes with time among patients who undergo total hip arthroplasty, thoracic surgery for treatment of non-small-cell lung cancer, or abdominal aortic aneurysm (AAA) repair. DESIGN: Prospective cohort study with serial evaluations of HRQL preoperatively and at 1, 6, and 12 months after surgery. SETTING: University tertiary care hospital. PATIENTS: Of 528 patients, more than 50 years of age, who were admitted for these elective procedures, 454 (86%) provided preoperative health status data and are members of the study cohort. At 12 months after surgery, 439 (93%) of the cohort was successfully contacted and 390 (90%) provided follow-up interviews. MEASUREMENTS AND MAIN RESULTS: The Medical Outcomes Study SF-36, the Specific Activity Scale, five validated health transition questions, and a 0 to 100 scale measure of global health were used to assess changes in health status at 1, 6, and 12 months after surgery. Change in health status as measured by the SF-36 demonstrated that physical function and role limitations due to physical health problems were worse 1 month after these three surgeries. However, by 6 months after surgery, most patients experienced significant gains in the majority of the dimensions of health, and these gains were sustained at 12 months after surgery. Longitudinal changes in the SF-36 were positively associated with responses to the five health transition questions, to changes on the Specific Activity Scale and global health rating question, and to clinical parameters for persons who had AAA repair. These findings indicate that the SF-36 has evidence of validity and is responsive to expected changes in HRQL after elective surgery for these procedures. CONCLUSIONS: For the total hip arthroplasty patients, responsiveness was greatest for the SF-36 scales that measure physical constructs. However, for the two other procedures and at various points of recovery, significant changes were observed for all eight subscales, suggesting that responsiveness was dependent on the type of surgery and the timing of follow-up, and that multidimensional measures are needed to fully capture changes in HRQL after surgery.
Extrapleural pneumonectomy to treat malignant mesothelioma may offer a significant survival advantage for selected patients. The role of effusion cytology in these patients has not been previously examined. To evaluate this, cytology, pathology, and medical records of 26 cases in 21 patients who underwent extrapleural pneumonectomy because of malignant mesothelioma were reviewed. Positive cytologic results were noted on average 13 months later than negative results. Recurrence was most common in the peritoneum, followed by the ipsilateral thorax and contralateral thorax. Five of 11 true-negative results were secondary to infection; cytologic analysis revealed neutrophils in each case. Four of 5 false-negative cases were from the ipsilateral thorax, and no mesothelial cells were found. When these 4 cases are excluded, the sensitivity of cytologic examination in this setting was 91%, and specificity was 100%. Effusion cytology in patients after extrapleural pneumonectomy is an effective means of diagnosing recurrent malignant mesothelioma.
PURPOSE: To evaluate the histopathologic findings of pulmonary nodules 1 cm or smaller detected at computed tomography (CT) that were removed at video-assisted thorascopic surgery. MATERIALS AND METHODS: Clinical, radiologic, and histopathologic findings were retrospectively reviewed in 64 patients (48 women, 16 men; aged 22-85 years) who underwent video-assisted thorascopic surgical resection of small pulmonary lesions present on CT scans. RESULTS: Sixty-four patients had a total of 65 lesions resected. Of the 64 patients, 37 (58%) patients had no known previous malignancy and 27 (42%) had previous malignancy. Overall, 58% (38 of 65 [95% confidence interval = 0.45, 0.73]) of these lesions were malignant. Among the patients without previous malignancy, 14 (38%) had lung carcinoma (10 [27%], primary bronchogenic carcinoma; four [11%], carcinoid). In patients with a previous malignancy, malignant lesions were diagnosed in 81% (22 of 27). This included seven (26%) patients with bronchogenic carcinoma as a second primary carcinoma. In patients without previous malignancy, benign lesions were diagnosed in 59% (22 of 37); in patients with previous malignancy, benign lesions were diagnosed in 18% (five of 27). CONCLUSION: A considerable number of the malignant lesions were primary bronchogenic carcinoma. In addition, diagnosis in patients with a previous malignancy other than suspected metastatic disease can substantially alter treatment. For these reasons, early biopsy with an acceptable technique for diagnosis of these lesions is recommended.
STUDY OBJECTIVE: Treatment of malignant mesothelioma (MM) at an early stage results in increased survival. Cytologic examination of pleural effusions is one of the first diagnostic techniques attempted in these patients. The objective of this study was to define the role of cytologic examination of pleural fluid in facilitating early diagnosis. DESIGN: The medical records and cytologic slides of patients with pleural MM were reviewed. SETTING: Medical records were reviewed from two institutions: a large general hospital and a cancer hospital. PATIENTS: Twenty-nine patients ranging in age from 32 to 81 years (mean, 59 years) met the study criteria. INTERVENTIONS: All patients had at least one cytologic pleural fluid examination. MEASUREMENTS AND RESULTS: The median time from initial symptoms to the diagnosis of MM was 8 weeks for all patients. For patients with a positive or suspicious cytologic result, the median was 4 weeks, and in those with a negative cytologic result, it was 12 weeks. The overall sensitivity of cytologic examination for the diagnosis of MM was 32%. Cytogenetic analysis of pleural fluid had a sensitivity of 56%, and was positive in 1 case in which results of cytologic examination were negative. Patients in whom the time from presentation to diagnosis was greater than 1 year all had negative cytologic results followed by long periods without further workup, despite a history of exposure to asbestos. CONCLUSIONS: A positive or suspicious cytologic result was associated with a decreased median time to diagnosis. Unfortunately, the sensitivity of cytologic examination for a diagnosis of MM was only 32%. Until better diagnostic techniques are developed, we recommend immediate pleural biopsy in patients in whom MM is suspected and cytologic evaluation of pleural fluid gives negative results.
PURPOSE: There is widespread acceptance that screening for lung cancer is not indicated, to our knowledge, because no randomized trial has demonstrated a reduction in mortality as a result of screening. The objectives of this work are to review prospective studies on lung cancer screening and to analyze the extent to which known biases may have influenced observed results. BACKGROUND: Four randomized controlled trials have been conducted. The Memorial-Sloan Kettering and Johns Hopkins Lung Projects compared annual chest radiographs (CXRs) in a control group with CXRs and sputum cytologic findings in an experimental group. Although both studies failed to demonstrate any difference in outcome by the addition of cytologic study to CXR, long-term survival in both studies was approximately three times that predicted by other data. Accordingly, these results are at least consistent with the hypothesis that the screening CXRs may have improved survival. Two randomized trials, the Mayo Lung Project and the Czechoslovak study, compared regular and frequent rescreening CXRs in an experimental group with sporadic and/or infrequent rescreening in a control group. RESULTS: Both the Mayo and Czech studies demonstrated a striking advantage for screening with respect to stage distribution, resectability, survival, and fatality. Nevertheless, mortality was somewhat higher in the screened groups in both studies. Survival and fatality comparisons in randomized trials can be confounded by overdiagnosis bias, lead-time bias, and length bias, while mortality is not subject to these biases. Accordingly, it is believed that a mortality reduction represents the strongest evidence for screening efficacy. Mortality is directly proportional to cumulative incidence. In both the Mayo and Czech studies, incidence of lung cancer was higher in the screened group. The higher cumulative incidence (which in the Mayo Lung Project was statistically significant) made possible the discordant findings of superior survival/fatality and inferior mortality in the screened populations. Overdiagnosis has been widely accepted to account for the "missing cases" in the control populations in the Mayo and Czech studies. However, epidemiologic and autopsy evidence as well as an outcome analysis of unresected early-stage screen-detected lung cancer demonstrates that screening does not lead to the overdiagnosis of lung cancer. Similarly, lead-time bias and length bias cannot account for the outcome differences in the Mayo Lung Project or Czech study. If survival and fatality comparisons (which suggest a striking benefit from screening) are not biased, then mortality comparisons (which suggest no benefit) cannot accurately reflect lung cancer death rates in these trials. Population heterogeneity may provide an explanation for how outcome differences may have been misrepresented by mortality comparisons in these two trials, as well as other large population-based randomized studies. CONCLUSIONS: Periodic screening CXRs lead to clinically meaningful improvements in stage distribution, resectability, survival, and fatality in lung cancer. Mortality reductions have not been demonstrated, but mortality did not accurately reflect lung cancer death rates in the Mayo Lung Project and Czechoslovak study. Accordingly, reconsideration of the desirability of periodic CXR screening may be appropriate for individuals at high risk of lung cancer.
The intrathoracic staging of lung cancer involves assessment of the primary tumor and potential sites of metastases. Imaging studies of the chest are sensitive in detecting intrathoracic abnormalities, but specific staging information generally requires a tissue biopsy. The instruments used to obtain this information include the bronchoscope, mediastinoscope, and thoracoscope. The complementary application of these instruments can provide valuable staging information while limiting the morbidity of surgical staging.
Mesothelioma is a rare disease for which neither single modality nor bimodality therapy improves survival. For this reason, from 1980 to 1995, we used trimodality therapy in an attempt to improve survival in selected patients at Brigham and Women's Hospital and Dana-Farber Cancer Institute. One hundred twenty patients underwent trimodality treatment involving extrapleural pneumonectomy followed by combination chemoradiotherapy. Twenty-seven women and 93 men (mean age, 56 years) were evaluable for response and treatment-related morbidity. The operative mortality rate was 5%, and 22% of patients experienced major morbidity. Cell type and nodal status were significant prognostic variables. The respective 2- and 5-year survival rates were 45% and 22% overall, 70% and 37% for patients with epithelial cell type, 20% and 0% for patients with sarcomatous or mixed-histologic-type tumors, and 74% and 39% for patients who were node-negative with epithelial histologic type. Positive resection margins impacted survival only in the case of full-thickness, transdiaphragmatic invasion. A revised staging system stratified survival with median intervals of 22, 17, and 11 months for stages I, II, and III disease, respectively (p=0.04). Thus, extrapleural pneumonectomy with adjuvant therapy is appropriate and effective treatment for patients with stage I disease according to the revised staging system.
Malignant pleural and pericardial effusions are a common problem in the treatment of patients with lung cancer, breast cancer, or lymphoma and may occur with any malignancy. These effusions are frequently symptomatic and, in the case of the pleural space, may be the presenting sign of cancer. In other patients, they represent markers of recurrent, disseminated, or advanced disease. Given the poor prognosis of most patients presenting with these effusions, reducing symptoms and improving quality of life are the primary goals of treatment. Permanent drainage and/or obliteration of the pleural or pericardial space are crucial to the effective management of the effusion and will provide long-term palliation. Immediate relief can be accomplished via external drainage, but definitive therapy may often also require interventional radiology, cardiology, and thoracic surgery, as well as medical and radiation oncology. The pathophysiology, diagnosis, and treatment of malignant pleural and pericardial effusions are discussed in this article.
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The current modalities used to treat diffuse malignant pleural mesothelioma (DMPM) have not been evaluated in the setting of prospective, multi-institutional randomized trials for two reasons: DMPM is a rare disease, and there is a lack of a widely accepted and standarized staging system. Several staging systems have been proposed in an effort to categorize patients with DMPM into homogeneous groups. These efforts have been hampered by a lack of correlation between staging and survival. In our institutional experience, the Brigham staging system has been able to stratify patients with similar survival. This is an institutional experience that needs validation in a multi-institutional setting and, furthermore, in a trial based on stage-specific adjuvant therapies.
Diffuse malignant pleural mesothelioma, a rare disease, is characterized by an aggressive local behavior and scant response to therapy. The first series using single modality therapy showed failure in terms of survival and local control. More recently, multimodality therapy has been used against this disease with better results, but still with more room for substantial improvement. The current multimodality series reported are isolated, single-institutional experiences with different treatment schemes, using different staging systems, most of which have not been validated. There is an enormous need for multiinstitutional prospective trials to evaluate the current treatment schemes in light of the steady increase in the incidence of this lethal tumor. The trimodality therapy used at the Brigham and Women's Hospital for selected patients is described.