Biomedical subjects

D J Sugarbaker

Publications and source records attributed to D J Sugarbaker.

At least 37 records · Page 2Linked to original sources

PubMed1999

The prognostic significance of lymph node micrometastasis in patients with esophageal carcinoma.

BACKGROUND: Lymph node metastasis is a well known feature of poor prognosis in patients with esophageal adenocarcinoma and squamous cell carcinoma. However, a significant proportion of apparently lymph node negative patients die early of metastatic disease. The aim of this study was to determine the prevalence and prognostic significance of occult lymph node metastasis in patients with esophageal adenocarcinoma and squamous cell carcinoma. METHODS: Lymph node sections from esophagectomy specimens of 78 patients with lymph node negative esophageal carcinoma (49 patients with adenocarcinoma and 29 with squamous cell carcinoma) were cut serially, it toto, and immunostained with the cytokeratin antibody AE1/AE3 and evaluated for occult lymph node metastasis. The results were correlated with the clinical and pathologic features and with patient survival. RESULTS: Fifteen of 49 patients (31%) with adenocarcinoma and 5 of 29 patients (17%) with squamous cell carcinoma had occult lymph node metastasis detected by cytokeratin staining. In the adenocarcinoma patients, the presence of occult lymph node metastasis showed a significant correlation with increasing depth of invasion, but was not associated significantly with any other clinical or pathologic feature. In the squamous cell carcinoma patients, the presence of occult lymph node metastasis did not correlate significantly with any clinical or pathologic parameter, except that patients with occult lymph node metastasis were more likely to have received preoperative chemotherapy or radiation therapy. Occult lymph node metastasis did not correlate with poorer survival rates in patients with either adenocarcinoma (Cox proportional hazards ratio: 1.42; P - 0.46) or squamous cell carcinoma (Cox proportional hazards ratio: 0.86; P = 0.90). CONCLUSIONS: Occult lymph node metastasis is not an independent poor prognostic feature in esophageal adenocarcinoma or squamous cell carcinoma. Therefore, the authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostication of patients with these malignancies.

Adenocarcinoma↗

PubMed1999

Expression of the focal adhesion protein paxillin in lung cancer and its relation to cell motility.

Lung cancer can lead to abnormalities of the actin cytoskeleton structure which may be important in transformation. In this study, we have investigated the expression of the cytoskeletal associated protein paxillin in lung cancer. Paxillin is a 68 kDa focal adhesion protein, with four tandem LIM domains at the C-terminus, involved in growth factor receptor, integrin and oncogenic signaling such as v-src, BCR/ABL, and E6 of the papilloma virus. In non-small cell lung cancer (NSCLC) cell lines, paxillin localized to the focal adhesions. The possible role of paxillin in lung cancer cells was assessed by overexpressing green fluorescence protein (GFP)-paxillin construct in two separate NSCLC cell lines (Calu-1 and H661). Over the course of 48 h, GFP-paxillin consistently caused the cells to become round and to decrease cell motility as compared to normal controls, GFP-N-terminus paxillin, or GFP-LIM transfected cells. Because some lung cancers may be quite aggressive and metastasize quickly, which may be related to the cytoskeleton, we determined the expression of paxillin in NSCLC and small cell lung cancer (SCLC) cell lines and patient tumor tissues. Expression of paxillin in NSCLC and SCLC cell lines were determined by Northern blot and Western blot analysis. The expression of paxillin was consistently low in SCLC cell lines, whereas there was paxillin expression in NSCLC cell lines. There was a variability of expression of paxillin in NSCLC tumor tissue as compared to normal lung tissue. In contrast, by immunohistochemistry, we show that there was no detectable expression of paxillin in 5/5 SCLC patients. This data suggests that absence or low level of paxillin protein expression may cause certain lung cancers, such as SCLC, to be more motile and possibly more aggressive.

3T3 Cells↗

PubMed1999

Cell motility as a prognostic factor in Stage I nonsmall cell lung carcinoma: the role of gelsolin expression.

BACKGROUND: Tumor cell motility is an important characteristic that facilitates the multistep process of tumor metastasis. Rac, ABP-280, and gelsolin are proteins that interact with actin and are important in cell motility. METHODS: The authors studied a cohort of 229 Stage I nonsmall cell lung carcinoma (NSCLC) patients who had a minimum of 3 years follow-up and had been previously analyzed for 22 clinical, pathologic, and molecular features, of which 9 had been found to provide significant prognostic information in a Cox proportional hazards model. Tumor sections were stained by the avidin-biotin complex method using monoclonal antibodies against rac, ABP-280, and gelsolin. RESULTS: In a pilot analysis of over 50 patients each, rac and ABP-280 were found to be moderately-to-highly expressed in the majority of tumors and to provide no prognostic information. Gelsolin expression was more variable and appeared to be negatively correlated with survival in the pilot population. In the larger 229-patient population, high focal gelsolin expression was seen in 32 tumors (14%) and conferred the highest relative risk (4.04) of cancer recurrence among all factors tested, compared with tumors that had no or low gelsolin expression. Moderate focal gelsolin expression, seen in 46 patients (20%), also conferred a significant risk of cancer recurrence, with a relative risk of 2.26 compared with tumors that had no or low gelsolin expression. Consideration of average gelsolin expression and of overall survival yielded similar results. CONCLUSIONS: Gelsolin expression appears to be a significant prognostic factor for cancer recurrence in cases of Stage I NSCLC.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

Lung cancer staging and treatment in multidisciplinary trials: Cancer and Leukemia Group B cooperative group approach. Thoracic Surgeons of CALGB.

BACKGROUND: Aggressive routine surgical staging is necessary to evaluate patients to be treated on cooperative oncology protocols. Less than 1% of lung cancer patients in the United States are currently being treated in a clinical trial. Only with results from large, prospective trials can the questions of neoadjuvant and adjuvant therapy be answered. METHODS: An outline describing the schema of preoperative patient evaluation, surgical staging, and the definition of surgical staging and resection procedures appropriate for patients considered for cooperative group protocol is presented. Current Cancer and Leukemia Group B (CALGB) protocols are used in the discussion as examples of this systematic approach. CONCLUSIONS: Over the next few years, it will be important to enter the maximum number of patients into combined modality studies to identify the role of neoadjuvant treatment in lung cancer. Entry of patients into protocols will also make their pathological specimens and clinical information available for basic science research related to treatment results. Adherence to a logical sequence of patient evaluation as outlined above will optimize patient care, as well as accrual to cooperative group studies.

Clinical Trials as Topic↗

PubMed1999

Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients.

OBJECTIVES: Our aim was to identify prognostic variables for long-term postoperative survival in trimodality management of malignant pleural mesothelioma. METHODS: From 1980 to 1997, 183 patients underwent extrapleural pneumonectomy followed by adjuvant chemotherapy and radiotherapy. RESULTS: Forty-three women and 140 men (age range 31-76 years) had a median follow-up of 13 months. The perioperative mortality rate was 3.8% (7 deaths) and the morbidity, 50%. Survival in the 176 remaining patients was 38% at 2 years and 15% at 5 years (median 19 months). Univariate analysis identified 3 prognostic variables associated with improved survival: epithelial cell type (52% 2-year survival, 21% 5-year survival, 26-month median survival; P =.0001), negative resection margins (44% at 2 years, 25% at 5 years, median 23 months; P =.02), and extrapleural nodes without metastases (42% at 2 years, 17% at 5 years, median 21 months; P =.004). Using the Cox proportional hazards, the relative risk of death was calculated for nonepithelial cell type (OR 3.0, CI 2.0-4.5; P <.0001), positive resection margins (OR 1.7, CI 1.2-2.6; P =.0082), and metastatic extrapleural nodes (OR 2.0, CI 1.3-3.2; P =.0026). Thirty-one patients with 3 positive variables had the best survival (68% 2-year survival, 46% 5-year survival, median 51 months; P =.013). A previously published staging system using these variables stratified survival (P <.05). CONCLUSIONS: (1) Multimodality therapy including extrapleural pneumonectomy is feasible in selected patients with malignant pleural mesotheliomas, (2) pre-resectional evaluation of extrapleural nodes may select patients for radical therapy, (3) microscopic resection margins affect long-term survival, highlighting the need for further investigation of locoregional control, and (4) patients with epithelial, margin-negative, extrapleural node-negative resection had extended survival.

Adult↗

PubMed1999

Patterns of recurrence and outcome for patients with clinical stage II non-small-cell lung cancer.

Forty-six patients with pathologic clinical stage II non-small-cell lung carcinoma underwent resection with or without adjuvant radiotherapy from 1989 through 1994. These patients were analyzed to determine patterns of recurrence and survival. Surgery consisted of pneumonectomy for 11 patients, bilobectomy for two patients, lobectomy for 29 patients, and wedge or segmental resection for four patients. Adjuvant radiotherapy was delivered to 29 patients, and the median total dose was 54 Gy (range, 44-60 Gy). Median follow-up time was 23 months for all patients and 25 months for surviving patients. Twenty-six of 46 patients have had recurrence. The site of first recurrence was locoregional for 9 of 46 patients (20%) and distant for 17 of 46 patients (37%). The median time to locoregional recurrence was 18 months for patients treated with radiotherapy and 13 months for patients treated without radiotherapy. An isolated locoregional recurrence (with no simultaneous distant recurrence) was seen in 2 of 28 evaluable patients (7%) treated with radiotherapy compared with 3 of 17 patients (18%) not treated with radiotherapy. For all patients, the 3-year disease-free survival rate was 52%, and the overall survival rate was 52%. Among patients treated with radiotherapy, the 3-year disease-free survival and overall survival rates were 56% and 56%, respectively, compared with 46% and 43%, respectively, for patients who did not receive radiotherapy (p values were not significant). The locoregional recurrence rate was 33% for patients with adenocarcinoma and 15% for those with squamous cell carcinoma. The distant recurrence rates by histologic characteristic were 56% and 20%, respectively. For patients with clinical stage II non-small-cell lung cancer, postoperative radiotherapy appears to improve locoregional control. However, the preponderance of recurrences remains distant. Further study is warranted with special emphasis on control of systemic disease.

Adult↗

PubMed1999

Multimodality treatment of malignant superior vena caval syndrome.

Malignant superior vena caval (SVC) syndrome due to non-small cell lung cancer is invariably fatal, with most therapy directed toward palliating the manifestations of the disease. A cure, by means of any modality, is unusual. We report a patient with SVC syndrome secondary to documented ipsilateral peritracheal nodal involvement (stage IIIB disease) who underwent neoadjuvant chemoradiotherapy and resection. At surgery, his superior vena cava was not involved and his tumor had been downstaged to stage I (T1 nanoseconds). He remains alive and free of disease 60 months after surgery. Neoadjuvant chemoradiotherapy may be used to downstage malignant SVC syndrome to resectable lesions in good functional candidates.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

Pleuropneumonectomy in the treatment of malignant pleural mesothelioma.

STUDY OBJECTIVES: Malignant pleural mesothelioma (MPM) is predominantly a local/regional disease that results in a survival time that ranges from 4 to 12 months without treatment. Single-modality therapy using surgery, chemotherapy, or radiotherapy alone is largely ineffective. The objective of the study was presentation of the use of pleuropneumonectomy in a multimodality treatment setting and the results. DESIGN: Didactic presentation. SETTING: Academic tertiary-care hospital. PATIENTS: One hundred eighty-three patients who underwent multimodality therapy. INTERVENTIONS: Of all the single-modality treatment approaches, pleuropneumonectomy has been associated most consistently with long-term disease-free survival and has provided the greatest amount of tumor cytoreduction. The technique of pleuropneumonectomy traditionally has been linked with high perioperative mortality and morbidity when compared with that of other cytoreductive techniques such as pleurectomy/decortication. Recently, improvements in operative mortality (< 5%) have been reported, largely due to improvements in patient selection and perioperative management. Multimodality therapy, including chemotherapy, radiotherapy, and extrapleural pneumonectomy, was used to treat patients. RESULTS: Outcomes were presented for 183 patients with MPM who underwent multimodality therapy. CONCLUSIONS: With the development of multimodality therapy, pleuropneumonectomy followed by sequential chemotherapy and radiotherapy has demonstrated a significant survival benefit, especially for patients who have epithelial tumor histology, tumor-free resection margins, and tumor-free extrapleural node status.

Antineoplastic Agents↗

PubMed1999

New surgical options for elderly lung cancer patients.

To understand the size of the aging population in the United States, the imminent need to include the elderly in clinical studies on lung cancer, and the safe potential of video-assisted thoracic surgery, and to change awareness of the elderly's need for and ability to undergo treatment for lung cancer, clinical studies of video-assisted thoracic surgery in patients > or = 70 years of age are presented. The elderly are a fast-growing part of the American population who are at high risk for lung cancer and should be included in clinical studies. Age alone should not be a contradiction to thoracic surgical interventions when video thoracoscopy is performed as treatment.

Age Factors↗

PubMed1999

Management of the solitary pulmonary nodule: role of thoracoscopy in diagnosis and therapy.

OBJECTIVES: The solitary pulmonary nodule remains a common clinical problem. The essential question is whether the lesion is malignant or not. This discussion presents the clinical practice and looks at the problem. DESIGN: Didactic. SETTING: Academic tertiary-care hospital. PATIENTS: Prospective thoracic database. INTERVENTIONS: Minimally invasive technique. RESULTS: The workup and treatment of the solitary pulmonary nodule is presented with particular emphasis on the role of minimally invasive techniques. A small single-institution series is referenced. CONCLUSIONS: The approach is safe and highly effective in diagnosing and often in treating solitary pulmonary nodules.

Carcinoma, Non-Small-Cell Lung↗

PubMed1999

Techniques of pneumonectomy. Pleural pneumonectomy.

This article reviews the preoperative assessment and selection of patients for extrapleural pneumonectomy, the surgical technique, and recent data outlining our experience with multimodality therapy for MPM.

Humans↗

PubMed1999

Malignant mesothelioma of the pleural space.

Malignant pleural mesothelioma is an aggressive tumor associated with exposure to asbestos. Although this disease is rare, with an annual incidence in the United States of 2,000 to 3,000 cases, a steady rise in cases has been reported. Malignant pleural mesothelioma has a variable clinical presentation and may be difficult to diagnose. Pathologically, the disease is subdivided into three microscopic subtypes: epithelial, sarcomatous, and mixed histologies. Although there is no widely accepted staging system for mesothelioma, the Butchart, TNM, and Brigham staging systems have been used most commonly. Diffuse malignant pleural mesothelioma is resistant to standard modes of therapy and, if untreated, results in death 4 to 12 months from the time of diagnosis. For selected patients, an aggressive approach combining radical surgery with chemotherapy and radiotherapy has demonstrated a long-term survival advantage. New and innovative therapeutic modalities are presently being investigated in an attempt to provide viable alternatives for patients with early and advanced disease.

Combined Modality Therapy↗

PubMed1998

Relation between preoperative inspiratory lung resistance and the outcome of lung-volume-reduction surgery for emphysema.

BACKGROUND: Surgery to reduce lung volume has recently been reintroduced to alleviate dyspnea and improve exercise tolerance in selected patients with emphysema. A reliable means of identifying patients who are likely to benefit from this surgery is needed. METHODS: We measured lung resistance during inspiration, static recoil pressure at total lung capacity, static lung compliance, expiratory flow rates, and lung volumes in 29 patients with chronic obstructive lung disease before lung-volume-reduction surgery. The changes in the forced expiratory volume in one second (FEV1) six months after surgery were related to the preoperatively determined physiologic measures. A response to surgery was defined as an increase in the FEV1 of at least 0.2 liter and of at least 12 percent above base-line values. RESULTS: Of the 29 patients, 23 had some improvement in FEV1 including 15 who met the criteria for a response to surgery. Among the variables considered, only preoperative lung resistance during inspiration predicted changes in expiratory flow rates after surgery. Inspiratory lung resistance correlated significantly and inversely with improvement in FEV1 after surgery (r=-0.63, P<0.001). A preoperative criterion of an inspiratory resistance of 10 cm of water per liter per second had a sensitivity of 88 percent (14 of 16 patients) and a specificity of 92 percent (12 of 13 patients) in identifying patients who were likely to have a response to surgery. CONCLUSIONS: Preoperative lung resistance during inspiration appears to be a useful measure for selecting patients with emphysema for lung-volume-reduction surgery.

Adult↗

PubMed1998

Clinical radiation pneumonitis and radiographic changes after thoracic radiation therapy for lung carcinoma.

BACKGROUND: The authors attempted to determine the incidence of and risk factors for clinical radiation pneumonitis in patients treated for lung carcinoma. They also sought to describe the corresponding posttreatment radiographic changes. METHODS: Between 1989-1993, 83 patients received curative radiation therapy for lung carcinoma. Of these, 39 patients were treated with definitive radiation therapy, and 44 patients were treated with adjuvant radiation therapy after surgical resection. The median radiation therapy dose was 54 gray (Gy), and the median treatment area was 182 cm2. Chest radiographs obtained after radiation therapy were reviewed and scored for margin definition, volume loss, and texture quality. RESULTS: A total of 17 patients (20%) developed clinical radiation pneumonitis (CRP). The median radiation therapy dose for the CRP cohort was 54 Gy, and the median treatment volume was 193 cm2. The median time to onset of symptoms was 3 weeks after radiation therapy, and the median duration of symptoms was 10 weeks. Of the 15 evaluable patients, symptoms resolved for 9 patients, improved but persisted for 4 patients, and CRP was fatal for 2 patients. The incidence of CRP was increased for patients with low performance status, comorbid lung disease, smoking history, low pulmonary function tests, and for those patients who did not undergo a surgical resection. Posttreatment radiographic changes were common and progressed with time. Radiographic changes were more pronounced in the CRP cohort, and extended outside the radiation therapy treatment field in the majority of patients (67%). CONCLUSIONS: Clinical radiation pneumonitis developed in 20% of lung carcinoma patients. Risk factors included low performance status, comorbid lung disease, smoking history, low pulmonary function tests, and the absence of a surgical resection. Posttreatment radiograph changes were common and progressed with time, and typically were not confined to the radiation therapy treatment field.

Adult↗

PubMed1998

Inflammatory cell distribution within and along asthmatic airways.

Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared with five patients with cystic fibrosis. For morphometric analysis, the airway wall was partitioned into an "inner" area (between basement membrane and smooth muscle) and an "outer" area (between smooth muscle and alveolar attachments). Large airways (with a perimeter greater than 3.0 mm) from patients with asthma or cystic fibrosis had a greater density of CD45-positive cells (p < 0.05) and eosinophils (p < 0.001) in the inner airway region compared with the same airway region in small airways. Furthermore, in small airways, asthmatic lungs showed a greater density of CD45-positive cells (p < 0.01) and eosinophils (p < 0.01) in the outer compared with the inner airway wall region. These observations indicate that there are regional variations in inflammatory cell distribution within the airway wall in patients with asthma that are not observed in airways from patients with cystic fibrosis. We speculate that this inflammatory cell density in peripheral airways in severe asthma may relate to the peripheral airway obstruction characteristic of this condition.

Adolescent↗

PubMed1998

Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.

Previously, we identified macrophage-stimulating protein (MSP) as being expressed during hamster lung injury induced by nitrosamine carcinogens. Transient, generalized epithelial-cell hyperplasia during the preneoplastic period, and eventually nonneuroendocrine (non-NE) lung tumors, are known to develop in these nitrosamine-treated hamsters. We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA (mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON in both normal and tumor tissue. MSP and RON could also constitute an autocrine/paracrine system in human NSCLC cell lines: five of 16 cell lines (squamous and adenosquamous) expressed both MSP and RON; and an additional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), mRNA for RON was not detectable in these cases. RON was functional in all tested RON mRNA-positive cell lines, with exogenous MSP inducing RON-mediated tyrosine phosphorylation. Treatment of a RON-positive adenosquamous carcinoma cell line with MSP additionally resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some NSCLCs. In conclusion, MSP and RON might represent an autocrine/paracrine system involved in the pathogenesis of lung cancer, although the nature of the biologic responses in different cell types might vary considerably.

Carcinoma, Non-Small-Cell Lung↗

PubMed1998

Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications.

PURPOSE: To retrospectively construct a comprehensive multivariate model of cancer recurrence and to design a molecular pathologic substaging system in stage I non-small-cell lung cancer (NSCLC). METHODS: All patients with stage I NSCLC resected at Brigham and Women's Hospital (Boston, MA) between 1984 and 1992 with adequate clinical follow-up were studied. The importance of three demographic characteristics, surgical extent, 11 pathologic features, and seven molecular factors on cancer-free survival was examined. RESULTS: Two hundred forty-four patients were studied, with 25 noncancer deaths and 80 patients with recurrent disease. Significant univariate predictors (P < .05) of cancer recurrence were age older than 60 years, male sex, wedge resection, World Health Organization (WHO) adenocarcinoma subtype solid tumor with mucin, lymphatic invasion, and p53 expression. Multivariate analysis identified nine independent predictors of recurrence: solid tumor with mucin, a wedge resection, tumor diameter of 4 cm or greater, lymphatic invasion, age older than 60 years, male sex, p53 expression, K-ras codon 12 mutation, and absence of H-ras p21 expression. Multivariate cancer-free survival (CFS) analysis in the 180 patients who underwent lobectomy or pneumonectomy led to the elimination of sex and age, which left six independent factors. CONCLUSION: Lobectomy or pneumonectomy should be performed in stage I NSCLC. Using the six independent factors for recurrent disease, we propose a pathologic molecular substaging system. Patients with two factors or less are graded Ia, with a 5-year CFS rate of 87%; those with three factors are graded Ib, with a 5-year CFS rate of 58%; and those with four factors or more are graded Ic, with a 5-year CFS rate of 21%.

Adult↗

PubMed1998

Multimodality management of malignant pleural mesothelioma.

In this article, we explain the current trimodality approach used to treat malignant pleural mesothelioma. Our current approach employs extrapleural pneumonectomy as the cytoreductive procedure followed by combination chemoradiotherapy. Trimodality therapy was performed at the Dana-Farber Cancer Institute/Brigham and Women's Hospital Thoracic Oncology Program. From 1980 to 1995, we prospectively followed up a series of 120 patients with confirmed malignant pleural mesothelioma who underwent trimodality therapy. Two- and 5-year survival rates for the entire cohort were 45% and 22%, respectively. Survival rates were 65% and 27%, respectively, at 2 and 5 years for patients with epithelial histology. Patients with sarcomatous or mixed histology had the poorest prognosis, with 2- and 5-year survival rates of 20% and 0%, respectively. For patients with epithelial tumors and negative nodes, survival at 2 and 5 years was 74% and 39%, respectively. Extrapleural pneumonectomy in the context of trimodality therapy is a potential surgical option for a selected group of patients with malignant pleural mesothelioma.

Combined Modality Therapy↗