Is transcatheter rescue management of a pulmonary artery bronchial fistula justified?

Endobronchial brachytherapy and interventional bronchology have changed the management of stage 3A (T4N0M0) non-small cell lung carcinoma. We discuss the case of a female patient who developed massive hemoptysis due to a fistula between the left pulmonary artery and stented left main bronchus. Although transcatheter management of the fistula was initially successful, the patient outcome secondary to coronary insult was poor. We present our management dilemma to highlight the need for careful consideration when selecting patients with heavily irradiated chests for endobronchial stenting.

Diagnosis of high-grade pulmonary neuroendocrine carcinoma by fine-needle aspiration biopsy: nonsmall-cell or small-cell type?

A consensus optimal therapy for large-cell neuroendocrine carcinoma of the lung has not been achieved since this entity was proposed in 1991. Accumulation of clinical data and investigation, however, can be greatly impeded by erroneous cytological diagnosis, based on which treatment may be initiated. To avoid erroneous diagnoses, cytological criteria need to be defined. Twenty cases of fine-needle aspiration specimens with a diagnosis of neuroendocrine tumor by either cytology or follow-up histology were retrospectively reviewed for cytomorphologic features. Patients' clinical data were also reviewed. Three cytomorphologic patterns were identified for large-cell neuroendocrine carcinoma, i.e., nonsmall-cell-like, small-cell-like and, mixed nonsmall-cell-small-cell-like. Small-cell-like large-cell neuroendocrine carcinoma can be mistaken for small-cell carcinoma. The most important differential features between these two entities are nuclear size and perceptibility of nucleoli of tumor cells.

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.

Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer.

PURPOSE: The aim of this study was to investigate the prognostic importance of codon 12 K-ras mutations in patients with early-stage non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We identified 260 patients with surgically resected stage I (n = 193) and stage II (n = 67) NSCLC with at least a 5-year follow-up. We performed polymerase chain reaction analysis of DNA obtained from paraffin-embedded NSCLC tissue, using mutation-specific probes for codon 12 K-ras. RESULTS: K-ras mutations were detected in 35 of 213 assessable specimens (16.4%). K-ras mutations were detected in 27 of 93 adenocarcinomas (29.0%), one of 61 squamous cell carcinomas (1.6%), five of 39 large-cell carcinomas (12.8%), and two of 20 adenosquamous carcinomas (10%) (P = .001). G to T transversions accounted for 71% of the mutations. There was no statistically significant difference in overall survival for all patients with K-ras mutations (median survival, 39 months) compared with patients without K-ras mutations (median survival, 53 months; P = .33). There was no statistically significant difference in overall or disease-free survival for subgroups with stage I disease, adenocarcinoma, or non-squamous cell carcinoma or for specific amino acid substitutions. The median survival time for stage II patients with K-ras mutations was 13 months, compared with 38 months for patients without K-ras mutations (P = .03). CONCLUSION: Codon 12 K-ras mutations were more common in adenocarcinomas than in squamous cell carcinomas. For the subgroup with stage II NSCLC, there was a statistically significant adverse effect on survival for the presence of K-ras mutations. However, when the entire group was considered, the presence of K-ras mutations was not of prognostic significance in this cohort of patients with resected early-stage NSCLC.

Prognostic markers in resected stage I and II non small-cell lung cancer: an analysis of 260 patients with 5 year follow-up.

We performed a retrospective analysis of potential prognostic markers in 260 patients with surgically resected stage I and II non small-cell lung cancer (NSCLC) with a minimum 5-year follow-up. Cox proportional hazard models and Wilcoxon tests were employed to analyze the effect of patient characteristics on survival and disease-free survival (DFS). In the univariate analysis, the following were significant predictors of shorter overall survival: N-stage (N1 vs N0) (p<0.001); T-stage (T2 vs T1) (p<0.001); antigen A (loss vs presence) (p<0.01); cough (present vs absent) (p=0.01); bcl-2 expression (positive vs negative) (p=0.03); age (>63.5 vs <63.5) (p=0.03); mucin (positive vs negative) (p<0.03). The following were significant predictors of shorter DFS: N-stage (p<0.001); T-stage (p=0.001); loss of antigen A (p=0.01); mucin expression (p<0.01); cough (p=0.02); Ki-67 expression (p=0.02) and negative bcl-2 expression (p=0.03). Analysis of survival difference for histologic subtype, degree of differentiation, aneuploidy, %S-phase, codon 12 K-ras mutation, and immunohistochemistry staining for Lewisy, p53, Rb, microvessel count, HER2, E-cadherin and neuroendocrine markers did not reach statistical significance. In multivariate analysis, the following predicted for shorter overall survival: N-stage (p<0.01), antigen A (p=0.01), age (p<0.01), and bcl-2 (p=0.05); and for DFS, N-stage (p<0.01), antigen A (p<0.01), Ki-67 (p=0.03), mucin (p=0.04) and T-stage (p=0.05). Of all the clinical-pathological, proliferative, and biological markers studied, only a few carried independent prognostic significance.

Prognostic significance of Lewis y antigen in resected stage I and II non-small cell lung cancer.

BACKGROUND: The role of Lewis y (Le(y)) antigen expression has been studied extensively in predicting the outcome of various malignancies. We evaluated the expression of Le(y) and its relationship to survival, disease-free survival and other clinicopathologic variables in patients with stage I and II non-small cell lung cancer (NSCLC). OBJECTIVE: To investigate the prognostic significance of Le(y) antigen expression in a large group of well characterized patients with resected stage I and II NSCLC. PATIENTS: Two hundred and sixty patients with surgically resected stage I (n = 193) and II (n = 67) NSCLC with at least 5-year follow-up were identified. RESULTS: The median survival for patients with negative expression of Le(y) (< 50% of cells that were positive) was 46 months, whereas for those with positive expression of Le(y) (> or = 50%), the median survival was 54 months (p = 0.99). The disease-free survival for patients with Le(y)(-) expression was 39 months and 34 months for patients with Le(y)(+) expression (p = 0.3). CONCLUSIONS: We found no relationship between loss of blood group antigen A and expression of Le(y). No statistically significant difference was found in survival between positive and negative expression of Le(y) antigen in patients with resected stage I and II NSCLC.

Multicenter VATS experience with mediastinal tumors.

BACKGROUND: The use of video-assisted thoracic surgery for diagnosis and treatment of mediastinal tumors in a multiinstitution patient population is not well understood. METHODS: We studied 48 cases from Cancer and Leukemia Group B thoracic surgeons. Of 21 men and 27 women, aged 41 +/- 16 years, 22 patients were asymptomatic. In the others, 92% of tumor-related symptoms improved or resolved after treatment. Five tumors involved the anterior compartment, 19 the middle, and 24 the posterior compartment. Diagnoses were typical for each compartment but also included uncommon problems such as superior vena cava hemangioma and a histoplasmosis cyst causing hoarseness. Of the lesions, a biopsy of 12 was done without excision and the rest were excised completely. Fifteen were cystic and 10 were malignant (8 biopsy only). Maximal dimensions were 5.2 +/- 3.3 cm. RESULTS: Operations were briefer for 24 posterior (93 +/- 41 min) than 5 anterior (195 +/- 46 min, p < 0.01) or 19 middle mediastinal tumors (170 +/- 78 min, p < 0.01). Although 96% had vital mediastinal relations, only six open conversions were performed because of bleeding (n = 3), large size, impaired exposure, or rib attachments, and no patient had morbidity beyond that expected for the thoracotomy. Postoperative stay was shorter for the nonconversion group (3.2 +/- 2.8 versus 5.5 +/- 2.1 days, p = 0.05), as was chest tube duration (1.7 +/- 1.4 days versus 3.2 +/- 1.9 days, p = 0.03). There were no postoperative deaths or major complications, but 7 patients had minor complications. During a mean of 20 months of surveillance (range, 1 to 52 months), one cyst recurred (asymptomatic) as did one sarcoma that was excised. CONCLUSIONS: Video-assisted thoracic surgery is a safe technique for benign mediastinal tumors, typically those in the middle and posterior mediastinum.

Prognostic significance of Ki-67 immunostaining and symptoms in resected stage I and II non-small cell lung cancer.

The proliferative rate of a tumor has been considered predictive of its clinical course. We evaluated the expression of the proliferative marker Ki-67 and its relationship to survival, disease-free survival and other clinicopathologic variables in both stage I and stage II non-small cell lung cancer (NSCLC). A total of 260 patients with surgically resected stage I (n = 193), and II (n = 67) NSCLC with at least 5 years follow-up were identified. The median survival for patients with low expression of Ki-67 (< or = 25%) was 54 months, while for those with high expression (> 25%), it was 45 months (P = 0.1). The disease-free survival in patients with low expression of Ki-67 was 59 months while it was only 32 months for patients with high Ki-67 (P = 0.1). Out of 136 patients, 84 (62%) had both increased S-phase (> 8%) and high Ki-67 (P = 0.001). A total of 28 of 30 patients who had loss of antigen A had high expression of Ki-67 (93.3%) (P = 0.03). Ki-67 expression was also higher in squamous cell (54/63, 85.7%) compared to nonsquamous cell cancer (70/108, 64%) (P = 0.03). We also analyzed for the presence of symptoms with survival. The presence of symptoms was not found to be statistically significant, for overall survival (P = 0.33) or disease-free survival (P = 0.72). When individual symptoms were analyzed, the presence of cough was statistically significant for both overall and disease-free survival. The median survival was 39 months for patients with cough, and 57 months for patients without cough (P = 0.04). Multivariate analysis showed higher N and T stages, presence of cough and loss of antigen A, predicted for poorer overall survival. Higher N and T stages, loss of antigen A, presence of mucin and cough and increased expression of Ki-67 predicted decreased disease-free survival. Although we did not find a statistically significant difference between low and high Ki-67, there was a trend for a poorer overall and disease-free survival in patients with high Ki-67 expression. Larger studies may be needed to prove a statistically significant effect of Ki-67 on survival. Future studies should assess the potential prognostic significance of the presence of symptoms (particularly cough) in addition to clinical-pathologic variables (such as T and N stage) and biological markers in patients with early stage NSCLC.

Controversies in the management of malignant thymoma.

The management of most thymomas is relatively straightforward: surgical resection remains the primary mode of therapy. However, the literature contains many contradictory points of view regarding histology and pathology, staging and its usefulness, the need for adjuvant therapy, and recently, the place of video-assisted surgery in the treatment of this tumor. This article is not a comprehensive guide to management but rather explores several of these controversial areas. Conclusions include the following: invasiveness remains the single most consistent factor in predicting outcome; surgery is the treatment of choice for thymoma whenever a complete resection can be accomplished; and incomplete resection may have some advantage over biopsy alone. The preponderance of evidence indicates that all thymomas except completely encapsulated stage I tumors should be treated with postoperative adjuvant radiation therapy in the hope of reducing the incidence of local relapse. Myasthenia can no longer be considered an adverse prognostic factor in thymoma; it may even confer a survival advantage, but this may be due to the preponderance of early-stage tumors discovered incidentally in myasthenic patients. Other associated autoimmune diseases confer a survival disadvantage. Demonstrating the equivalence of minimally invasive thoracoscopic approaches to standard thymectomy will take many years of investigation. Some promising reports on response to chemotherapy have led to the development of a phase II intergroup study to assess the value of chemotherapy in advanced thymoma.

Is there a place for surgery in central small cell lung cancer?

Despite radiographic complete remission after standard induction therapy, 75% of SCLC patients will have tumor in the resected specimen. This and the high rate of local recurrence indicates that surgery may assume a greater role in the future if better control can be obtained for distant disease and local relapse thus becomes the mode of death.

Blood group antigen A and flow cytometric analysis in resected early-stage non-small cell lung cancer.

The loss of blood group antigen A on tumor tissue has been reported to be a strong adverse prognostic marker for patients with resected non-small cell lung cancer (NSCLC). Results have varied with respect to the prognostic significance of flow cytometric data. We sought to confirm the prognostic significance of blood group antigen A loss and flow cytometry in a large cohort of patients with early-stage NSCLC. Two hundred and sixty patients with surgically resected stage I (n = 193) and II (n = 67) NSCLC with at least a 5-year follow-up were identified. Using paraffin-embedded primary tumor, immunohistochemical stains for blood group antigen A were performed on 90 patients with blood type A or AB. The DNA index and percentage of cells in S phase were successfully obtained on 188 and 152 patients, respectively. The median survival time of the patients with primary tumors negative for blood group antigen A was 38 months (n = 36), compared with 98 months (n = 54) for those with antigen A-positive tumors (P < 0.01). The median disease-free survival times for antigen A-negative and -positive tumors were 26 months and 98 months, respectively (P < h 0.01). The median survival time of the patients with aneuploid tumors was 51 months (n = 131), compared with 50 months (n = 57) for those with diploid tumors (P = 0.42). The median survival time of the patients with S phase >8% was 44 months (n = 105), compared with 60 months (n = 47) for those with S phase

Patterns of disease failure after trimodality therapy of nonsmall cell lung carcinoma pathologic stage IIIA (N2). Analysis of Cancer and Leukemia Group B Protocol 8935.

BACKGROUND: The impact of sequential trimodality therapy on the pattern of first site disease failure in pathologic Stage IIIA (N2) nonsmall cell lung carcinoma (NSCLC) was analyzed. METHODS: Seventy-four eligible patients with histologically documented Stage IIIA (N2) NSCLC underwent sequential trimodality therapy on Cancer and Leukemia Group B (CALGB) Protocol 8935. Treatment consisted of 2 cycles of induction cisplatin at 100 mg/m2 intravenously (i.v.) (Days 1 and 29) and vinblastine at 5 mg/m2 i.v. weekly for 5 weeks followed by surgery. Surgery included a thoracotomy with resection of the primary tumor and hilar lymph nodes and a mediastinal lymph node dissection. Patients with resected disease then received an additional a cycles of cisplatin at 100 mg/m2 i.v. and vinblastine at 5 mg/m2 i.v. biweekly for 2 total of 4 doses followed by consolidative thoracic irradiation. Patients with completely resected disease received 54 Gray (Gy) whereas those with incompletely resected disease received 59.4 Gy at 1.8 Gy/fraction (fx) once a day. Patients with unresectable disease underwent thoracic radiation therapy (TRT) treatments only to 59.4 Gy at 1.8 Gy/fx without any additional chemotherapy. Disease recurrence was determined by clinical, radiographic, or histologic criteria. Pattern of disease failure was identified by site of involvement at first recurrence as indicated by the CALGB Respiratory Follow-Up Form. RESULTS: Sixty-three of the 74 patients completed the induction chemotherapy as planned. Forty-six of the 63 patients underwent resection of disease whereas the remaining 17 were unresectable. Thirty-three of the 46 resected patients completed the entire adjuvant postoperative chemoradiation treatment as planned. Ten of 17 patients with unresectable disease completed postsurgical TRT. At a median follow-up interval of 27 months (range, 4-43), the 3-year overall survival and failure-free survival were 23% and 18%, respectively, for all 74 eligible patients. Overall, disease failure has occurred in 52 (70%) of the 74 eligible patients: local only: 13 (25%); distant only: 16 (31%); and both local and distant: 23 (44%), (P = not significant [NS]). Ten patients progressed during induction chemotherapy: local only: six patients; and both local and distant failure: four patients. Twenty-eight of 46 resected patients recurred: local only: 1 (4%); both local and distant failure: 11 (39%); and distant only: 16 (57%); (P < 0.001). Disease progression occurred in 14 of 17 patients with unresectable disease: local only: 6; both local and distant sites: 8. Among the 52 total patients experiencing disease relapse, isolated or combined local failure occurred commonly among patients during induction chemotherapy (n = 10, [28%]), in those with unresectable disease (n = 14, [39%]), or in those with resected disease (n = 12, [33%]), (P = NS). However, isolated or combined distant failure was more likely to occur among patients with resected disease (n = 27, [69%]) than either during induction chemotherapy (n = 4, [10%]) or in those with unresected disease (n = 8, [21%]), (P < 0.05). Among patients who relapsed, brain metastases occurred in 13 of 52 (25%) patients overall and in 12 of 28 (43%) patients with resected disease. CONCLUSIONS: Overall, disease failure was just as likely to occur in local, distant, or combined sites on CALGB Protocol 8935 using sequential trimodality therapy in the treatment of pathologic Stage IIIA (N2) NSCLC: Isolated or combined local failure occurred commonly during sequential tri-modality therapy whereas isolated or combined distant relapse was prevalent among patients with resected disease. In addition, isolated local failure was rare among patients with resected disease. The pattern of disease failure on CALGB Protocol 8935 reflects the biology of locoregional NSCLC as much as the therapeutic impact of trimodality therapy.

Thymoma mimicking lymphoblastic lymphoma: a pitfall in fine-needle aspiration biopsy interpretation.

Lymphocyte-rich thymoma often contains lymphoblasts and lymphoblastic lymphoma often infiltrates the thymus gland. Although these two neoplasms are clinically distinct in most case, their cytologic features may be similar on biopsy. We describe a fine-needle aspiration biopsy of a thymoma in a 50-yr-old man to increase awareness of this pitfall in cytologic interpretation.

Pulmonary veno-occlusive disease presenting with thrombosis of pulmonary arteries.

Pulmonary veno-occlusive disease is a rare cause of pulmonary hypertension. An unusual case presenting with thrombosis of the right pulmonary artery and serological evidence of autoimmunity is reported.

Results of cancer and leukemia group B protocol 8935. A multiinstitutional phase II trimodality trial for stage IIIA (N2) non-small-cell lung cancer. Cancer and Leukemia Group B Thoracic Surgery Group.

From October 1989 to February 1992, 74 patients with mediastinoscopically staged IIIA (N2) non-small-cell lung cancer from 30 CALGB-affiliated hospitals received two cycles of preresectional cisplatin and vinblastine chemotherapy. Patients with responsive or stable disease underwent standardized surgical resection and radical lymphadenectomy. Patients who underwent resection received sequential adjuvant therapy with two cycles of cisplatin and vinblastine, followed by thoracic irradiation (54 Gy after complete resection and 59.4 Gy after incomplete resection or no resection at 1.8 Gy per fraction). There were no radiographic complete responses to the neoadjuvant chemotherapy, although 65 (88%) patients had either a response or no disease progression. During induction chemotherapy, disease progressed in seven patients (9%). Sixty-three patients (86%) had exploratory thoracotomy, and 46 of those (75%) had resectable lesions. A complete surgical resection was accomplished in 23 patients, and 23 patients had an incomplete resection with either a diseased margin or diseased highest node resected. Operative mortality was 3.2% (2/63). In 10 patients (22% of the 46 having resection) the disease was pathologically downstaged. There was no correlation between radiographic response to the induction chemotherapy and downstaging at surgical resection. The full protocol was completed by 33 patients (45% of original cohort). Overall survival at 3 years was 23%. Patients undergoing resection had significantly improved survival at 3 years compared with patients not having resection: 46% for complete resection (median 20.9 months), 25% for incomplete resection (median 17.8 months), and 0% for no resection (median 8.5 months). Five deaths occurred during the treatment period. A total of 18 of the 46 (39%) patients who underwent resection are either alive and disease-free or have died without recurrence.

Pleuropulmonary blastoma simulating an empyema in a young child.

Pleuropulmonary blastoma is a rare childhood malignancy that may simulate an empyema both clinically and radiographically. A 3-year-old boy with fever, cough, and abdominal pain developed complete opacification of the left hemithorax with contralateral mediastinal shift over the course of several weeks. At thoracotomy, a pleuropulmonary blastoma was discovered. The radiology, pathology, and clinical course of this rare neoplasm are discussed.

Preoperative evaluation of stage I and stage II non-small cell lung cancer.

The appropriate preoperative evaluation for occult metastasis in patients with potentially resectable lung cancer remains controversial. The records of 265 patients with stage I and II non-small cell lung cancers who underwent resection with curative intent were reviewed to determine if there was a survival benefit of negative preoperative scanning to detect metastases. A minimum of 5 years of follow-up was possible for all long-term survivors. Patients having preoperative bone scans, brain imaging, and abdominal imaging had no increased survival over those without such evaluation (using Kaplan-Meier survival curves). Additionally, no difference was found in the time to first recurrence between these groups, and the site of recurrence was independent of a negative preoperative scan for that location. These data, using patient outcome as the basis of our conclusion, support a policy of reserving expensive preoperative metastatic evaluations only for those patients with clinical evidence of metastatic disease.

Effect of early versus delayed hypoxic environment on neonatal rabbits.

We developed a low-cost, nonsurgical small animal model simulating the condition of cyanotic heart disease. Six groups of New Zealand white rabbits were studied: Group (1-C), 1-week-old control rabbits (n = 9) reared in room air; Group (1-H), 1-week-old rabbits placed in a hypoxic environment (10% O2) at birth (n = 5); Group (1-H-3), 1-week-old rabbits (n = 11) reared in room air for 3 days and then placed under hypoxic conditions identical to those for Group (1-C); Group (4-C), 4-week-old control rabbits (n = 12); Group (4-H), 4-week-old rabbits placed in hypoxia since birth (n = 11); Group (4-H-3), 4-week-old rabbits kept in room air after birth for 3 days (n = 7) before being exposed to hypoxia. Animals were anesthetized, heparinized, and instrumented for measurement of hemodynamic parameters. Right ventricular (RV) hypertrophy and hematocrit were assessed. Lung tissue was analyzed using quantitative morphometric techniques to assess arterial size, number, and muscularity. Group (1-H) and Group (4-H) developed RV hypertrophy, pulmonary hypertension, and erythrocytosis. The RV hypertrophy developed rapidly, as early as 1 week of age and became so pronounced by 4 weeks as to result in high mortality rate (35%). None of the animals in Groups (1-H-3) or (4-H-3) died while chronic changes of hypoxemia still developed. Placing rabbits after birth in room air for 3 days before exposing them to hypoxia appeared to play a protective role, moderating the development of pulmonary hypertension and severe RV hypertrophy. The effects of hypoxia appear to be at least partially dependent on the time of exposure. Utilizing our low-cost model will allow future work, including study of the effects of chronic hypoxemia on systemic ventricle exposed to an ischemic insult.