Stereotactic radiosurgery for patients with nonsmall cell lung carcinoma metastatic to the brain

BACKGROUND: A retrospective study of patients undergoing stereotactic radiosurgery for one to four brain metastases from nonsmall lung cell carcinoma (NSCLC) was performed to document outcomes and risks. METHODS: Seventy-seven patients underwent radiosurgery during a 7-year interval; 71 also underwent whole brain radiation therapy. Univariate and multivariate analyses were used to determine significant prognostic factors affecting survival. RESULTS: The overall median survival was 10 months after radiosurgery, and 15 months from the diagnosis of brain metastases. Five factors significantly affected survival: extent of systemic disease, presence of a neurologic deficit, size of the intracranial tumor, initial imaging appearance of intratumoral necrosis, and initial resection of the primary tumor of the chest. Median survival time was 26 months in a subgroup of patients with no extracranial metastases, no neurologic deficits, and a small tumor without necrosis. The authors evaluated 91 tumors with imaging. Local tumor control was achieved in 77 lesions (85%) and tumoral radiation necrosis developed in 4 lesions (4.4%). Nineteen new metastatic tumors developed during the observation interval. CONCLUSIONS: Stereotactic radiosurgery for NSCLC brain metastases is effective and is associated with few complications. The early detection of brain metastases and treatment with radiosurgery combined with radiation therapy provide the opportunity for extended high quality survival.     

First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine

BACKGROUND: Docetaxel and vinorelbine are active agents in the treatment of nonsmall cell lung carcinoma (NSCLC). The efficacy and toxicity of this combination was evaluated in a Phase II study in patients with advanced NSCLC. METHODS: Forty-six chemotherapy-naive patients (44 men and 2 women with a median age of 64 years) with NSCLC (11 with Stage IIIB and 35 with Stage IV disease) were entered into the study; the World Health Organization (WHO) performance status was 0, 1, and 2 in 32, 11, and 3 patients, respectively. Patients received vinorelbine (25 mg/m2) on Day 1 and docetaxel (100 mg/m2) on Day 2 in cycles repeated every 3 weeks. Granulocyte-colony stimulating factor was given to all patients from Day 3 to Day 10. RESULTS: One hundred and seventy-seven courses of chemotherapy were administered. Adverse events included WHO Grade 4 neutropenia (15 patients), Grade 3/4 thrombocytopenia (3 patients), Grade 3 anemia (2 patients), Grade 2 and 3 neurotoxicity (7 patients and 1 patient, respectively), and Grade 3 fatigue (2 patients). Twenty patients (43%) required hospitalization: 11 (24%) for neutropenic fever (2 deaths from sepsis), and 9 (20%) for nonneutropenic pulmonary infections (2 deaths from cardiopulmonary insufficiency). The median overall survival was 5 months and the 1-year survival was 24%. Four complete responses (9.8%) and 11 partial responses (26.8%) (overall response rate of 36.6%; 95% confidence interval, 21.8-51.3%) were documented in 41 evaluable patients (intent-to-treat: 32.6%). Stable and progressive disease occurred in 13 patients each (31.7%). The median duration of response was 5 months and the median time to progression was 3 months (6 months for the responders). CONCLUSIONS: This schedule of docetaxel and vinorelbine combination is effective but its relatively high incidence of complicated neutropenia precludes its general use in patients with advanced NSCLC.     

Neuroendocrine differentiation is an independent prognostic factor in chemotherapy-treated nonsmall cell lung carcinoma

BACKGROUND: Neuroendocrine differentiation can be identified in 10-30% of patients with nonsmall cell lung carcinoma (NSCLC) by immunohistochemical or electron microscopic techniques. However, its clinical significance is not well established. METHODS: Tumors from 107 patients with Stage IIIA, IIIB, and IV NSCLC treated with cisplatin/etoposide with or without hydrazine in the North Central Cancer Treatment Group and Mayo Clinic protocols were analyzed immunohistochemically with antibodies to chromogranin A (CGA), Leu 7 (CD 57), and synaptophysin (SY). These results were compared with clinical outcomes. RESULTS: Keratin AE1/AE3, used as a control, was positive in 99.1% of cases; 34.6% had positive staining for at least 1 neuroendocrine marker, and 11.3% had positive staining for 2 or more markers. CGA was positive in 4.7%, Leu 7 in 18.7%, and SY in 24.3% of cases. A significant increase in survival was seen in patients with tumors expressing any one neuroendocrine marker or any combination of neuroendocrine markers (P < or = 0.01). There was no correlation between the presence of neuroendocrine differentiation and either response to chemotherapy or time to disease progression (P > 0.3), nor was there any correlation between chemotherapy response, time to progression, or survival with staining intensity or percent of cells positive per case. CONCLUSIONS: Neuroendocrine differentiation may be of prognostic significance in patients with advanced stage NSCLC treated with chemotherapy.     

Localization of tumor suppressor activity important in nonsmall cell lung carcinoma on chromosome 11q

Loss of heterozygosity on chromosome 11q23 is observed at high frequency in human nonsmall cell lung carcinomas (NSCLCs), suggesting the presence of a tumor suppressor gene. Previous analysis of DNA from 79 patients identified a commonly deleted segment of 5 centimorgans. Complementation analysis was used to further localize a putative tumor suppressor gene. Three yeast artificial chromosome (YAC) clones spanning the minimal loss of heterozygosity region were modified, and spheroplast fusion was used to transfer them into human A549 NSCLC or murine Lewis lung carcinoma (LLC) cell lines. The resulting yeast x human hybrid cell lines containing an intact copy of a 1.6-Mb YAC, 939b12, showed reduced growth in vitro. Injection of parental A549 cells into athymic (nu/nu) mice resulted in tumor formation at 27 of 28 injection sites. In contrast, two independent 939b12-containing cell lines formed tumors at only 3 of 20 injection sites. 939b12 also suppressed tumor formation by LLC NSCLC cells in nude mice, but YACs 785e12 and 911f2, which flank 939b12, had no suppressor activity. Further localization of tumor suppression activity on 939b12 was accomplished by introduction of defined fragmentation derivatives into A549 cells and by analysis of YACs that were broken on transfer into LLC cells. This complementation approach localized tumor suppression activity to the central 700 kb of 939b12 and provides a functional assay for positional cloning of this tumor suppressor gene.     

Is the chest radiograph a reliable tool in the assessment of tumor response after radiotherapy in nonsmall cell lung carcinoma?

BACKGROUND: The purpose of this study was to evaluate whether the chest radiograph is a reliable tool to assess response to radiotherapy. MATERIALS AND METHODS: Pre- and post-treatment chest radiographs and computed tomographs (CT) of 63 patients with nonsmall cell lung cancer (NSCLC) treated by radiotherapy were reviewed by four observers with regard to suitability for tumor measurement, and response. Suitability for tumor measurement was expressed as the number of measurable diameters. In addition, the consequences to clinical outcome were studied by survival analysis. RESULTS: The CT turned out to be more suited for tumor measurement before as well as after radiotherapy, resulting in an increase of the number of measurable cases. The number of measurable cases with CT was 52 (83%) as compared to 28 (44%) with chest radiography. Especially in case of centrally localized tumors, the presence of an atelectasis, or squamous cell carcinoma, CT contributed to a higher rate of measurable cases. The interobserver agreement with regard to response using chest radiograph was good (mean kappa = 0.74). In 25 of 28 cases (89%) measurable with CT as well as with chest radiograph, response was equally classified. When CT was used, the median survival of the responders was 14.2 months as compared to 6.8 months of the nonresponders. When chest radiograph was used, the median survival of these groups was 12.0 and 6.6 months respectively, which was not significantly different when response was assessed by CT. CONCLUSION: We conclude that CT is more suited for tumor measurement because more measurable lesions can be found and more evaluable lesions on chest radiograph become measurable on CT. The chest radiograph does have a valuable role to play in those lesions that are measurable because of the good interobserver agreement with regard to the response classification, the high overall agreement between CT and chest radiograph in case of measurable cases, and the lack of important differences with regard to survival.     

Thoracotomy for postchemotherapy resection of pulmonary residual tumor mass in patients with nonseminomatous testicular germ cell tumors: aggressive surgical resection is justified

BACKGROUND: Atrioventricular association is a key criterion for arrhythmia diagnosis. Its use in a defibrillator should significantly reduce the incidence of inappropriate shocks. Therefore, we evaluated the diagnostic accuracy of an algorithm that uses dual-chamber sensing and analysis of atrioventricular association to discriminate ventricular from supraventricular arrhythmias in a prototype of an implantable defibrillator. METHODS AND RESULTS: The algorithm performed a stepwise analysis of arrhythmias. The rhythm was first classified on the basis of cycle lengths. Each episode was then classified as supraventricular or ventricular in origin on the basis of the stability of cycle lengths and atrioventricular association. This algorithm was evaluated in 156 episodes of induced sustained tachycardias. Eighty-nine tachycardias were taken from the Ann Arbor electrogram library; the others were recorded in 50 patients during electrophysiological studies. The atrial and ventricular signals were stored on an external recorder and then injected into an external prototype of a defibrillator system. The algorithm correctly diagnosed 96% of ventricular tachycardia episodes, 100% of ventricular fibrillation episodes, and 92% of double-tachycardia episodes. The mean detection time for ventricular tachycardia was 2.6 +/- 0.8 seconds, and for ventricular fibrillation, it was 2.1 +/- 0.4 seconds. The positive predictive values for the diagnoses of atrial fibrillation and atrial flutter were 92% and 86%, respectively. For ventricular tachycardia and ventricular fibrillation, the values were 95% and 100%, respectively. CONCLUSIONS: Analysis of atrioventricular association promotes reliable differentiation between ventricular and supraventricular tachycardias and should enhance the diagnostic capabilities of implantable defibrillators.     

Autologous tumor killing activity as a prognostic factor in primary resected nonsmall cell carcinoma of the lung

BACKGROUND: Cytotoxic activity of peripheral blood lymphocytes obtained during surgery against autologous fresh tumor cells has been reported. However, the role of lymphocyte autologous tumor killing or natural killer activity during the postoperative period remains obscure. In this article, the authors describe the importance of postoperative autologous tumor killing activity as a prognostic factor in patients with primary resected nonsmall cell lung carcinoma (NSCLC) after long term follow-up. METHODS: Forty-two patients who had resection of NSCLC, with primary culture of autologous tumor cells taken successfully, were studied. Cytotoxic activity against autologous, allogenic NSCLC and K562 leukemia cells was examined using peripheral blood lymphocytes obtained during the 2 weeks immediately following surgery. Factors related to prognosis were analyzed by univariate and multivariate analyses. RESULTS: The overall 5- and 10-year survival rates for the NSCLC patients were 40.5% and 27.5%, respectively. Statistical analysis of survival curves revealed a significant difference with regard to T classification (P = 0.025), N classification (P = 0.0015), stage (P = 0.028), and postoperative autologous tumor killing activity (P = 0.0008); there were no significant differences in relation to age, gender, histology, differentiation, visceral pleural invasion, resectability, surgical method, allogeneic tumor killing activity, or natural killer activity. Multivariate analysis demonstrated a significant correlation between disease recurrence and N classification (P = 0.0003), T classification (P = 0.023), stage (P = 0.001), and autologous tumor killing activity (P = 0.007), indicating independent prognostic significance. The phenotypes of the effector cells involved in autologous tumor killing activity were CD3(+), CD4(-), CD8(+), and CD11b(-). Autologous tumor killing activity was inhibited by competing unlabeled autologous tumor cells. CONCLUSIONS: Autologous tumor killing activity during the 2 weeks immediately following surgery is an important prognostic factor in resected NSCLC.     

Single agent versus combination chemotherapy in patients with advanced nonsmall cell lung carcinoma: a meta-analysis of response, toxicity, and survival

Cyclosporin A (CsA) induces osteoporosis but not through direct activation of osteoclasts. CsA also inhibits cell-mediated mineralization in marrow stromal cell culture, whereas the tyrphostin AG-1478 increases mineralization. These antagonistic effects on mineralization were used to discern molecules that underwent phosphorylation changes in association with their opposing effects on mineralization. In parallel, quantitative changes in Src protein were followed. Multiple dexamethasone (DEX)-stimulated stromal cell cultures were grown with and without a mineralization-inhibiting dose (0.1 microM) of CsA and were harvested on different days of DEX stimulation. Immunoblots of gel-fractionated cell extracts showed that the most noticeable changes in tyrosine phosphorylated proteins (TPP) were seen on day 8 of DEX stimulation. At least 15 TPP bands, mostly smaller than 53 kDa, were more prominent in CsA-treated cultures on day 8. Under CsA, Src protein quantity decreased on day 8, but its cleavage product (52/54 kDa) was sixfold more abundant then on day 7. Day 8 was chosen to test the effect of AG-1478 on the CsA-induced TPP changes. Dimethyl sulfoxide (DMSO) alone, the solvent of AG-1478, increased mineralization in CsA-treated versus CsA-untreated cultures and slightly decreased Src and its cleavage product. AG-1478 at 5 microM, in CsA cultures increased the specific alkaline phosphatase activity threefold, with a slight change in mineralization relative to controls grown with DMSO alone. This was accompanied by decreased intensity of several TPP bands smaller than 36 kDa. In contrast, treatment with 50 microM of AG-1478 increased the intensity of TPP bands at the same molecular size range. This high AG-1478 dose decreased cell counts selecting mineralizing cells. The results indicate that increased Src protein cleavage product on day 8 by CsA is associated with mineralization inhibition, which is opposed by DMSO and 50-microM AG-1478, thus antagonizing the effect of CsA on mineralization. Direct or indirect interaction between Src and TPP, antagonistically affected by CsA and AG-1478, is likely to underlay cellular control of mineralization. Changes in p19 and p29 intensity showed association with mineralization that was reflected by a significant direct and inverse correlation, respectively, with calcium precipitation per cell.     

A case of survival for 50 months after resection of cerebellar metastasis of squamous cell lung carcinoma

The patient was a 64-year-old male with squamous cell carcinoma of the left lung, associated with intrapulmonary metastasis. Eleven months after lobectomy, a single metastasis occurred in the left cerebellum. This was resected, and radiation therapy was performed. Fifty months after the resection, the patient is still alive without recurrence. Based on the present case, we consider that, in the case of single brain metastasis, surgical therapy is desirable because long-term survival can be expected with surgical resection even for a cerebellar metastasis.     

Female sex hormone receptor status in advanced hepatocellular carcinoma and outcome after surgical resection

BACKGROUND: There is a limited amount of data regarding the estrogen receptor (ER) and progesterone receptor (PgR) status of hepatocellular carcinomas (HGCs), and the relationship between receptor status and clinicopathologic features of tumors has not been reported. METHODS: Between April 1992 and December 1993, cancerous tissues for cytosolic preparation and receptor quantification in a monoclonal solid-phase enzyme immunoassay were obtained from 28 patients undergoing resection, three patients with total hepatectomy and subsequent liver transplantation, and two patients suffering from nonresectable HCC. RESULTS: ER and PgR were detected in the HCCs of 13 (39%) and 6 patients (18%), respectively. A lower age was observed among the female patients whose receptor status was negative for ER or PgR or both, as compared with the respective receptor-positive groups. No significant differences with respect to tumor stage and grading could be observed. There was one perioperative death (3%). In patients undergoing curative resection, 1-year survival in the ER(+) group was significantly lower than in the ER(-) group (40% versus 79%, p < 0.05). The 2-year survival rates in the ER(+) and ER(-) groups were 40% and 71%, respectively. A comparable trend did not become evident for PgR(+) and PgR(-) patients. CONCLUSIONS: Our data suggest a negative effect of an ER(+) tumor on patient survival after curative resection of advanced HCC.     

Overexpression of Glut1 and Glut3 in stage I nonsmall cell lung carcinoma is associated with poor survival

We report the electrophysiologic findings of myoclonus in a patient with Huntington's disease (HD). This patient was studied postoperatively after a bilateral fetal cell transplant in his striatum. Incomplete transient improvement was seen in the myoclonus, followed by gradual deterioration. The myoclonus itself had a cortical correlate and was associated with an enlarged somatosensory evoked potential (SEP), consistent with the presence of cortical reflex myoclonus. An enlarged SEP has not been previously reported in myoclonus associated with HD. The postulated mechanisms for myoclonus, when it occurs in HD, have differed in the literature. The reason for the transient improvement of the myoclonus following transplantation is unclear, but this case raises the possibility that basal ganglia circuits may modulate cortical myoclonic activity.     

Cancer resection on the residual lung after pneumonectomy for bronchogenic carcinoma

BACKGROUND: After pneumonectomy for bronchogenic carcinoma, the residual lung may be the site of a new lung cancer or metastatic spread. METHODS: From 1989 to 1995, 13 patients with carcinoma on the residual lung after pneumonectomy for lung cancer were operated on. Three segmentectomies and 7 simple wedge resections were performed, 2 patients had multiple wedge resections, and 1 patient had an exploratory thoracotomy. Nine patients had a primary metachronous bronchogenic carcinoma, 3 had metastases from bronchogenic carcinoma, and no definite conclusion was reached in 1 case. RESULTS: No postoperative mortality was observed. Four patients had postoperative complications. The mean postoperative hospital stay was 14 days. Seven patients are alive, including 5 patients without evidence of disease. Six patients died of their disease, all with pulmonary recurrences. The overall median survival was 19 months, with a probability of survival at 3 years (Kaplan-Meier) of 46% (95% confidence interval, 22% to 73%). CONCLUSIONS: Limited pulmonary resection for lung cancer after pneumonectomy for bronchogenic carcinoma is feasible with very low morbidity. In highly selected patients, surgical resection might prolong survival.     

Combined surgical treatment of malignant lung tumors

Elevated titers of antibodies against different antigens of Epstein-Barr virus (EBV) are found in some immunodeficient states, malignancies or in autoimmune disorders. We examined EBV serology in the group of 22 patients with autoimmune thyroiditis as compared with the group of 35 healthy volunteers. Titers of antibodies against viral capsid antigen (IgG-VCA) were more often found in the group of patients than in the control group (p = 0.000 35 for younger than 40 years and p = 0.00115 for older than 40 years) and the positivity of antibodies against early antigen (IgG-EA-D/DR) was also significantly more often found in the group of patients (p = 0.0031 and p = 0.0019 respectively) than in the control group.     

Ultrastructural study of the urothelial lysosomal system in patients with transitional cell carcinoma after transurethral resection and interferon therapy

OBJECTIVE: To evaluate the diagnostic value of flow cytometric DNA analysis of bronchial washing and lavage fluids in lung cancer. METHODS: The cellular DNA contents of bronchial washing and lavage fluids from 68 patients (43 with lung cancer and 25 with benign pulmonary disorder) were analyzed by flow cytometry, and the diagnostic value of this method in lung cancer was compared with that of fiberoptic bronchoscopic biopsy and brushing. RESULTS: The presence of aneuploidy was used as a diagnostic criterion, the sensitivity of DNA analysis was 81%, and the specificity was 92%. The positive rate of aneuploidy in central lung cancer (29) was 83%, and there was no statistical difference when compared with biopsy (90%) and brushing (69%). The positive rate of aneuploidy in peripheral lung cancer (14) was 79%, significantly higher than biopsy (29%) (P < 0.025) and brushing (29%) (P < 0.025). In a few patients from both central and peripheral lung cancer groups, biopsy and brushing appeared negative, but aneuploidy was obtained from cytometry. CONCLUSION: These results suggest that flow cytometric DNA analysis of bronchial washing and lavage fluids may be a valuable adjunctive method in the diagnosis of lung cancer, particularly in peripheral lung cancer.     

Prolonged survival in selected patients following surgical resection for pulmonary metastasis from hepatocellular carcinoma

BACKGROUND: Pulmonary metastasis is the commonest site of extrahepatic spread from hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the efficacy of surgical management in patients with solitary pulmonary metastases from HCC. METHODS: This was a retrospective study of patients with HCC admitted for hepatectomy from July 1972 to June 1995. The records of patients who had a pulmonary resection for histologically proven pulmonary recurrence after curative hepatectomy were selected for analysis. RESULTS: In the study interval, 380 patients with HCC underwent hepatectomy. Some 48 patients (12.6 per cent) developed pulmonary metastases documented pathologically or radiologically. Nine (seven men and two women) were suitable for curative pulmonary resection. The median disease-free survival between hepatectomy and appearance of the lung metastasis was 21 months. The median survival after pulmonary resection was 42 months, and the 1-, 2- and 5-year survival rates were 100, 78 and 67 per cent respectively. CONCLUSION: Pulmonary resection for metastases from HCC resulted in long-term survival in these highly selected patients.     

Advanced renal cell carcinoma: treatment with xenogeneic immune ribonucleic acid and appropriate surgical resection

Herein we describe the first clinical treatment of renal cell carcinoma in humans with xenogeneic immune ribonucleic acid. Twelve patients with advanced renal cell carcinoma have been treated by appropriate operations to remove tumor bulk followed by specific passive immunotherapy. Xenogeneic specific immune ribonucleic acid was prepared from the spleen of normal sheep that had received 4 weekly injections of a homogenate of renal cell carcinoma. Results indicate that 1) xenogeneic specific immune ribonucleic acid can safely be given to humans without local or systemic toxicity, 2) there is a suggestion of clinical benefit, since only 2 patients have had progression of known metastases during treatment with immune ribonucleic acid and 3) xenogeneic immune ribonucleic acid can enhance the immune response to renal cell carcinoma, as demonstrated by in vitro lymphocytoxicity tests.     

Prediction of exercise capacity after lung resection in patients with chronic airflow limitation

To assess the usefulness of a method for predicting postoperative peak oxygen uptake based on lost lung function after lung resection (VO2peak-PPO) and to establish the underlying physiological foundation for the relation between VO2peak-PPO and the measured postoperative value VO2peak-PO), we studied 29 patients (26 men) [age 60 (SD9)] with chronic airflow limitation [FEV1 = 66 (SD13)%] undergoing lobectomy or major pulmonary resection to treat lung cancer. The patients were assigned to groups according to whether postoperative exercise tolerance was considered to be limited by exhaustion of ventilatory reserve (LV) or not (NLV). Data to estimate postoperative pulmonary function was obtained one week before surgery: patients performed pulmonary function tests and exercise tests on a treadmill; dyspnea was also evaluated and perfusion scintigraphs were obtained. Pulmonary function, exercise tolerance and dyspnea were evaluated again approximately five months after surgery. The mean difference between VO2peak-PPO and VO2peak-PO was -0.034 (CI 0.293 to -0.348) l.min-1 and the between-group correlation coefficient was 0.76. The correlation between VO2peak-PPO and VO2peak-PO was 0.86 (SE 0.1) [0.89 (SE 0.13) for LV (n = 14) patients and 0.85 (SE 0.16) for NLV (n = 15) patients]. The correlations after adjusting for preoperative VO2peak-PPO were 0.73 (SE 0.2) and 0.35 (SE 0.27) for LV and NLV patients, respectively. We conclude that VO2peak-PPO provides a valid but only moderately precise estimate of VO2peak-PO. Only in LV patients is there a true relation between a decrease in VO2peak and loss of lung function.