A multi-analyte serum test for the detection of non-small cell lung cancer.

BACKGROUND: In this study, we appraised a wide assortment of biomarkers previously shown to have diagnostic or prognostic value for non-small cell lung cancer (NSCLC) with the intent of establishing a multi-analyte serum test capable of identifying patients with lung cancer. METHODS: Circulating levels of 47 biomarkers were evaluated against patient cohorts consisting of 90 NSCLC and 43 non-cancer controls using commercial immunoassays. Multivariate statistical methods were used on all biomarkers achieving statistical relevance to define an optimised panel of diagnostic biomarkers for NSCLC. The resulting biomarkers were fashioned into a classification algorithm and validated against serum from a second patient cohort. RESULTS: A total of 14 analytes achieved statistical relevance upon evaluation. Multivariate statistical methods then identified a panel of six biomarkers (tumour necrosis factor-α, CYFRA 21-1, interleukin-1ra, matrix metalloproteinase-2, monocyte chemotactic protein-1 and sE-selectin) as being the most efficacious for diagnosing early stage NSCLC. When tested against a second patient cohort, the panel successfully classified 75 of 88 patients. CONCLUSIONS: Here, we report the development of a serum algorithm with high specificity for classifying patients with NSCLC against cohorts of various 'high-risk' individuals. A high rate of false positives was observed within the cohort in which patients had non-neoplastic lung nodules, possibly as a consequence of the inflammatory nature of these conditions.

Modulation of tumor-infiltrating lymphocyte cytolytic activity against human non-small cell lung cancer.

The cytokines expressed in tumor microenvironments are thought to be important mediators of both the host immune response and tumor survival. The source of these cytokines includes tumor cells, infiltrating leukocytes, fibroblasts, and other stromal elements. We previously reported that tumor-infiltrating lymphocytes (TIL) from human non-small cell lung cancer (NSCLC) express predominantly type 1 cytokines, which are known to enhance cell-mediated immunity. The purpose of this study is to assess the cytokine mRNA expression of human NSCLC primary cell lines and the capacity of the tumor-associated cytokines to modulate the development of TIL cytolytic activity against the autologous tumor. Cytokine mRNA expression was determined by RT-PCR and the capacity of TIL to kill autologous lung tumor cells was measured by the chromium-51 (51Cr) release assay. All NSCLC primary cell lines expressed mRNA for IL-4, IL-6, and transforming growth factor-beta1 (TGFbeta1), whereas IL-10 was expressed in only 1/7 cell lines. When added to TIL cultures stimulated with anti-CD3+IL-2, IL-4 and IL-10 enhanced and TGF-beta1 suppressed the development of TIL cytolytic activity against autologous tumor cells. The effects of IL-6 were inconsistent and for the group, were not statistically significant. These results demonstrate that human NSCLC cells express cytokines with the capacity to regulate the in situ anti-tumor immune response. However, the effects of tumor-derived cytokines varied qualitatively and quantitatively suggesting the balance between specific type 2 cytokines or TGF-beta1 within tumor microenvironments may influence prognosis or response to immunotherapy.

Cytokine biosynthesis by tumor-infiltrating T lymphocytes from human non-small-cell lung carcinoma.

PURPOSE: The purpose of this work was to assess the capacity of tumor-infiltrating leukocytes (TIL) from human non-small-cell lung carcinoma (NSCLC) specimens to synthesize type-1 and type-2 cytokines. METHODS: TIL were isolated from tumors following digestion with collagenase/DNase and further enriched by ficoll-hypaque gradient centrifugation. Membrane phenotypes and intracellular cytokine protein expression of TIL were assessed by flow cytometry. RESULTS: The majority of TIL expressed the CD3 antigen with a CD4:CD8 ratio of approximately 2:1. Other leukocytes such as macrophages (CD14), B lymphocytes (CD20), and natural killer (NK) cells (CD56) were also found to infiltrate the tumors, but in significantly lower numbers. Owing to the limited recovery of non-CD3(+) leukocytes, our analysis of cytokine biosynthesis has focused on T lymphocytes. In the absence of activation, a small percentage of CD3(+) TIL synthesized cytokines ( <4%). Following activation with anti-CD3+interleukin-2 (IL-2), CD3(+) TIL synthesized predominantly a type-1 cytokine profile; however, the type-2 cytokines, IL-6 and IL-10, were also detected in a small percentage of infiltrating cells. Following activation with phorbol 12-myristate 13-acetate + ionomycin, CD3(+) TIL also expressed more type-1 than type-2 cytokines and in significantly greater numbers of cells. The CD3(+)CD8(+) component of the TIL synthesized only type-1 cytokines, whereas the CD3(+)CD4(+) component synthesized both type-1 and type-2 cytokines. CONCLUSION: These results show that the majority of the TIL isolated from NSCLC specimens are T lymphocytes with the capacity to synthesize type-1 cytokines.

Chondroma and chondrosarcoma.

A chondrosarcoma is the most common primary malignant tumor of the chest wall. It usually presents on the anterior chest wall arising from the costochondral arches or sternum. It may occur as the result of malignant degeneration of a benign chondroma. Both chondrosarcomas and benign chondromas present as painful, slow-growing, hard, fixed, and nontender anterior chest wall masses. Microscopic differentiation between the two tumors is difficult and the treatment for both tumors is wide excision with a margin of at least 4 cm. Chemotherapy is ineffective and radiation therapy is used only for patients with tumors that are either not amenable to surgical resection or have positive resection margins.

Indications for pneumonectomy. Pneumonectomy for malignant disease.

The anatomic extent of a pulmonary malignancy usually dictates the need for pneumonectomy to achieve a complete resection. The requirement for a pneumonectomy can frequently be predicted by accurate clinical staging, but may also be required due to intraoperative findings relating to tumor invasion or nodal spread. Completion pneumonectomy is usually reserved for locally recurrent lung cancer or early to late complications following pulmonary resection. Malignant involvement of the carina frequently requires sleeve pneumonectomy.

Pericardial effusion: subxiphoid pericardiostomy versus percutaneous catheter drainage.

BACKGROUND: Optimal management of cardiac tamponade resulting from pericardial effusion remains controversial. METHODS: Cardiac tamponade in 117 patients was treated with either subxiphoid pericardiostomy (n = 94) or percutaneous catheter drainage (n = 23). Percutaneous catheter drainage was used for patients with hemodynamic instability that precluded subxiphoid pericardiostomy. Effusions were malignant in 75 (64%) of 117 patients and benign in 42 (36%) of 117. RESULTS: Subxiphoid pericardiostomy had no operative deaths and a complication rate of 1.1% (1 of 94). In contrast, percutaneous drainage had significantly (p < 0.05) higher mortality and complication rates of 4% (1 of 23) and 17% (4 of 23), respectively. Patients with an underlying malignancy had a median survival of 2.2 months, with a 1-year actuarial survival rate of 13.8%. In comparison, patients with benign disease had a median survival of 42.8 months and a 1-, 2-, and 4-year actuarial survival rate of 79%, 73%, and 49%, respectively (p < 0.05). Effusions recurred in 1 (1.1%) of 94 patients after subxiphoid pericardiostomy compared with 7 (30.4%) of 23 patients with percutaneous drainage (p < 0.0001). CONCLUSIONS: Benign and malignant pericardial tamponade can be safely and effectively managed with subxiphoid pericardiostomy. Percutaneous catheter drainage should be reserved for patients with hemodynamic instability.

Breast carcinoma metastases.

With careful selection of patients, complete resection of pulmonary metastases from breast carcinoma may be a useful therapeutic option. Such a treatment appears to offer a significant survival benefit when compared with medical treatment alone, or with incomplete resection.

Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation.

We previously observed encouraging results and acceptable toxicity in phase II trials testing preoperative split-course thoracic radiation and simultaneous cisplatin, etoposide, and 5-fluorouracil in stage III non-small cell lung cancer patients. We decided to delete 5-fluorouracil and to incorporate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into our combined-modality treatment. The first group of patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 2, etoposide 50 mg orally days 1 to 5 and 8 to 12, cisplatin 50 mg/m2 on day 21, and paclitaxel 35 mg/m2 escalated to 45 mg/m2 on days 1 and 8. Group 2 patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 1, etoposide 45 mg/m2 intravenously daily on days 2 to 5, and paclitaxel 80 mg/m2 (escalating to 120 mg/m2) on day 1. Patients in group 3 received carboplatin dosed at an area under the concentration-time curve of 4 on day 1 and paclitaxel 120 mg/m2 (escalating to 140 mg/m2) on day 1. Each patient received radiation 2 Gy daily on days 1 to 5 and 8 to 12, and a total of two cycles was given at 28-day intervals. Twenty-one patients received preoperative chemoradiotherapy: group 1, five patients; group 2, 11 patients; and group 3, five patients. Thoracotomy was not done in five patients due to cerebrovascular accident in one and progressive tumor in four. The remaining 16 patients had the following procedures: pneumonectomy, eight; lobectomy, six; chest wall resection, one; and no resection, one. Postoperative complications included bronchopleural fistula in one patient each in groups 1 and 3, hypoxia in one patient in group 1, pulmonary hypertension in one patient in group 2, pneumonia in one patient in group 2, and adult respiratory distress syndrome in one patient in group 3, which proved lethal. Thus, six of 16 patients had serious postoperative complications. The relatively high incidence of postoperative bronchopulmonary complications suggests that the use of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic radiation may not be feasible.

Escalating paclitaxel doses combined with carboplatin/etoposide and thoracic radiotherapy as preoperative or definitive treatment for stage III non-small cell lung cancer.

We have evaluated escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin, cisplatin, etoposide, and concurrent thoracic radiotherapy in patients with stage III non-small cell lung cancer. Dose-limiting toxicity was observed at paclitaxel 90 mg/m2. Subsequent modifications resulted in a new regimen, which consists of a 3-hour paclitaxel infusion on day 1 (three dose levels: 80, 100, and 120 mg/m2), etoposide 40 mg/m2 intravenously over 1 hour daily on days 2 to 5, and carboplatin given at an area under the concentration-time curve of 4 mg/mL x min on day 1 after paclitaxel. Treatment courses were repeated every 28 days. Eleven patients considered eligible for surgery received two courses. Nonsurgical patients (five) received three courses. No episodes of grade > or = 3 nausea and vomiting, dermatitis, anorexia, esophagitis, or thrombocytopenia were observed. The dose-limiting toxicity (grade 4 granulocytopenia) occurred in three of five patients at 120 mg/m2 paclitaxel (level 3). Grade 3 radiation pneumonitis was observed in three patients. Nine patients have undergone pulmonary resection: four pneumonectomies, four lobectomies, and one segmental resection. No operative deaths, respiratory insufficiency, or cardiovascular complications were observed. Clinical partial remissions have been observed in 11 of 16 patients overall, and two histologic complete remissions were achieved in nine surgical patients. Our preliminary results show that pulmonary resection is feasible following treatment with radiation and concurrent paclitaxel-containing chemotherapy. Although the maximum tolerated paclitaxel dose in the present study was relatively low, favorable initial responses warrant further study of paclitaxel-containing combination chemotherapy and concurrent radiation. We next plan to delete etoposide from our chemoradiotherapy regimen and escalate the paclitaxel dose.

Retreatment of recurrent invasive thymoma with platinum, doxorubicin, and cyclophosphamide.

Invasive thymoma recently has been shown to be sensitive to combination chemotherapy and in some cases to be relatively indolent. Two cases of extensive thymoma which responded to primary treatment with a combination of a platinum compound (carboplatin or cisplatin), doxorubicin (Adriamycin), and cyclophosphamide (or PAC) are described. Tumor progression occurred 14 (case 1) and 60 months (case 2) after completion of initial PAC therapy and was treated with the same regimen resulting in a second remission, which lasted 6 months in case 1 and is continuing at 8 months in case 2. Similar reports of secondary responses using the same chemotherapy have been described in breast, lung, and ovarian cancers, as well as in Hodgkin's lymphomas. Our observations suggest that retreatment with the same platinum-based regimen should be considered in patients who have progressive thymomas following a previous chemotherapeutic response and a disease-free interval of greater than 12 months.

Historical developments in the management of empyema.

The diagnosis and treatment of empyema was first described by Hippocrates over 2000 years ago. Virtually nothing else pertaining to this disease was recorded until the early 18th century. Since that time, numerous treatments have been described including open and closed tube drainage, thoracentesis, and thoracoplasty.

Carboplatin/etoposide/radiation plus escalating doses of paclitaxel in stage III non-small cell lung cancer: a preliminary report.

Large randomized studies have shown superior survival results for sequential chemoradiotherapy compared with radiation alone in stage III non-small cell lung cancer. Similarly, chemotherapy followed by surgery was associated with longer survival than surgery alone in small randomized trials. Despite these results, disease recurs in most stage III patients. To improve these results, we are studying escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with platinum/etoposide and simultaneous thoracic irradiation as preoperative and curative therapy. Initially, paclitaxel was given at a starting dose of 35 mg/m2 intravenously (i.v.) over 24 hours on days 1 and 8; carboplatin (area under the concentration time curve) 4 mg/mL.min) i.v. was given on day 2 and etoposide 5 mg/d orally on days 1 to 5 and 8 to 12; cisplatin 50 mg/m2 i.v. was given on day 23, and radiation 2 Gy was given on days 1 to 5 and 8 to 12. Courses were repeated every 28 days. Four of five patients treated at the second paclitaxel dose level (90 mg/m2) experienced grade 4 toxicity. The treatment regimen was changed to paclitaxel given at a starting dose of 80 mg/m2 i.v. over 3 hours on day 1, carboplatin (area under the concentration time curve 4 mg/mL.min) i.v. given immediately after paclitaxel, etoposide 40 mg/m2 i.v. given over 1 hour on days 2 to 5, and radiation 2 Gy given on days 1 to 5 and 8 to 12. No grade 4 toxicity was observed in five patients treated at the first paclitaxel dose level (80 mg/m2). After two courses, pulmonary resection (lobectomy and pneumonectomy) was performed without fatalities in five patients. Although more data are needed, pulmonary resection appears feasible following treatment with this paclitaxel-containing regimen. Patient accrual is continuing to determine the maximum tolerated dose of paclitaxel.

Sleeve lobectomy.

Sleeve lobectomy is the alternative procedure to pneumonectomy. It can be an operation of choice for lung cancer, if technically feasible, and is the ideal procedure for low grade pulmonary malignancies and inflammatory bronchial strictures. Precise radiologic bronchoscopic assessment defines the need and probability for sleeve lobectomy. Close adherence to precise technical principles will achieve excellent clinical results with a low morbidity and mortality.

Subxiphoid pericardial drainage for pericardial tamponade.

As a result of recent reports and enthusiasm for video-assisted thorascopic pericardiectomy, we reviewed our experience with subxiphoid pericardial drainage. From August 15, 1988, to June 7, 1993, 155 patients underwent subxiphoid pericardial drainage for pericardial effusion associated with pericardial tamponade. The group comprised 85 female (55%) and 70 male patients whose ages ranged from 5 weeks to 88 years. The procedure was carried out with general anesthesia in 113 patients (72%) and with local anesthesia and sedation in 42 patients. Underlying cancer was present in 82 patients; 73 patients had benign disease. Follow-up is complete in all patients. The overall 30-day mortality was 20%; in patients with cancer it was 32.9% (27/82) versus 5.4% (4/73) for patients with benign disease. No postoperative death was attributed to the surgical procedure. Recurrent pericardial tamponade necessitating further surgical intervention occurred in four patients (2.5%), two with cancer (2.4%) and two with benign disease (2.7%). Median survival after subxiphoid pericardial drainage in patients with benign disease was more than 800 days versus 83 days in patients with cancer (p < 0.01). Median survival after pericardial drainage in patients with cancer who had malignant pericardial effusion was 56 days compared with 105 days for patients with cancer who did not have tumor in the pericardium (p < 0.05). We believe that subxiphoid drainage is the procedure of choice for patients with pericardial tamponade. It is accomplished quickly, is associated with minimal morbidity, and prevents recurrent tamponade in 97.4% (151/155) of patients.

Current status of neoadjuvant therapy for non-small cell lung cancer.

Any program of therapy for clinically advanced non-small cell lung cancer (NSCLC) that would increase the incidence of local tumor control and decrease the likelihood of distant metastatic disease would be of obvious benefit. The objective of neoadjuvant therapy is to eradicate the primary tumor and micrometastatic disease. In the past 10 years, many trials have been completed to evaluate neoadjuvant therapy and they have included sequential chemoradiotherapy, concurrent chemoradiotherapy, chemotherapy/surgery, and chemoradiation/surgery. These trials have predominately been phase 2 trials and have demonstrated that chemotherapy is generally well tolerated, surgery is technically feasible, and operative morbidity and mortality are not excessive. Long-term survival for patients with clinically advanced NSCLC is improved when compared with historic controls. These trials have demonstrated a greater than 50% clinical response rate and in approximately 20% of patients who have undergone resections, the tumor is sterilized. This latter group of patients demonstrate significantly improved survival. Cost-benefit ratios and quality of life have yet to be evaluated. Final determination of the effectiveness of neoadjuvant therapy for NSCLC awaits completion of phase 3 trials.