Doxofylline and respiratory mechanics. Short-term effects in mechanically ventilated patients with airflow obstruction and respiratory failure.

To assess the short-term effects of a methylxanthine (doxofylline) on respiratory mechanics in mechanically ventilated patients with airway obstruction and respiratory failure, nine consecutive patients were examined within three days from the onset of mechanical ventilation. Flow, changes in pulmonary volume, and Paw were measured using a ventilator (Servo 900C). End-expiratory and end-inspiratory airway occlusion was performed to measure PEEPi, Cstrs, Rrsmax, and Rrsmin. Measurements were performed before and at 5, 15, and 30 minutes after an intravenous loading dose of doxofylline (5 to 6 mg/kg). We found that doxofylline determined, on the average, a marked decrease in respiratory resistance (Rrsmax and Rrsmin, -27.2 percent and -36.5 percent, respectively) without significant changes in Cstrs and Pmax. The PEEPi, reflecting pulmonary dynamic hyperinflation, was also significantly decreased by doxofylline (-41 percent, on the average). The Pmax was not reliable for evaluation of a single patient, since changes in the elastic pressure can offset changes in the resistive one. No patient experienced significant side effects due to doxofylline. We conclude that (1) the effects of therapy can be assessed noninvasively at bedside in critically ill patients; (2) doxofylline is a rapid and efficient bronchodilator in mechanically ventilated patients with ARF and airflow obstruction; and (3) the decrease in the respiratory resistance and PEEPi, associated with an improved mechanical efficiency of the respiratory muscles at a lower pulmonary volume, can provide better conditions for the patient-ventilator interaction and for weaning.

Multimodal management of stages III-IVa malignant thymoma.

PURPOSE: The optimal therapy for locally advanced malignant thymoma is controversial. We review our experience with a multimodal approach in 63 consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and 20 stage IVa disease. Surgery with radical intent was initially performed in 30 cases, while 33 cases not amenable to radical surgery underwent neoadjuvant treatment (radiotherapy in 8 and chemotherapy in 25) before surgical reassessment. All patients, whether or not surgically resected, received radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight stage III and four stage IVa). With the addition of patients radically operated with neoadjuvant treatment, the radical resection rate increased from 46 to 65% in stage III patients, and from 0 to 20% in those with stage IVa disease, respectively. Radical surgery was associated with longer progression free survival and overall survival according to both univariate analysis ( P< 0.001 and P<0.01, respectively) and multivariate analysis after adjustment for age, gender, histology and disease stage ( P<0.001 and <0.02, respectively). Progression free survival (median 56.9 months) was slightly lower in patients undergoing radical surgery after neoadjuvant approaches than in those radically resected ab initio (median not achieved), but overall survival (median not achieved) was similar in both groups. Subtotal surgical resection promoted complete response to subsequent radiation therapy. This condition significantly correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an independent prognostic parameter in locally advanced thymoma treated with a multimodal approach. Preoperative treatment to increase the complete resection rate could improve the overall survival of these patients.

Dose-response effects and time course of effects of inhaled fenoterol on respiratory mechanics and arterial oxygen tension in mechanically ventilated patients with chronic airflow obstruction.

To investigate the dose-response relationship and the time course of the effects of fenoterol (a selective beta 2-adrenergic agonist) on respiratory function in mechanically ventilated patients with acute respiratory failure due to exacerbation of chronic airflow obstruction (CAO), seven consecutive acutely ill patients were studied within 3 days of the onset of mechanical ventilation. Airflow, airway pressure, and changes in lung volume were measured with the transducers of the 900 C Servo Ventilator, the last by electronic integration. The end-expiratory lung volume (EELV), the intrinsic positive end-expiratory pressure (PEEPi), the static respiratory compliance (Cstrs), maximum and minimum respiratory resistance (Rrsmax and Rrsmin), and arterial oxygen tension (PaO2), were measured under control conditions (all patients were receiving aminophylline infused at a constant rate) 5, 15, and 30 min after administration of 4 ml aerosolized saline solution and 5, 15, and 30 min after inhalation of 0.4, 0.8, and 1.2 mg fenoterol. After the last dose, measurements were repeated at 60, 120, and 180 min. We found that, on average, while saline did not cause any significant change in respiratory mechanics, a low dose (0.4 mg) of inhaled fenoterol was followed by a rapid (5 min) and significant decrease in Rrsmax (-33%), Rrsmin (-28%), EELV (-34%), and PEEPi (-44%), with a slight but not significant further fall with higher doses. However, changes were short-lasting, and by 2 h after the end of administration were no longer significant. PaO2 dropped significantly on average, with a maximum mean fall of 15 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)

Paclitaxel administration on days 1 and 8 every 21 days in anthracycline-pretreated metastatic breast cancer patients. A multicenter phase II trial.

Paclitaxel is now included in second- and even first-line regimens in advanced breast cancer. The optimal dose and schedule of this drug, however, still remain a matter of investigation. A group of 57 consecutive patients with advanced breast cancer previously treated with anthracycline-containing regimens were submitted to treatment with single-agent paclitaxel administered at 130 mg/m2 on days 1 and 8 every 21 days. Of the 57 patients, 56 were fully evaluable, and of these 25 had an absolute anthracycline resistance, 14 a relative resistance and 17 were potentially sensitive. The median age of the patients was 57 years (range 33-71 years), their median performance status was 1 (0-3), and 27 (47%) had liver involvement, 17 (30%) lung involvement, 30 (53%) bone involvement and 15 (26%) skin/lymph node involvement. Toxicity was recorded in 295 cycles. This scheme was well tolerated, the dose-limiting toxicities being hematological and neurological. Grade 3/4 leukopenia was observed in 20% of patients at nadir, while grade 3 leukopenia was observed in 3% of patients at recycle. Only one patient experienced febrile neutropenia. Grade 2/3 neurotoxicity was observed in 26% of patients, leading to drug withdrawal in three. The treatment was given on an outpatient basis in all patients and the median relative dose intensity of 86.6 mg/m2 per week was 100% of the planned dose (range 75-100%). Three patients (5%) attained a complete clinical response and 12 (21%) a partial response for an overall response rate of 26% (95% confidence interval 18-38%), while 30 (53%) attained disease stabilization and 11 progressed (19%). Time to progression in responding patients was 10.3 months, and the median overall survival of the entire population was 15.4 months. To conclude, paclitaxel administration on days 1 and 8 every 21 days was active and manageable in advanced breast cancer patients previously treated with anthracyclines. The response obtained was durable.

Low dose carboplatin (AUC 4.5) combined with vinorelbine in the treatment of advanced non-small cell lung cancer: a single institution phase II study.

Platinum compounds and vinorelbine (VNB) are active in the treatment of non-small cell lung cancer (NSCLC), but moderate toxicity has been reported. The aims of the present study were to assess activity and tolerability of low dose carboplatin (CBDCA): 4.5 AUC according to Calvert formula on day 1, combined with vinorelbine: 25 mg/m2 on days 1 and 8, administered every 4 weeks. Eighty-five advanced NSCLC patients entered the study; all of them were evaluable for toxicity and 83 were evaluable for activity. According to an intent to treat analysis, 26 patients attained a partial response (30.5%; 95% CI 20.5-40.5), 27 (31.7%) obtained a disease stabilization and 30 (35%) progressed. This regimen appeared to be modestly toxic, grade 3-4 leukopenia and thrombocytopenia were observed in less than 5% of cases and grade 2 neuropathy in 10% of cases. Median time to progression and overall survival were 7 and 9 months, respectively. In conclusion, low dose CBDCA (administered following Calvert's formula) and VNB combination is an active and very well tolerated cytotoxic regimen in the treatment of advanced NSCLC. The application of the Calvert formula may have contributed to limit the side effects related to CBDCA.

Gemcitabine plus cisplatin in the treatment of patients with advanced non-small cell lung cancer: a phase II study.

BACKGROUND: Lung cancer is the leading cause of cancer death in men worldwide; most cases are not suitable for radical surgery at diagnosis and palliative treatment remains the primary goal of therapy. Cisplatin and gemcitabine are among the most active cytotoxic agents for the treatment of non-small cell lung cancer (NSCLC): they have non-overlapping toxicity and preclinical studies have demonstrated their potential synergistic interaction. PATIENTS AND METHODS: The aims of the present study were to assess the activity and tolerability of cisplatin 80 mg/m2 on day 1, combined with gemcitabine 1000 mg/m2 on days 1 and 8, administered every 3 weeks. A total of 46 consecutive patients with advanced NSCLC entered this study; all of them were evaluable for toxicity and for activity. RESULTS: According to an intent-to-treat analysis, 15 patients attained a partial response (33%), 9 (20%) obtained a disease stabilisation and 22 (47%) progressed. This regimen appeared to be modestly toxic, with grades 3-4 leukopenia and thrombocytopenia observed in 10% and 6% of cases respectively; grade 3 vomiting appeared in 12 patients (26%) and grade 3 mucositis in 1 patient. The median time-to-progression and overall survival were 200 and 400 days, respectively. CONCLUSION: Our study of gemicitabine + cisplatin on stage IV NSCLC patients achieved favourable results in terms of toxicity and overall survival.

Respiratory resistance and intrinsic positive end-expiratory pressure (PEEPi) in patients with the adult respiratory distress syndrome (ARDS).

Fourteen consecutive ARDS patients were examined within 24 h from the onset of mechanical ventilation to determine respiratory resistance (Rrs) and compliance (Cstrs), and to assess the influence of "intrinsic" positive end-expiratory pressure (PEEPi) on the measurement of Cstrs. Flow, pressure, and changes in lung volume were measured with the transducers of the Servo 900C Siemens ventilator. Airway occlusion was performed with the end-inspiratory and end-expiratory buttons of the ventilator. We found PEEPi (3.0 +/- 2.6 cm H2O) in ten of the fourteen patients. Without the correction for PEEPi, Cstrs was underestimated by 13.9 +/- 10% on average in the group as a whole (fourteen patients), and by 19.5 +/- 5.9% in the ten ARDS patients with PEEPi. Maximum and minimum respiratory resistance (Rrsmax and Rrsmin), and frequency-dependence of Rrs were also measured. On average, there was a marked frequency-dependence of resistance, as manifested by the difference between Rrsmax and Rrsmin, with an increase of both Rrsmin (7.7 +/- 4.2 cm H2O.l-1.s) and Rrsmax (14.3 +/- 5.0 cm H2O.l-1.s). The added resistance of the endotracheal tubes and ventilator tubings was flow dependent, and averaged 13.2 +/- 2.9 cm H2O.l-1.s.(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory mechanics during the first day of mechanical ventilation in patients with pulmonary edema and chronic airway obstruction.

We investigated the early changes of respiratory mechanics in mechanically ventilated patients with acute respiratory failure (ARF): 8 patients after acute exacerbation of chronic airway obstruction (CAO), 8 patients with cardiogenic pulmonary edema (CPE), and 8 patients with adult respiratory distress syndrome (ARDS). The patients were studied within the first day from the onset of mechanical ventilation. Flow, changes in lung volume, and airway pressure were measured using the 900C Servo Ventilator. End-inspiratory and end-expiratory occlusions of the airway were performed to obtain respiratory compliance and resistance. We found that: (1) acute exacerbation of CAO was characterized by high respiratory resistance (reflecting in part time-constant inequalities within the lung) and severe pulmonary hyperinflation, with "intrinsic" PEEP (PEEPi) up to 22 cm H2O (mean [SD], 13.5 [6.7] cm H2O); (2) PEEPi, even if not high, was present in almost all patients with pulmonary edema, averaging 3.8 and 3.0 cm H2O in ARDS and CPE, respectively; (3) respiratory resistance was increased in patients with CPE and ARDS who had no history of airway disease; (4) patients with ARDS were characterized also by low compliance (mean [SD], 0.035 [0.005] L/cm H2O) and high resistance, the latter also reflecting a substantial component caused by time-constant inequalities; (5) in all 24 patients, static respiratory compliance (and its reciprocal, elastance) was significantly correlated with the pulmonary oxygenation index, i.e., the PaO2/PAO2 ratio. We conclude that early assessment of respiratory mechanics in mechanically ventilated patients with ARF can provide better understanding of the patients' conditions as well as guidelines for therapeutic approach and weaning attempts.

Independent factors predict supranormal CA 15-3 serum levels in advanced breast cancer patients at first disease relapse.

Data currently available are insufficient to demonstrate a real utility for CA 15-3 in the diagnosis, staging or surveillance of breast cancer patients following primary treatment. The aim of this study was to determine if there was a correlation between supranormal CA 15-3 serum levels and clinical and biological variables in breast cancer patients at first disease relapse. From October 1988 to March 1998, 430 consecutive patients entered the study. Overall CA 15-3 sensitivity was 60.7%. Elevated CA 15-3 levels were found more frequently in patients with liver metastases (74.6%) and in those with pleural effusion (75.7%). CA 15-3 sensitivity was 70.4% in patients with estrogen-receptor-positive (ER+) primary tumors and 45.9% in those with estrogen-receptor-negative (ER-) tumors (p < 0.0001). In patients with a limited extent of disease, marker sensitivity was 57.7% in ER+ tumors and 25.7% in ER- tumors (p < 0.0001). Logistic regression analysis showed ER status, disease extent and pleural effusion as independent variables associated with CA 15-3 positivity. The multivariate Cox analysis showed ER and disease extent as independent variables predicting overall survival, whereas CA 15-3 failed to be statistically significant. CA 15-3 was an independent variable only when the disease extent variable was removed. This study suggests that CA 15-3 in advanced breast cancer patients is a marker of both disease extent and ER status. The direct relationship with ER status indicates that CA 15-3 diagnostic sensitivity in the early detection of disease recurrence could be greater in ER+ patients than in ER- ones. Furthermore, this suggests that patients with elevated CA 15-3 levels could have disease that is more sensitive to hormone manipulation than those with normal CA 15-3 values.