Yvon Cormier

Randomized Phase IIB Trial of BLP25 Liposome Vaccine in Stage IIIB and IV Non–Small-Cell Lung Cancer

PURPOSE To evaluate the effect of BLP25 liposome vaccine (L-BLP25) on survival and toxicity in patients with stage IIIB and IV non-small-cell lung cancer (NSCLC). Secondary objectives included health-related quality of life (QOL) and immune responses elicited by L-BLP25. PATIENTS AND METHODS Patients with an Eastern Cooperative Oncology Group performance status of 0 to 2 and stable or responding stage IIIB or IV NSCLC after any first-line chemotherapy were prestratified by stage and randomly assigned to either L-BLP25 plus best supportive care (BSC) or BSC alone. Patients in the L-BLP25 arm received a single intravenous dose of cyclophosphamide 300 mg/m2 followed by eight weekly subcutaneous immunizations with L-BLP25 (1,000 microg). Subsequent immunizations were administered at 6-week intervals. RESULTS The survival results indicate a median survival time of 4.4 months longer for patients randomly assigned to the L-BLP25 arm (88 patients) compared with patients assigned to the BSC arm (83 patients; adjusted hazard ratio [HR] = 0.739; 95% CI, 0.509 to 1.073; P = .112). The greatest effect was observed in stage IIIB locoregional (LR) patients, for whom the median survival time for the L-BLP25 arm has not yet been reached compared with 13.3 months for the BSC arm (adjusted HR = 0.524; 95% CI, 0.261 to 1.052; P = .069). No significant toxicity was observed. QOL was maintained longer in patients on the L-BLP25 arm. CONCLUSION L-BLP25 maintenance therapy in patients with advanced NSCLC is feasible with minimal toxicity. The survival difference of 4.4 months observed with the vaccine did not reach statistical significance. In the subgroup of patients with stage IIIB LR disease, a strong trend in 2-year survival in favor of L-BLP25 was observed.

Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non–Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10

PURPOSE Adjuvant cisplatin-based chemotherapy (ACT) is now an accepted standard for completely resected stage II and III A non-small-cell lung cancer (NSCLC). Long-term follow-up is important to document persistent benefit and late toxicity. We report here updated overall survival (OS) and disease-specific survival (DSS) data. PATIENTS AND METHODS Patients with completely resected stage IB (T2N0, n = 219) or II (T1-2N1, n = 263) NSCLC were randomly assigned to receive 4 cycles of vinorelbine/cisplatin or observation. All efficacy analyses were performed on an intention-to-treat basis. Results Median follow-up was 9.3 years (range, 5.8 to 13.8; 33 lost to follow-up); there were 271 deaths in 482 randomly assigned patients. ACT continues to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). ACT resulted in significantly prolonged DSS (HR, 0.73; 95% CI, 0.55 to 0.97; P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms. CONCLUSION Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm.

Utility of nocturnal home oximetry for case finding in patients with suspected sleep apnea hypopnea syndrome.

The sleep apnea hypopnea syndrome (SAHS) is characterized by repetitive episodes of complete or partial upper airway obstruction leading to nocturnal sleep fragmentation and daytime hypersomnolence. Its incidence is estimated between 1% and 10% [1-3]. The morbidity and mortality (reported to be 12.5% and 35%, respectively, in untreated patients [4, 5]), can be diminished with effective treatment [4, 6-8], and thus early diagnosis is warranted. Definitive sleep studies necessitate hospitalization, overnight monitoring by a technician, and a 4- to-6 hour interpretation time. Several simplified methods that use ambulatory recordings to measure arterial oxyhemoglobin saturation (Sao 2), thoracoabdominal movements, heart rate, or breathing sounds or all three [9-11] can be used to evaluate patients suspected of having SAHS. Sleep-related breathing abnormalities are frequently accompanied by repetitive oxygen desaturations [12] that can be used to identify and characterize abnormal respiratory events during polysomnographic studies [13]. Home measurement of nighttime oxygen saturation levels using oximetry recording has been considered to be unreliable [14], because even 20 to 30 seconds of apnea can result in minimal Sao 2 changes [15] and because it does not effectively exclude substantial sleep apnea [16, 17]. These findings were based on the decrease in the Sao 2 level, and the number of times the Sao 2 level decreased below a fixed threshold; however, evidence exists that depth of the decreases in nocturnal Sao 2 levels do not always parallel the presence of sleep-induced breathing disorders [18]. The amount of apnea-related desaturation depends on several factors including the baseline Sao 2 level; the expiratory reserve volume; the total apnea time; and the different apnea types [19, 20]. Therefore, an apnea of a fixed duration will result in a wide range of decreases in Sao 2 levels from one patient to another and from one apnea event to the other, in the same patient. Further, the definition of apnea is based on the absence of airflow and not on the presence of desaturation. Therefore, considering only a fixed decrease in Sao 2 levels or a decrease below the Sao 2 threshold as suggestive criteria of respiratory abnormalities may lead to a misinterpretation of nocturnal oximetry test results. Thus, we reasoned that the interpretation of the Sao 2 recording based on the presence of repetitive fluctuations in the Sao 2 signal without rigid criteria for the amplitude of the Sao 2 decline should improve its accuracy as a test for detecting SAHS. Because a valid nocturnal home oximetry test would greatly decrease the costs of diagnosing these patients, we evaluated its utility for diagnosing SAHS using these criteria. Methods Patients A total of 240 consecutive outpatients referred to our sleep clinic (216 men, 24 women; ages 24 to 68 years; body mass index, 31.7 0.8 kg/m2 [mean SE]) were included in our study. They were clinically suspected of having SAHS because of loud snoring; nocturnal choking and awakenings or apneic events or all three reported by a bedmate; bad sleep quality; and daytime hypersomnolence. None had previously been investigated by home or sleep laboratory recordings. The review board on human studies in our institution approved the experimental protocol, and each patient gave his or her informed consent to participate in the study. Protocol Patients were prospectively evaluated by a single night nocturnal home oximetry test followed by a conventional polysomnographic study. Patients were asked to avoid alcohol consumption for at least 12 hours before the different studies. The ambulatory Sao 2 recording was done with a Biox IVA oximeter (Ohmeda, Louisville, Colorado) with a finger probe at a 0.5 Hz sampling frequency. The patients were instructed in the use of the oximeter by the sleep laboratory technician. They were told to install the finger probe, to check that the Sao 2 and pulse rate values appeared on the screen, and to begin the recording by pressing the key corresponding to the high-frequency sampling mode when they turned off the lights. They interrupted the recording if they awoke during the night and stopped it when they awoke in the morning. The home recording was done twice in 18 patients who did not sleep well during the first home recording. No treatment was initiated between home oximetry and the polysomnographic sleep study, and the patients weights remained unchanged. The sleep study was done within 1 month of the home Sao 2 monitoring (range, 1 to 4 weeks). Sleep studies included the determination of sleep stages (electroencephalogram, C4A1 and C3A1; electroculogram; submental electromyogram); nasal and mouth airflow with thermocouples (Grass Instruments, Quincy, Massachusetts); Sao 2 with a Criticare 504 ear oximeter (CSI, Waukesha, Wisconsin); electrocardiogram; and thoracoabdominal movements by respiratory inductive plethysmography (Respitrace, Ambulatory Monitoring, Ardsley, New York) calibrated by the isovolume method [21]. Intrathoracic pressures were recorded with an esophageal balloon in 105 patients. All measurements were recorded on a 16-channel polygraph (Model 78; Grass Instruments) running at 10 mm/s. Sleep stages were defined in 30-second periods according to standard criteria [22]. An apneic event was defined as a cessation of the oronasal flow for at least 10 seconds, and hypopnea was defined as a 50% decrease in the sum signal of the Respitrace associated with a desaturation greater than 4% [23]. An arousal was defined by the simultaneous transition to a lighter sleep stage with eye movements and an increase in electromyographic activity of less than 15 seconds [24]. Data Analysis and Statistical Analysis Polysomnographic recordings were manually interpreted by trained technicians who were unaware of the results of the oximetry (these recordings were interpreted before the sleep study). Home oximetry was classified as abnormal (suspicion of sleep-related breathing abnormalities) in the presence of repetitive episodes [mean for the whole night greater than 10/h] of transient desaturation followed by a rapid return to the baseline Sao 2 level using no minimum decrease in Sao 2 levels and no threshold. Figure 1 illustrates typical examples of abnormal oximetry recordings that were considered compatible with sleep-induced respiratory disorders. Abnormalities of the oximetry recording were of two types: deep repetitive desaturation episodes Figure 1, top) or low-amplitude periodic Sao 2 fluctuations Figure 1, bottom). The diagnosis of SAHS was confirmed when the apnea plus hypopnea index obtained by the sleep study was greater than 10. The individual baseline Sao 2 values obtained during home oximetry and polysomnographic study were compared by a Student paired t-test. The accuracy of home oximetry was evaluated by a contingency analysis with a two-tail Fisher exact test. Figure 1. Typical examples of abnormal, nocturnal arterial oxyhemoglobin saturation tracings. Top. Bottom. o o Results Almost all patients reported normal sleep quality and duration of sleep during the home oximetry recording. The diagnosis of SAHS was confirmed in 110 of the 240 patients studied. In this group, the apnea plus hypopnea index and the arousal index were 38.1 2.5/h and 36.8 2.7/h (mean SE), respectively. The mean total apnea time (percentage of total sleep time spent in apnea) was 13.1% (CI, 10.8% to 15.4%), and obstructive apnea represented 72.4% of total apnea time (CI, 66.7% to 78.1%). The baseline Sa (o)2 value was 95.2% 0.1% during home recording and was 95.7% 0.1% during the polysomnographic study (P > 0.05). Oximetry was abnormal in 176 patients, which included all but 2 of those with SAHS. In the SAHS group, 41 oximetry tests were interpreted as abnormal despite decreases in Sao 2 levels of less than 4% that did not reach 90% (see Figure 1, bottom). Nocturnal home oximetry was normal (absence of Sao 2 fluctuations, Figure 2 in all 62 patients who had no sleep disordered breathing. Figure 2. Typical example of a normal home oximetry recording. o The overall results of the home oximetry and polysomnographic testing are detailed in Figure 3. Based on a cutoff point of 10/h, home oximetry testing had a sensitivity of 108/110 or 98.2% (CI, 93.6% to 99.8%) and a specificity of 62/130 or 47.7% (CI, 38.8% to 56.6%). Given that 110 of 240 (46%) patients had sleep apnea, the likelihood of sleep apnea increased to 61.4% with a positive test and decreased to 3.1% with a negative test. The main characteristics of the patients with true and false results are reported in Table 1. The two patients who had a false-negative home oximetry recording (using a cutoff point of 10/h) had an apnea hypopnea index of 16.1/h and 14/h, respectively, and a body mass index of 27.1 kg/m2 and 32.5 kg/m2, respectively. Table 1. Characteristics of the Patients in the Different Groups* Figure 3. Contingency Tables Comparing the Results of the Home Oximetry and Polysomnographic Recordings Using Two Different Diagnosis Thresholds of the Apnea-Plus-Hypopnea Index (AHI). To specify the influence of the abnormal apnea-plus-hypopnea index threshold on these results, we analyzed our data using a different cutoff point of 20/h [4]. Using this cutoff point, 176 patients had an abnormal home oximetry test, and the diagnosis of SAHS was confirmed in 75 of them. Home oximetry test results were normal in the 64 patients without SAHS with no false-negative results (see Figure 3). Therefore, we used these SAHS diagnostic criteria, a sensitivity for nocturnal home oximetry testing of 100%; a specificity of 38.8%; a positive predictive value of 42.6%; and a negative predictive value of 100% Figure 3 [P < 104]. The reproducibility of our interpretation criteria was verified in 60 randomly selected home oximetry recordings interpreted blindly by two physicians. The concordance between the two interpretations was 95%. Discus

Obesity and Asthma: A Specific Phenotype?

BACKGROUND Obesity is associated with an increased prevalence of asthma, especially in women, and appears to be more severe in the obese. This study aimed to determine if obese subjects have a specific asthma phenotype. METHODS Forty-four consecutive obese subjects (body mass index [BMI] > or = 30 kg/m(2)) and 44 consecutive nonobese subjects (BMI < 25 kg/m(2)), all with asthma, completed an asthma control questionnaire, and underwent methacholine challenge with symptom perception scores, and sputum induction for differential cell count. BMI, waist circumference, and waist-to-hip ratio also were measured. RESULTS Despite similar expiratory flows, bronchodilator response, airway responsiveness to methacholine, and symptom perception scores, asthma control was poorer in obese subjects than in nonobese subjects (p = 0.005). Total lung capacity (p = 0.01), expiratory reserve volume (p < 0.0001), functional residual capacity (p < 0.0001), and residual volume (p = 0.006) were lower in obese subjects than in nonobese subjects. Induced-sputum eosinophil and neutrophil counts were similar in both groups, although there was an inverse correlation between sputum eosinophils and waist circumference and a trend for a similar relationship for BMI. Blood serum C-reactive protein (p = 0.009) and fibrinogen (p = 0.0004) levels were higher in obese subjects than in nonobese subjects. CONCLUSION Obese people with asthma had poorer asthma control than nonobese asthmatics despite similar symptoms perception. Bronchial and systemic inflammatory characteristics and the specific pattern of pulmonary function changes suggest a different phenotype of asthma in these subjects. TRIAL REGISTRATION Clinicaltrials.gov Identifier: NCT00532363 and NCT00532831.

Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma

The benefits of polychemotherapy in advanced (Stage III) non‐small‐cell bronchogenic carcinoma remain uncertain. In attempt to answer the important question whether treatment improves well‐being and survival in these patients, we did a prospective, randomized, single‐blind study to compare polychemotherapy to a placebo. Thirty‐nine consecutive patients were enrolled. Twenty received a drug combination consisting of: methotrexate, doxorubicine hydrochloride (Adriamycin), cyclophosphamide, and lomustine (CCNU) (MACC). The other group (19 subjects) received a placebo physically comparable to MACC. The two groups were initially comparable in terms of age, sex, clinical status, and tumor burden. In the treated group, seven patients had a radiologic response (more than 50% reduction in the tumor size), and the tumor stabilized in an additional five subjects. There were no responders in the placebo group. Median survival was 30.5 weeks for the MACC group compared to 8.5 weeks in the placebo group (P < 0.0005, Gehan‐Wilcoxon). We conclude that polychemotherapy (in this case MACC) significantly benefits patients with advanced non‐small‐cell lung cancer.

Cephalometric measurements in snorers, non-snorers, and patients with sleep apnoea.

Cephalometry is often used to assess patients with sleep apnoea but whether these measurements differ from those in non-apnoeic snorers and how they are influenced by age is not clear. Cephalometric radiographs of patients with sleep apnoea were compared with those of snorers without sleep apnoea and those of non-snorers. Fifty two snorers with suspected sleep apnoea had a conventional sleep study and were divided into two groups: those with an apnoea-hypopnoea index greater than 10/h (n = 40, sleep apnoea group) and those whose apnoea-hypopnoea index was 10/h or less (n = 12, snorer group). The cephalometric measurements in these patients were compared with those of 34 non-snoring control subjects. Controls were subdivided into two groups: control group 1 included 17 subjects similar in age to the sleep apnoea and snorer groups (mean (SD) age 50.0 (10.9), 50.7 (9.4), and 50.6 (9.7) years); control group 2 included 15 young men (25.4 (2.6) years). The distance from the mandibular plane to the hyoid bone (MP-H) and the length of the soft palate were greater in the patients with sleep apnoea (28.7 (7.8) and 43.6 (5.0) mm) than in the snorers (23.7 (4.2) and 40.3 (4.9 mm). The MP-H was similar in snorers and age matched control subjects, but was significantly greater in the older than in the younger control subjects (22.1 (6.1) vs 17.0 (6.8]. The soft palate was longer in subjects who snored (both sleep apnoea patients and snorers) than in control subjects. The MP-H distance significantly correlated with age for all subjects (snorers and controls) and for the control subjects alone. This study shows that non-apnoeic snorers have cephalometric abnormalities that differ from those of patients with sleep apnoea and that cephalometric values are influenced by the subjects age.

A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage 1B and II non small cell lung cancer (NSCLC) Intergroup JBR.10

7018 Background: In meta-analyses platinum based adjuvant chemotherapy using 2nd generation regimens increased cure rate by 5% in completely resected NSCLC. JBR.10 was undertaken to determine whether the 3rd generation regimen VIN/CIS prolonged survival in this clinical setting. METHODS Patients with completely resected stage 1 (T2N0) or stage 2 (excluding T3N0) NSCLC were stratified by nodal status (N0 vs. N1) and ras mutation status (present vs. absent vs. unknown) and randomised to receive 4 cycles of VIN (25mg/m2 weekly x 16 weeks) plus CIS (50mg/m2 days 1 and 8 q 4 weeks x 4) or follow up alone; VIN dose was reduced from 30mg/m2 shortly after the study started due to unacceptable toxicity. The endpoints of the study were survival (OS), recurrence-free survival (RFS), quality of life (QOL) and toxicity. RESULTS 482 patients were randomized between 1994 and 2001. PATIENTS age 61 years, 65% male, 51% PS 1, 53% N1, 24% ras mutation present. 45% of patients had T2N0, 40% T2N1 and 15% T1N1. 53% had adenocarcinoma. Grade 4 neutropenia, was common with febrile neutropenia in 7%, predominantly in patients receiving VIN 30mg/m2. The commonest non-hematologic toxicities for VIN/CIS patients were fatigue (77%), nausea (76%), anorexia (53%), vomiting (46%), sensory neuropathy (45%) and constipation (44%). Two patients died of drug-related toxicity [1 febrile neutropenia, 1 pulmonary fibrosis]. The most common cause of death was NSCLC (including 1 patient with 2nd primary NSCLC), while 3 patients died from toxicity related to later anti-cancer therapy, 9 patients died of other primary malignancies, and 21 from other causes. Overall survival was significantly prolonged for VIN/CIS patients (94 months vs. 73 months; HR 0.69, p=0.011), as was RFS (not reached vs. 46.7 months; HR 0.6, p 0.0003). 5-year survival for VIN/CIS patients was 69% compared to 54% for patients followed expectantly. 38 patients developed 2nd malignancies. CONCLUSIONS This is the first randomized clinical trial demonstrating that a 3rd generation platinum-based doublet prolongs OS and RFS after surgery in early stage NSCLC. [Table: see text].

Recent Advances in Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis (HP) is a pulmonary disease with symptoms of dyspnea and cough resulting from the inhalation of an allergen to which the subject has been previously sensitized. The diagnosis of HP most often relies on an array of nonspecific clinical symptoms and signs developed in an appropriate setting, with the demonstration of interstitial markings on chest radiographs, serum precipitating antibodies against offending antigens, a lymphocytic alveolitis on BAL, and/or a granulomatous reaction on lung biopsies. The current classification of HP in acute, subacute, and chronic phases is now challenged, and a set of clinical predictors has been proposed. Nonspecific interstitial pneumonitis, usual interstitial pneumonia, and bronchiolitis obliterans organizing pneumonia may be the sole histologic expression of the disease. Presumably, like in idiopathic interstitial pneumonia, acute exacerbations of chronic HP may occur without further exposure to the offending antigen. New offending antigens, such as mycobacteria causing hot tub lung and metalworking fluid HP, have recently been identified and have stimulated further research in HP.

Classification of hypersensitivity pneumonitis: a hypothesis.

Background: Regardless of the causative antigen, hypersensitivity pneumonitis (HP) is usually classified as ‘acute’, ‘subacute’ or ‘chronic’. Considerable confusion still surrounds this classification because there are no widely accepted criteria to distinguish the various stages. The objective of this study wasto determine whether the current classification of HP truly reflects categories of patients with distinct clinical features. Methods: Data obtained from a large prospective multicenter cohort study (the HP Study) were used to divide a cohort of patients with HP into a limited number of categories (clusters) with maximally differing clinical patterns, without prejudgment. The results of this cluster analysis were compared with the current classification of HP (acute, subacute or chronic). Results: 168 patients were included in the analysis. A 2-cluster solution best fitted the data. Patients in cluster 1 (41 patients) had more recurrent systemic symptoms (chills and body aches) and normal chest radiographs than those in cluster 2 (127 patients) who showed significantly more clubbing, hypoxemia, restrictive patterns on pulmonary function tests and fibrosis on high-resolution computed tomography (HRCT). All p values were <0.0001, using Fisher’s exact test. Nodular opacities were seen on HRCT as often in cluster 1 as in cluster 2. There was considerable disagreement between the current classification of HP and the results of our analysis. Conclusion: The current classification of acute, subacute and chronic HP is not supported by our analysis. Subacute HP is particularly difficult to define.

Comparison of Endotoxin Exposure Assessment by Bioaerosol Impinger and Filter-Sampling Methods

ABSTRACT Environmental assessment data collected in two prior occupational hygiene studies of swine barns and sawmills allowed the comparison of concurrent, triplicate, side-by-side endotoxin measurements using air sampling filters and bioaerosol impingers. Endotoxin concentrations in impinger solutions and filter eluates were assayed using theLimulus amebocyte lysate assay. In sawmills, impinger sampling yielded significantly higher endotoxin concentration measurements and lower variances than filter sampling with IOM inhalable dust samplers. Analysis of variance for repeated measures showed that this association remained after controlling for other factors such as replicate, sawmill, sawmill operation, wood type, and interaction terms. Endotoxin concentrations in the swine barns were 10-fold higher on average than in sawmills. These samples demonstrated comparable endotoxin concentration estimates for impinger and filter methods although the variability was lower using the impinger method. In both occupational settings, side-by-side replicates were more uniform for the impinger samples than for the filter samples. This study demonstrates that impinger sampling is an acceptable method for quantitation of area endotoxin concentrations. Further, when sampling is performed with impingers for airborne microorganism quantitation, these same impinger solutions can yield valid endotoxin exposure estimates, negating the need for additional filter sampling.