Paolo Paoletti

Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease. Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions. Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.

Lung involvement in essential mixed cryoglobulinemia

Abstract Lung function studies were performed in 23 patients with the syndrome of essential mixed cryoglobulinemia. Signs of exposure to hepatitis B virus were present in nine (HBV+) and absent in 14 (HBV−). Pulmonary symptoms were generally absent or moderate except in three patients who presented with either asthma, hemoptysis or pleurisy together with the other manifestations of the disease. On the contrary, tests indicative of small airways disease, such as forced end-expiratory flow (FEF 0.75-0.85VC ) and maximal expiratory flow at low lung volume (Vmax 0.75VC ) were markedly altered (61.9 per cent and 40.4 per cent of the expected values, respectively). Other lung function tests, such as residual volume (RV), airway resistance (Raw), FEF 0.25-0.75VC , maximal expiratory flow at 50 per cent vital capacity (VC)(Vmax 0.50VC ) showed smaller deviations from normal, whereas vital capacity (VC), total lung capacity (TLC), forced expiratory volume in 1 second (FEV 1 ), FEV 1 :VC, RV:TLC and intrathoracic gas volume (ITGV) were within the normal limits. Nine of 14 of the HBV− patients showed impairment of gas exchange, measured as alveoloarterial oxygen gradient D(A-a)O 2 , which, on the contrary, was always within normal limits in the nine HBV+ patients. The difference between the two groups was significant (28.4 mm Hg and 18.6 mm Hg, respectively, p

Evaluation of DNA damage in leukocytes of ex-smokers by single cell gel electrophoresis

Single cell gel electrophoresis (SCGE), or comet assay, appears to be a promising tool to estimate DNA damage at the single cell level and it provides information on the presence of damage among individual cells. A follow-up study of 90 smokers who ceased smoking was undertaken to determine the possible decrease of DNA damage in their leukocytes. Before beginning the trial, volunteers smoked on average 26.1 +/- 8.4 cigarettes/day. Comet length did not correlate with the number of cigarettes/day or with the condensate tar content. At the end of the study, 28 volunteers had abandoned the trial, 40 volunteers relapsed into smoking at different times, but with a reduced number of cigarettes/day, whereas 22 fully succeeded in smoking cessation. Throughout the 5 sampling times, a great variability of comet length at individual level was found. However, after 1 year of follow-up, comet length means were found to be significantly shorter (p < 0.0001) in those volunteers who completely quit smoking compared to those who relapsed into smoking (27.2 +/- 1.6 vs. 31.9 +/- 5.1 microns, respectively), irrespective of the amount of cigarettes previously smoked. No effect of age or sex was found. Six months later, these results were confirmed by a further study carried out on a reduced sample of volunteers. The present data strongly suggest that, in spite of the great variability observed, 1 year of smoking cessation is associated with a significant reduction of DNA damage in circulating leukocytes.

Nicotine dependence, psychological distress and personality traits as possible predictors of smoking cessation. Results of a double-blind study with nicotine patch.

AIM Nicotine replacement therapy (NRT) is an effective treatment for smokers who want to quit, however, the rates of successful quitting can be improved even more. In this context, nicotine dependence (assessed via the Fagerström Tolerance Questionnaire, FTQ), psychological distress (measured via the Symptom Rating Test, SRT), and personality traits (evaluated via the Adult Eysenck Personality Inventory, AEPI) were evaluated as possible predictors of smoking cessation. RESULTS A total of 297 cigarette smokers were followed for one year as part of a NRT double-blind, parallel group, randomized trial. Baseline nicotine dependence (weeks 12 and 26: p<0.05), AEPI neuroticism (weeks 12 and 52: p<0.05), and AEPI psychoticism (weeks 12 and 52: p<0.05) scores significantly influenced the outcome of smoking cessation during one-year of follow-up. An increase in psychological distress during follow-up was associated with a lower probability of quitting smoking (p=0.000). CONCLUSIONS Nicotine dependence, neuroticism, psychoticism and, over time, psychological distress were the main factors influencing the long-term outcome (i.e., up to 12 months) of smoking cessation under NRT.

Presence and persistence of serum anti-benzo[apyrene diolepoxide-DNA adduct antibodies in smokers: Effects of smoking reduction and cessation

Among biomarkers of tobacco smoke (TS)‐induced genotoxic damage, benzo[a]pyrene diolepoxide‐DNA adducts (BPDE‐DNA) are extensively studied. Adducted DNA becomes antigenic and antibodies anti‐BPDE‐DNA (BPDE‐DNA‐Abs) may be found in serum of exposed subjects. Little is known about the persistence of BPDE‐DNA, and no study has been performed to evaluate the persistence of BPDE‐DNA‐Abs after cessation of exposure. Fifty heavy smokers, enrolled in a smoking cessation program with nicotine patch substitution therapy, were evaluated for the presence of BPDE‐DNA‐Abs before (w0) and 1, 3, 6 and 12 weeks (w1–12) after the start of the program. Nicotine or placebo patches were randomly assigned to the subjects. BPDE‐DNA‐Abs were determined in serum by non‐competitive ELISA. After the start of the cessation program, 28 subjects quit smoking (group Q) and the other 22 reduced by about 75% the number of cigarettes smoked per day (group R). At the start of the program (w0) 8% of subjects were positive. At w1 the prevalence of positivity had increased both in subjects who quit smoking (Q: 21%) and in subjects who had reduced the number of cigarettes per day (R: 27%). Positivity remained stable up to w12 (21%) for group Q, whereas it increased to 41% in group R. Serum BPDE‐DNA‐Abs can be detected in smokers, and their persistence for months after smoking cessation suggests their usefulness for relatively long‐term surveys. The low percentage of positivity in actual heavy smokers and the increase in antibody positivity with smoking cessation or reduction must be taken into account when interpretating serum BPDE‐DNA‐Ab measurement in exposed individuals. Int. J. Cancer, 70:145–149, 1997.

Lung function in essential mixed cryoglobulinemia: A short-term follow-up

SummaryLung involvement in essential mixed cryoglobulinemia (EMC) has been recently described. In order to assess whether patients with EMC experience an accelerated deterioration of lung function, nineteen patients (17 females, 2 males;49.6±6.6 years) underwent a short-term follow-up of lung function, chest X-ray and serologic investigations. Reduction of forced expiratory flows and presence of roentgenologic signs of interstitial involvement were confirmed in the baseline evaluation. In addition, a decrease of diffusing capacity was shown. After a mean interval of 15 months, no significant change in lung function was found, with the exception of decrease in maximal expiratory flow at 50% of forced vital capacity, total lung capacity, functional residual capacity, coefficient of transfer of CO. A slight decrease of hemolitic complement (CH50) and of complement fraction (C3) was also observed. This study suggests that patients with EMC tend to have an involvement of pulmonary interstitial space, possibly related to immune complex deposition, but they do not show a severe decline of lung function. Periodical assessment of lung function and chest X-ray is, however, worthwhile.

CO Diffusing Capacity in a General Population Sample: Relationships with Cigarette Smoking and Airflow Obstruction

The single-breath carbon monoxide diffusing capacity (DLCOsb) was measured together with ventilatory lung function tests as part of a survey of a general population sample living in Northern Italy (n = 2,481). Based on answers to an interviewer-administered questionnaire, subjects free of respiratory symptoms or diseases were identified. Data from subjects who had never regularly smoked cigarettes were used to derive reference equations for the test indexes, and data from the remaining subjects who had smoked were used to derive regression equations incorporating a term expressing cigarette consumption (cube root of pack-years) and a term indicating current smoking decrement, in order to obtain expected DLCOsb percent predicted. Neither number of cigarettes smoked daily or duration of smoking, in smokers, nor duration of smoking or years since quitting smoking, in ex-smokers, entered significantly the multiple-regression model. The mean values of DLCOsb were only slightly affected by the increasing degree of airway obstruction. When subjects with confirmed asthma were analyzed, after stratifying for different levels of FEV1/FVC ratio, increased mean value of DLCOsb (over 100%) was found in those with an FEV1/FVC ratio between 75 and 65%. This cross-sectional analysis suggests that there is a decrease in DLCOsb with cumulative cigarette consumption even in healthy subjects. Further, it confirms the clinical observations of high DLCOsb values in asthmatic patients, at least in those with an initial degree of chronic airflow obstruction.

S09-01 - Nicotine dependence, psychological distress, personality traits as possible predictors of smoking cessation. Results of a double-blind study with nicotine patch

Objectives Although Nicotine replacement therapy (NRT) is an effective treatment for smokers who want to quit, the rates of smoking cessation can be still improved. In an effort to increase these proportions, factors that may influence the occurrence of relapse have been increasingly studied (e.g. pharmacotherapy, socio-demographic characteristics) and there has been a growing interest in psychological and psychiatric clinical factors. Methods Nicotine dependence (assessed via the Fagerstrom Tolerance Questionnaire, FTQ), psychological distress (measured via the Symptom Rating Test, SRT), and personality traits (evaluated via the Adult Eysenck Personality Inventory, AEPI) were evaluated as possible predictors of smoking cessation in a sample of 297 cigarette smokers followed for one year as part of a NRT double-blind, parallel group, randomized trial. Results Baseline nicotine dependence (weeks 12 and 26: p Conclusions Nicotine dependence, neuroticism, psychoticism and, over time, psychological distress were the main factors influencing the long-term outcome (i.e., up to 12 months) of smoking cessation under NRT. Thus, psychological distress and personality characteristics should be evaluated in smokers who apply for assistance in smoking cessation with the aim to have a complete assessment and propose tailor-made interventions.